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Kidney services worldwide are increasingly using digital health technologies to deliver care. This includes kidney electronic patient-reported outcome (ePRO) systems: ambulatory digital technologies that enable the capture of PRO data electronically from people with kidney disease remotely and in real time to be shared with their kidney care team. Current kidney ePRO systems commonly aim to support the monitoring and management of symptoms in patients with kidney disease. The majority have thus far only been implemented in research settings and are not yet routinely used in clinical practice, leaving their readiness for real-world implementation largely unknown. Compared with paper-based PRO collection, ePRO systems have certain advantages, which we categorize as efficiency benefits (e.g., lower administrative burden), direct patient care benefits (e.g., automated PRO-based patient education), and health system and research benefits (e.g., collecting ePRO data once for multiple purposes). At the same time, kidney ePRO systems come with drawbacks, such as their potential to exacerbate existing inequities in care and outcomes and to negatively affect staff burden and patients' experience of kidney care. Areas that hold promise for expediting the development and uptake of kidney ePRO systems at the local, organizational, and national level include harnessing national kidney registries as enabling infrastructures; using novel data-driven technologies (e.g., computerized adaptive test systems, configurable dashboards); applying implementation science and action research approaches to enhance translation of ePRO research findings into clinical practice; and engaging stakeholders, including patients and carers, health care professionals, policymakers, payers, ePRO experts, technology providers, and organizations that monitor and improve the quality of kidney services., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The effect of plasma hepcidin concentrations on the long-term risk of developing adverse cardiovascular outcomes in people with type 2 diabetes mellitus (T2DM) is unclear., Methods: We followed for a median of 55.6 months 213 outpatients with established T2DM (45.5% women, mean age 69 ± 10 years; BMI 28.7 ± 4.7 kg/m 2 ; median diabetes duration 11 years). Baseline plasma ferritin and hepcidin concentrations were measured with an electrochemiluminescence immunoassay and mass spectrometry-based assay, respectively. The primary study outcome was a composite of all-cause mortality or incident nonfatal cardiovascular events (inclusive of myocardial infarction, permanent atrial fibrillation, ischemic stroke, or new hospitalization for heart failure)., Results: 42 patients developed the primary composite outcome over a median follow-up of 55.6 months. After stratifying patients by baseline hepcidin tertiles [1st tertile: median hepcidin 1.04 (IQR 0.50-1.95) nmol/L, 2nd tertile: 3.81 (IQR 3.01-4-42) nmol/L and 3rd tertile: 7.72 (IQR 6.37-10.4) nmol/L], the risk of developing the primary composite outcome in patients in the 3rd tertile was double that of patients in the 1st and 2nd tertile combined (unadjusted hazard ratio [HR] 2.32, 95%CI 1.27-4.26; p = 0.007). This risk was not attenuated after adjustment for age, sex, adiposity measures, smoking, hypertension, statin use, antiplatelet medication use, plasma hs-C-reactive protein and ferritin concentrations (adjusted HR 2.53, 95%CI 1.27-5.03; p = 0.008)., Conclusions: In outpatients with T2DM, higher baseline hepcidin concentrations were strongly associated with an increased long-term risk of overall mortality or nonfatal cardiovascular events, even after adjustment for established cardiovascular risk factors, plasma ferritin concentrations, medication use, and other potential confounders., (© 2024. The Author(s).)

Background: The success of big data initiatives depends on public support. Public involvement and engagement could be a way of establishing public support for big data research., Objective: This review aims to synthesize the evidence on public involvement and engagement in big data research., Methods: This scoping review mapped the current evidence on public involvement and engagement activities in big data research. We searched 5 electronic databases, followed by additional manual searches of Google Scholar and gray literature. In total, 2 public contributors were involved at all stages of the review., Results: A total of 53 papers were included in the scoping review. The review showed the ways in which the public could be involved and engaged in big data research. The papers discussed a broad range of involvement activities, who could be involved or engaged, and the importance of the context in which public involvement and engagement occur. The findings show how public involvement, engagement, and consultation could be delivered in big data research. Furthermore, the review provides examples of potential outcomes that were produced by involving and engaging the public in big data research., Conclusions: This review provides an overview of the current evidence on public involvement and engagement in big data research. While the evidence is mostly derived from discussion papers, it is still valuable in illustrating how public involvement and engagement in big data research can be implemented and what outcomes they may yield. Further research and evaluation of public involvement and engagement in big data research are needed to better understand how to effectively involve and engage the public in big data research., International Registered Report Identifier (irrid): RR2-https://doi.org/10.1136/bmjopen-2021-050167., (©Piotr Teodorowski, Elisa Jones, Naheed Tahir, Saiqa Ahmed, Sarah E Rodgers, Lucy Frith. Originally published in Journal of Participatory Medicine (https://jopm.jmir.org), 16.08.2024.)

Background: Worldwide, respiratory syncytial virus (RSV) infections are among the most common causes of infant hospitalization. Host genetic factors influencing the risk and severity of RSV infection are not well known., Methods: We conducted a genome-wide association study (GWAS) to investigate single-nucleotide polymorphisms (SNPs) associated with severe RSV infections using a nested case-control design based on 2 Danish cohorts. We compared SNPs from 1786 children hospitalized with RSV to 45 060 controls without an RSV-coded hospitalization. We performed gene-based testing, tissue enrichment, gene-set enrichment, and a meta-analysis of the 2 cohorts. Finally, an analysis of potential associations between the severity of RSV infection and genetic markers was performed., Results: We did not detect any significant genome-wide associations between SNPs and RSV infection or the severity of RSV. We did find potential loci associated with RSV infections on chromosome 5 in 1 cohort but failed to replicate any signals in both cohorts., Conclusions: Despite being the largest GWAS of severe RSV infection, we did not detect any genome-wide significant loci. This may be an indication of a lack of power or an absence of signal. Future studies might include mild illness and need to be larger to detect any significant associations., Competing Interests: Potential conflicts of interest . T. F. K. served as principal investigator (unpaid) in a Pfizer RSV vaccine trial, outside the submitted work. A. J. P. partnered with AstraZeneca for development of a COVID-19 vaccine. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Rationale: Despite evidence demonstrating a prognostic role for computed tomography (CT) scans in idiopathic pulmonary fibrosis (IPF), image-based biomarkers are not routinely used in clinical practice or trials. Objectives: To develop automated imaging biomarkers using deep learning-based segmentation of CT scans. Methods: We developed segmentation processes for four anatomical biomarkers, which were applied to a unique cohort of treatment-naive patients with IPF enrolled in the PROFILE (Prospective Observation of Fibrosis in the Lung Clinical Endpoints) study and tested against a further United Kingdom cohort. The relationships among CT biomarkers, lung function, disease progression, and mortality were assessed. Measurements and Main Results: Data from 446 PROFILE patients were analyzed. Median follow-up duration was 39.1 months (interquartile range, 18.1-66.4 mo), with a cumulative incidence of death of 277 (62.1%) over 5 years. Segmentation was successful on 97.8% of all scans, across multiple imaging vendors, at slice thicknesses of 0.5-5 mm. Of four segmentations, lung volume showed the strongest correlation with FVC ( r  = 0.82; P  < 0.001). Lung, vascular, and fibrosis volumes were consistently associated across cohorts with differential 5-year survival, which persisted after adjustment for baseline gender, age, and physiology score. Lower lung volume (hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.96-0.99]; P  = 0.001), increased vascular volume (HR, 1.30 [95% CI, 1.12-1.51]; P  = 0.001), and increased fibrosis volume (HR, 1.17 [95% CI, 1.12-1.22]; P  < 0.001) were associated with reduced 2-year progression-free survival in the pooled PROFILE cohort. Longitudinally, decreasing lung volume (HR, 3.41 [95% CI, 1.36-8.54]; P  = 0.009) and increasing fibrosis volume (HR, 2.23 [95% CI, 1.22-4.08]; P  = 0.009) were associated with differential survival. Conclusions: Automated models can rapidly segment IPF CT scans, providing prognostic near and long-term information, which could be used in routine clinical practice or as key trial endpoints.

Background: Hospitalized COVID-19 patients with troponin elevation have a higher prevalence of cardiac abnormalities than control individuals. However, the progression and impact of myocardial injury on COVID-19 survivors remain unclear., Objectives: This study sought to evaluate myocardial injury in COVID-19 survivors with troponin elevation with baseline and follow-up imaging and to assess medium-term outcomes., Methods: This was a prospective, longitudinal cohort study in 25 United Kingdom centers (June 2020 to March 2021). Hospitalized COVID-19 patients with myocardial injury underwent cardiac magnetic resonance (CMR) scans within 28 days and 6 months postdischarge. Outcomes were tracked for 12 months, with quality of life surveys (EuroQol-5 Dimension and 36-Item Short Form surveys) taken at discharge and 6 months., Results: Of 342 participants (median age: 61.3 years; 71.1% male) with baseline CMR, 338 had a 12-month follow-up, 235 had a 6-month CMR, and 215 has baseline and follow-up quality of life surveys. Of 338 participants, within 12 months, 1.2% died; 1.8% had new myocardial infarction, acute coronary syndrome, or coronary revascularization; 0.8% had new myopericarditis; and 3.3% had other cardiovascular events requiring hospitalization. At 6 months, there was a minor improvement in left ventricular ejection fraction (1.8% ± 1.0%; P < 0.001), stable right ventricular ejection fraction (0.4% ± 0.8%; P = 0.50), no change in myocardial scar pattern or volume (P = 0.26), and no imaging evidence of continued myocardial inflammation. All pericardial effusions (26 of 26) resolved, and most pneumonitis resolved (95 of 101). EuroQol-5 Dimension scores indicated an overall improvement in quality of life (P < 0.001)., Conclusions: Myocardial injury in severe hospitalized COVID-19 survivors is nonprogressive. Medium-term outcomes show a low incidence of major adverse cardiovascular events and improved quality of life. (COVID-19 Effects on the Heart; ISRCTN58667920)., Competing Interests: Funding Support and Author Disclosures This work was supported by NIHR (National Institute for Health and Care Research) and UK Research and Innovation (COV0254). West Yorkshire and Humber Clinical Research Network (CV070) funded the patient information leaflet translation. Dr Berry has received British Heart Foundation support (RE/18/6134217). Dr Artico received funding from the European Association of Cardiovascular Imaging (EACVI Research Grant App000073878). Dr McCann is funded by a NIHR Research Professorship (RP-2017-08-ST2-007). Dr Manisty is funded by a NIHR Clinician Scientist Award (CS-2015-15-003). Drs Ferreira, Piechnik, and Neubauer acknowledge the NIHR Oxford BRC for support of this study. Dr Bucciarelli-Ducci is in part supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS (National Health Service) Foundation Trust and the University of Bristol. Additional support was provided by the NIHR Leicester Biomedical Research Centre and the NIHR Leeds Clinical Research Facility. Dr Dweck is supported by the British Heart Foundation (FS/SCRF/21/32010). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. Dr Moon has served on Advisory Boards for Sanofi and Genzyme. Dr Miller has served on Advisory Boards for Novartis, Boehringer Ingelheim and Lilly Alliance, and AstraZeneca; serves as an advisor for HAYA Therapeutics and PureTech Health; and has received research support from Amicus Therapeutics, Guerbet Laboratories Limited, Roche, and Univar Solutions B.V. Dr Bucciarelli-Ducci is the chief executive officer (part-time) of the Society for Magnetic Resonance. Dr Berry is employed by the University of Glasgow, which holds research and/or consultancy agreements with AstraZeneca, Abbott Vascular, Boehringer Ingelheim, GlaxoSmithKline, HeartFlow, Opsens, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Obeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in PBC patients improve with OCA therapy., Methods: Patients randomized to OCA (5-10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score-weighted EC group was derived from a US healthcare claims database., Results: In the RCT, the primary endpoint occurred in 28.6% of OCA (n=168) and 28.9% of placebo patients (n=166; intent-to-treat [ITT] analysis hazard ratio [HR]=1.01, 95% CI=0.68-1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting (IPCW) and as-treated analyses shifted the HR to favor OCA. In the EC (n=1051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR=0.39; 95% CI=0.22-0.69; P=0.001). No new safety signals were identified in the RCT., Conclusions: Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the ITT estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Inclusion in public health research of young people from low-income households and those from minority ethnic groups remains low. It is recognised that there is a need to change the way in which research is conducted so that it becomes more inclusive. The aim of this work was to identify novel and innovative ways to maximise recruitment and inclusion of diverse participants when doing co-production within very short time frames for emergency responses., Method: We conducted interviews with young people from low-income and minority ethnic backgrounds, and members or leaders of groups or organisations supporting or representing young people from underserved communities., Results: A total of 42 participants took part in an interview. This included 30 young people from low income or minority ethnic backgrounds and 12 community leaders/service providers. Of the 30 young people, 26 participants identified as female and 12 participants identified as being from a minority ethnic background. Participants discussed a number of interrelated barriers to research involvement and identified ways in which barriers may be reduced. Prejudice and discrimination experienced by young people from underserved communities has led to substantial mistrust of educational and governmental establishments. Rigid and unfamiliar research practices further limit the involvement of young people. Four themes were identified as ways of supporting involvement, including: making opportunities available for young people, adaptations to research governance, understanding and acknowledging challenges faced by young people, and ensuring reciprocal benefits., Conclusion: This research explored barriers to engagement in rapid public health co-production. Working with communities to co-produce rapid recruitment and research procedures to suit the needs and the context in which young people live is necessary., (© 2024. The Author(s).)

Purpose: Standardization of eye care data is important for clinical interoperability and research . We aimed to address gaps in the representations of glaucoma examination concepts within Systemized Nomenclature of Medicine - Clinical Terms (SNOMED-CT), the preferred terminology of the American Academy of Ophthalmology., Design: Study of data elements., Methods: Structured eye exam data fields from two electronic health records (EHR) systems (Epic Systems and Medisoft) were compared against existing SNOMED-CT codes for concepts representing glaucoma examination findings 3 . Glaucoma specialists from multiple institutions were surveyed to identify high-priority gaps in representation, which were discussed among the SNOMED International Eye Care Clinical Reference Group. Proposals for new codes to address the gaps were formulated and submitted for inclusion in SNOMED-CT., Main Outcome Measures: Gaps in SNOMED-CT glaucoma examination concept representations RESULTS: We identified several gaps in SNOMED-CT regarding glaucoma examination concepts. A survey of glaucoma specialists identified high-priority data elements within the categories of tonometry and gonioscopy. For tonometry, there was consensus that we need to define new codes related to maximum intraocular pressure (IOP) and target IOP, and to delineate all methods of measuring IOP. These new codes were proposed and successfully added to SNOMED-CT for future use. Regarding gonioscopy, the current terminology did not include the ability to denote the gonioscopic grading system used (e.g., Shaffer or Spaeth), degree of angle pigmentation, iris configuration (except for plateau iris), and iris approach. There was also no ability to specify eye laterality or angle quadrant for gonioscopic findings. We proposed a framework for representing gonioscopic findings as observable entities in SNOMED-CT., Discussion: There are existing gaps in the standardized representation of findings related to tonometry and gonioscopy within SNOMED-CT. These are important areas for evaluating clinical outcomes and enabling secondary use of EHR data for glaucoma research. This international, multi-institutional collaborative process enabled identification of gaps, prioritization, and development of data standards to address these gaps., Conclusion: Addressing these gaps and augmenting SNOMED-CT coverage of glaucoma examination findings could enhance clinical documentation and future research efforts related to glaucoma., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To quantify the potential advantages of using 10 year risk prediction models for cardiovascular disease, in combination with risk thresholds specific to both age and sex, to identify individuals at high risk of cardiovascular disease for allocation of statin treatment., Design: Prospective open cohort study., Setting: Primary care data from the UK Clinical Practice Research Datalink GOLD, linked with hospital admissions from Hospital Episode Statistics and national mortality records from the Office for National Statistics in England, 1 January 2006 to 31 May 2019., Participants: 1 046 736 individuals (aged 40-85 years) with no cardiovascular disease, diabetes, or a history of statin treatment at baseline using data from electronic health records., Main Outcome Measures: 10 year risk of cardiovascular disease, calculated with version 2 of the QRISK cardiovascular disease risk algorithm (QRISK2), with two main strategies to identify individuals at high risk: in strategy A, estimated risk was a fixed cut-off value of ≥10% (ie, as per the UK National Institute for Health and Care Excellence guidelines); in strategy B, estimated risk was ≥10% or ≥90th centile of age and sex specific risk distributions., Results: Compared with strategy A, strategy B stratified 20 241 (149.8%) more women aged ≤53 years and 9832 (150.2%) more men aged ≤47 years as having a high risk of cardiovascular disease; for all other ages the strategies were the same. Assuming that treatment with statins would be initiated in those identified as high risk, differences in the estimated gain in cardiovascular disease-free life years from statin treatment for strategy B versus strategy A were 0.14 and 0.16 years for women and men aged 40 years, respectively; among individuals aged 40-49 years, the numbers needed to treat to prevent one cardiovascular disease event for strategy B versus strategy A were 39 versus 21 in women and 19 versus 15 in men, respectively., Conclusions: This study quantified the potential gains in cardiovascular disease-free life years when implementing prevention strategies based on age and sex specific risk thresholds instead of a fixed risk threshold for allocation of statin treatment. Such gains should be weighed against the costs of treating more younger people with statins for longer., Competing Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from British Heart Foundation (BHF), BHF Cambridge Centre for Research Excellence, National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, Chinese Scholarship Council, NIHR Blood and Transplant Research Unit (BTRU) in Donor Health and Genomics, NIHR BTRU in Donor Health and Behaviour, and Innovative Medicines Initiative-2 Joint Undertaking for the submitted work; MA is an employee of AstraZeneca; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Few previous studies have considered the experiences of people with long covid returning to work beyond symptoms in terms of employer and other support factors. The aim of this research was to understand the experience of returning to work for those with long covid symptoms in contrast to the non-long covid group who had not experienced COVID-19 during the time restrictions were imposed to limit the spread of COVID-19 infection. Twenty-one participants with long covid and 13 participants who had not had COVID-19 were interviewed. Themes were identified from transcripts using framework analysis. Participants with long covid experienced difficulties returning to work, particularly from fatigue, cognitive symptoms and breathlessness. Symptoms were heterogeneous and fluctuated in severity over time. A lack of understanding from colleagues and managers sometimes led to a premature return to work without adequate support, associated with further long covid relapse. Outside-of-work, support was salient for a successful return to work. The standard phased return offered by employers may be too short and rigid for some people with long covid. They may benefit from a tailored intervention to support a return to work that targets symptom management, and engages with work colleagues, managers, and family members., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Boutry et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In the context of early disease detection, machine learning (ML) has emerged as a vital tool. Feature selection (FS) algorithms play a crucial role in ensuring the accuracy of predictive models by identifying the most influential variables. This study, focusing on a retrospective cohort of 4778 COVID-19 patients from Iran, explores the performance of various FS methods, including filter, embedded, and hybrid approaches, in predicting mortality outcomes. The researchers leveraged 115 routine clinical, laboratory, and demographic features and employed 13 ML models to assess the effectiveness of these FS methods based on classification accuracy, predictive accuracy, and statistical tests. The results indicate that a Hybrid Boruta-VI model combined with the Random Forest algorithm demonstrated superior performance, achieving an accuracy of 0.89, an F1 score of 0.76, and an AUC value of 0.95 on test data. Key variables identified as important predictors of adverse outcomes include age, oxygen saturation levels, albumin levels, neutrophil counts, platelet levels, and markers of kidney function. These findings highlight the potential of advanced FS techniques and ML models in enhancing early disease detection and informing clinical decision-making., (© 2024. The Author(s).)

Aims: We investigated the prevalence, clinical characteristics, and prognosis of patients with heart failure (HF) with improved ejection fraction (HFimpEF)., Methods and Results: We used data from BIOSTAT-CHF including patients with a left ventricular ejection fraction (LVEF) ≤40% at baseline who had LVEF re-assessed at 9 months. HFimpEF was defined as a LVEF >40% and a LVEF ≥10% increase from baseline at 9 months. We validated findings in the ASIAN-HF registry. The primary outcome was a composite of time to HF rehospitalization or all-cause mortality. In BIOSTAT-CHF, about 20% of patients developed HFimpEF, that was associated with a lower primary event rate of all-cause mortality (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.28-0.97, p = 0.040) and the composite endpoint (HR 0.46, 95% CI 0.30-0.70, p < 0.001) compared with patients who remained in persistent HF with reduced ejection fraction (HFrEF). The findings were similar in the ASIAN-HF (HR 0.40, 95% CI 0.18-0.89, p = 0.024, and HR 0.29, 95% CI 0.17-0.48, p < 0.001). Five independently common predictors for HFimpEF in both BIOSTAT-CHF and ASIAN-HF were female sex, absence of ischaemic heart disease, higher LVEF, smaller left ventricular end-diastolic and end-systolic diameter at baseline. A predictive model combining only five predictors (absence of ischaemic heart disease and left bundle branch block, smaller left ventricular end-systolic and left atrial diameter, and higher platelet count) for HFimpEF in the BIOSTAT-CHF achieved an area under the curve of 0.772 and 0.688 in the ASIAN-HF (due to missing left atrial diameter and platelet count)., Conclusions: Approximately 20-30% of patients with HFrEF improved to HFimpEF within 1 year with better clinical outcomes. In addition, the predictive model with clinical predictors could more accurately predict HFimpEF in patients with HFrEF., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Frailty is a complex, age-related clinical condition that involves multiple contributing factors and raises the risk of adverse outcomes in older people. Given global population ageing trends, the growing prevalence and incidence of frailty pose significant challenges to health and social care systems in both high-income and lower-income countries. In this review, we highlight the disproportionate representation of research on frailty screening and management from high-income countries, despite how lower-income countries are projected to have a larger share of older people aged ≥60. However, more frailty research has been emerging from lower-income countries in recent years, paving the way for more context-specific guidelines and studies that validate frailty assessment tools and evaluate frailty interventions in the population. We then present further considerations for contextualising frailty in research and practice in lower-income countries. First, the heterogeneous manifestations of frailty call for research that reflects different geographies, populations, health systems, community settings and policy priorities; this can be driven by supportive collaborative systems between high-income and lower-income countries. Second, the global narrative around frailty and ageing needs re-evaluation, given the negative connotations linked with frailty and the introduction of intrinsic capacity by the World Health Organization as a measure of functional reserves throughout the life course. Finally, the social determinants of health as possible risk factors for frailty in lower-income countries and global majority populations, and potential socioeconomic threats of frailty to national economies warrant proactive frailty screening in these populations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background and Objectives: METHODS: A structured search strategy encompassing databases including MEDLINE, Embase, CINAHL Plus, PsycINFO and Cochrane Library was implemented from inception to October 2023. Included studies focused on interventions targeting opioid reduction in adults following major surgeries. The risk of bias was evaluated using Cochrane risk-of-bias tool V.2 (RoB 2) and non-randomised studies of interventions (ROBINS-I) tools, and Cohen's d effect sizes were calculated. BCTs were identified using a validated taxonomy., Results: 22 studies, comprising 7 clinical trials and 15 cohort studies, were included, with varying risks of bias. Educational (n=12), guideline-focused (n=3), multifaceted (n=5) and pharmacist-led (n=2) interventions demonstrated diverse effect sizes (small-medium n=10, large n=12). A total of 23 unique BCTs were identified across studies, occurring 140 times. No significant association was observed between the number of BCTs and effect size, and interventions with large effect sizes predominantly targeted healthcare professionals. Key BCTs in interventions with the largest effect sizes included behaviour instructions, behaviour substitution, goal setting (outcome), social support (practical), social support (unspecified), pharmacological support, prompts/cues, feedback on behaviour, environmental modification, graded tasks, outcome goal review, health consequences information, action planning, social comparison, credible source, outcome feedback and social reward., Conclusions: Understanding the dominant BCTs in highly effective interventions provides valuable insights for future opioid tapering strategy implementations. Further research and validation are necessary to establish associations between BCTs and effectiveness, considering additional influencing factors., Prospero Registration Number: CRD42022290060., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Fetal alcohol spectrum disorder (FASD) is a leading cause of neurodevelopmental disability globally. International organizations have highlighted an urgent need for improved prevention, diagnosis, and support. However, the evidence base needed to inform this is thought to be limited. We conducted two complementary reviews to (i) describe trends in the volume and characteristics of original FASD research articles (Review 1) and (ii) compare the volume of published research on FASD to that of other neurodevelopmental disorders (Review 2). In Review 1, we systematically searched MEDLINE, Embase, CINAHL and PsycInfo for original studies with FASD terms in the title, published between 2000 and 2023. We summarised study characteristics including the article topic(s), sample population, country of origin, and publication year using quantitative content analysis and time-series plots. A total of 854 studies were eligible. Studies showed a relative focus on diagnosis and screening, compared to prevention and intervention. FASD research originated from 31 countries, however most countries (68%) had fewer than 10 articles published over the 23-year review period. In Review 2, we searched PubMed for records published between 2000 and 2023 with FASD, autism, or attention-deficit-hyperactivity disorder (ADHD) terms in the title. We compared the volume of records for these conditions using descriptive statistics and time-series plots. Of the 64,069 records retrieved, 2% were for FASD, compared to 60% for autism and 38% for ADHD. FASD remains considerably under-researched. While there has been an increase in the number of original FASD research articles published annually over time, this is much lower than expected compared to publication trends for other neurodevelopmental conditions, and the wider scientific literature. Further research is needed to understand the impact of FASD across the lifespan, to inform evidence-based policy and support, and to advance progress in strength-based, stigma-reducing approaches to FASD research and practice., (© 2024 The Author(s). Alcohol, Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.)

Background and Aims: Tumour rupture (TR) signifies stage III disease and requires treatment intensification, which includes radiotherapy. We studied the associations between radiological, surgical and pathology TR in children with Wilms tumour (WT) in a United Kingdom multicentre clinical study., Patients and Methods: The IMPORT (Improving Population Outcomes for Renal Tumours of Childhood) study registered 712 patients between 2012 and 2021. Children with TR on central radiology review (CRR) at diagnosis and/or indication of preoperative TR on surgical forms were included. Correlation between radiology/surgery/pathology findings was made., Results: Total 141 patients had TR identified (69 on CRR, 43 on surgical form and 29 on both), and 124/141 had images available for CRR, and 98/124 had features suggestive of TR on diagnostic CRR (63 magnetic resonance imaging/35 computed tomography). TR was limited to the renal fossa in 47/98 (48%) and intraperitoneal in 51/98 (52%). Three of 98(3%) had upfront surgery, and 87/95 (92%) had TR confirmed on post-chemotherapy preoperative scans. Among 80/98 (82%) cases with TR on CRR and available surgical forms, TR was not confirmed on surgery or pathology in 38/80, giving a false-positive rate of 48%. Preoperative TR was indicated on 72 surgical forms, with images available for CRR in 55. Twenty-six of 55 (47%) were false-negative for TR on CRR and of those 10/26 (38%) had TR confirmed on pathology., Conclusions: Radiology alone should not be used to define TR, as it does not accurately correlate with surgical or pathology findings, and therefore cannot be relied upon for definitive staging and treatment. A multidisciplinary team should take the decision regarding the final abdominal stage and treatment using a multimodality approach considering clinical, radiological, surgical and pathological findings., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Gene misexpression is the aberrant transcription of a gene in a context where it is usually inactive. Despite its known pathological consequences in specific rare diseases, we have a limited understanding of its wider prevalence and mechanisms in humans. To address this, we analyzed gene misexpression in 4,568 whole-blood bulk RNA sequencing samples from INTERVAL study blood donors. We found that while individual misexpression events occur rarely, in aggregate they were found in almost all samples and a third of inactive protein-coding genes. Using 2,821 paired whole-genome and RNA sequencing samples, we identified that misexpression events are enriched in cis for rare structural variants. We established putative mechanisms through which a subset of SVs lead to gene misexpression, including transcriptional readthrough, transcript fusions, and gene inversion. Overall, we develop misexpression as a type of transcriptomic outlier analysis and extend our understanding of the variety of mechanisms by which genetic variants can influence gene expression., Competing Interests: Declaration of interests The authors declare the following interests: T.V. has received PhD studentship funding from AstraZeneca. J.M. completed this work while employed by the University of Cambridge but is now an employee of Genomics plc. S.P. is a current employee and stockholder of AstraZeneca. D.J.R. is an employee of NHS Blood and Transplant. A.B. is currently an employee of Bayer AG, Research and Early Development Precision Medicine, Research & Development, Pharmaceutical Division, Wuppertal, DE. A.P. is a current employee and stockholder of AstraZeneca. D.S.P. is a current employee and stockholder of AstraZeneca. K.K. is a current employee and stockholder of AstraZeneca. J.D. serves on scientific advisory boards for AstraZeneca, Novartis, and UK Biobank and has received multiple grants from academic, charitable, and industry sources outside of the submitted work. M.I. is a trustee of the Public Health Genomics (PHG) Foundation, is a member of the Scientific Advisory Board of Open Targets, and has a research collaboration with AstraZeneca, which is unrelated to this study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The proximal part of the small intestine, including duodenum and jejunum, is not only dedicated to nutrient digestion and absorption but is also a highly regulated immune site exposed to environmental factors. Host-protective responses against pathogens and tolerance to food antigens are essential functions in the small intestine. The cellular ecology and molecular pathways to maintain those functions are complex. Maladaptation is highlighted by common immune-mediated diseases such as coeliac disease, environmental enteric dysfunction or duodenal Crohn's disease. An expanding spectrum of more than 100 rare monogenic disorders inform on causative molecular mechanisms of nutrient absorption, epithelial homeostasis and barrier function, as well as inflammatory immune responses and immune regulation. Here, after summarizing the architectural and cellular traits that underlie the functions of the proximal intestine, we discuss how the integration of tissue immunopathology and molecular mechanisms can contribute towards our understanding of disease and guide diagnosis. We propose an integrated mechanism-based taxonomy and discuss the latest experimental approaches to gain new mechanistic insight into these disorders with large disease burden worldwide as well as implications for therapeutic interventions., (© 2024. Springer Nature Limited.)

Purpose of Review: The approval of resmetirom brings great hope to patients with metabolic dysfunction-associated steatohepatitis (MASH). The purpose of this review is to explore its impact on the global health environment. The implementation of multidisciplinary management MASH is proposed., Recent Findings: Resmetirom has benefits in the treatment of MASH, and its safety and effectiveness have been studied. The adverse events (AEs) need to be noticed. To improve patient outcomes, a multimodal approach with medication such as resmetirom, combined with metabolic and bariatric surgery (MBS) and lifestyle interventions can be conducted. MASH, a liver disease linked with obesity, is a challenging global healthcare burden compounded by the absence of any approved pharmacotherapy. The recent conditional approval by the Food and Drug Administration (FDA) in the United States of resmetirom, an oral, liver-directed, thyroid hormone receptor beta-selective agonist, marks a significant milestone, offering a treatment option for adults with non-cirrhotic MASH and who have moderate to advanced liver fibrosis. This narrative review discusses the efficacy and safety of resmetirom and its role in the therapeutic landscape of MASH treatment. Despite the promising hepatoprotective effect of resmetirom on histological liver endpoints, its use need further research, particularly regarding ethnic differences, effectiveness and cost-effectiveness, production scalability, social acceptance and accessibility. In addition, integrating resmetirom with other multidisciplinary therapeutic approaches, including lifestyle changes and MBS, might further improve clinical liver-related and cardiometabolic outcomes of individuals with MASH. This review highlights the importance of a comprehensive treatment strategy, supporting continued innovation and collaborative research to refine treatment guidelines and consensus for managing MASH, thereby improving clinical patient outcomes in the growing global epidemic of MASH. Studies done to date have been relatively short and ongoing, the course of the disease is highly variable, the conditions of various patients vary, and given this complex clinical phenotype, it may take many years of clinical trials to show long-term benefits., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Housing is an important wider determinant of health. Private Rented Sector (PRS) housing is generally the worst quality of housing stock across tenures. Although a wide range of interventions are available to local governments to manage and improve the quality of PRS housing and therefore the health of tenants, there is limited evidence about the extent to which these are used. This study aims to explore what drives the use of different interventions in different local governments, to better understand and inform local strategies., Methods: As the first realist evaluation on this topic, the range of available interventions was informed by a Local Government Association toolkit. Consistent with realist approaches, retroductive analysis of intervention-context-mechanism-outcome configurations helped to develop and refine Initial Programme Theories (IPTs). Data sources included local government housing documents, a survey and eleven semi-structured interviews with housing officers., Results: Using data for 22 out of the 30 local governments in the South West region of the United Kingdom, eight IPTs were developed which act on different levels from individual PRS team leaders to system wide. The IPTs include a belief in market forces, risk adverse to legal challenge, attitude to enforcement, relational approaches to partnership working, job security and renumeration, financial incentives drive action, and system-level understanding of the drivers of poor health, inequalities and opportunities for cost-savings. The findings suggest that limited objective health outcomes are being used to understand impact, which hinders interpretation of the effectiveness of all mechanisms., Conclusion: Interventions that bring about positive outcomes in managing PRS housing are unlikely to be universal; they depend on the context which differs across place and over time. The proposed IPTs highlight the need for strategies to be tailored considering the local context and should be evaluated in subsequent phases of study., (© 2024. The Author(s).)

Background: People with Parkinson's Disease (PwP) have a higher rate of hospitalisation compared to the general population. Little is known about the impact of having a co-resident and their health on hospitalisation rates of PwP., Methods: We utilised Clinical Practice Research Datalink (CPRD) GOLD data (2010-2015) to identify PwP and co-residents. We classed either the fittest or youngest adult as the primary caregiver in each household. Caregiver health was classified by the Cambridge Multimorbidity Score (CMS), primary care utilisation and prescriptions. We calculated the hospitalisation (elective, emergency) incidence rate ratios (IRRs) for PwP who lived alone compared to those with a caregiver using negative binomial regression, and whether worse caregiver health predicted higher risk of admissions., Results: We identified 3254 PwP and 4007 family members. PwP who lived alone were less likely to have an elective admission (0.79; 95 % CI 0.69-0.91) and more likely to have an emergency admission (1.40; 95 % CI 1.70-1.54). Worse caregiver health, as measured by the CMS, was associated with an increased risk of emergency admission (IRR 1.35; 95 % CI 1.17-1.57), but this attenuated and was consistent with chance in the fully adjusted model (1.04; 95 % CI 0.95-1.13). No strong associations were seen between caregiver health and elective admissions., Conclusion: PwP who live alone are at increased risk of emergency and less likely to have elective hospital admissions. It is important that health care providers support such people and ensure they receive equitable access to the potential benefits of elective procedures., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Emily Henderson reports financial support was provided by Gatsby Charitable Foundation. Yoav Ben-Shlomo reports financial support was provided by Parkinson's UK. Yoav Ben-Shlomo reports financial support was provided by Royal Osteoporosis Society. Yoav Ben-Shlomo reports financial support was provided by UKRIMedical Research Council. Yoav Ben-Shlomo reports financial support was provided by Healthcare Quality Improvement Partnership. Yoav Ben-Shlomo reports financial support was provided by John Templeton Foundation. Yoav Ben-Shlomo reports financial support was provided by Wellcome Trust. YBS has received consultancy payment from Human Centric DD LTD and Parkinson's UK both of which are unrelated to this piece of research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Emma Tenison reports financial support was provided by Gatsby Charitable Foundation. Emma Tenison reports a relationship with Royal United Hospitals Bath NHS Foundation Trust that includes: employment. Emma Tenison reports a relationship with The Neurology Academy that includes: speaking and lecture fees. Emma Tenison reports a relationship with University of Bristol that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: StandingTall uses eHealth to deliver evidence-based balance and functional strength exercises. Clinical trials have demonstrated improved balance, reduced falls and fall-related injuries and high adherence. This study aimed to evaluate the implementation of StandingTall into health services in Australia and the UK., Methods: Two hundred and forty-six participants (Australia, n = 184; UK, n = 62) were recruited and encouraged to use StandingTall for 2 h/week for 6-months. A mixed-methods process evaluation assessed uptake and acceptability of StandingTall. Adherence, measured as % of prescribed dose completed, was the primary outcome., Results: The study, conducted October 2019 to September 2021 in Australia and November 2020 to April 2022 in the UK, was affected by COVID-19. Participants' mean age was 73 ± 7 years, and 196 (81%) were female. Of 129 implementation partners (e.g. private practice clinicians, community exercise providers, community service agencies) approached, 34% (n = 44) agreed to be implementation partners. Of 41 implementation partners who referred participants, 15 (37%) referred ≥5. Participant uptake was 42% (198/469) with mean adherence over 6 months being 41 ± 39% of the prescribed dose (i.e. 39 ± 41 min/week) of exercise. At 6 months, 120 (76%) participants indicated they liked using StandingTall, 89 (56%) reported their balance improved (moderately to a great deal better) and 125 (80%) rated StandingTall as good to excellent. For ongoing sustainability, health service managers highlighted the need for additional resources., Conclusions: StandingTall faced challenges in uptake, adoption and sustainability due to COVID-19 and a lack of ongoing funding. Adherence levels were lower than the effectiveness trial, but were higher than other exercise studies. Acceptance was high, indicating promise for future implementation, provided sufficient resources and support are made available., Trial Registration: Australian and New Zealand Clinical Trials Registry ACTRN12619001329156., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Aims: Research in diabetes-related foot conditions (DRFC) often focuses on ulcer-related care, whilst the patient experience and influence of sociodemographic factors are under-researched. This systematic review investigated patient-reported outcomes and experience in people with DRFC., Methods: Multiple databases were searched from inception to 16 August 2023. All original articles that assessed any patient-reported outcome or experience in DRFC and reported participant ethnicity were included. Data were synthesized using a sequential contingent approach. Study quality was assessed using study design-specific tools., Results: Twenty-three studies were included (11 qualitative, 11 quantitative and one mixed-methods). DRFC had a largely negative impact on various life dimensions, including social and daily life, work, emotional and psychological well-being, necessitating dependence on others in the form of emotional, social and/or religious support, which were experienced differently by different groups. Patient DRFC knowledge and self-care habits were typically suboptimal, and levels of hope and feeling of control over their condition varied between groups. Outcomes varied slightly between ethnicities across studies, with some ethnicity-specific themes identified such as beliefs about disease cause and footwear habits. Quantitative and qualitative findings were mostly congruent., Conclusions: DRFC profoundly and negatively impacts patient-reported outcomes and experience, with limited evidence suggesting an influence of ethnicity., (© 2024 The Author(s). Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Importance: The ways in which we access, acquire, and use data in clinical trials have evolved very little over time, resulting in a fragmented and inefficient system that limits the amount and quality of evidence that can be generated., Observations: Clinical trial design has advanced steadily over several decades. Yet the infrastructure for clinical trial data collection remains expensive and labor intensive and limits the amount of evidence that can be collected to inform whether and how interventions work for different patient populations. Meanwhile, there is increasing demand for evidence from randomized clinical trials to inform regulatory decisions, payment decisions, and clinical care. Although substantial public and industry investment in advancing electronic health record interoperability, data standardization, and the technology systems used for data capture have resulted in significant progress on various aspects of data generation, there is now a need to combine the results of these efforts and apply them more directly to the clinical trial data infrastructure., Conclusions and Relevance: We describe a vision for a modernized infrastructure that is centered around 2 related concepts. First, allowing the collection and rigorous evaluation of multiple data sources and types and, second, enabling the possibility to reuse health data for multiple purposes. We address the need for multidisciplinary collaboration and suggest ways to measure progress toward this goal.

Background: The COVID-19 pandemic necessitated the widespread roll-out of teleconsultations across primary care services in the UK. The media's depiction of remote consultations, especially regarding their safety, is not well established. These insights are important: newspapers' coverage of healthcare-related news can influence public perception, national policy, and clinicians' job satisfaction., Aim: To explore how the national newspapers in the UK depicted both the direct and indirect consequences of the remote-first approach on patient safety., Design and Setting: We performed thematic analysis of newspaper articles that discussed patient safety in primary care teleconsultations, which were published between 21 January 2021 and 22 April 2022., Method: We identified relevant articles using the LexisNexis Academic UK database. We categorised data from these articles into codes before developing these into emergent themes through an iterative process., Results: Across the 57 articles identified, the main safety concern identified was missed and/or delayed diagnoses over tele-appointment(s), while isolated cases of inappropriate prescribing were also reported. The media reported that the transition to a remote-first approach reduced the accessibility to primary care appointments for some groups (especially patients with lower digital literacy or access) and heightened the burden on other healthcare services; in particular, there were reports of patient care being compromised across NHS emergency departments., Conclusion: The print media predominantly reported negative impacts of remote consultations on patient safety, particularly involving missed and/ or delayed diagnoses. Our work highlights the importance of further exploration into the safety of remote consultations, and the impact of erroneous media reporting on policies and policymakers., (© The Authors.)

Background: A clinical tool to estimate the risk of treatment-resistant schizophrenia (TRS) in people with first-episode psychosis (FEP) would inform early detection of TRS and overcome the delay of up to 5 years in starting TRS medication., Aims: To develop and evaluate a model that could predict the risk of TRS in routine clinical practice., Method: We used data from two UK-based FEP cohorts (GAP and AESOP-10) to develop and internally validate a prognostic model that supports identification of patients at high-risk of TRS soon after FEP diagnosis. Using sociodemographic and clinical predictors, a model for predicting risk of TRS was developed based on penalised logistic regression, with missing data handled using multiple imputation. Internal validation was undertaken via bootstrapping, obtaining optimism-adjusted estimates of the model's performance. Interviews and focus groups with clinicians were conducted to establish clinically relevant risk thresholds and understand the acceptability and perceived utility of the model., Results: We included seven factors in the prediction model that are predominantly assessed in clinical practice in patients with FEP. The model predicted treatment resistance among the 1081 patients with reasonable accuracy; the model's C-statistic was 0.727 (95% CI 0.723-0.732) prior to shrinkage and 0.687 after adjustment for optimism. Calibration was good (expected/observed ratio: 0.999; calibration-in-the-large: 0.000584) after adjustment for optimism., Conclusions: We developed and internally validated a prediction model with reasonably good predictive metrics. Clinicians, patients and carers were involved in the development process. External validation of the tool is needed followed by co-design methodology to support implementation in early intervention services.

Background: Autistic people have a high likelihood of developing mental health difficulties but a low chance of receiving effective mental healthcare. Therefore, there is a need to identify and examine strategies to improve mental healthcare for autistic people., Aims: To identify strategies that have been implemented to improve access, experiences of care and mental health outcomes for autistic adults, and to examine evidence on their acceptability, feasibility and effectiveness., Method: A co-produced systematic review was conducted. MEDLINE, PsycINFO, CINHAL, medRxiv and PsyArXiv were searched. We included all study designs reporting acceptability or feasibility outcomes and empirical quantitative study designs reporting effectiveness outcomes. Data were synthesised using a narrative approach., Results: A total of 30 articles were identified. These included 16 studies of adapted mental health interventions, eight studies of service improvements and six studies of bespoke mental health interventions developed for autistic people. There was no conclusive evidence on effectiveness. However, most bespoke and adapted approaches appeared to be feasible and acceptable. Identified adaptations appeared to be acceptable and feasible, including increasing knowledge and detection of autism, providing environmental adjustments and communication accommodations, accommodating individual differences and modifying the structure and content of interventions., Conclusion: Many identified strategies are feasible and acceptable, and can be readily implemented in services with the potential to make mental healthcare more suitable for autistic people, but important research gaps remain. Future research should address these and investigate a co-produced package of service improvement measures.

Transcranial magnetic stimulation (TMS) is an FDA-approved neuromodulation treatment for major depressive disorder (MDD), thought to work by altering dysfunctional brain connectivity pathways, or by indirectly modulating the activity of subcortical brain regions. Clinical response to TMS remains highly variable, highlighting the need for baseline predictors of response and for understanding brain changes associated with response. This systematic review examined brain connectivity features, and changes in connectivity features, associated with clinical improvement following TMS in MDD. Forty-one studies met inclusion criteria, including 1097 people with MDD. Most studies delivered one of two types of TMS to left dorsolateral prefrontal cortex and measured connectivity using resting-state functional MRI. The subgenual anterior cingulate cortex was the most well-studied brain region, particularly its connectivity with the TMS target or with the "executive control network" of brain regions. There was marked heterogeneity in findings. There is a need for greater understanding of how cortical TMS modulates connectivity with, and the activity of, subcortical regions, and how these effects change within and across treatment sessions., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Importance: Overweight and obesity affect 340 million adolescents worldwide and constitute a risk factor for poor mental health. Understanding the association between body mass index (BMI) and mental health in adolescents may help to address rising mental health issues; however, existing studies lack comprehensive evaluations spanning diverse countries and periods., Objective: To estimate the association between BMI and mental health and examine changes over time from 2002 to 2018., Design, Setting, and Participants: This was a repeated multicountry cross-sectional study conducted between 2002 and 2018 and utilizing data from the Health Behaviour in School-aged Children (HBSC) survey in Europe and North America. The study population consisted of more than 1 million adolescents aged 11 to 15 years, with all surveyed children included in the analysis. Data were analyzed from October 2022 to March 2023., Main Outcomes and Measures: Mental health difficulties were measured by an 8-item scale for psychological concerns, scoring from 0 to 32, where a higher score reflects greater psychosomatic issues. BMI was calculated using weight divided by height squared and adjusted for age and sex. Data were fitted by multilevel generalized additive model. Confounders included sex, living with parents, sibling presence, academic pressure, the experience of being bullied, family affluence, screen time, and physical activity., Results: Our analysis of 1 036 869 adolescents surveyed from 2002 to 2018, with a mean (SD) age of 13.55 (1.64) years and comprising 527 585 girls (50.9%), revealed a consistent U-shaped association between BMI and mental health. After accounting for confounders, adolescents with low body mass and overweight or obesity had increased psychosomatic symptoms compared to those with healthy weight (unstandardized β, 0.14; 95% CI, 0.08 to 0.19; unstandardized β, 0.27; 95% CI, 0.24 to 0.30; and unstandardized β, 0.62; 95% CI, 0.56 to 0.67, respectively), while adolescents with underweight had fewer symptoms (unstandardized β, -0.18; 95% CI, -0.22 to -0.15). This association was observed across different years, sex, and grade, indicating a broad relevance to adolescent mental health. Compared to 2002, psychosomatic concerns increased significantly in 2006 (unstandardized β, 0.19; 95% CI, 0.11 to 0.26), 2010 (unstandardized β, 0.14; 95% CI, 0.07 to 0.22), 2014 (unstandardized β, 0.48; 95% CI, 0.40 to 0.56), and 2018 (unstandardized β, 0.82; 95% CI, 0.74 to 0.89). Girls reported significantly higher psychosomatic concerns than boys (unstandardized β, 2.27; 95% CI, 2.25 to 2.30). Compared to primary school, psychosomatic concerns rose significantly in middle school (unstandardized β, 1.15; 95% CI, 1.12 to 1.18) and in high school (unstandardized β, 2.12; 95% CI, 2.09 to 2.15)., Conclusions and Relevance: Our study revealed a U-shaped association between adolescent BMI and mental health, which was consistent across sex and grades and became stronger over time. These insights emphasize the need for targeted interventions addressing body image and mental health, and call for further research into underlying mechanisms.

Developmental and epileptic encephalopathies (DEEs) are characterized by pharmacoresistant seizures and developmental delay. Patients with DEEs experience multiple seizure types, including tonic-clonic seizures (TCS) that can be generalized tonic-clonic (GTCS) or focal evolving to bilateral tonic-clonic (FBTCS). Fenfluramine (FFA) has demonstrated efficacy in reduction of TCS in patients with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and other DEEs. Using the PRISMA-ScR (Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Review) guidelines, we performed a scoping review to describe changes in TCS in patients treated with FFA. A comprehensive search of five literature databases was conducted up to February 14, 2023. Studies were included if they reported change in GTCS or TCS (but not FBTCS) after treatment with FFA in patients with DEEs. Duplicate patients and studies with unclear efficacy data were excluded. Fourteen of 422 studies met the eligibility criteria. Data extracted and evaluated by expert clinicians identified 421 unique patients with DS (in nine studies), CDKL5 deficiency disorder, SCN8A-related disorder, LGS, SCN1B-related disorder, and other DEEs. The median percent reduction in GTCS or TCS from baseline was available in 10 studies (n = 328) and ranged from 47.2% to 100%. Following FFA treatment, 10 studies (n = 144) reported ≥50% reduction in GTCS or TCS from baseline in 72% of patients; in nine of those (n = 112), 54% and 29% of patients achieved ≥75% and 100% reduction in GTCS or TCS from baseline, respectively. Overall, this analysis highlighted improvements in GTCS or TCS frequency when patients were treated with FFA regardless of the DEE evaluated. Future studies may confirm the impact of FFA on TCS reduction and on decreased premature mortality risk (including sudden unexpected death in epilepsy), improvement in comorbidities and everyday executive function, decreased health care costs, and improvement in quality of life., (© 2024 UCB BIOPHARMA SRL and The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: We evaluated the effect of long-term intensive metabolic control with hybrid closed-loop (CL) on residual C-peptide secretion and glucose control compared with standard insulin therapy in youth with type 1 diabetes over 48 months., Research Design and Methods: Following the 24-month primary phase of a multicenter, randomized, parallel trial of 96 newly diagnosed youth aged 10 to 16.9 years, participants were invited to an extension phase using treatment allocated at randomization. They continued with hybrid CL using the Cambridge algorithm or standard insulin therapy (control) until 48 months after diagnosis. Analysis was by intention-to-treat., Results: At 24 months after diagnosis, 81 participants (mean ± SD age 14 ± 2 years) continued in the extension phase (47 CL, 34 control). There was no difference in fasting C-peptide corrected for fasting glucose at 48 months between groups (CL: 5 ± 9 vs. control: 6 ± 14 pmol/L per mmol/L; mean adjusted difference -2 [95% CI -7, 4; P = 0.54]). Central laboratory HbA1c remained lower in the CL group by 0.9% (10 mmol/mol [95% CI 0.2, 1.5; 3, 17 mmol/mol); P = 0.009). Time in target range of 3.9 to 10.0 mmol/L was 12 percentage points (95% CI 3, 20; P = 0.008) higher in the CL group compared with control. There were 11 severe hypoglycemic events (6 CL, 5 control) and 7 diabetic ketoacidosis events (3 CL, 4 control) during the extension phase., Conclusions: Improved glycemic control was sustained over 48 months after diagnosis with CL insulin delivery compared with standard therapy in youth with type 1 diabetes. This did not appear to confer a protective effect on residual C-peptide secretion., (© 2024 by the American Diabetes Association.)

Diabetes mellitus is a central driver of multiple long-term conditions (MLTCs), but population-based studies have not clearly characterized the burden across the life course. We estimated the age of onset, years of life spent and loss associated with diabetes-related MLTCs among 46 million English adults. We found that morbidity patterns extend beyond classic diabetes complications and accelerate the onset of severe MLTCs by 20 years earlier in life in women and 15 years earlier in men. By the age of 50 years, one-third of those with diabetes have at least three conditions, spend >20 years with them and die 11 years earlier than the general population. Each additional condition at the age of 50 years is associated with four fewer years of life. Hypertension, depression, cancer and coronary heart disease contribute heavily to MLTCs in older age and create the greatest community-level burden on years spent (813 to 3,908 years per 1,000 individuals) and lost (900 to 1,417 years per 1,000 individuals). However, in younger adulthood, depression, severe mental illness, learning disabilities, alcohol dependence and asthma have larger roles, and when they occur, all except alcohol dependence were associated with long periods of life spent (11-14 years) and all except asthma associated with many years of life lost (11-15 years). These findings provide a baseline for population monitoring and underscore the need to prioritize effective prevention and management approaches., (© 2024. The Author(s).)

We discovered high-titer neutralizing autoantibodies against interleukin-10 in a child with infantile-onset inflammatory bowel disease (IBD), a phenocopy of inborn errors of interleukin-10 signaling. After B-cell-depletion therapy and an associated decrease in the anti-interleukin-10 titer, conventional IBD therapy could be withdrawn. A second child with neutralizing anti-interleukin-10 autoantibodies had a milder course of IBD and has been treated without B-cell depletion. We conclude that neutralizing anti-interleukin-10 autoantibodies may be a causative or modifying factor in IBD, with potential implications for therapy. (Funded by the National Institute for Health and Care Research and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Statins have multiple benefits in patients with metabolic-associated steatotic liver disease (MASLD)., Aim: To explore the effects of statins on the long-term risk of all-cause mortality, liver-related clinical events (LREs) and liver stiffness progression in patients with MASLD., Methods: This cohort study collected data on patients with MASLD undergoing at least two vibration-controlled transient elastography examinations at 16 tertiary referral centres. Cox regression analysis was performed to examine the association between statin usage and long-term risk of all-cause mortality and LREs stratified by compensated advanced chronic liver disease (cACLD): baseline liver stiffness measurement (LSM) of ≥10 kPa. Liver stiffness progression was defined as an LSM increase of ≥20% for cACLD and from <10 kPa to ≥10 or LSM for non-cACLD. Liver stiffness regression was defined as LSM reduction from ≥10 kPa to <10 or LSM decrease of ≥20% for cACLD., Results: We followed up 7988 patients with baseline LSM 5.9 kPa (IQR 4.6-8.2) for a median of 4.6 years. At baseline, 40.5% of patients used statins, and cACLD was present in 17%. Statin usage was significantly associated with a lower risk of all-cause mortality (adjusted HR=0.233; 95% CI 0.127 to 0.426) and LREs (adjusted HR=0.380; 95% CI 0.268 to 0.539). Statin usage was also associated with lower liver stiffness progression rates in cACLD (HR=0.542; 95% CI 0.389 to 0.755) and non-cACLD (adjusted HR=0.450; 95% CI 0.342 to 0.592), but not with liver stiffness regression (adjusted HR=0.914; 95% CI 0.778 to 1.074)., Conclusions: Statin usage was associated with a relatively lower long-term risk of all-cause mortality, LREs and liver stiffness progression in patients with MASLD., Competing Interests: Competing interests: TC-FY reported serving as an advisory committee member and a speaker for Gilead Sciences outside the submitted work. EAT reported receiving personal fees as advisory board member for Boehringer, Novo Nordisk, Pfizer and Siemens; receiving speaker fees from Echosens, Novo Nordisk and AbbVie outside the submitted work. HH reported personal fees from AstraZeneca, personal fees from Bristol Myers-Squibb, personal fees from MSD, personal fees from Novo Nordisk, personal fees from Boehringer Ingelheim, personal fees from KOWA and personal fees from GW Phara outside the submitted work, and grants from AstraZeneca, grants from Echosens, grants from Gilead Sciences, grants from Intercept, grants from MSD, grants from Novo Nordisk and grants from Pfizer outside the submitted work. JB reported receiving grants and personal fees from Echosens outside the submitted work. JLC reported receiving other from Echosens Clinical Trials during the conduct of the study; grants from Roche Pharma and other from Gilead Advisory Board outside the submitted work. WKC reported serving as consultant or advisory board member for Zuellig Pharma, Abbott, Roche, AbbVie, Boehringer Ingelheim and Novo Nordisk; and a speaker for Novo Nordisk, Abbott, Echosens, Viatris and Hisky Medical. AJS reported receiving grants from Intercept, personal consulting fees from Gilead, grants from Merck, personal consulting fees from Pfizer, grants and personal consulting fees from Eli Lilly, grants and personal consulting fees from Novo Nordisk, Boehringer Ingelheim, Novartis, Histoindex, and stock options from Genfit, Tiziana, Durect, Inversago and personal consulting fees from Genentech, ALnylam, Regeneron, Zydus, LG chem, Hanmi, Madrigal, Path AI, 89 Bio and stock options from Galmed outside the submitted work. VdL reported receiving non-financial support from Echosens during the conduct of the study. PNN reported receiving grants from Novo Nordisk, advisory board and personal consulting fees, honoraria for lectures and travel expenses from Novo Nordisk, personal consulting and advisory board fees from Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, Bristol-Myers Squibb, Pfizer, MSD, Sun Pharma, Eli Lilly, Madrigal, GSK and non-financial support for educational events from AiCME outside the submitted work. LC reported receiving personal fees for consulting and speakers bureau from Echosens during the conduct of the study; personal consultancy fees from Boston pharmaceutical and Gilead, speaker bureau and consultancy personal fees from GSK, personal speaker bureau fees from Inventiva, personal consultancy fees from Madrigal, personal Consultancy fees from MSD and Novo Nordisk, personal consultancy fees from Pfizer, Sagimet and Siemens Healthineers outside the submitted work. CF reported being in the full-time employment of Echosens during the conduct of the study. GL-HW reported receiving personal fees from Echosens during the conduct of the study; grants from Gilead Sciences Research outside the submitted work. MS-WC reported being in the full-time employment of Echosens during the conduct of the study. MR-G reported receiving personal fees from Echosens outside the submitted work. SUK reported personal fees from Gilead Sciences, personal fees from GSK, personal fees from Bayer, personal fees from Eisai, personal fees from AbbVie, personal fees from Echosens, personal fees from MSD, personal fees from Bristol-Myers Squibb and personal fees from AstraZeneca outside the submitted work, and grants from AbbVie, grants from Bristol-Myers Squibb, and grants from Gilead Sciences outside the submitted work. VW-SW reported receiving personal speaker fees from Abbott, consultant and speaker fees from AbbVie, personal consultant fees from Boehringer Ingelheim, Echosens, Gilead Sciences, grants from Gilead Sciences, personal consultant fees from Intercept, Inventiva, Novo Nordisk, personal consultant fees from Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, personal speaker fees from Unilab, personal consultant fees from Visirna, and being a cofounder of Illuminatio outside the submitted work. CDB has received grant support from Echosens. No other disclosures were reported., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Telemedicine has been promoted as an effective way of managing type-2 diabetes (T2DM) in primary care. However, the effectiveness of telemedicine is unclear. We investigated the clinical and cost-effectiveness of different telemedicine interventions for people with T2DM, compared to usual care., Methods: We searched Medline, Embase, Cochrane, CINHAL, ProQuest and EconLit for randomized controlled trials (RCTs) that examined the effectiveness of telemedicine interventions on clinical outcomes (HbA1c, body mass index [BMI], weight, diastolic blood pressure [DBP], systolic blood pressure [SBP], fasting blood glucose, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, total cholesterol and triglyceride) in adults with T2DM, published in English from inception until 31 December 2022. Meta-analyses were conducted using random-effects models pooling mean differences, heterogeneity was quantified using the I 2 statistic. Publication bias was assessed using funnel plots, Egger tests and trim and fill. Subgroup analyses included type of telemedicine intervention, telemedicine mode of delivery and type of healthcare professionals. This study was registered with PROSPERO, CRD 42022375128., Results: Of the 4093 records identified, 21 RCTs, 10,732 participants from seven regions, were included. Reported interventions included telephone (k = 16 studies), internet-based (k = 2), videoconference (k = 2) and telephone and emails (k = 1). We observed no statistically significant differences between synchronous or asynchronous telemedicine interventions compared to usual care for HbA1c (-0.08% (-0.88 mmol/mol); 95% CI: -0.18, 0.02), BMI (0.51 kg/m 2 ; 95% CI: -0.21, 1.22), SBP (-1.48 mmHg; 95% CI: -3.22, 0.26), DBP (3.23 mmHg; 95% CI: -0.89, 7.34), HDL-cholesterol (0.01 mmol/L; 95% CI: -0.03, 0.05), LDL-cholesterol (0.08 mmol/L; 95% CI: -0.22, 0.37), triglycerides (-0.08 mmol/L, 95% CI: -0.31, -0.15), total cholesterol (-0.10 mmol/L; 95% CI: -0.25, 0.04) and weight (-0.50 kg; 95% CI: -1.21, 0.21)., Conclusions: Telemedicine was as effective as usual care in improving health outcomes of people with T2DM. They can provide a safe solution in times of rising demands for primary healthcare services, or in extreme events, like a global pandemic. More high-quality RCTs are needed on the cost evaluation of telemedicine., (© 2024 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: The anti-IgE monoclonal antibody omalizumab is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during 1 year of omalizumab treatment. Methods: One-year open-label Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 patients with severe (Global Initiative for Asthma step 4/5) uncontrolled atopic asthma (at least two severe exacerbations in the previous year) taking high-dose inhaled corticosteroids and long-acting β-agonists with or without maintenance oral corticosteroids. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE); and 16-52 weeks, to assess late responses based on ⩾50% reduction in exacerbations or mOCS dose. All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. Measurements and Main Results: A total of 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ⩾50% and 57% (37 of 65) taking mOCSs had reduced their dose by ⩾50%. The primary outcomes 2,3-dinor-11-β-PGF2α, GETE score, and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five volatile organic compounds and five plasma lipid biomarkers strongly predicted the ⩾50% reduction in exacerbations (receiver operating characteristic areas under the curve of 0.780 and 0.922, respectively) and early responses (areas under the curve of 0.835 and 0.949, respectively). In an independent cohort, gas chromatography/mass spectrometry biomarkers differentiated between severe and mild asthma. Conclusions: This is the first discovery of omics biomarkers that predict improvement in asthma with biologic agent treatment. Prospective validation and development for clinical use is justified.

Background: Cold homes are associated with an increased risk of adverse health outcomes for older people. To mitigate this risk, homes need to be heated to an appropriate temperature. This review aims to identify interventions designed to improve heating and temperatures within homes and summarize its impact on health, health service utilization and cost effectiveness., Methods: A rapid review was conducted. Studies assessing the effects of structural, financial, or behavioural interventions designed to improve home temperatures of residents aged 18+ years were eligible. Searches were carried out in four databases. A search for grey literature, and backward and forward citation searching were performed. Data were summarized in a narrative synthesis and mapped using EPPI-Reviewer and EPPI-Mapper software., Results: Eighteen studies reported across 19 publications were included. Structural interventions were associated with better mental health and quality of life, a reduction in health service utilization, and improvements in satisfaction with internal home temperature, social interactions and financial difficulties. The impact on physical health outcomes varied by age, gender and long-term conditions. Evidence about the impact of behavioural interventions was inconsistent., Conclusion: Structural improvements to increase home temperatures may offer the potential to improve some aspects of health. However, the impact on physical health, including which groups are most likely to benefit, is unclear. Key gaps include the lack of evidence about the impact of financial interventions, and the impact of all types of interventions, on quality of life, mortality and costs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Public Health Association.)

Background: There is good evidence describing pharmacy workforce and service provision in general critical care units. However, no data exist from adult extracorporeal membrane oxygenation (ECMO) centres., Aim: To describe workforce characteristics, pharmacy service provision, and pharmaceutical care activities in critical care units (CCUs) providing an adult ECMO service in the United Kingdom (UK) and compare to national staffing standards for CCUs., Method: We conducted a multicentre, cross-sectional electronic survey inviting one pharmacy professional response per UK ECMO centre. We collated information on workforce, service provision, and pharmaceutical care activities provided by pharmacy teams in adult CCUs with an ECMO service., Results: The survey response rate was 90.9%: representatives of 10/11 tertiary hospitals providing ECMO services responded. Median critical care pharmacist to critical care bed was 1:12.1 (IQR: 1:9.4-1:14.9). Most centres (90.0%) did not meet national standards for pharmacy professionals to critical care bed staffing ratios for weekday services. Total critical care beds covered by the critical care pharmacy team varied across the UK: median (IQR) - 45 (37-80) beds. Two centres funded pharmacist time for ECMO activity, and one centre funded a pharmacy technician post. Median peak ECMO activity was 4 ECMO patients in a single day (IQR: 3-5). Most respondents reported reduced pharmacy service at weekends compared to weekday, with limited on-site support., Conclusion: Most responding ECMO centres in the UK reported pharmacy staffing ratios below nationally agreed critical care standards. There was high variability in clinical pharmacy services to ECMO patients over 7 days., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: To perform a network meta-analysis to determine the effectiveness of lifestyle interventions in exercise tolerance and quality of life (QoL) in people with HFpEF., Methods: Ten databases were searched for randomized controlled trials that evaluated a diet and/or exercise intervention in people with heart failure with preserved ejection fraction until May 2022. The co-primary outcomes were peak oxygen uptake (V̇O 2peak ) and Quality of Life as assessed by the Minnesota Living with Heart Failure Questionnaire (MLHFQ). We synthesized data using network meta-analysis., Results: We identified 13 trials, including a total of 869 participants, and we incorporated 6 different interventions. Improvements in V̇O 2peak compared to controls were seen for all exercise interventions (2.88 [95% CI: 1.36; 4.39] mL/kg/min) for high-intensity interval training (HIIT); 2.37 [95% CI: 1.02; 3.71] mL/kg/min for low-intensity exercise (LIT) combined with a hypocaloric diet; 2.05 [95% CI: 0.81; 3.29] mL/kg/min for moderate-intensity continuous training (MICT); 1.94 [95% CI: 0.59; 3.29] mL/kg/min for LIT; 1.85 [95% CI: 0.27; 3.44] mL/kg/min for MICT combined with resistance training) but not a hypocaloric diet alone (1.26 [95%CI: -0.08; 2.61] mL/kg/min). Only HIIT (-14.45 [95%CI: -24.81; -4.10] points) and LIT (95% CI: -11.05 [-20.55; -1.54] mL/kg/min) significantly improved MLHFQ scores. Network meta-analysis indicated that HIIT was the most effective intervention for improving both V̇O 2peak (mean improvement 2.88 [95% CI: 1.36; 4.39] mL/kg/min, follow-up range, 4 weeks-3 years) and QoL (-14.45 [95% CI: -24.81; -4.10] points, follow-up range, 12-26 weeks) compared to usual care., Conclusions: This network meta-analysis indicates that HIIT is the most effective lifestyle intervention studied to improve exercise capacity and QoL, with mean improvements exceeding the minimum clinically meaningful thresholds. HIIT is likely to be an underused management strategy in HFpEF, but further studies are needed to confirm long-term improvements in symptoms and clinical outcomes., Competing Interests: Disclosures The authors have no disclosures or conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common chronic liver disease globally, affecting more than a third of the world's adult population. This comprehensive narrative review summarizes the global incidence and prevalence rates of MASLD and its related adverse hepatic and extrahepatic outcomes. We also discuss the substantial economic burden of MASLD on healthcare systems, thus further highlighting the urgent need for global efforts to tackle this common and burdensome liver condition. We emphasize the clinical relevance of early interventions and a holistic approach that includes public health strategies to reduce the global impact of MASLD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The development and deployment of single-cell genomic technologies have driven a resolution revolution in our understanding of the immune system, providing unprecedented insight into the diversity of immune cells present throughout the body and their function in health and disease. Waldeyer's ring is the collective name for the lymphoid tissue aggregations of the upper aerodigestive tract, comprising the palatine, pharyngeal (adenoids), lingual, and tubal tonsils. These tonsils are the first immune sentinels encountered by ingested and inhaled antigens and are responsible for mounting the first wave of adaptive immune response. An effective mucosal immune response is critical to neutralizing infection in the upper airway and preventing systemic spread, and dysfunctional immune responses can result in ear, nose, and throat pathologies. This review uses Waldeyer's ring to demonstrate how single-cell technologies are being applied to advance our understanding of the immune system and highlight directions for future research.

Cardiovascular diseases remain the number one cause of death globally. Cardiovascular disease risk scores are an integral tool in primary prevention, being used to identify individuals at the highest risk and guide the assignment of preventive interventions. Available risk scores differ substantially in terms of the population sample data sources used for their derivation and, consequently, in the absolute risks they assign to individuals. Differences in cardiovascular disease epidemiology between the populations contributing to the development of risk scores, and the target populations in which they are applied, can result in overestimation or underestimation of cardiovascular disease risks for individuals, and poorly informed clinical decisions. Given the wide plethora of cardiovascular disease risk scores available, identification of an appropriate risk score for a target population can be challenging. This Review provides an up-to-date overview of guideline-recommended cardiovascular disease risk scores from global, regional, and national contexts, evaluates their comparative characteristics and qualities, and provides guidance on selection of an appropriate risk score., Competing Interests: Declaration of interests SK reports grants from British Heart Foundation, grants from National Institute for Health and Care Research, and grants from Health Data Research UK, during the conduct of the Review. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

It has been shown using proton magnetic resonance spectroscopy ( 1 H MRS) that, in a group of females, whole-body insulin resistance was more closely related to accumulation of saturated intramyocellular lipid (IMCL) than to IMCL concentration alone. This has not been investigated in males. We investigated whether age- and body mass index-matched healthy males differ from the previously reported females in IMCL composition (measured as CH 2 :CH 3 ) and IMCL concentration (measured as CH 3 ), and in their associations with insulin resistance. We ask whether saturated IMCL accumulation is more strongly associated with insulin resistance than other ectopic and adipose tissue lipid pools and remains a significant predictor when these other pools are taken into account. In this group of males, who had similar overall insulin sensitivity to the females, IMCL was similar between sexes. The males demonstrated similar and even stronger associations of IMCL with insulin resistance, supporting the idea that a marker reflecting the accumulation of saturated IMCL is more strongly associated with whole-body insulin resistance than IMCL concentration alone. However, this marker ceased to be a significant predictor of whole-body insulin resistance after consideration of other lipid pools, which implies that this measure carries no more information in practice than the other predictors we found, such as intrahepatic lipid and visceral adipose tissue. As the marker of saturated IMCL accumulation appears to be related to these two predictors and has a much smaller dynamic range, this finding does not rule out a role for it in the pathogenesis of insulin resistance., (© 2024 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background CT performed for various clinical indications has the potential to predict cardiometabolic diseases. However, the predictive ability of individual CT parameters remains underexplored. Purpose To evaluate the ability of automated CT-derived markers to predict diabetes and associated cardiometabolic comorbidities. Materials and Methods This retrospective study included Korean adults (age ≥ 25 years) who underwent health screening with fluorine 18 fluorodeoxyglucose PET/CT between January 2012 and December 2015. Fully automated CT markers included visceral and subcutaneous fat, muscle, bone density, liver fat, all normalized to height (in meters squared), and aortic calcification. Predictive performance was assessed with area under the receiver operating characteristic curve (AUC) and Harrell C-index in the cross-sectional and survival analyses, respectively. Results The cross-sectional and cohort analyses included 32166 (mean age, 45 years ± 6 [SD], 28833 men) and 27 298 adults (mean age, 44 years ± 5 [SD], 24 820 men), respectively. Diabetes prevalence and incidence was 6% at baseline and 9% during the 7.3-year median follow-up, respectively. Visceral fat index showed the highest predictive performance for prevalent and incident diabetes, yielding AUC of 0.70 (95% CI: 0.68, 0.71) for men and 0.82 (95% CI: 0.78, 0.85) for women and C-index of 0.68 (95% CI: 0.67, 0.69) for men and 0.82 (95% CI: 0.77, 0.86) for women, respectively. Combining visceral fat, muscle area, liver fat fraction, and aortic calcification improved predictive performance, yielding C-indexes of 0.69 (95% CI: 0.68, 0.71) for men and 0.83 (95% CI: 0.78, 0.87) for women. The AUC for visceral fat index in identifying metabolic syndrome was 0.81 (95% CI: 0.80, 0.81) for men and 0.90 (95% CI: 0.88, 0.91) for women. CT-derived markers also identified US-diagnosed fatty liver, coronary artery calcium scores greater than 100, sarcopenia, and osteoporosis, with AUCs ranging from 0.80 to 0.95. Conclusion Automated multiorgan CT analysis identified individuals at high risk of diabetes and other cardiometabolic comorbidities. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Pickhardt in this issue.

Background: Understanding of ethnic disparities in suicide in England and Wales is poor as ethnicity is not recorded on death certificates. Using linked data, we examined variations, by sex, in suicide rates in England and Wales by ethnicity and migrant and descendant status., Methods: Using the Office for National Statistics 2012-19 mortality data linked to the 2011 census from the Public Health Research Database, we calculated the age-standardised suicide rates by sex for each of the 18 self-identified ethnicity groups in England and Wales. We present rates by age, sex, and methods used for suicide by ethnic group. We estimated age-adjusted and sex-adjusted incidence rate ratios (IRRs) using Poisson regression models for each minority ethnic group compared with the majority population. We involved people with lived experience in the research., Findings: Overall, 31 644 suicide deaths occurred over the study period, including 3602 (11%) in people from minority ethnic backgrounds, with a mean age of death of 43·3 years (SD 17·0, range 13-96). Almost all minority ethnic groups had a lower rate of suicide than the White British majority, apart from individuals who identified as being from a Mixed heritage background or White Gypsy or Irish Travellers. In females who identified as Mixed White and Caribbean, the suicide IRR was 1·79 (95% CI 1·45-2·21) compared with the White British majority; in those who identified as White Gypsy or Irish Travellers, the IRR was 2·26 (1·42-3·58). Rates in males identifying as from these two groups and those identifying as White Irish were similar to the White British majority. Compared with the non-migrant population, migrants had a lower rate of suicide regardless of ethnicity, but in the descendant population, people from a Mixed ethnicity background had a higher risk of suicide than the White British majority., Interpretation: There are ethnic disparities in suicide mortality in England and Wales, but the reasons for this are unclear. The higher rate in previously overlooked minority ethnic groups warrants further attention., Funding: Wellcome Trust., Competing Interests: Declaration of interests DK reports grants and personal fees from the Wellcome Trust, the Centre for Pesticide Suicide Prevention, and the UK Department of Health and Social Care. DK is a steering group member of the Migration Health and Development Research Initiative and the UK National Suicide Prevention Alliance; she receives no fees for this work. NK reports grants and personal fees from the UK Department of Health and Social Care, the National Institute for Health and Care Research (NIHR), the National Institute for Health and Care Excellence (NICE), and the Healthcare Quality and Improvement Partnership, outside the submitted work; and work with NHS England on national quality improvement initiatives for suicide and self-harm. He sits on the Department of Health and Social Care's (England) National Suicide Prevention Strategy Advisory Group. He has chaired and been the Topic Advisor for NICE guideline committees for self-harm and depression. LR is an ONS employee. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Some studies have shown that the incidence of type 2 diabetes increases after a diagnosis of COVID-19, although the evidence is not conclusive. However, the effects of the COVID-19 vaccine on this association, or the effect on other diabetes subtypes, are not clear. We aimed to investigate the association between COVID-19 and incidence of type 2, type 1, gestational and non-specific diabetes, and the effect of COVID- 19 vaccination, up to 52 weeks after diagnosis., Methods: In this retrospective cohort study, we investigated the diagnoses of incident diabetes following COVID-19 diagnosis in England in a pre-vaccination, vaccinated, and unvaccinated cohort using linked electronic health records. People alive and aged between 18 years and 110 years, registered with a general practitioner for at least 6 months before baseline, and with available data for sex, region, and area deprivation were included. Those with a previous COVID-19 diagnosis were excluded. We estimated adjusted hazard ratios (aHRs) comparing diabetes incidence after COVID-19 diagnosis with diabetes incidence before or in the absence of COVID-19 up to 102 weeks after diagnosis. Results were stratified by COVID-19 severity (categorised as hospitalised or non-hospitalised) and diabetes type., Findings: 16 669 943 people were included in the pre-vaccination cohort (Jan 1, 2020-Dec 14, 2021), 12 279 669 in the vaccinated cohort, and 3 076 953 in the unvaccinated cohort (both June 1-Dec 14, 2021). In the pre-vaccination cohort, aHRs for the incidence of type 2 diabetes after COVID-19 (compared with before or in the absence of diagnosis) declined from 4·30 (95% CI 4·06-4·55) in weeks 1-4 to 1·24 (1·14-1.35) in weeks 53-102. aHRs were higher in unvaccinated people (8·76 [7·49-10·25]) than in vaccinated people (1·66 [1·50-1·84]) in weeks 1-4 and in patients hospitalised with COVID-19 (pre-vaccination cohort 28·3 [26·2-30·5]) in weeks 1-4 declining to 2·04 [1·72-2·42] in weeks 53-102) than in those who were not hospitalised (1·95 [1·78-2·13] in weeks 1-4 declining to 1·11 [1·01-1·22] in weeks 53-102). Type 2 diabetes persisted for 4 months after COVID-19 in around 60% of those diagnosed. Patterns were similar for type 1 diabetes, although excess incidence did not persist beyond 1 year after a COVID-19 diagnosis., Interpretation: Elevated incidence of type 2 diabetes after COVID-19 is greater, and persists for longer, in people who were hospitalised with COVID-19 than in those who were not, and is markedly less apparent in people who have been vaccinated against COVID-19. Testing for type 2 diabetes after severe COVID-19 and the promotion of vaccination are important tools in addressing this public health problem., Funding: UK National Institute for Health and Care Research, UK Research and Innovation (UKRI) Medical Research Council, UKRI Engineering and Physical Sciences Research Council, Health Data Research UK, Diabetes UK, British Heart Foundation, and the Stroke Association., Competing Interests: Declaration of interests NC is compensated by AstraZeneca for membership of data monitoring and safety committees for clinical trials. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Importance: The prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone., Objective: To assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes., Data Sources: Literature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023., Study Selection: Two blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria., Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach., Main Outcomes and Measures: Overall and disease-free survival, postoperative morbidity, and mortality., Results: The analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperative and/or perioperative chemotherapy plus surgery (HR, 0.78 [95% CrI, 0.64-0.91]; 3-year difference, 90 deaths per 1000 patients) showed longer overall survival than surgery alone. Comparing the 2 modalities yielded similar overall survival (HR, 1.04 [95% CrI], 0.83-1.28]; 3-year difference, 15 deaths per 1000 patients fewer for CRT). Similarly, disease-free survival was longer for both modalities compared with surgery alone. Postoperative morbidity was more frequent after CRT plus surgery (odds ratio [OR], 2.94 [95% CrI, 1.01-8.59]) than surgery alone. Postoperative mortality was not significantly more frequent after CRT plus surgery than surgery alone (OR, 2.50 [95% CrI, 0.66-10.56]) or after chemotherapy plus surgery than CRT plus surgery (OR, 0.44 [95% CrI, 0.08-2.00])., Conclusions and Relevance: In this meta-analysis of patients with AEG, both preoperative CRT and preoperative and/or perioperative chemotherapy were associated with longer survival without relevant differences between the 2 modalities. Thus, either of the 2 treatments may be recommended to patients.