Ca2+ Entry Units in a Superfast Fish Muscle

Over the past two decades, mounting evidence has demonstrated that a mechanism known as store-operated Ca2+ entry (SOCE) plays a crucial role in sustaining skeletal muscle contractility by facilitating Ca2+ influx from the extracellular space during sarcoplasmic reticulum (SR) Ca2+ depletion. We recently demonstrated that, in exercised fast-twitch muscle from mice, the incidence of Ca2+ entry units (CEUs), newly described intracellular junctions between dead-end longitudinal transverse tubular (T-tubule) extensions and stacks of sarcoplasmic reticulum (SR) flat cisternae, strictly correlate with both the capability of fibers to maintain contractions during fatigue and enhanced Ca2+ influx via SOCE. Here, we tested the broader relevance of this result across vertebrates by searching for the presence of CEUs in the vocal muscles of a teleost fish adapted for extended, high-frequency activity. Specifically, we examined active vs. inactive superfast sonic muscles of plainfin midshipman (Porichthys notatus). Interestingly, muscles from actively humming territorial males had a much higher incidence of CEU SR stacks relative to territorial males that were not actively vocalizing, strengthening the concept that assembly of these structures is dynamic and use-dependent, as recently described in exercised muscles from mice. Our results support the hypothesis that CEUs represent a conserved mechanism, across vertebrates, for enabling high levels of repetitive muscle activity, and also provide new insights into the adaptive mechanisms underlying the unique properties of superfast midshipman sonic muscles

Violation of Bells inequality using continuous variable measurements

A Bell inequality is a fundamental test to rule out local hidden variable model descriptions of correlations between two physically separated systems. There have been a number of experiments in which a Bell inequality has been violated using discrete-variable systems. We demonstrate a violation of Bells inequality using continuous variable quadrature measurements. By creating a four-mode entangled state with homodyne detection, we recorded a clear violation with a Bell value of $B = 2.31 \pm 0.02$. This opens new possibilities for using continuous variable states for device independent quantum protocols.Comment: 5 pages, 4 figures, lette

Evaluations of Lifestyle, Dietary, and Pharmacologic Treatments for Pediatric Non-Alcoholic Fatty Liver Disease—a Systematic Review

Background & Aims: There are no approved treatments for pediatric non-alcoholic fatty liver disease (NAFLD) and there is a lack of consensus on the best outcome measure for randomized controlled trials. We performed a systematic review of treatments tested for pediatric NAFLD, the degree of heterogeneity in trial design, and endpoints analyzed in these studies. Methods: We searched publication databases and clinical trial registries through January 7, 2018 for randomized controlled trials (published and underway) of children (<18 years) with NAFLD. We assessed improvements in histologic features, radiologic and biochemical markers of reduced fibrosis, metabolic syndrome parameters, and adverse events. The quality of the trials was assessed using a modified version of the Cochrane risk of bias tool. Results: Our final analysis included 21 randomized controlled trials, comprising 1307 participants (mean age, 12.6 years; 63% male; mean duration of intervention, 8 months). Most studies evaluated weight loss with lifestyle intervention (n=8), oral polyunsaturated fatty acid treatment (PUFAs, n=6), or oral antioxidant treatment (n=7). Biomarkers of NAFLD decreased with weight loss, but most studies did not include histologic data. Trials of antioxidants were heterogeneous; some reported reduced histologic features of steatohepatitis with no effect on triglycerides or insulin resistance. PUFAs and probiotics reduced radiologic markers of steatosis, insulin resistance, and levels of triglycerides. Only 38% of the trials had biopsy-proven NAFLD as an inclusion criterion. There was heterogeneity in trial primary endpoints; 10 studies (48%) used levels of aminotransferases or ultrasonography findings as a primary endpoint and only 3 trials (14%) used histologic features as the primary endpoint. We identified 13 randomized controlled trials that are underway in children with NAFLD. None of the protocols include collection of liver biopsies; 9 trials (69%) will use magnetic resonance imaging quantification of steatosis as a primary outcome. Conclusion: In a systematic review of published and active randomized controlled trials of children with NAFLD, we found a large amount of heterogeneity in study endpoints and inclusion criteria. Few trials included histologic analyses. Antioxidants appear to reduce some features of steatohepatitis. Effects of treatment with lifestyle modification, PUFAs, or probiotics have not been validated with histologic analysis. Trials that are underway quantify steatosis magnetic resonance imaging—outcomes are anticipated

Infant feeding knowledge, perceptions and practices among women with and without HIV in Johannesburg, South Africa: a survey in healthcare facilities

BACKGROUND: South Africa has a history of low breastfeeding rates among women with and without Human Immunodeficiency Virus (HIV). In this study, we assessed infant feeding knowledge, perceptions and practices among pregnant and postpartum women with and without HIV, in the context of changes in infant feeding and Prevention of Mother-to-Child Transmission of HIV (PMTCT) guidelines. METHODS: This was a cross-sectional survey conducted from April 2014 to March 2015 in 10 healthcare facilities in Johannesburg, South Africa. A total of 190 pregnant and 180 postpartum women (74 and 67, respectively, were HIV positive) were interviewed using a semi-structured questionnaire. Multiple regression analyses assessed factors associated with an intention to exclusively breastfeed, and exclusive breastfeeding of infants less than six months of age. RESULTS: Women with HIV had better overall knowledge on safe infant feeding practices, both in general and in the context of HIV infection. There were however gaps in knowledge among women with and without HIV. Information from healthcare facilities was the main source of information for all groups of women in the study. A greater percentage of women without HIV 80.9% (93/115), reported an intention to exclusively breastfeed, compared to 64.9% (48/74) of women with HIV, p = 0.014. Not having HIV was positively associated with a reported intention to breastfeed, Adjusted Odds Ratio (AOR) 3.60, 95% CI 1.50, 8.62. Other factors associated with a reported intention to exclusively breastfeed were prior breastfeeding experience and higher knowledge scores on safe infant feeding practices in the context of HIV infection. Among postpartum women, higher scores on general knowledge of safe infant feeding practices were positively associated with reported exclusive breastfeeding, AOR 2.18, 95% CI 1.52, 3.12. Most women perceived that it was difficult to exclusively breastfeed and that cultural factors were a barrier to exclusive breastfeeding. CONCLUSIONS: While a greater proportion of women are electing to breastfeed, HIV infection and cultural factors remain an important influence on safe infant feeding practices. Healthcare workers are the main source of information, and highlight the need for accurate and consistent messaging for both women with and without HIV

What is the best strategy for investigating abnormal liver function tests in primary care? Implications from a prospective study

OBJECTIVE: Evaluation of predictive value of liver function tests (LFTs) for the detection of liver-related disease in primary care. DESIGN: A prospective observational study. SETTING: 11 UK primary care practices. PARTICIPANTS: Patients (n=1290) with an abnormal eight-panel LFT (but no previously diagnosed liver disease). MAIN OUTCOME MEASURES: Patients were investigated by recording clinical features, and repeating LFTs, specific tests for individual liver diseases, and abdominal ultrasound scan. Patients were characterised as having: hepatocellular disease; biliary disease; tumours of the hepato-biliary system and none of the above. The relationship between LFT results and disease categories was evaluated by stepwise regression and logistic discrimination, with adjustment for demographic and clinical factors. True and False Positives generated by all possible LFT combinations were compared with a view towards optimising the choice of analytes in the routine LFT panel. RESULTS: Regression methods showed that alanine aminotransferase (ALT) was associated with hepatocellular disease (32 patients), while alkaline phosphatase (ALP) was associated with biliary disease (12 patients) and tumours of the hepatobiliary system (9 patients). A restricted panel of ALT and ALP was an efficient choice of analytes, comparing favourably with the complete panel of eight analytes, provided that 48 False Positives can be tolerated to obtain one additional True Positive. Repeating a complete panel in response to an abnormal reading is not the optimal strategy. CONCLUSIONS: The LFT panel can be restricted to ALT and ALP when the purpose of testing is to exclude liver disease in primary care

Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus During Macrophage Cell Death.

RATIONALE: Pulmonary aspergillosis is a lethal mould infection in the immunocompromised host. Understanding initial control of infection, and how this is altered in the immunocompromised host, is a key goal for understanding the pathogenesis of pulmonary aspergillosis. OBJECTIVES: To characterise the outcome of human macrophage infection with Aspergillus fumigatus, and how this is altered in transplant recipients on calcineurin inhibitor immunosuppressants. METHODS: We defined the outcome of human macrophage infection with Aspergillus fumigatus, and the impact of calcineurin inhibitors, through a combination of single cell fluorescence imaging, transcriptomics, proteomics, and in vivo studies. MEASUREMENTS AND MAIN RESULTS: Macrophage phagocytosis of Aspergillus fumigatus enabled control of 90% of fungal germination. However fungal germination in the late phagosome led to macrophage necrosis. During programmed necroptosis, we observed frequent cell-cell transfer of Aspergillus fumigatus between macrophages which assists subsequent control of germination in recipient macrophages. Lateral transfer occurred through actin-dependent exocytosis of the late endosome in a vasodilator-stimulated phosphoprotein (VASP) envelope. Its relevance to the control of fungal germination was also shown by direct visualisation in our zebrafish aspergillosis model in vivo. The calcineurin inhibitor FK506/tacrolimus reduced cell death and lateral transfer in vitro by 50%. This resulted in uncontrolled fungal germination in macrophages and hyphal escape. CONCLUSIONS: These observations identify programmed necrosis-dependent lateral transfer of Aspergillus fumigatus between macrophages as an important host strategy for controlling fungal germination. This process is critically dependent on calcineurin. Our studies provide fundamental insights into the pathogenesis of pulmonary aspergillosis in the immunocompromised host

P112 Influence of Cuff Blood Pressure Accuracy on Identification of Isolated Systolic Hypertension

Abstract Introduction Isolated systolic hypertension (ISH) is the most common form of hypertension in older people. However, accurate identification of ISH may be hindered because cuff blood pressure (BP) underestimates systolic BP (SBP) and overestimates diastolic BP (DBP). This study aimed to determine the influence of cuff BP accuracy on the identification of ISH. Methods Cuff BP and invasive aortic BP were measured simultaneous (or near-simultaneously) in 1737 subjects (63 ± 12 years, 68% male) during coronary angiography. Data was derived from 32 studies, using 20 different cuff BP devices, from the Invasive Blood Pressure Consortium (INSPECT). ISH was defined as ≥140/<90 mmHg according to cuff BP and invasive aortic BP. Results According to cuff BP, 25% of subjects (n = 430) had ISH, however, 37% (n = 648) were identified with ISH from invasive aortic BP. There was 77% concordance between cuff and invasive BP for identifying ISH. Among the 23% (n = 408) of subjects misclassified by cuff BP, 38% (n = 155) of misclassification was from SBP underestimation (mean: −16.6, 95% CI: −18.9 to −13.9 mmHg), whereas 35% (n = 143) was from DBP overestimation (15.6, 11.9 to 19.0 mmHg) and 20% (n = 83) from SBP overestimation (17.6, 14.4 to 20.5 mmHg). Subjects misclassified were on average 2.7 years older and had greater body mass index (0.8 kg/m2) than those correctly classified. Conclusion Approximately one quarter of older subjects have ISH misclassified, mostly because of underestimation of cuff SBP and overestimation of cuff DBP. This demonstrates a need to improve the accuracy of cuff BP methods for greater precision in identifying ISH

Large-scale physically accurate modelling of real proton exchange membrane fuel cell with deep learning

Proton exchange membrane fuel cells, consuming hydrogen and oxygen to generate clean electricity and water, suffer acute liquid water challenges. Accurate liquid water modelling is inherently challenging due to the multi-phase, multi-component, reactive dynamics within multi-scale, multi-layered porous media. In addition, currently inadequate imaging and modelling capabilities are limiting simulations to small areas (<1 mm2) or simplified architectures. Herein, an advancement in water modelling is achieved using X-ray micro-computed tomography, deep learned super-resolution, multi-label segmentation, and direct multi-phase simulation. The resulting image is the most resolved domain (16 mm2 with 700 nm voxel resolution) and the largest direct multi-phase flow simulation of a fuel cell. This generalisable approach unveils multi-scale water clustering and transport mechanisms over large dry and flooded areas in the gas diffusion layer and flow fields, paving the way for next generation proton exchange membrane fuel cells with optimised structures and wettabilities

Use of the Behavior Assessment Tool in 18 Pilot Residency Programs

Background: The purpose of this study was to determine the feasibility and evaluate the effectiveness of the American Board of Orthopaedic Surgery Behavior Tool (ABOSBT) for measuring professionalism. Methods: Through collaboration between the American Board of Orthopaedic Surgery and American Orthopaedic Association\u27s Council of Residency Directors, 18 residency programs piloted the use of the ABOSBT. Residents requested assessments from faculty at the end of their clinical rotations, and a 360° request was performed near the end of the academic year. Program Directors (PDs) rated individual resident professionalism (based on historical observation) at the outset of the study, for comparison to the ABOSBT results. Results: Nine thousand eight hundred ninety-two evaluations were completed using the ABOSBT for 449 different residents by 1,012 evaluators. 97.6% of all evaluations were scored level 4 or 5 (high levels of professional behavior) across all of the 5 domains. In total, 2.4% of all evaluations scored level 3 or below reflecting poorer performance. Of 431 residents, the ABOSBT identified 26 of 32 residents who were low performers (2 or more \u3c level 3 scores in a domain) and who also scored below expectations by the PD at the start of the pilot project (81% sensitivity and 57% specificity), including 13 of these residents scoring poorly in all 5 domains. Evaluators found the ABOSBT was easy to use (96%) and that it was an effective tool to assess resident professional behavior (81%). Conclusions: The ABOSBT was able to identify 2.4% low score evaluations ( Level of Evidence: Level II