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A major consequence of insulin binding its receptor on fat and muscle cells is the stimulation of glucose transport into these tissues. This is achieved through an increase in the exocytic trafficking rate of the facilitative glucose transporter GLUT4 from intracellular stores to the cell surface. Delivery of GLUT4 to the cell surface requires the formation of functional SNARE complexes containing Syntaxin 4, SNAP23, and VAMP2. Insulin stimulates the formation of these complexes and concomitantly causes phosphorylation of Syntaxin 4. Here, we use a combination of biochemistry and cell biological approaches to provide a mechanistic link between these observations. We present data to support the hypothesis that Tyr-115 and Tyr-251 of Syntaxin 4 are direct substrates of activated insulin receptors, and that these residues modulate the protein's conformation and thus regulate the rate at which Syntaxin 4 forms SNARE complexes that deliver GLUT4 to the cell surface. This report provides molecular details on how the cell regulates SNARE-mediated membrane traffic in response to an external stimulus.

This paper serves as an update to the previous RESNA Position on the Application of Power Wheelchairs for Pediatric Users with more current and additional scientific literature. This document contains typical clinical applications and best evidence from the literature supporting the application of power mobility (PM) for young children and to assist practitioners in decision-making and justification. It is RESNA' s position that age, limited vision or cognition, behavioral issues, and the ability to walk or propel a manual wheelchair short distances should not, in and of themselves, be used as discriminatory factors against providing PM for children. RESNA recommends early utilization of PM for children with mobility limitations as medically necessary, to promote integration and psycho-social development, reduce passive dependency, and to enhance participation, function, and independence.

Adipocytes are key to metabolic regulation, exhibiting insulin-stimulated glucose transport that is underpinned by the insulin-stimulated delivery of glucose transporter type 4 (SLC2A4, also known and hereafter referred to as GLUT4)-containing vesicles to the plasma membrane where they dock and fuse, and increase cell surface GLUT4 levels. Adipocytokines, such as adiponectin, are secreted via a similar mechanism. We used genome editing to knock out syntaxin-4, a protein reported to mediate fusion between GLUT4-containing vesicles and the plasma membrane in 3T3-L1 adipocytes. Syntaxin-4 knockout reduced insulin-stimulated glucose transport and adiponectin secretion by ∼50% and reduced GLUT4 levels. Ectopic expression of haemagglutinin (HA)-tagged GLUT4 conjugated to GFP showed that syntaxin-4-knockout cells retain significant GLUT4 translocation capacity, demonstrating that syntaxin-4 is dispensable for insulin-stimulated GLUT4 translocation. Analysis of recycling kinetics revealed only a modest reduction in the exocytic rate of GLUT4 in knockout cells, and little effect on endocytosis. These analyses demonstrate that syntaxin-4 is not always rate limiting for GLUT4 delivery to the cell surface. In sum, we show that syntaxin-4 knockout results in reduced insulin-stimulated glucose transport, depletion of cellular GLUT4 levels and inhibition of adiponectin secretion but has only modest effects on the translocation capacity of the cells. This article has an associated First Person interview with Hannah L. Black and Rachel Livingstone, joint first authors of the paper., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Background: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD)., Aim: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab., Results: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure., Conclusion: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Introduction: The regulated delivery of the glucose transporter GLUT4 from intracellular stores to the plasma membrane underpins insulin-stimulated glucose transport. Insulin-stimulated glucose transport is impaired in skeletal muscle of patients with type-2 diabetes, and this may arise because of impaired intracellular trafficking of GLUT4. However, molecular details of any such impairment have not been described. We hypothesized that GLUT4 and/or levels of proteins involved in intracellular GLUT4 trafficking may be impaired in skeletal muscle in type-2 diabetes and tested this in obese individuals without and without type-2 diabetes., Methods: We recruited 12 participants with type-2 diabetes and 12 control participants. All were overweight or obese with BMI of 25-45 kg/m 2 . Insulin sensitivity was measured using an insulin suppression test (IST), and vastus lateralis biopsies were taken in the fasted state. Cell extracts were immunoblotted to quantify levels of a range of proteins known to be involved in intracellular GLUT4 trafficking., Results: Obese participants with type-2 diabetes exhibited elevated fasting blood glucose and increased steady state glucose infusion rates in the IST compared with controls. Consistent with this, skeletal muscle from those with type-2 diabetes expressed lower levels of GLUT4 (30%, p = .014). Levels of Syntaxin4, a key protein involved in GLUT4 vesicle fusion with the plasma membrane, were similar between groups. By contrast, we observed reductions in levels of Syntaxin16 (33.7%, p = 0.05), Sortilin (44%, p = .006) and Sorting Nexin-1 (21.5%, p = .039) and -27 (60%, p = .001), key proteins involved in the intracellular sorting of GLUT4, in participants with type-2 diabetes., Conclusions: We report significant reductions of proteins involved in the endosomal trafficking of GLUT4 in skeletal muscle in obese people with type 2 diabetes compared with age- and weight-matched controls. These abnormalities of intracellular GLUT4 trafficking may contribute to reduced whole body insulin sensitivity., (© 2022 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Introduction: In the management of acute hospital admissions during the COVID-19 pandemic, safe patient cohorting depends on robust admission diagnostic strategies. It is essential that screening strategies are sensitive and rapid, to prevent nosocomial transmission of COVID-19 and maintain patient flow., Methods: We retrospectively identified all COVID-19 positive and suspected cases at our institution screened by reverse transcription polymerase chain reaction (RT-PCR) between 4 April and 28 June 2020. Using RT-PCR positivity within 7 days as our reference standard, we assessed sensitivity and net-benefit of three admission screening strategies: single admission RT-PCR, composite admission RT-PCR and CXR and repeat RT-PCR with 48 h., Results: RT-PCR single-test sensitivity was 91.5% (87.8%-94.4%) versus 97.7% (95.4%-99.1%) (p = 0.025) for RT-PCR/CXR composite testing and 95.1% (92.1%-97.2%) (p = 0.03) for repeated RT-PCR. Net-benefit was 0.83 for single RT-PCR versus 0.89 for RT-PCR/CXR and 0.87 for repeated RT-PCR at 0.02% threshold probability., Conclusion: The RT-PCR/CXR composite testing strategy was highly sensitive when screening patients at the point of hospital admission. Real-world sensitivity of this approach was comparable to repeat RT-PCR testing within 48 h; however, faster facilitating improved patient flow., (© 2022 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Purpose: Excessive accumulation of free fatty acids in the coronary arteries can lead to coronary artery disease (CAD). Quantification of epicardial adipose tissue (EAT) and pericardial adipose tissue (PAT) is beneficial to understand its relationship with CAD, hypertension (HT), and diabetes., Material and Methods: This retrospective study included 54 patients who underwent CT coronary angiogram using a multidetector row CT scanner. The EAT and PAT volumes from cardiac images were quantified using Image J software. The severity of CAD was graded using the CAD-RADS score., Results: Twenty-nine patients had no CAD, 21 patients had significant CAD, and 4 patients had insignificant CAD. Out of 21 patients with significant CAD, 14 had involvement of multiple coronary arteries. The EAT and PAT volumes were higher in patients with HT, DM, CAD-present group and significant-CAD-present group, but this was not statistically significant except the PAT volume with respect to diabetes. Significant correlation was found between EAT volume and calcium score ( p = 0.035) and between EAT volume and total cholesterol level ( p = 0.017). Significant differences in the EAT volumes were found in different CAD-RADS categories in the right coronary artery (RCA). From the threshold values, it was observed that CAD can develop in LAD even at lower of EAT and PAT volumes., Conclusions: Quantification of EAT and PAT volumes is beneficial in understanding its relationship with the presence and severity of coronary artery disease and its risk factors., Competing Interests: The authors report no conflict of interest., (© Pol J Radiol 2022.)

Objective: Diabetes among individuals with low BMI (<19 kg/m2) has been recognized for >60 years as a prevalent entity in low- and middle-income countries (LMICs) and was formally classified as "malnutrition-related diabetes mellitus" by the World Health Organization (WHO) in 1985. Since the WHO withdrew this category in 1999, our objective was to define the metabolic characteristics of these individuals to establish that this is a distinct form of diabetes., Research Design and Methods: State-of-the-art metabolic studies were used to characterize Indian individuals with "low BMI diabetes" (LD) in whom all known forms of diabetes were excluded by immunogenetic analysis. They were compared with demographically matched groups: a group with type 1 diabetes (T1D), a group with type 2 diabetes (T2D), and a group without diabetes. Insulin secretion was assessed by C-peptide deconvolution. Hepatic and peripheral insulin sensitivity were analyzed with stepped hyperinsulinemic-euglycemic pancreatic clamp studies. Hepatic and myocellular lipid contents were assessed with 1H-nuclear magnetic resonance spectroscopy., Results: The total insulin secretory response was lower in the LD group in comparison with the lean group without diabetes and the T2D group. Endogenous glucose production was significantly lower in the LD group than the T2D group (mean ± SEM 0.50 ± 0.1 vs. 0.84 ± 0.1 mg/kg · min, respectively; P < 0.05). Glucose uptake was significantly higher in the LD group in comparison with the T2D group (10.1 ± 0.7 vs. 4.2 ± 0.5 mg/kg · min; P < 0.001). Visceral adipose tissue and hepatocellular lipids were significantly lower in LD than in T2D., Conclusions: These studies are the first to demonstrate that LD individuals in LMICs have a unique metabolic profile, suggesting that this is a distinct entity that warrants further investigation., (© 2022 by the American Diabetes Association.)

Purpose: To explore parent and therapist experiences of early power mobility following participation in a Power Mobility Day - a 60-90 min play-based session where children with mobility limitations (<6 years of age) experienced four different early power mobility devices., Method: Participants were purposefully selected from parents and therapists who took part in Power Mobility Days as part of a larger cross-sectional study. One semi-structured interview with each participant was conducted via telephone. Interviews were audio-recorded, transcribed, and analyzed using a content analysis approach., Results: Of 35 adults approached, 11 parents and 11 occupational or physical therapists completed interviews averaging 20 min (range 10-45 min), one week to three months after the session. Participants were parents or therapists of children aged 12 to 48 months of age with a variety of neuromotor diagnoses from different areas of the province. The overarching theme Empowering Children and Families to Explore was developed from themes: Earlier Experiences ; A Novel Introduction ; and Moving Forward ., Conclusion: Power Mobility Days provided a welcoming and inclusive child- and family-led introduction to power mobility. This novel approach may help change both therapists' and families' perception of child potential and perspectives on power mobility as an intervention.IMPLICATIONS FOR REHABILITATION:Exploratory sessions can provide a novel introduction to power mobility interventions.Child enjoyment has a reciprocal impact on family engagement with early power mobility.Experiential child- and family-led learning can increase awareness of power mobility options and possibilities.

Objectives: Risk of hospital-acquired COVID-19 (HA-COVID-19) infection is increased by cohorting infected and non-infected patients together in assessment areas, whist awaiting laboratory PCR results. Molecular point-of-care tests (mPOCT) reduce time to results and improve patient flow but the impact on HA-COVID-19 is unknown., Methods: In this pre and post implementation study patients were evaluated across two time periods: March 1st to August 13th 2020, prior to the introduction of mPOCT in medical admissions areas, and 14th August 2020 to 1st April 2021, after mPOCT introduction. The primary outcome was proportion of HA-COVID-19 infection among all COVID-19 positive patients. Secondary outcome measures included time to SARS-CoV-2 results, length of time spent in the medical assessment area and comparison of local, regional and national proportions of HA-COVID-19., Results: 1988 patients were admitted through the acute medicine admission cohorting area and tested for SARS-CoV-2 prior to introducing mPOCT and 4640 afterwards. Median (IQR) time to SARS-CoV-2 result was 6.5 (2.1-17.9) hours prior to introducing mPOCT and 1.0 (0.8-1.3) hours afterwards (p < 0.0001). Median (IQR) duration in the assessment cohort area was 12.0 (4.8-20.6) hours prior to introduction of POCT and 3.2 (2.0-5.6) hours afterwards (p < 0.0001). The proportion of hospital-acquired COVID-19 cases was 108 (16.5%) of 654 prior to introducing mPOCT compared with 168 (9.4%) of 1782 afterwards, (HR 0.55, 95%CI 0.43-0.70; p < 0.0001). In the period following the introduction of mPOCT up to 1st April 2021 the median proportion of HA-COVID-19 was 13.6% (95%CI 8.2-18.9%) locally, compared with 43.8% (95%CI 37.8-49.9%) for all acute NHS trusts regionally and 30.9% (95%CI 28.4-33.5%) for all NHS trusts nationally., Conclusions: Routine mPOCT for SARS-CoV-2 was associated with reduced time to results, time spent in admission cohort areas, and hospital-acquired COVID-19, compared to laboratory PCR., Competing Interests: Declaration of Competing Interest None TWC has received speaker fees, honoraria, consultancy fees, travel reimbursement, and equipment and consumables free of charge for the purposes of research outside of this submitted study, from BioFire diagnostics and BioMerieux. He has received speaker fees and discounted equipment and consumables from QIAGEN. He has received consultancy fees from Shionogi, Synairgen research, Randox laboratories and Cidara therapeutics. He has been a member of advisory boards for Roche, Janssen and Cepheid. He is a member of two independent data monitoring committees for trials sponsored by Roche. He has acted as the UK chief investigator for a trial sponsored by Janssen, (Copyright © 2022 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Postural management is a multi-disciplinary approach incorporating a comprehensive schedule of daily and night-time positions, equipment and physical activity to help maintain or improve body structures and function and increase activity and participation. Postural management may play a role in preventing contracture, deformity, pain, and asymmetry. This article provides an overview of the evidence supporting use of postural management to positively influence hip health in individuals with cerebral palsy, functioning as Gross Motor Classification System (GMFCS) levels IV or V. Sitting or lying without changing position for more than 8 hours, unsupported supine lying and asymmetrical or windswept postures are associated with pain and hip subluxation/dislocation. Although high-quality experimental research is still limited by many factors, there is limited evidence of harm, and most individuals at GMFCS IV or V require positioning supports to enable participation and function and ease caregiving. Clinical recommendations combining research and clinical opinion support the early use of comfortable positioning routines and/or equipment to reduce time spent in sustained asymmetrical or potentially harmful sitting and lying positions. Supported standing, active weightbearing and stepping are recommended to promote active movement and position change when possible, depending on individual, family and caregiver routines and preferences.

Objectives: Dexamethasone has now been incorporated into the standard of care for COVID-19 hospital patients. However, larger intensive care unit studies have failed to show discernible improvements in mortality in the recent wave. We aimed to investigate the impacts of these factors on disease outcomes in a UK hospital study., Methods: This retrospective observational study reports patient characteristics, interventions and outcomes in COVID-19 patients from a UK teaching hospital; cohort 1, pre 16th June-2020 (pre-dexamethasone); cohort 2, 17th June to 30th November-2020 (post-dexamethasone, pre-VOC 202,012/01 as dominant strain); cohort 3, 1st December-2020 to 3rd March-2021 (during establishment of VOC202012/01 as the dominant strain)., Results: Dexamethasone treatment was more common in cohorts 2 and 3 (42.7% and 51.6%) compared with cohort 1 (2.5%). After adjusting for risk, odds of death within 28 days were 2-fold lower in cohort 2 vs 1 (OR:0.47,[0.27,0.79],p = 0.006). Mortality was higher cohort 3 vs 2 (20% vs 14%); but not significantly different to cohort 1 (OR: 0.86,[0.64, 1.15],p = 0.308)., Conclusions: The real world finding of lower mortality following dexamethasone supports the published trial evidence and highlights ongoing need for research with introduction of new treatments and ongoing concern over new COVID-19 variants., (Copyright © 2021. Published by Elsevier B.V.)