Maintenance of neuronal TDP-43 expression requires axonal lysosome transport.

TDP-43 mislocalization and pathology occurs across a range of neurodegenerative diseases, but the pathways that modulate TDP-43 in neurons are not well understood. We generated a Halo-TDP-43 knock-in iPSC line and performed a genome-wide CRISPR interference FACS-based screen to identify modifiers of TDP-43 levels in neurons. A meta-analysis of our screen and publicly available screens identified both specific hits and pathways present across multiple screens, the latter likely responsible for generic protein level maintenance.

Overfeeding and overweight rapidly reprogram inflammatory signaling.

Epidemiologic studies have shown a continuous increase in mortality risk associated with overweight, thus highlighting the health risks beginning before the onset of obesity. However, early changes in inflammatory signaling induced by an obesogenic diet remain largely unknown since studies of obesity typically utilize models induced by months of continuous exposure to a high-fat diet. Here, we investigated how short-term overfeeding remodels inflammatory signaling.

Physiotherapists' Experiences and Perceived Acceptability of Delivering a Knee Bracing Intervention for People With Symptomatic Knee Osteoarthritis in a Randomised Trial (PROP OA): A Qualitative Study.

Objectives: To explore physiotherapists' experiences and perceived acceptability of delivering a bracing intervention for knee osteoarthritis (OA) in the 'PROvision of braces for Patients with knee OA' (PROP OA) randomised controlled trial.

Method: Semi-structured telephone interviews with consenting physiotherapists who received the PROP OA training programme and delivered the knee bracing intervention (advice, information and exercise instruction plus knee brace matched to patients' clinical and radiographic presentation and with adherence support). Interviews were recorded and transcribed verbatim.

Early-life sodium restriction programs autonomic dysfunction and salt sensitivity in male C57BL/6J mice.

Preterm birth increases the risk of cardiometabolic disease in adulthood. Infants born during the second trimester of pregnancy, a critical period of hypothalamic development, are at risk of sodium (Na) depletion due to renal immaturity and large urine Na losses. We previously demonstrated in male mice that Na restriction during the equivalent mouse hypothalamic development period [postnatal day (PD)21-PD42] programs long-term changes in energy balance via increased thermogenic sympathetic nervous activity.

The CO-produced Psychosocial INtervention delivered by GPs to young people after self-harm (COPING): protocol for a feasibility study.

Background: Self-harm in young people is a growing concern and reducing rates a global priority. Rates of self-harm documented in general practice have been increasing for young people in the UK in the last two decades, especially in 13-16-year-olds. General practitioners (GPs) can intervene early after self-harm but there are no effective treatments presently available.

Angiotensin in the Arcuate: Mechanisms Integrating Cardiometabolic Control: The 2022 COH Mid-Career Award for Research Excellence.

The American Heart Association has identified obesity as a primary impediment to ongoing improvements in cardiovascular diseases, including hypertension. Although drugs, exercise, diets, and surgeries can each cause weight loss, few subjects maintain a reduced weight over the long term. Dysfunctional integrative control (ie, adaptation) of resting metabolic rate (RMR) appears to underlie this failed weight maintenance, yet the neurobiology of physiological and pathophysiological RMR control is poorly understood.

Understanding and supporting young people exposed to online misinformation about eczema.

The traditional patient-clinician relationship is changing as young people and their families often now turn to the internet and social media for health information, treatment advice and support. Much of that content, however, is unregulated, unverified and inaccurate, which leads to the dissemination of health misinformation. Healthcare professionals working with young people with eczema and their families need to understand why young people turn to social media for health information, identify trends in online misinformation about eczema, and provide alternative, trustworthy sources of information.

An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.

Introduction: Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization.

Tumors, Treatments, and Trust: Cancer Characteristics, Outcomes, and Screening Uptake in Transgender and Gender-Diverse Patients.

Background: More than 2.5 million adults in the United States identify as transgender or gender-diverse (TGD), but little data exist on cancer screening and care for this population. We examined cancer characteristics, screening adherence, genetic testing, and provider inclusive language for TGD patients with cancer.

Identifying carers in general practice (STATUS QUO): a multicentre, cross-sectional study in England.

Objectives: To determine General Practice (GP) recording of carer status and the number of patients self-identifying as carers, while self-completing an automated check-in screen prior to a GP consultation.

Design: A descriptive cross-sectional study.

Setting: 11 GPs in the West Midlands, England.

Ultrasound-mediated gene delivery specifically targets liver sinusoidal endothelial cells for sustained FVIII expression in hemophilia A mice.

The ability to target the native production site of factor VIII (FVIII)-liver sinusoidal endothelial cells (LSECs)-can improve the outcome of hemophilia A (HA) gene therapy. By testing a matrix of ultrasound-mediated gene delivery (UMGD) parameters for delivering a GFP plasmid into the livers of HA mice, we were able to define specific conditions for targeted gene delivery to different cell types in the liver. Subsequently, two conditions were selected for experiments to treat HA mice via UMGD of an endothelial-specific human FVIII plasmid: low energy (LE; 50 W/cm, 150 μs pulse duration) to predominantly target endothelial cells or high energy (HE; 110 W/cm, 150 μs pulse duration) to predominantly target hepatocytes.

Online behavioural interventions for children and young people with eczema: a quantitative evaluation.

Background: Two online behavioural interventions (one website for parents/carers of children with eczema; and one for young people with eczema) have been shown in randomised controlled trials to facilitate a sustained improvement in eczema severity.

Aim: To describe intervention use and examine potential mediators of intervention outcomes and contextual factors that may influence intervention delivery and outcomes.

Design And Setting: Quantitative process evaluation in UK primary care.

Human growth factor-mediated signalling through lipid rafts regulates stem cell proliferation, development and survival of .

Although the mechanisms by which schistosomes grow and develop in humans are poorly defined, their unique outer tegument layer, which interfaces with host blood, is considered vital to homeostasis of the parasite. Here, we investigated the importance of tegument lipid rafts to the biology of in the context of host-parasite interactions. We demonstrate the temporal clustering of lipid rafts in response to human epidermal growth factor (EGF) during early somule development, concomitant with the localization of anteriorly orientated EGF receptors (EGFRs) and insulin receptors, mapped using fluorescent EGF/insulin ligand.

Cost-effectiveness of two online interventions supporting self-care for eczema for parents/carers and young people.

Objective: To estimate the cost-effectiveness of online behavioral interventions (EczemaCareOnline.org.uk) designed to support eczema self-care management for parents/carers and young people from an NHS perspective.

Differences in Fluid, Electrolyte, and Energy Balance in C57BL/6J Mice () in Metabolic Caging at Thermoneutral or Standard Room Temperatures.

The recommends mice be pair or group housed and provided with nesting materials. These provisions support social interactions and are also critical for thermoregulatory behaviors such as huddling and burrowing. However, studies of fluid and electrolyte balance and digestive function may involve use of metabolic caging (MC) systems in which mice are housed individually on wire-mesh floors that permit quantitative collection of urine and feces.

Undertaking multi-centre randomised controlled trials in primary care: learnings and recommendations from the PULsE-AI trial researchers.

Background: Conducting effective and translational research can be challenging and few trials undertake formal reflection exercises and disseminate learnings from them. Following completion of our multicentre randomised controlled trial, which was impacted by the COVID-19 pandemic, we sought to reflect on our experiences and share our thoughts on challenges, lessons learned, and recommendations for researchers undertaking or considering research in primary care.

Methods: Researchers involved in the Prediction of Undiagnosed atriaL fibrillation using a machinE learning AlgorIthm (PULsE-AI) trial, conducted in England from June 2019 to February 2021 were invited to participate in a qualitative reflection exercise.

An P93S variant dysregulates TDP-43 and causes corticobasal syndrome.

As genetic testing has become more accessible and affordable, variants of uncertain significance (VUS) are increasingly identified, and determining whether these variants play causal roles in disease is a major challenge. The known disease-associated Annexin A11 (ANXA11) mutations result in ANXA11 aggregation, alterations in lysosomal-RNA granule co-trafficking, and TDP-43 mis-localization and present as amyotrophic lateral sclerosis or frontotemporal dementia. We identified a novel VUS in ANXA11 (P93S) in a kindred with corticobasal syndrome and unique radiographic features that segregated with disease.

The long-term safety of topical corticosteroids in atopic dermatitis: A systematic review.

Background: Topical corticosteroids (TCS) are a first-line treatment for eczema, but there are concerns about their safety when used long-term.

Objectives: To systematically review adverse effects associated with longer-term use of TCS for eczema.

Methods: Randomised controlled trials (RCTs), cohort and case-control studies reporting adverse effects of TCS (comparators: no TCS treatment, other topicals) in patients with eczema were identified.

Skin changes associated with ageing.

Major skin changes are one of the many features occurring with ageing and it is estimated that 70% of older people have skin problems (All-Party Parliamentary Group on Skin (APPGS), 2000). A report into skin diseases in older people highlighted that they were noted to suffer from a lack of sensitivity to their skin care needs and related problems; furthermore, training was lacking for healthcare professionals and service provision was not planned (APPGS, 2000). The aim of this article is to highlight the importance of skin care in the older person and increase the nurse's knowledge of skin changes associated with age.

A multicomponent intervention to reduce daily sitting time in office workers: the SMART Work & Life three-arm cluster RCT.

Background: Office workers spend 70-85% of their time at work sitting. High levels of sitting have been linked to poor physiological and psychological health. Evidence shows the need for fully powered randomised controlled trials, with long-term follow-up, to test the effectiveness of interventions to reduce sitting time.