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Aim: Non-invasive diagnostics for metabolic dysfunction-associated fatty liver disease (MAFLD) remain challenging. We aimed to identify novel key genes as non-invasive biomarkers for MAFLD, elucidate causal relationships between biomarkers and MAFLD and determine the role of immune cells as potential mediators., Materials and Methods: Utilizing published transcriptome data of patients with biopsy-proven MAFLD, we applied linear models for microarray data, least absolute shrinkage and selector operation (LASSO) regressions and receiver operating characteristic (ROC) curve analyses to identify and validate biomarkers for MAFLD. Using the expression quantitative trait loci database and a cohort of 778 614 Europeans, we used Mendelian randomization to analyse the causal relationships between key biomarkers and MAFLD. Additionally, mediation analysis was performed to examine the involvement of 731 immunophenotypes in these relationships., Results: We identified 31 differentially expressed genes, and LASSO regression showed three hub genes, IGFBP2, PEG10, and P4HA1, with area under the receiver operating characteristic (AUROC) curve of 0.807, 0.772 and 0.791, respectively, for identifying MAFLD. The model of these three genes had an AUROC of 0.959 and 0.800 in the development and validation data sets, respectively. This model was also validated using serum-based enzyme-linked immunosorbent assay data from MAFLD patients and control subjects (AUROC: 0.819, 95% confidence interval: 0.736-0.902). PEG10 was associated with an increased MAFLD risk (odds ratio = 1.106, p = 0.032) via inverse variance-weighted analysis, and about 30% of this risk was mediated by the percentage of CD11c + CD62L- monocytes., Conclusions: The MAFLD panels have good diagnostic accuracy, and the causal link between PEG10 and MAFLD was mediated by the percentage of CD11c + CD62L- monocytes., (© 2024 John Wiley & Sons Ltd.)

Background: Missed opportunities to reduce numbers of primary major lower-limb amputation and increase limb-salvage procedures when treating chronic limb-threatening ischaemia have previously been identified in the literature. However, the potential economic savings for healthcare providers when salvaging a chronic limb-threatening ischaemia-affected limb have not been well documented., Methods: A model using National Health Service healthcare usage and cost data for 1.6 million individuals and averaged numbers of primary surgical procedures for chronic limb-threatening ischaemia from England and Wales in 2019-2021 was created to perform a budget impact analysis. Two scenarios were tested: the averaged national rates of major lower-limb amputation (above the ankle joint), angioplasty, open bypass surgery or arterial endarterectomy in the National Vascular Registry (current scenario); and revascularization rates adjusted based on the lowest amputation rate reported by the National Vascular Registry at the time of the study (hypothetical scenario). The primary outcome was the net impact on costs to the National Health Service over 12 months after the index procedure., Results: In the current scenario, the proportions of different index procedures were 10% for lower-limb major amputation, 55% for angioplasty, 25% for open bypass surgery and 10% for arterial endarterectomy. In the hypothetical scenario, the procedure rates were 3% for major lower-limb amputation, 59% for angioplasty, 27% for open bypass surgery and 11% for arterial endarterectomy. For 16 025 index chronic limb-threatening ischaemia procedures, the total care cost in the current scenario was €243 924 927. In the hypothetical scenario, costs would be reduced for index procedures (-€10 013 814), community care (-€633 943) and major cardiovascular events (-€383 407), and increased for primary care (€59 827), outpatient appointments (€120 050) and subsequent chronic limb-threatening ischaemia-related surgery (€1 179 107). The net saving to the National Health Service would be €9 645 259., Conclusion: A shift away from primary major lower-limb amputation towards revascularization could lead to substantial savings for the National Health Service without major cost increases later in the care pathway, indicating that care decisions taken in hospitals have wider benefits., (© Crown copyright 2024.)

Objectives: An independent evaluation was undertaken to investigate the perceived impact of installing digital screens in a group of community pharmacies as an approach to provide public health messaging., Methods: Community pharmacy staff were interviewed prior to screen installation to investigate experience and perceptions of conventional public health campaigns using written materials. Staff were interviewed after the digital screen installation to investigate their opinions of the installation and its impact on public health delivery in the pharmacy. Patients and public representatives were recruited to visit the pharmacies and asked to complete a survey about what they observed and thought about the public health messaging. Interviews were transcribed verbatim and thematically analysed. Surveys consisted of open, closed, and rating questions. The results of which were descriptively analysed., Key Findings: Community pharmacy staff found paper-based campaigns work-intensive and created paper wastage. The digital screen installation was received positively by pharmacy staff and patient, and public representatives found them eye-catching and engaging. Staff were unable to report any conversations with members of the public triggered by the screens, but the patient and public volunteers were able to recall some of the health messages., Conclusions: Digital messaging is common practice and digital screens are already in use in areas where patients and the public have conventionally been in attendance, e.g. GP surgeries. Digital screens in community pharmacy for public health messaging could be considered an inevitable progression for public health messaging given concerns about wastage and up-to-date information. The impact, however, on triggering healthier choices and lifestyles requires further investigation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society.)

Ecological momentary assessment (EMA) is a way to evaluate experiences in everyday life. It is a powerful research tool but can be complex and challenging for beginners. Application of EMA in audiological research brings with it opportunities and challenges that differ from other research disciplines. This tutorial discusses important considerations when conducting EMA studies in hearing care. While more research is needed to develop specific guidelines for the various potential applications of EMA in hearing research, we hope this article can alert hearing researchers new to EMA to pitfalls when using EMA and help strengthen their study design. The current article elaborates study design details, such as choice of participants, representativeness of the study period for participants' lives, and balancing participant burden with data requirements. Mobile devices and sensors to collect objective data on the acoustic situation are reviewed alongside different possibilities for EMA setups ranging from online questionnaires paired with a timer to proprietary apps that also have access to parameters of a hearing device. In addition to considerations for survey design, a list of questionnaire items from previous studies is provided. For each item, an example and a list of references are given. EMA typically provides data sets that are rich but also challenging in that they are noisy, and there is often unequal amount of data between participants. After recommendations on how to check the data for compliance, reactivity, and careless responses, methods for statistical analysis on the individual level and on the group level are discussed including special methods for direct comparison of hearing device programs.

Background and Objectives: Homophily represents the extent to which people feel others are like them and encourages the uptake of activities they feel people like them do. Currently, there are no data on blood donor homophily with respect to (i) people's representation of the average prototypical UK blood donor and (ii) the degree of homophily with this prototype for current donors, non-donors, groups blood services wish to encourage (ethnic minorities), those who are now eligible following policy changes (e.g., men-who-have-sex-with-men: MSM) and recipients. We aim to fill these gaps in knowledge., Materials and Methods: We surveyed the UK general population MSM, long-term blood recipients, current donors, non-donors and ethnic minorities (n = 785) to assess perceptions of the prototypical donor in terms of ethnicity, age, gender, social class, educational level and political ideology. Homophily was indexed with respect to age, gender and ethnicity., Results: The prototypical UK blood donor is perceived as White, middle-aged, middle-class, college-level educated and left-wing. Current donors and MSM are more homophilous with this prototype, whereas recipients and ethnic minorities have the lowest homophily. Higher levels of homophily are associated with an increased likelihood of committing to donate., Conclusion: The prototype of the UK donor defined this as a White activity. This, in part, may explain why ethnic minorities are less likely to be donors. As well as traditional recruitment strategies, blood services need to consider broader structural changes such as the ethnic diversity of staff and co-designing donor spaces with local communities., (© 2024 The Author(s). Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Mortality from human immunodeficiency virus (HIV)-associated tuberculosis (TB) is high, particularly among hospitalized patients. In 433 people with HIV hospitalized with symptoms of TB, we investigated plasma matrix metalloproteinases (MMP) and matrix-derived biomarkers in relation to TB diagnosis, mortality, and Mycobacterium tuberculosis (Mtb) bloodstream infection (BSI). Compared to other diagnoses, MMP-8 was elevated in confirmed TB and in Mtb-BSI, positively correlating with extracellular matrix breakdown products. Baseline MMP-3, -7, -8, -10, and PIIINP were associated with Mtb-BSI and 12-week mortality. These findings implicate MMP dysregulation in pathophysiology of advanced HIV-TB and support MMP inhibition as a host-directed therapeutic strategy for HIV-TB., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Substantial increases in UK consulting rates, mean consultation duration, and clinical workload were observed between 2007 and 2014. To the authors' knowledge, no analysis of more recent trends in clinical workload has been published to date. This study updates and builds on previous research, identifying underlying changes in population morbidity levels affecting demand for primary health care., Aim: To describe the changes in clinical workload in UK primary care since 2005., Design and Setting: Retrospective cohort study using GP primary care electronic health records data from 824 UK general practices., Method: Over 500 million anonymised electronic health records were obtained from IQVIA Medical Research Data to examine consulting rates with GPs and practice nurses together with the duration of these consultations to determine total patient-level workload per person-year., Results: Age-standardised mean GP direct (face-to-face and telephone) consulting rates fell steadily by 2.0% a year from 2014 to 2019. Between 2005 and 2019 mean GP direct consulting rates fell by 5.8% overall whereas mean workload per person-year increased by 25.8%, owing in part to a 36.9% increase in mean consultation duration. Indirect GP workload almost tripled over the 15 years, contributing to a 48.3% increase in overall clinical workload per person-year. The proportion of the study population with ≥3 serious chronic conditions increased from 9.7% to 16.1%, accounting for over a third of total clinical workload in 2019., Conclusion: Findings show sustained increases in consulting rates, consultation duration, and clinical workload until 2014. From 2015, however, rising demand for health care and a larger administrative workload have led to capacity constraints as the system nears saturation., (© The Authors.)

Competing Interests: Dr Berry is employed by the University of Glasgow, which holds consultancy and research agreements with companies that have interests in the management of angina. The companies include Abbott Vascular, AstraZeneca, Auxilius Pharma, Boehringer Ingelheim, CorFlow, Coroventis, HeartFlow, Siemens Healthcare, Therox, and Valo Health. The other authors report no conflicts.

People with end-stage kidney disease (ESKD) often exhibit impaired cardiac structure and function, which may contribute to poor exercise capacity. This study used multimodal exercise testing to investigate the central and peripheral mechanisms of exercise limitation in adults with ESKD, also comparing in-centre hemodialysis (ICHD) to home hemodialysis (HHD). Seventeen adults (55.5 ± 14.5 years; n = 14 male; n = 12 HHD) participated. Resting cardiac examinations, followed by submaximal cycling cardiopulmonary exercise testing (CPET) and functional exercise testing, revealed cardiac structural abnormalities (increased left ventricular mass) and cardiac injury. Aerobic fitness in adults with ESKD was low, with pulmonary oxygen uptake (V̇O 2 ) at the gas exchange threshold (GET) occuring at 39 ± 8% predicted V̇O 2peak . O 2 pulse, an estimate of stroke volume (SV), was higher in HHD at rest (p = 0.05, ES = 0.58) and during unloaded cycling (p = 0.05, ES = 0.58) compared to ICHD. However, thoracic bioreactance derived SV at the GET was significantly higher in adults receiving ICHD versus HHD (p = 0.01, ES = 0.74). In adults with ESKD, cardiac output was positively associated with V̇O 2 at the GET (r = 0.61, p = 0.04). This study highlights prevalent exercise dysfunction in adults with ESKD undergoing dialysis, with potential distinct differences between in-centre and home hemodialysis, mechanistically linked to underlying cardiac abnormalities., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Treatments for osteoarthritis (OA) are limited. Previous small studies suggest that the antirheumatic drug methotrexate may be a potential treatment for OA pain., Objective: To assess symptomatic benefits of methotrexate in knee OA (KOA)., Design: A multicenter, randomized, double-blind, placebo-controlled trial done between 13 June 2014 and 13 October 2017. (ISRCTN77854383; EudraCT: 2013-001689-41)., Setting: 15 secondary care musculoskeletal clinics in the United Kingdom., Participants: A total of 207 participants with symptomatic, radiographic KOA and knee pain (severity ≥4 out of 10) on most days in the past 3 months with inadequate response to current medication were approached for inclusion., Intervention: Participants were randomly assigned 1:1 to oral methotrexate once weekly (6-week escalation 10 to 25 mg) or matched placebo over 12 months and continued usual analgesia., Measurements: The primary end point was average knee pain (numerical rating scale [NRS] 0 to 10) at 6 months, with 12-month follow-up to assess longer-term response. Secondary end points included knee stiffness and function outcomes and adverse events (AEs)., Results: A total of 155 participants (64% women; mean age, 60.9 years; 50% Kellgren-Lawrence grade 3 to 4) were randomly assigned to methotrexate ( n  = 77) or placebo ( n  = 78). Follow-up was 86% ( n  = 134; methotrexate: 66, placebo: 68) at 6 months. Mean knee pain decreased from 6.4 (SD, 1.80) at baseline to 5.1 (SD, 2.32) at 6 months in the methotrexate group and from 6.8 (SD, 1.62) to 6.2 (SD, 2.30) in the placebo group. The primary intention-to-treat analysis showed a statistically significant pain reduction of 0.79 NRS points in favor of methotrexate (95% CI, 0.08 to 1.51; P  = 0.030). There were also statistically significant treatment group differences in favor of methotrexate at 6 months for Western Ontario and McMaster Universities Osteoarthritis Index stiffness (0.60 points [CI, 0.01 to 1.18]; P  = 0.045) and function (5.01 points [CI, 1.29 to 8.74]; P  = 0.008). Treatment adherence analysis supported a dose-response effect. Four unrelated serious AEs were reported (methotrexate: 2, placebo: 2)., Limitation: Not permitting oral methotrexate to be changed to subcutaneous delivery for intolerance., Conclusion: Oral methotrexate added to usual medications demonstrated statistically significant reduction in KOA pain, stiffness, and function at 6 months., Primary Funding Source: Versus Arthritis., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0303.

Aim: To analyse the association between serum bile acid (BA) profile and heart failure (HF) with preserved ejection fraction (HFpEF) in patients with metabolic dysfunction-associated fatty liver disease (MAFLD)., Methods: We enrolled 163 individuals with biopsy-proven MAFLD undergoing transthoracic echocardiography for any indication. HFpEF was defined as left ventricular ejection fraction >50% with at least one echocardiographic feature of HF (left ventricular diastolic dysfunction, abnormal left atrial size) and at least one HF sign or symptom. Serum levels of 38 BAs were analysed using ultra-performance liquid chromatography coupled with tandem mass spectrometry., Results: Among the 163 patients enrolled (mean age 47.0 ± 12.8 years, 39.3% female), 52 (31.9%) and 43 (26.4%) met the HFpEF and pre-HFpEF criteria, and 38 serum BAs were detected. Serum ursodeoxycholic acid (UDCA) and hyocholic acid (HCA) species were lower in patients with HFpEF and achieved statistical significance after correction for multiple comparisons. Furthermore, decreases in glycoursodeoxycholic acid and tauroursodeoxycholic acid were associated with HF status., Conclusions: In this exploratory study, specific UDCA and HCA species were associated with HFpEF status in adults with biopsy-confirmed MAFLD., (© 2024 John Wiley & Sons Ltd.)

Purpose of Review: Pulmonary hypertension is a heterogeneous condition with significant morbidity and mortality. Computer tomography (CT) plays a central role in determining the phenotype of pulmonary hypertension, informing treatment strategies. Many artificial intelligence tools have been developed in this modality for the assessment of pulmonary hypertension. This article reviews the latest CT artificial intelligence applications in pulmonary hypertension and related diseases., Recent Findings: Multistructure segmentation tools have been developed in both pulmonary hypertension and nonpulmonary hypertension cohorts using state-of-the-art UNet architecture. These segmentations correspond well with those of trained radiologists, giving clinically valuable metrics in significantly less time. Artificial intelligence lung parenchymal assessment accurately identifies and quantifies lung disease patterns by integrating multiple radiomic techniques such as texture analysis and classification. This gives valuable information on disease burden and prognosis. There are many accurate artificial intelligence tools to detect acute pulmonary embolism. Detection of chronic pulmonary embolism proves more challenging with further research required., Summary: There are numerous artificial intelligence tools being developed to identify and quantify many clinically relevant parameters in both pulmonary hypertension and related disease cohorts. These potentially provide accurate and efficient clinical information, impacting clinical decision-making., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Limited evidence is available about the variability of appetitive responses within individuals after an acute bout of exercise. The present study aimed to assess the consistency and individual variability of post-exercise appetitive responses in healthy individuals. Twenty participants (10 females, 23.9 ± 4.1 years, 22.5 ± 2.0 kg m -2 ) joined the laboratory to perform four sessions separated by a minimum of 5 days: i) a control session with a rest period before and an ad libitum lunch (REST), and ii) three identical exercise sessions (EX) with a 30-min moderate-intensity (60-70% of predicted maximal heart rate) walking bout ending 25 min before the ad libitum lunch. Subjective appetite sensations were assessed before and after the meal at regular intervals, and satiety quotients were calculated. Food reward was assessed by the Leeds Food Preference Questionnaire before and after lunch. For each EX session, the difference with the REST session was calculated (Δ = EX - REST). Energy and macronutrient intake were consistent in response to exercise (all intraclass correlation coefficients (ICC) > 0.8) while results showed that post-exercise subjective appetite sensations and satiety quotients varied across the three EX sessions (almost all ICC < 0.7). Food reward was overall consistent in response to exercise before the test meal but not after. When considering the changes (Δ), the results showed no or poor consistency for most of the appetitive outcomes. To conclude, energy and macronutrient intake, as well as pre-meal food reward, are consistent after exercise in healthy individuals, while subjective appetite sensations are not stable within individuals across the sessions. Regarding the variations from REST to EX sessions, the results suggest that the individual changes observed are only random day-to-day variations., Competing Interests: Declaration of competing interest The authors 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 Elsevier Ltd. All rights reserved.)

Background: High proportions of Mycobacterium tuberculosis cells in sputum containing triacylglycerol-rich lipid bodies have been shown to be associated with treatment failure or relapse following antituberculous chemotherapy. Although lipid body determination is a potential biomarker for supporting clinical trial and treatment decisions, factors influencing variability in sputum frequencies of lipid body-positive (%LB + ) M tuberculosis in patients are unknown. We aimed to test our hypothesis that exposure to host-generated NO and M tuberculosis strains are factors associated with differences in sputum %LB + ., Methods: In this observational study, we determined %LB + frequencies before treatment by microscopy in patients with smear-positive tuberculosis from two separate prospective observational study settings (Gondar, Ethiopia, recruited between May 1, 2010, and April 30, 2011, and Fajara, The Gambia, who provided sputum samples before treatment between May 5, 2010, and Dec 22, 2011). In Ethiopia, fractional exhaled nitric oxide (FeNO) was measured as a biomarker of host NO, and M tuberculosis strain differences were determined by spoligotyping. Treatment response was assessed by percentage weight change after 7 months. In The Gambia, treatment responses were assessed as change in BMI and radiographic burden of disease after 6 months. Sputum M tuberculosis isolates were studied in vitro for their %LB + and triacylglycerol synthase 1 (tgs1) mRNA responses to NO exposure. Propidium iodide staining was used as a measure of NO strain toxicity. Correlation between in vitro %LB + frequencies following NO exposure and those of the same strain in sputum was examined with linear regression and Dunnett's multiple comparison test., Findings: In Ethiopia, 73 patients who were smear positive for pulmonary tuberculosis were recruited (43 [59%] were male and 30 [41%] were female). Of these, the %LB + in the sputum of 59 patients showed linear correlation with log 10 FeNO (r 2 =0·28; p<0·0001) and an association with strain spoligotype was suggested. Seven M tuberculosis strains from The Gambia showed different dose-responses to NO in vitro, demonstrated by changing lipid body content, tgs1 transcription, and bacterial toxicity. In sputum %LB + frequencies correlated with in vitro %LB + responses to NO of the corresponding isolate. In a subset of 34 patients across both cohorts, higher sputum %LB + frequencies before treatment were associated with weaker responses to treatment than lower sputum %LB + frequencies., Interpretation: M tuberculosis strain and exposure to host-generated NO are associated with sputum %LB + . Our results support the use of M tuberculosis strain-dependent sputum %LB + as a predictive biomarker of treatment response., Funding: The Medical Research Council, the University of Leicester, and the University of Gondar., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Long-term tezepelumab treatment in the DESTINATION study (NCT03706079) resulted in reduced asthma exacerbations, reduced biomarker levels, and improved lung function and symptom control in patients with severe, uncontrolled asthma., Objective: To explore the time course of changes in biomarkers and clinical manifestations after treatment cessation after 2 years of tezepelumab treatment., Methods: DESTINATION was a 2-year, phase 3, multicenter, randomized, placebo-controlled, double-blind study of tezepelumab treatment in patients (12-80 years old) with severe asthma. Patients received their last treatment doses at week 100 and could enroll in an extended follow-up period from weeks 104 to 140. Change over time in key biomarkers and clinical outcomes were assessed in tezepelumab vs placebo recipients for 40 weeks after stopping treatment., Results: Of 569 patients enrolled in the extended follow-up period, 426 were included in the analysis (289 received tezepelumab and 137 placebo). In the 40-week period after the last tezepelumab dose, blood eosinophil counts, fractional exhaled nitric oxide levels, and Asthma Control Questionnaire-6 scores gradually increased from weeks 4 to 10, with a gradual reduction in pre-bronchodilator forced expiratory volume in 1 second such that blood eosinophil counts, fractional exhaled nitric oxide levels, and clinical outcomes returned to placebo levels; however, none of these outcomes returned to baseline levels. Total IgE levels increased later from week 28 and remained well below placebo and baseline levels during the 40-week period after the last tezepelumab dose., Conclusion: This analysis reveals the benefits of continued tezepelumab treatment in the management of patients with severe, uncontrolled asthma, compared with stopping treatment after 2 years., Trial Registration: ClinicalTrials.gov Identifier: NCT03706079., Competing Interests: Disclosures Prof Brightling has received grants and consultancy fees from 4D Pharma, Areteia Therapeutics, AstraZeneca, Chiesi, Genentech, GSK, Global Access Diagnostics (formerly Mologic), Novartis, Regeneron Pharmaceuticals, Roche, and Sanofi. Dr Caminati has received fees from AstraZeneca for serving on advisory boards and has received speaker fees from GSK and Sanofi. Dr Llanos and Dr Caveney are employees of Amgen and own stock in Amgen. Dr Kotalik, Dr Lundahl, Ms Gołąbek, Dr Martin, and Dr Ponnarambil are employees of AstraZeneca and may own stock or stock options in AstraZeneca. Dr Griffiths was an employee of AstraZeneca at the time of the study. Prof Israel has served as a consultant to and received personal fees from 4D Pharma, AB Science, Amgen, AstraZeneca, Avillion, Biometry, Cowen, Equillium, Genentech, GSK, Merck, Novartis, Pneuma Respiratory, PPS Health, Regeneron Pharmaceuticals, Sanofi, Sienna Biopharmaceuticals, and Teva Pharmaceuticals; has received nonfinancial support from Circassia Pharmaceuticals, Teva Pharmaceuticals, and Vorso Corp; and has received clinical research grants from AstraZeneca, Avillion, Genentech, Gossamer Bio, Novartis, and Sanofi. Prof Pavord has received speaker fees from Aerocrine AB, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi, and Teva Pharmaceuticals; has received payments for organization of educational events from AstraZeneca, GSK, Regeneron Pharmaceuticals, Sanofi, and Teva Pharmaceuticals; has received consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia Pharmaceuticals, Dey Pharma, Genentech, GSK, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RespiVert, Sanofi, Schering-Plough, and Teva Pharmaceuticals; has received international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Napp Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, and Teva Pharmaceuticals; and has received a research grant from Chiesi. Prof Wechsler has received consulting, advisory or speaker fees from Amgen, Areteia Therapeutics, AstraZeneca, Avalo Therapeutics, Boehringer Ingelheim, Celldex Therapeutics, Cellergy Pharma, Cerecor, CytoReason, Eli Lilly, Equillium, GSK, Incyte, Kinaset Therapeutics, Merck, Novartis, Om Pharma, Overtone Therapeutics/Foresite Labs, Phylaxis Bioscience, PULMATRiX, Rapt Therapeutics, Regeneron Pharmaceuticals, Roche/Genentech, Sanofi/Genzyme, Sentien Biotechnologies, Sound Biologics, Tetherex Pharmaceuticals, Teva Pharmaceuticals, Upstream Bio and Verona Pharma. Prof Porsbjerg has received grants and consultancy fees from ALK-Abelló, AstraZeneca, Chiesi, GSK, Novartis, Sanofi, and Teva Pharmaceuticals. Dr Corren has received grants and personal fees from AstraZeneca, Genentech, and Vectura; and has received grants from Optinose, Sanofi, and Teva Pharmaceuticals., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

While advanced liver disease was previously considered to be an acquired bleeding disorder, there is increasing recognition of an associated prothrombotic state with patients being at higher risk of atrial fibrillation (AF) and stroke and venous thromboembolism (VTE) including portal vein thrombosis (PVT). We review the available literature on epidemiology, pathophysiology, and risk factors and provide guidance on anticoagulant management of these conditions in adults with cirrhosis. In patients with Child-Pugh A or B cirrhosis and AF, we recommend anticoagulation with standard-dose direct oral anticoagulants (DOACs) in accordance with cardiology guideline recommendations for patients without liver disease. In those with Child-Pugh C cirrhosis, there is inadequate evidence with respect to the benefit and risk of anticoagulation for stroke prevention in AF. In patients with cirrhosis and acute deep vein thrombosis or pulmonary embolism, we recommend anticoagulation and suggest use of either a DOAC or low-molecular-weight heparin (LMWH)/vitamin K antagonist (VKA) in Child-Pugh A or B cirrhosis and LMWH alone (or as a bridge to VKA in patients with a normal baseline international normalized ratio) in Child-Pugh C cirrhosis. We recommend anticoagulation for patients with cirrhosis and symptomatic PVT. We suggest anticoagulation for those with asymptomatic, progressing PVT and recommend continuing extended anticoagulation for liver transplant candidates with PVT., Competing Interests: Declaration of competing interests S.C. has received speaker or advisory board fees from AstraZeneca, BMS/Pfizer, Fresenius Kabi, Leo Pharma, and Servier. A.C. has served as a consultant for MingSight Pharmaceuticals, the New York Blood Center, Sanofi, and Synergy, and has received authorship royalties from UpToDate. A.G. has received travel/conference awards from Octapharma and CSL Behring. N.G. has received consulting fees or travel awards from Bayer, Bristol-Myers Squibb/Pfizer, LEO Pharma, and Diagnostica Stago. V.H.G. has received speaker fees from Cook Medical and Gore Medical. K.M. has received speaker fees from Alexion, Bayer, and CSL Behring; fees for participation in trial steering committees for Bayer and AstraZeneca; consulting fees from uniQure and Therini, and fees for participation in data monitoring and endpoint adjudication committee for Octapharma. D.M.S. has received honoraria paid indirectly to her research institute from AstraZeneca, BMS-Pfizer, Roche, and Servier for educational presentations. D.M.S. is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease. L.R. has received speaker or advisory fees from Chugai and Hemab. S.S. and T.L. have no competing interests to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS., Methods: This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed., Findings: Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator., Interpretation: On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS., Funding: Biogen., Competing Interests: Declaration of interests LHvdB: advisory board for Amylyx, Biogen, Cytokinetics, Denali, QurAlis, Corcept, Novartis, Ferrer, and Sanofi. JDR: advisory board for Expansion Therapeutics and Sanofi and receives support from AbbVie Foundation, ALS Association, ALS Finding a Cure Foundation, American Airlines, Answer ALS Foundation, Aviators Against ALS, Bruce Edwards Foundation, Calico, Caterpillar Foundation, Chan Zuckerberg Initiative, Fishman Family Foundation, F Prime, Glaxo Smith Kline, Microsoft, M Armstrong, Muscular Dystrophy Association, National Football League, National Institutes of Health, Stay, Strong Vs ALS, Team Gleason, The Judith and Jean Pape Adams Charitable Foundation, Travelers Insurance, and the US Department of Defense. PJS: advisory board member for Aclipse Therapeutics, Benevolent AI, Biogen, Bristol Meyers Squibb, Darby Rimmer Foundation, Lilly, Novartis, Quell Therapeutics, QurAlis, Samsara Therapeutics, and Pangea Botanica; receives research support from US Department of Defense, EU Horizon 2020, EU Innovative Medicines Initiative, Fight MND, LifeArc, the Medical Research Council, MND Association, My Name'5 Doddie Foundation, NIHR, Pfizer, Quell Therapeutics, SwanBio, and Wolfson Foundation; and has received support for clinical trials participation from Alexion, Biogen, the EU Horizon programme, and UK NIHR. SB: received research funding from National Institutes of Health, American Academy of Neurology, American Association for Electrodiagnostic and Neuromuscular Medicine (AANEM), Muscular Dystrophy Association, OrphAI Therapeutics, Biogen, Ionis, Medicinova, Novartis, Orion, Voyager Therapeutics, and Denali Therapeutics; honoraria for patient and clinician educational activities related to ALS from AANEM Foundation, McCourt Foundation, and Medscape; institutional consulting or advisory board fees from OrphAI Therapeutics and Biogen; and platform trial coordination centre activities from HEALEY ALS. MB: consultant to Alector, Annexon, Arrowhead, Biogen, Denali, Eli Lilly, Novartis, Roche, Sanofi, UniQure, and Woolsey; clinical trial site investigator for Biogen and Orphazyme; and intellectual property licensed to Biogen and Orphazyme. RCB: advisory board for MT Pharma, has a consulting role with Biogen, has Equity in Neuroquestions LLC, and receives a recurring annual gift from a patient's family for research on neuralgic amyotrophy. AG: ad hoc consultant for genetic testing for Biogen; consultant on ALS trial design for Alexion, AL-S Pharma, Calico, Cytokinetics, and Sanofi; and CMO at QurAlis. JDG: institution was contracted by Biogen as a trial site and was paid for those services; received grants from Muscular Dystrophy Association and National Institutes of Health The Amyotrophic Lateral Sclerosis Association and received commercial sponsorships for clinical trials from Amylyx, Biogen, Cytokinetics, and Neuralstem. OH: funding from Science Foundation Ireland (grants SFI 16/RC/3948 and 20/SP/8953); received consulting fees from Accelsior, Biogen, Cytokinetics, Denali, Novartis, Orion, and Wave Pharmaceuticals; and is Editor-in-Chief of the journal Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. VL: institution was contracted by Biogen as a trial site and was paid for those services; and Chair of independent data monitoring committee at Vico Therapeutics and member of independent data monitoring committees at QurAlis and Cyclo Therapeutics. TM: consultant to Amylyx, Biogen, Cytokinetics, and QurAlis. BO: serves as a consultant for Columbia University/Tsumura, MediciNova, Biogen, UniQure, Amylyx, and Mitsubishi and has research grants from Columbia University/Tsumura, Biogen, MediciNova, Cytokinetics, Mitsubishi, Calico, Novartis, Sanofi, Ashvattha, and TARGET ALS. GLP: medical advisory roles for Amylyx, Avanir, Biogen, Catalyst, Cytokinetics, MT Pharma, Otsuka, and the US Department of Defense. JR: serves on advisory boards to Libra, Golgi, and Transposon and consultant to Verge, Iris, and Zydus. MW: consultant to Allmiral, Biogen, Mitsubishi Tanabe Pharma, Neuraxpharm, and Novartis. LZ: received honorarium for being on a Biogen advisory board. PJ-n and FR: paid employees of Ionis Pharmaceuticals. LL, DG, MM, JI, SS, SG, and SF: employees of and may hold stock in Biogen. TAF, ALG, and SE: employees of Biogen at the time the study was conducted. CES: declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Importance: Previous research indicates that mental disorders may be transmitted from one individual to another within social networks. However, there is a lack of population-based epidemiologic evidence that pertains to the full range of mental disorders., Objective: To examine whether having classmates with a mental disorder diagnosis in the ninth grade of comprehensive school is associated with later risk of being diagnosed with a mental disorder., Design, Setting, and Participants: In a population-based registry study, data on all Finnish citizens born between January 1, 1985, and December 31, 1997, whose demographic, health, and school information were linked from nationwide registers were included. Cohort members were followed up from August 1 in the year they completed ninth grade (approximately aged 16 years) until a diagnosis of mental disorder, emigration, death, or December 31, 2019, whichever occurred first. Data analysis was performed from May 15, 2023, to February 8, 2024., Exposure: The exposure was 1 or more individuals diagnosed with a mental disorder in the same school class in the ninth grade., Main Outcomes and Measures: Being diagnosed with a mental disorder during follow-up., Results: Among the 713 809 cohort members (median age at the start of follow-up, 16.1 [IQR, 15.9-16.4] years; 50.4% were males), 47 433 had a mental disorder diagnosis by the ninth grade. Of the remaining 666 376 cohort members, 167 227 persons (25.1%) received a mental disorder diagnosis during follow-up (7.3 million person-years). A dose-response association was found, with no significant increase in later risk of 1 diagnosed classmate (HR, 1.01; 95% CI, 1.00-1.02), but a 5% increase with more than 1 diagnosed classmate (HR, 1.05; 95% CI, 1.04-1.06). The risk was not proportional over time but was highest during the first year of follow-up, showing a 9% increase for 1 diagnosed classmate (HR, 1.09; 95% CI, 1.04-1.14), and an 18% increase for more than 1 diagnosed classmate (HR, 1.18; 95% CI, 1.13-1.24). Of the examined mental disorders, the risk was greatest for mood, anxiety, and eating disorders. Increased risk was observed after adjusting for an array of parental, school-level, and area-level confounders., Conclusions and Relevance: The findings of this study suggest that mental disorders might be transmitted within adolescent peer networks. More research is required to elucidate the mechanisms underlying the possible transmission of mental disorders.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb + ) children and adults who are at risk of (confirmed single IAb + ) or living with (multiple IAb + ) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb + ; (2) when people who are IAb + are initially identified there is a need for confirmation using a second sample; (3) single IAb + individuals are at lower risk of progression than multiple IAb + individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care., (© 2024. American Diabetes Association and European Association for the Study of Diabetes.)

Background: Despite widespread use of combination antiretroviral therapy, people with HIV (PWH) continue to have an increased risk of admission to and mortality in the intensive care unit (ICU). Mortality risk after hospital discharge is not well described. Using retrospective data on adult PWH (≥18 years) admitted to ICU from 2000-2019 in an HIV-referral centre, we describe trends in 1-year mortality after ICU admission., Methods: One-year mortality was calculated from index ICU admission to date of death; with follow-up right-censored at day 365 for people remaining alive at 1 year, or day 7 after ICU discharge if lost-to-follow-up after hospital discharge. Cox regression was used to describe the association with calendar year before and after adjustment for patient characteristics (age, sex, Acute Physiology and Chronic Health Evaluation II [APACHE II] score, CD4+ T-cell count, and recent HIV diagnosis) at ICU admission. Analyses were additionally restricted to those discharged alive from ICU using a left-truncated design, with further adjustment for respiratory failure at ICU admission in these analyses., Results: Two hundred and twenty-one PWH were admitted to ICU (72% male, median [interquartile range] age 45 [38-53] years) of whom 108 died within 1-year (cumulative 1-year survival: 50%). Overall, the hazard of 1-year mortality was decreased by 10% per year (crude hazard ratio (HR): 0.90 (95% confidence interval: 0.87-0.93)); the association was reduced to 7% per year (adjusted HR: 0.93 (0.89-0.98)) after adjustment. Conclusions were similar among the subset of 136 patients discharged alive (unadjusted: 0.91 (0.84-0.98); adjusted 0.92 (0.84, 1.02))., Conclusions: Between 2000 and 2019, 1-year mortality after ICU admission declined at this ICU. Our findings highlight the need for multi-centre studies and the importance of continued engagement in care after hospital discharge among PWH., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: In suspected non-ST-segment elevation myocardial infarction (NSTEMI), this presumed diagnosis may not hold true in all cases, particularly in patients with nonobstructive coronary arteries (NOCA). Additionally, in multivessel coronary artery disease, the presumed infarct-related artery may be incorrect., Objectives: This study sought to assess the diagnostic utility of cardiac magnetic resonance (CMR) before invasive coronary angiogram (ICA) in suspected NSTEMI., Methods: A total of 100 consecutive stable patients with suspected acute NSTEMI (70% male, age 62 ± 11 years) prospectively underwent CMR pre-ICA to assess cardiac function (cine), edema (T 2 -weighted imaging, T 1 mapping), and necrosis/scar (late gadolinium enhancement). CMR images were interpreted blinded to ICA findings. The clinical care and ICA teams were blinded to CMR findings until post-ICA., Results: Early CMR (median 33 hours postadmission and 4 hours pre-ICA) confirmed only 52% (52 of 100) of patients had subendocardial infarction, 15% transmural infarction, 18% nonischemic pathologies (myocarditis, takotsubo, and other forms of cardiomyopathies), and 11% normal CMR; 4% were nondiagnostic. Subanalyses according to ICA findings showed that, in patients with obstructive coronary artery disease (73 of 100), CMR confirmed only 84% (61 of 73) had MI, 10% (7 of 73) nonischemic pathologies, and 5% (4 of 73) normal. In patients with NOCA (27 of 100), CMR found MI in only 22% (6 of 27 true MI with NOCA), and reclassified the presumed diagnosis of NSTEMI in 67% (18 of 27: 11 nonischemic pathologies, 7 normal). In patients with CMR-MI and obstructive coronary artery disease (61 of 100), CMR identified a different infarct-related artery in 11% (7 of 61)., Conclusions: In patients presenting with suspected NSTEMI, a CMR-first strategy identified MI in 67%, nonischemic pathologies in 18%, and normal findings in 11%. Accordingly, CMR has the potential to affect at least 50% of all patients by reclassifying their diagnosis or altering their potential management., Competing Interests: Funding Support and Author Disclosures The OxAMI study is supported by a British Heart Foundation (BHF) Centre of Research Excellence (CRE) Oxford (RE/13/1/30181), and the National Institute for Health Research Oxford Biomedical Research Centre. Dr Shanmuganathan has received funding from the Alison Brading Memorial Graduate Scholarship in Medical Science, Lady Margaret Hall, University of Oxford. Dr Burrage has received support from a British Heart Foundation Clinical Research Training Fellowship (FS/19/65/34692). Dr Gara has received a European Society of Cardiology, EACVI Research grant. Dr Piechnik has received support from the BHF CRE Oxford (RE/18/3/34214); and has patent authorship rights for U.S. patent 9285446 B2 (systems and methods for Shortened Look Locker Inversion Recovery [Sh-MOLLI] cardiac gated mapping of T1), granted March 15, 2016; intellectual properties are owned and managed by Oxford University Innovations. Dr Channon has received funding from a BHF Chair award (CH/16/1/32013). Dr Ferreira has received funding from the BHF, BHF CRE Oxford, and National Institute for Health Research Oxford Biomedical Research Center. The funders were not involved in the design and conduct of the study, in the collection, analysis, and interpretation of the data, and in the preparation, review, or approval of the manuscript. 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.)

Background: Pulmonary hypertension (PH) is a heterogeneous disease with a poor prognosis. Accurate risk stratification is essential for guiding treatment decisions in pulmonary arterial hypertension (PAH). Although various risk models have been developed for PAH, their comparative prognostic potential requires further exploration. Additionally, the applicability of risk scores in PH groups beyond group 1 remains to be investigated., Research Question: Are risk scores originally developed for PAH predictive in PH groups 1 through 4?, Study Design and Methods: We conducted a comprehensive analysis of outcomes among patients with incident PH enrolled in the multicenter worldwide Pulmonary Vascular Research Institute GoDeep meta-registry. Analyses were performed across PH groups 1 through 4 and further subgroups to evaluate the predictive value of PAH risk scores, including the Registry to Evaluate Early and Long-Term PAH Disease Mangement (REVEAL) Lite 2, REVEAL 2.0, European Society of Cardiology/European Respiratory Society 2022, Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 3-strata, and COMPERA 4-strata., Results: Eight thousand five hundred sixty-five patients were included in the study, of whom 3,537 patients were assigned to group 1 PH, whereas 1,807 patients, 1,635 patients, and 1,586 patients were assigned to group 2 PH, group 3 PH, and group 4 PH, respectively. Pulmonary hemodynamics were impaired with median mean pulmonary arterial pressure of 42 mm Hg (interquartile range, 33-52 mm Hg) and pulmonary vascular resistance of 7 Wood units (WU) (interquartile range, 4-11 WU). All risk scores were prognostic in the entire PH population and in each of the PH groups 1 through 4. The REVEAL scores, when used as continuous prediction models, demonstrated the highest statistical prognostic power and granularity; the COMPERA 4-strata risk score provided subdifferentiation of the intermediate-risk group. Similar results were obtained when separately analyzing various subgroups (PH subgroups 1.1, 1.4.1, and 1.4.4; PH subgroups 3.1 and 3.2; group 2 with isolated postcapillary PH vs combined precapillary and postcapillary PH; patients of all groups with concomitant cardiac comorbidities; and severe [> 5 WU] vs nonsevere PH)., Interpretation: This comprehensive study with real-world data from 15 PH centers showed that PAH-designed risk scores possess predictive power in a large PH cohort, whether considered as common to the group or calculated separately for each PH group (1-4) and various subgroups., Trial Registry: ClinicalTrials.gov; No.: NCT05329714; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. Y. has received personal fees from MSD. H. G. has received personal fees from Actelion, AstraZeneca, Bayer, BMS, GossamerBio, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. M. R. W. reports personal fees from MorphogenIX, Janssen, Chiesi, and Aerami; grants from British Heart Foundation and NIHR; and personal fees from MSD, Benevolent AI, and Tiakis Biotech, outside the submitted work. L. H. reports personal fees and nonfinancial support from Janssen and personal fees from MSD, Gossamer, and Altavant. D. G. K. reports support for the present manuscript from the Sheffield Biomedical Research Centre and consulting fees and other payments from Jansen Pharmaceuticals, Ferrer, Altavant, MSD, and United therapeutics. P. M. H. reports personal fees from Merck Co. S. Y. C. reports personal fees from Janssen, Bayer, Pfizer, United Therapeutics, and Acceleron Pharma and is a director, officer, and shareholder of Synhale Therapeutics. S. O. reports personal fees from MSD, Janssen, and Gallenica-Ferrer. H. A. G. has received fees from Actelion, AstraZeneca, Bayer, GSK, Janssen-Cilag, Lilly, Novartis, OMT, Pfizer, and United Therapeutics. M. J. R. has received support from Janssen Pharmaceutica and Bayer Pharma AG and speaker fees from Janssen Pharmaceutica and OMT. S. S. reports personal fees from Gossamer Bio, Merck, Keros, Janssen, United Therapeutics, and Liquidia. K. T. has received personal fees from Bayer, AstraZeneca, and Gossamer. W. S. has received consultancy fees from United Therapeutics, Tiakis Biotech AG, Liquidia, Pieris Pharmaceuticals, Abivax, Pfitzer, and Medspray BV. None declared (M. Fünderich, A.L., Y. S., O. T., A. J. S., R. T. Z., P. G. W., M. Frauendorf, A. Arvanitaki, G. G., K. S., H. R. C., R. F., I. A. G., E. B., J. S. A., A. P., S. G., A. Anthi, R. W. M., J. W., F. G.), (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background There have been growing concerns about the wellbeing of staff in inpatient mental health settings, with studies suggesting that they have higher burnout and greater work-related stress levels than staff in other healthcare sectors. When addressing staff wellbeing, psychological safety can be a useful concept. However, there is no measure of psychological safety that is suitable for use in inpatient mental health settings. Edmondson (1999) is the most commonly used measure of psychological safety, but it was designed for use in general physical healthcare settings. As inpatient mental health settings are unique environments, transferability of knowledge from physical to mental healthcare settings cannot be assumed. Methods We sought to develop questionnaire items that capture psychological safety amongst healthcare staff working in acute inpatient mental healthcare settings. We used the nominal group technique, a consensus method involving rounds of discussion, idea generation and item rating/ranking to identify priorities. Twenty-eight stakeholders participated, including 4 who had lived experience of mental health problems, 11 academics and 18 healthcare professionals (eight participants identified with more than one category). The study involved a workshop with three parts: 1) an overview of current research and limitations of the Edmondson (1999) measure as outlined above, 2) discussion on what items should be retained from the Edmondson (1999) measure, and 3) discussion on what items should be added to the Edmondson (1999) measure. Results Twenty-one items were generated and retained to capture psychological safety in inpatient mental health settings. These measure professionals' sense of being valued by their team and organisation, feeling supported at work, feeling physically safe and protected from physical harm, and knowing they can raise concerns about risk and safety. Conclusion This is the first study to generate questionnaire items suitable for measuring staff psychological safety in mental health settings. These have been generated via a consensus method to ensure stakeholder's views are reflected. Further research is needed to evaluate factor structure, internal reliability and convergent validity., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Quality in Health Care.)

Background and Aims: Circulating proenkephalin (PENK) is a stable endogenous polypeptide with fast response to glomerular dysfunction and tubular damage. This study examined the predictive value of PENK for renal outcomes and mortality in patients with acute coronary syndromes (ACS)., Methods: Proenkephalin was measured in plasma in a prospective multicentre ACS cohort from Switzerland (n=4787) and in validation cohorts from the UK (n=1141), Czechia (n=927), and Germany (n=220). A biomarker-enhanced risk score (KID-ACS score) for simultaneous prediction of in-hospital acute kidney injury (AKI) and 30-day mortality was derived and externally validated., Results: On multivariable adjustment for established risk factors, circulating PENK remained associated with in-hospital AKI (per log2 increase: adjusted odds ratio [OR] 1.53, 95% confidence interval [CI] 1.13-2.09, P=0.007) and 30-day mortality (adjusted hazard ratio [HR] 2.73, 95% CI 1.85-4.02, P<0.001). The KID-ACS score integrates PENK and showed an area under the receiver operating characteristic curve (AUC) of 0.72 (95% CI 0.68-0.76) for in-hospital AKI, and of 0.91 (95% CI 0.87-0.95) for 30-day mortality in the derivation cohort. Upon external validation, KID-ACS achieved similarly high performance for in-hospital AKI (Zurich: AUC 0.73, 95% CI 0.70-0.77; Czechia: AUC 0.75, 95% CI 0.68-0.81; Germany: AUC 0.71, 95% CI 0.55-0.87) and 30-day mortality (UK: AUC 0.87, 95% CI 0.83-0.91; Czechia: AUC 0.91, 95% CI 0.87-0.94; Germany: AUC 0.96, 95% CI 0.92-1.00) outperforming the CA-AKI score and the GRACE 2.0 score, respectively., Conclusions: Circulating PENK offers incremental value for predicting in-hospital AKI and mortality in ACS. The simple 6-item KID-ACS risk score integrates PENK and provides a novel tool for simultaneous assessment of renal and mortality risk in patients with ACS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: People with dysfunctional breathing (DB) experience symptoms such as air hunger and breathing pattern irregularities. The condition is often comorbid with other respiratory conditions, as well as anxiety and depression. Illness perceptions, the beliefs an individual has of an illness may explain health and wellbeing outcomes., Methods: In this cross-sectional study we examined the illness perceptions of those diagnosed with DB, symptom severity and psychosocial outcomes of depression, anxiety and impact on daily living. Data were analysed using tests of comparison and regression analysis., Results: 82 people diagnosed with DB completed the brief illness perception questionnaire, the Nijmegen symptoms questionnaire and questionnaires measuring mood and impact on daily living. The illness perceptions of those with DB were overall negative. There was a positive correlation between illness perceptions and mood, indicating that the stronger the beliefs that individuals had that DB is a serious condition, the more negative their mood. Illness perceptions significantly predicted psychosocial outcomes, even when controlling for demographic factors and symptom severity (depression: adj. R 2 =.352, F(10,51)=4.32, p<.001; anxiety: adj. R 2 =.40, F(11,47)=4.55, p<.001; impact on daily living: adj. R 2 = .33, F(8,53)=4.79, p<.001 )., Conclusions: This is the first study to examine illness perceptions held by those diagnosed with DB. Our study found significant relationships between illness perceptions and psychosocial outcomes. It is possible that psychological interventions that target illness perceptions may also improve outcomes.

Introduction: People with Parkinson's disease (PwPD) present motor alterations which can impact daily life tasks that require speed and/or accuracy of movement., Objective: A sub analysis of NCT01439022, aiming to estimate the extent to which two different exercise training protocols (global and handwriting upper limb exercise training) impact reaction time, travel speed, and accuracy in PwPD., Methods: Seventy PwPD, right-side dominant were randomised 1:1 into two six-month training protocol groups; 35 PwPD performed global exercise training and 35 performed specific training (handwriting upper limb exercise movements). Assessments of speed-accuracy and trade-off were carried out at baseline, after 3 and 6 months of training, and at a 12-month follow-up. The current study used data from a previous publication of a randomised controlled trial that included a 6-month self-managed community exercise programme for PwPD. For the present study we included only the participants who completed the Fitts' task during the baseline assessment., Results: In the upper limb assessments, no main effects were found for the number of touches, but the exercise group showed a marginal increase over time on the left side. Error averages on the left side decreased significantly for the exercise group from baseline to 6 and 12 months. The exercise group also presented a lower Error CoV and the Reaction Time CoV increased on the right side. Significant findings for Fitts r on the left side indicated lower values for the exercise group, with improvements continuing at 12 months., Conclusion: We report the potential of global exercise interventions to facilitate improvements in reaction time and travel speed, as well as other motor control metrics, with lasting effects at 12 months, particularly on the non-dominant side., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Moraes 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.)

Background: Obesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown., Objectives: In this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function., Methods: Echocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values., Results: Overall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, -6.13 mL; 95% CI: -9.85 to -2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: -1.99 cm 2 ; 95% CI: -3.60 to -0.38 cm 2 ; P = 0.016; EMD in RV end-systolic area: -1.41 cm 2 ; 95% CI: -2.42 to -0.40] cm 2 ; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: -5.63 cm/s; 95% CI: -9.42 to -1.84 cm/s; P = 0.0037), E/A (early/late mitral inflow velocity) ratio (EMD: -0.14; 95% CI: -0.24 to -0.04; P = 0.0075), and E/e' (early mitral inflow velocity/early diastolic mitral annular velocity) average (EMD: -0.79; 95% CI: -1.60 to 0.01; P = 0.05). These associations were not modified by diabetes or atrial fibrillation status. Semaglutide did not significantly affect left ventricular dimensions, mass, or systolic function. Greater weight loss with semaglutide was associated with greater reduction in LA volume (P interaction  = 0.033) but not with changes in E-wave velocity, E/e' average, or RV end-diastolic area., Conclusions: In the STEP-HFpEF Program echocardiography substudy, semaglutide appeared to improve adverse cardiac remodeling compared with placebo, further suggesting that treatment with semaglutide may be disease modifying among patients with obesity-related HFpEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470)., Competing Interests: Funding Support and Author Disclosures The STEP-HFpEF and STEP-HFpEF DM trials were sponsored by Novo Nordisk A/S. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Eli Lilly, MyoKardia, National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr Ostrominski has received grant support from the NIH (5T32HL007604-39). Dr Wang has received grant support from American College of Cardiology/Association of BlackCardiologists Merck Research Fellowship; and her institution has received fees for core lab services from Cytokinetics and Bristol Myers Squibb. Dr Shah has received support from research grants from the NIH (U54 HL160273, R01 HL140731, and R01 HL149423); has received research funding from AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, BridgeBio, Bristol Myers Squibb, Corvia, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Borlaug has received research support from the NIH and the US Department of Defense; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, NGM Biopharmaceuticals, Novo Nordisk, NXT Medical, and VADovations; and is named inventor (US patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Butler has served as a consultant to 3live, Abbott, American Regent, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Impulse Dynamics, Imbria, Innolife, Inventiva, Janssen, Lexicon, Lilly, LivaNova, Medtronic, Merck, Novartis, Novo Nordisk, Occlutech, Pfizer, Pharmacosmos, PharmaIN, Roche, Sequana, SQ Innovation, and Vifor. Dr Davies has served as a consultant, Advisory Board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; has served as an Advisory Board member and speaker for AstraZeneca; has served as an Advisory Board member for Medtronic, Pfizer, and ShouTi Pharma; has served as a speaker for Amgen, Novartis, and Sanofi; and has received grants as an investigator in support of investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. Dr Kitzman has received support from the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and NIH (grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, 14 U24AG059624, and U01HL160272); has received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences. Dr Verma has received speaker and/or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. Drs Abildstrøm, Nygaard Einfeldt, and Rasmussen are employees and shareholders of Novo Nordisk A/S. Dr Abhayaratna has received honoraria or speaker fees as an Advisory Board member or speaker for Amgen, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Ahmed has received honoraria and/or consulting fees from Abbott, AstraZeneca, Medtronic, Novo Nordisk, Occlutech, Pharmacosmos, and Vifor. Dr Chopra has received speaker fees from AstraZeneca, Boehringer Ingelheim, Cipla, Dr Reddy’s, Lupin, Novartis, Novo Nordisk, Mankind, Pfizer, Sanofi, Sun Pharma, and Torrent. Dr Ito has received honoraria and/or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Mochida, Novartis, and Novo Nordisk. Dr Merkely has received speaker fees and/or research payments from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, DUKE Clinical Institute, Medtronic, and Novartis; and has received institutional grants from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, DUKE Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo, and Vifor. Dr Núñez has received honoraria and/or consulting fees from Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Pfizer, Novartis, Novo Nordisk, Rovi, and Vifor. Dr Senni has received honoraria and/or consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, MSD, Novartis, Novo Nordisk, and Vifor. Dr van der Meer has received institutional payments for consultancy fees and/or grants from AstraZeneca, Boehringer Ingelheim, BridgeBio, Ionis, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharma Nord, and Vifor. Dr Wolf has received honoraria and/or consulting or speaker fees for serving as an Advisory Board member, consultant, or speaker from Novo Nordisk, Novartis, Bayer, Boehringer Ingelheim, and UCB. Dr Petrie has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novo Nordisk, Novartis, Pharmacosmos, Roche, and SQ Innovations; and has served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor. Dr Kosiborod has served as a consultant or on an Advisory Board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca and Vifor. Dr Ben-Gal has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: Herpes zoster (shingles) is normally diagnosed clinically. Timely diagnosis is important so that antiviral treatment can be started soon after rash onset., Aim: To assess whether a practice-level educational intervention, aimed at non-clinical patient-facing staff, improves the timely assessment of patients with shingles., Design and Setting: This was a cluster randomised study within a trial (SWAT) with nested qualitative study in general practices in England., Method: Practices were cluster randomised 1:1, stratified by centre and minimised by practice list size and Index of Multiple Deprivation score. Intervention practices were sent educational materials, highlighting the common presenting features of shingles and what action to take if suspected. The primary and secondary outcomes were the mean proportion of patients per practice seen within 72 and 144 h of rash onset, respectively. Comparison between groups was conducted using linear regression, adjusting for randomisation variables. Semi-structured interviews with practice staff in intervention practices explored views and opinions about the intervention., Results: In total, 67 practices were enrolled; 34 randomised to the intervention and 33 to the control. The mean difference in proportion of patients seen within 72 and 144 h was -0.132 (95% confidence interval [CI] = -0.308 to 0.043) and -0.039 (95% CI = -0.158 to 0.080), respectively. In intervention practices, 90.9% reported distributing the educational materials; however, engagement with these was suboptimal. Twelve participants were interviewed, and the poster component of the intervention was said to be easiest to implement., Conclusion: Our educational intervention did not improve the timely assessment of patients with shingles. This may be the result of poor intervention engagement., (© The Authors.)

An oral Controlled Human Infection Model (CHIM) with wild-type S . Typhi was re-established allowing us to explore the development of immunity. In this model, ~55% of volunteers who received the challenge reached typhoid diagnosis criteria (TD), while ~45% did not (NoTD). Intestinal macrophages are one of the first lines of defense against enteric pathogens. Most organs have self-renewing macrophages derived from tissue-resident progenitor cells seeded during the embryonic stage; however, the gut lacks these progenitors, and all intestinal macrophages are derived from circulating monocytes. After infecting gut-associated lymphoid tissues underlying microfold (M) cells, S . Typhi causes a primary bacteremia seeding organs of the reticuloendothelial system. Following days of incubation, a second bacteremia and clinical disease ensue. S . Typhi likely interacts with circulating monocytes or their progenitors in the bone marrow. We assessed changes in circulating monocytes after CHIM. The timepoints studied included 0 hours (pre-challenge) and days 1, 2, 4, 7, 9, 14, 21 and 28 after challenge. TD participants provided extra samples at the time of typhoid diagnosis, and 48-96 hours later (referred as ToD). We report changes in Classical Monocytes -CM-, Intermediate Monocytes -IM- and Non-classical Monocytes -NCM-. Changes in monocyte activation markers were identified only in TD participants and during ToD. CM and IM upregulated molecules related to interaction with bacterial antigens (TLR4, TLR5, CD36 and CD206). Of importance, CM and IM showed enhanced binding of S . Typhi. Upregulation of inflammatory molecules like TNF-α were detected, but mechanisms involved in limiting inflammation were also activated (CD163 and CD354 downregulation). CM upregulated molecules to interact/modulate cells of the adaptive immunity, including T cells (HLA-DR, CD274 and CD86) and B cells (CD257). Both CM and IM showed potential to migrate to the gut as integrin α4β7 was upregulated. Unsupervised analysis revealed 7 dynamic cell clusters. Five of these belonged to CM showing that this is the main population activated during ToD. Overall, we provide new insights into the changes that diverse circulating monocyte subsets undergo after typhoid diagnosis, which might be important to control this disease since these cells will ultimately become intestinal macrophages once they reach the gut., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Toapanta, Hu, Shirey, Bernal, Levine, Darton, Waddington, Pollard and Sztein.)

Objectives: The aim of this study was to quantify changes in peak bending moments at the distal tibia, peak patellofemoral joint contact forces and peak Achilles tendon forces during a high-intensity run to fatigue at middle-distance speed., Design: Observational study., Methods: 16 high-level runners (7 female) ran on a treadmill at the final speed achieved during a preceding maximum oxygen uptake test until failure (~3 min). Three-dimensional kinetics and kinematics were used to derive and compare tibial bending moments, patellofemoral joint contact forces and Achilles tendon forces at the start, 33 %, 67 % and the end of the run., Results: Average running speed was 5.7 (0.4) m·s -1 . There was a decrease in peak tibial bending moments (-6.8 %, p = 0.004) from the start to the end of the run, driven by a decrease in peak bending moments due to muscular forces (-6.5 %, p = 0.001), whilst there was no difference in peak bending moments due to joint reaction forces. There was an increase in peak patellofemoral joint forces (+8.9 %, p = 0.026) from the start to the end of the run, but a decrease in peak Achilles tendon forces (-9.1 %, p < 0.001)., Conclusions: Running at a fixed, high-intensity speed to failure led to reduced tibial bending moments and Achilles tendon forces, and increased patellofemoral joint forces. Thus, the altered neuromechanics of high-intensity running to fatigue may increase patellofemoral joint injury risk, but may not be a mechanism for tibial or Achilles tendon overuse injury development., Competing Interests: Declaration of interest statement There are no reported conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Combining information from multiple GWASs for a disease and its risk factors has proven a powerful approach for development of polygenic risk scores (PRSs). This may be particularly useful for type 2 diabetes (T2D), a highly polygenic and heterogeneous disease where the additional predictive value of a PRS is unclear. Here, we use a meta-scoring approach to develop a metaPRS for T2D that incorporated genome-wide associations from both European and non-European genetic ancestries and T2D risk factors. We evaluated the performance of this metaPRS and benchmarked it against existing genome-wide PRS in 620,059 participants and 50,572 T2D cases amongst six diverse genetic ancestries from UK Biobank, INTERVAL, the All of Us Research Program, and the Singapore Multi-Ethnic Cohort. We show that our metaPRS was the most powerful PRS for predicting T2D in European population-based cohorts and had comparable performance to the top ancestry-specific PRS, highlighting its transferability. In UK Biobank, we show the metaPRS had stronger predictive power for 10-year risk than all individual risk factors apart from BMI and biomarkers of dysglycemia. The metaPRS modestly improved T2D risk stratification of QDiabetes risk scores for 10-year risk prediction, particularly when prioritising individuals for blood tests of dysglycemia. Overall, we present a highly predictive and transferrable PRS for T2D and demonstrate that the potential for PRS to incrementally improve T2D risk prediction when incorporated into UK guideline-recommended screening and risk prediction with a clinical risk score.

Competing Interests: REJB is funded by the Oxford National Institute for Health and Care Research Biomedical Research Centre, Oxford, UK, through the JDRF/Wellcome Strategic Award (4-SRA-2017-473-A-N; 107212/A/15/Z) and is part of EDENT1FI, which is supported by the Innovative Health Initiative Joint Undertaking under grant agreement 101132379. REJB has been an independent advisor for Provention Bio. She has received speaking honoraria for the EASD Rising stars symposium sponsored by Sanofi and speaking honoraria and travel support for a Medscape educational event; payment for both went into a university educational fund. KJG is an employee of Sanford Health and Sanford Research with grant support from the Helmsley Charitable Trust.. KJG has been a site principal investigator for multicentre clinical trials sponsored by Provention Bio. KJG serves on an advisory board for the North Carolina Early Check Screening Program. KJG has received support from JDRF and The American Diabetes Association to present at meetings.

Background: Healthcare systems are operating under substantial pressures. Clinicians and managers are constantly having to make adaptations, which are typically improvised, highly variable and not coordinated across teams. This study aimed to identify and describe the types of everyday pressures in intensive care and the adaptive strategies staff use to respond, with the longer-term aim of developing practical and coordinated strategies for managing under pressure., Methods: We conducted qualitative semi-structured interviews with 20 senior multidisciplinary healthcare professionals from intensive care units (ICUs) in 4 major hospitals in the UK. The interviews explored the everyday pressures faced by intensive care staff and the strategies they use to adapt. A thematic template analysis approach was used to analyse the data based on our previously empirically developed taxonomy of pressures and strategies., Results: The principal source of pressure described was a shortage of staff with the necessary skills and experience to care for the increased numbers and complexity of patients which, in turn, increased staff workload and reduced patient flow. Strategies were categorised into anticipatory (in advance of anticipated pressures) and on the day. The dynamic and unpredictable demands on ICUs meant that strategies were mostly deployed on the day, most commonly by flexing staff, prioritisation of patients and tasks and increasing modes of communication and support., Conclusions: ICU staff use a wide variety of adaptive strategies at times of pressure to minimise risk and maintain a reasonable standard of care for patients. These findings provide the foundation for a portfolio of strategies, which can be flexibly employed when under pressure. There is considerable potential for training clinical leaders and teams in the effective use of adaptive strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: More evidence for patterns of healthcare utilisation and associated costs among people receiving opioid agonist therapy (OAT) is needed. We investigated primary and secondary healthcare usage and costs among methadone and buprenorphine recipients in England., Methods: We conducted a cohort study using the Clinical Practice Research Datalink GOLD and Aurum databases of patients who were prescribed OAT between 1 January 2007 and 31 July 2019. The cohort was linked to Hospital Episode Statistics admitted patient care, outpatient and emergency department data, neighbourhood- and practice-level Index of Multiple Deprivation quintiles and mortality records. Negative binomial regression models were applied to estimate weighted rate ratios (wRR) of healthcare utilisation. Total and mean costs were calculated using Unit Costs of Health and Social Care and the National Healthcare Service Payment by Results National Tariffs., Results: Among 12,639 patients observed over 39,016 person-years, we found higher rate of hospital admissions (wRR 1.18; 1.08-1.28) among methadone compared with buprenorphine recipients. The commonest hospital discharge diagnoses among methadone patients were infectious diseases (19.2%), mental and behavioural disorders (17.0%) and drug-related poisoning (16.5%); the three commonest among buprenorphine patients were mental and behavioural diseases (21.5%), endocrine (13.8%) and genitourinary system diseases (13.1%). Methadone patients had similar mean costs compared with buprenorphine patients (cost difference: £539.01; 432.11-1006.69)., Discussion and Conclusions: Differences in healthcare utilisation frequency for methadone versus buprenorphine recipients were observed. The differences in associated costs were mainly driven by hospital admissions. These findings offer valuable insights for optimising care strategies and resource allocation for OAT recipients., (© 2024 The Author(s). Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Background: Patients with COPD frequently develop pulmonary hypertension (PH-COPD). Severe PH-COPD, identified by a pulmonary vascular resistance (PVR) >5 Wood Units (WU), is closely linked to impaired transplant-free survival. The impact of PH-targeting pharmacotherapy in this context remains unclear., Research Question: Is PH-targeted therapy associated with improved transplant-free survival in PH-COPD?, Study Design and Methods: This study included PVRI GoDeep meta-registry patients with PH-COPD and available right heart catheterization at diagnosis. We investigated PH-targeted therapy prevalence and its association with transplant-free survival using diverse statistical methods, including Cox regression and subgroup analyses based on PH severity, comorbidities, and pulmonary function tests. Immortal time bias was addressed through a landmark approach., Results: As of December 2023, the GoDeep meta-registry included 26981 patients (28% PH-Group 1, 13% PH-Group 2, 12% PH-Group 3, 10% PH-Group 4, 2% PH-Group 5, 26% undefined and 9% control). Out of these, 836 patients were diagnosed as PH-COPD and included in this analysis, with median age 66 [59,73]years, FEV1 51 [34,69]%predicted, mPAP 35 [28,44]mmHg, PVR 5 [4,8]WU, cardiac index 2.5 [2.0,2.9]L/min.m2, and mostly WHO functional class III were included. 5-year transplant-free survival was 42%, significantly worse than group 1 PH. A multivariable Cox proportional hazards model identified PVR, but not FEV1 as a major predictor of outcome. 418 patients (50%) received phosphodiesterase-5 inhibitor (PDE5i) therapy, which was associated with significantly reduced mortality: hazard ratio 0.65 [0.57,0.75] for the entire PH-COPD cohort and 0.83 [0.74,0.94] when performing landmark analysis. This PDE5i effect was robustly reproduced when performing subgroup analyses for patients with moderate/severe PH, various comorbidities, and supplemental oxygen requirement, and when assessing the impact of unobserved confounders., Interpretation: PH-COPD patients exhibit poor transplant-free survival, with PVR being a predictor of mortality. In this meta-registry, PDE5i therapy was associated with a significant reduction in mortality across all tested models., (Copyright © 2024. Published by Elsevier Inc.)

Background: The extent to which COVID-19 diagnosis and vaccination during pregnancy are associated with risks of common and rare adverse pregnancy outcomes remains uncertain. We compared the incidence of adverse pregnancy outcomes in women with and without COVID-19 diagnosis and vaccination during pregnancy., Methods: We studied population-scale linked electronic health records for women with singleton pregnancies in England and Wales from 1 August 2019 to 31 December 2021. This time period was divided at 8th December 2020 into pre-vaccination and vaccination roll-out eras. We calculated adjusted hazard ratios (HRs) for common and rare pregnancy outcomes according to the time since COVID-19 diagnosis and vaccination and by pregnancy trimester and COVID-19 variant., Findings: Amongst 865,654 pregnant women, we recorded 60,134 (7%) COVID-19 diagnoses and 182,120 (21%) adverse pregnancy outcomes. COVID-19 diagnosis was associated with a higher risk of gestational diabetes (adjusted HR 1.22, 95% CI 1.18-1.26), gestational hypertension (1.16, 1.10-1.22), pre-eclampsia (1.20, 1.12-1.28), preterm birth (1.63, 1.57-1.69, and 1.68, 1.61-1.75 for spontaneous preterm), very preterm birth (2.04, 1.86-2.23), small for gestational age (1.12, 1.07-1.18), thrombotic venous events (1.85, 1.56-2.20) and stillbirth (only within 14-days since COVID-19 diagnosis, 3.39, 2.23-5.15). HRs were more pronounced in the pre-vaccination era, within 14-days since COVID-19 diagnosis, when COVID-19 diagnosis occurred in the 3rd trimester, and in the original variant era. There was no evidence to suggest COVID-19 vaccination during pregnancy was associated with a higher risk of adverse pregnancy outcomes. Instead, dose 1 of COVID-19 vaccine was associated with lower risks of preterm birth (0.90, 0.86-0.95), very preterm birth (0.84, 0.76-0.94), small for gestational age (0.93, 0.88-0.99), and stillbirth (0.67, 0.49-0.92)., Interpretation: Pregnant women with a COVID-19 diagnosis have higher risks of adverse pregnancy outcomes. These findings support recommendations towards high-priority vaccination against COVID-19 in pregnant women., Funding: BHF, ESRC, Forte, HDR-UK, MRC, NIHR and VR., Competing Interests: G Smith: GSK. Consultant and member of expert panel for RSV vaccination in pregnancy. GSK. Member of Data Safety Monitoring Committee for trials of RSV vaccination in pregnancy Moderna. Member of Data Safety Monitoring Committee for trials of RSV vaccination in pregnancy. No other conflicts of interest to be disclosed. D A Lawlor: European Research Council, Research grant administered by University of Bristol. No conflict with this paper; and Diabetes UK, Research grant administered by University of Bristol. No conflict with this paper., (© 2024 The Authors.)

MySkinSelfie is a mobile phone application for skin self-monitoring, enabling secure sharing of patient-captured images with healthcare providers. This retrospective study assessed MySkinSelfie's role in remote skin cancer assessment at two centres for urgent (melanoma and squamous cell carcinoma) and nonurgent skin cancer referrals, investigating the feasibility of using patient-captured images without dermoscopy for remote diagnosis. The total number of lesions using MySkinSelfie was 814, with a mean patient age of 63 years. Remote consultations reduced face-to-face appointments by 90% for basal cell carcinoma and by 63% for referrals on a 2-week waiting list. Diagnostic concordance (consultant vs. histological diagnosis) rates of 72% and 83% were observed for basal cell carcinoma (n = 107) and urgent skin cancers (n = 704), respectively. Challenges included image quality, workflow integration and lack of dermoscopy. Higher sensitivities were observed in recent artificial intelligence algorithms employing dermoscopy. While patient-captured images proved useful during the COVID-19 pandemic, further research is needed to explore the feasibility of widespread patient-led dermoscopy to enable direct patient-to-artificial intelligence diagnostic assessment., Competing Interests: Conflicts of interest P.H. collaborated in designing MySkinSelfie, the mobile application (app) discussed in this report. However, his involvement in the design of the app had no influence on the design, methodology, data analysis or reporting of this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Importance: Selective laser trabeculoplasty (SLT) is becoming the recommended first choice in the treatment of open-angle glaucoma (OAG). However, whether repeat SLT can be recommended regardless of initial response remains controversial., Objective: To assess the potential of OAG and ocular hypertension (OHT) undergoing repeat laser to respond favorably to SLT, termed responsiveness to SLT., Design, Setting, and Participants: This post hoc analysis of the Laser in Glaucoma and Ocular Hypertension Trial in China (LiGHT China) was conducted from March 2015 to April 2023 in Zhongshan Ophthalmic Center. Of 1376 newly diagnosed OAG and OHT eyes of 771 adults in the original trial, 180 eyes of 105 participants were included in the present study, which underwent initial and repeat SLT as primary treatments., Exposures: Standard SLT was the primary treatment. Repeat SLT was the first choice of treatment escalation regardless of initial response. IOP reduction after SLT and the duration of effect were analyzed. The maximum reduction in IOP within 2 years after initial SLT and repeat SLT was used to identify potential nonresponsiveness., Main Outcomes and Measures: IOP reduction 2 months after SLT., Results: A total of 180 eyes from 105 Chinese participants (mean [SD] age, 45.6 [14.5] years; 58 [55.2%] male and 47 [44.8%] female) underwent repeat SLT. Initial SLT and repeat SLT were both associated with a reduction in IOP (mean, 4.5 mm Hg; 95% CI, 3.9 to 5.1; P < .001 and mean, 3.3 mm Hg; 95% CI, 2.7 to 3.8; P < .001, respectively). The mean (SD) IOP after repeat SLT was 15.8 (3.4) mm Hg, similar to 16.0 (4.0) mm Hg after initial SLT (difference, -0.4mm Hg; 95% CI, -1.0 to 0.3; P = .24). Duration of effect after repeat SLT was longer than after initial SLT (1043 days vs 419 days; hazard ratio, 0.38; 95% CI, 0.29 to 0.50; P < .001). IOP reduction after initial SLT was uncorrelated with that after repeat SLT, and 153 eyes (85.0%) responded favorably to SLT at least once. A subset of 27 eyes (15.0%) was identified as potentially nonresponsive and found distinctive with older age (mean [SD], 54.1 [12.5] years vs 44.2 [14.2] years; difference, 10.5 years; 95% CI, 2.9 to 18.1; P = .009), higher proportion of female participants (difference, 27.5%; 95% CI, 3.6 to 51.5; P = .03), and lower baseline IOP (difference, -3.2 mm Hg; 95% CI, -5.2 to -1.3; P = .001)., Conclusions and Relevance: These post hoc analyses showed that most cases of OAG and OHT were highly responsive to SLT and support the consideration of repeat SLT regardless of initial response, while individuals who are nonresponsive to this treatment may have specific features.

Importance: Associations have been found between COVID-19 and subsequent mental illness in both hospital- and population-based studies. However, evidence regarding which mental illnesses are associated with COVID-19 by vaccination status in these populations is limited., Objective: To determine which mental illnesses are associated with diagnosed COVID-19 by vaccination status in both hospitalized patients and the general population., Design, Setting, and Participants: This study was conducted in 3 cohorts, 1 before vaccine availability followed during the wild-type/Alpha variant eras (January 2020-June 2021) and 2 (vaccinated and unvaccinated) during the Delta variant era (June-December 2021). With National Health Service England approval, OpenSAFELY-TPP was used to access linked data from 24 million people registered with general practices in England using TPP SystmOne. People registered with a GP in England for at least 6 months and alive with known age between 18 and 110 years, sex, deprivation index information, and region at baseline were included. People were excluded if they had COVID-19 before baseline. Data were analyzed from July 2022 to June 2024., Exposure: Confirmed COVID-19 diagnosis recorded in primary care secondary care, testing data, or the death registry., Main Outcomes and Measures: Adjusted hazard ratios (aHRs) comparing the incidence of mental illnesses after diagnosis of COVID-19 with the incidence before or without COVID-19 for depression, serious mental illness, general anxiety, posttraumatic stress disorder, eating disorders, addiction, self-harm, and suicide., Results: The largest cohort, the pre-vaccine availability cohort, included 18 648 606 people (9 363 710 [50.2%] female and 9 284 896 [49.8%] male) with a median (IQR) age of 49 (34-64) years. The vaccinated cohort included 14 035 286 individuals (7 308 556 [52.1%] female and 6 726 730 [47.9%] male) with a median (IQR) age of 53 (38-67) years. The unvaccinated cohort included 3 242 215 individuals (1 363 401 [42.1%] female and 1 878 814 [57.9%] male) with a median (IQR) age of 35 (27-46) years. Incidence of most outcomes was elevated during weeks 1 through 4 after COVID-19 diagnosis, compared with before or without COVID-19, in each cohort. Incidence of mental illnesses was lower in the vaccinated cohort compared with the pre-vaccine availability and unvaccinated cohorts: aHRs for depression and serious mental illness during weeks 1 through 4 after COVID-19 were 1.93 (95% CI, 1.88-1.98) and 1.49 (95% CI, 1.41-1.57) in the pre-vaccine availability cohort and 1.79 (95% CI, 1.68-1.90) and 1.45 (95% CI, 1.27-1.65) in the unvaccinated cohort compared with 1.16 (95% CI, 1.12-1.20) and 0.91 (95% CI, 0.85-0.98) in the vaccinated cohort. Elevation in incidence was higher and persisted longer after hospitalization for COVID-19., Conclusions and Relevance: In this study, incidence of mental illnesses was elevated for up to a year following severe COVID-19 in unvaccinated people. These findings suggest that vaccination may mitigate the adverse effects of COVID-19 on mental health.

Objectives: Our aim was to identify which patients are likely to stay in hospital longer following total hip replacement surgery., Design: Longitudinal, observational study used routinely collected data., Setting: Data were collected from an NHS Trust in South-West England between 2016 and 2019., Participants: 2352 hip replacement patients had complete data and were included in analysis., Primary and Secondary Outcome Measures: Three measures of length of stay were used: a count measure of number of days spent in hospital, a binary measure of ≤7 days/>7 days in hospital and a binary measure of remaining in hospital when medically fit for discharge., Results: The mean length of stay was 5.4 days following surgery, with 18% in hospital for more than 7 days, and 11% staying in hospital when medically fit for discharge. Longer hospital stay was associated with older age (OR=1.06, 95% CI 1.05 to 1.08), being female (OR=1.42, 95% CI 1.12 to 1.81) and more comorbidities (OR=3.52, 95% CI 1.45 to 8.55) and shorter length of stay with not having had a recent hospital admission (OR=0.44, 95% CI 0.32 to 0.60). Results were similar for remaining in hospital when medically fit for discharge, with the addition of an association with highest socioeconomic deprivation (OR=2.08, 95% CI 1.37 to 3.16)., Conclusions: Older, female patients with more comorbidities and from more socioeconomically deprived areas are likely to remain in hospital for longer following surgery. This study produced regression models demonstrating consistent results across three measures of prolonged hospital stay following hip replacement surgery. These findings could be used to inform surgery planning and when supporting patient discharge following surgery., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Immunodeficiency-Centromeric instability-Facial dysmorphism (ICF) syndrome is an inborn error of immunity characterized by progressive immune dysfunction and multi-organ disease usually treated with antimicrobial prophylaxis and immunoglobulin substitution. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but data on outcome are scarce. We provide a detailed description of disease characteristics and HSCT outcome in an international cohort of ICF syndrome patients. Eighteen patients (including all four genotypes) were enrolled. Main HSCT indications were infections (83%), enteropathy/failure to thrive (56%), immune dysregulation (22%) and myelodysplasia/haematological malignancy (17%). Two patients underwent pre-emptive HSCT after early diagnosis. Patients were transplanted between 2003-2021, at median age 4.3 years (range 0.5-19), after myeloablative or reduced-intensity conditioning, from matched sibling or matched family donors, matched unrelated or mismatched donors in 39%, 50% and 12% of cases respectively. Overall survival was 83% (all deaths occurred within the first 5 months post-HSCT; mean follow-up 54 months (range 1-185)). Acute GvHD occurred in 35% of patients, severe (grade III) in two (12%), while none developed chronic GvHD. At latest follow-up (median 2.2 years (range 0.1-14)), complete donor chimerism was achieved in 15/17 surviving patients. All survivors demonstrated normalized T and B cell numbers. Immunoglobulin substitution independence was achieved in all but two patients. All survivors recovered from pre-transplant infections, enteropathy/failure to thrive and immune dysregulation. All three patients transplanted at young age (≤ 3 years), after early diagnosis, survived. The favourable clinical and immunological HSCT outcome in this cohort of patients supports the timely use of this curative treatment in ICF syndrome., (© 2024. The Author(s).)

Background: Diabetes mellitus (DM) significantly impacts cardiovascular outcomes, particularly in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). The presence of polyvascular disease further complicates the prognosis due to the increased burden of atherosclerosis and comorbidities. This study was designed to investigate the combined impact of DM and polyvascular disease on outcomes in patients with AMI and CS., Method: Using the National Inpatient Sample database, we analyzed 39,140 patients with AMI complicated by CS and known polyvascular disease. The patients were stratified by diabetes status. The study assessed in-hospital major adverse cardiovascular and cerebrovascular events (MACCE), mortality, cerebrovascular accident (CVA) and major bleeding. Multivariable logistic regression models were used to examine the association between in-hospital outcomes and diabetes, adjusting for baseline differences., Results: Of the study population, 54% had DM. The patients with DM were younger (69.5 vs. 72.1 years, p < 0.001) and more likely to be female (36.7% vs. 34.2%, p < 0.001). After adjustment, the patients with DM showed a 17% increased mortality risk (aOR 1.17, 95% CI: 1.11-1.23, p < 0.001) and a higher risk of major adverse cardiovascular and cerebrovascular events (aOR 1.05, 95% CI: 1.01-1.10, p = 0.020)., Conclusions: DM significantly impacts outcomes in patients with AMI complicated by CS and polyvascular disease, leading to increased mortality risk, longer hospital stays, and higher healthcare costs. These findings underscore the need for targeted interventions and specialized care strategies for this high-risk population.

Background: Gay, bisexual, and other men who have sex with men (GBMSM) face a disproportionate burden of sexually transmitted infections and are eligible for targeted vaccinations for hepatitis A (HAV), hepatitis B (HBV), human papilloma virus (HPV) and mpox. This study examines the sociodemographic characteristics, sexual behaviours, and sexual healthcare service (SHS) use associated with vaccination uptake., Methods: We undertook analyses of RiiSH-Mpox - an online, community-based survey with GBMSM recruited via social media and dating apps. We calculated vaccination uptake (≥1 dose) among eligible GBMSM. Bivariate and multivariable logistic regression was performed to identify factors independently associated with vaccination uptake among eligible participants., Results: Reported uptake in eligible GBMSM was around two-thirds for each of the vaccinations considered: mpox 69% (95% confidence interval (CI): 66%-72%), HAV 68% (CI:65%-70%), HBV 72% (CI:69%-74%) and HPV 65% (CI:61%-68%). Vaccination course completion (receiving all recommended doses) ranged from 75% (HBV) to 89% (HAV) among eligible GBMSM. Individuals who represented missed opportunities for vaccination ranged from 22 to 30% of eligible SHS attendees. Younger participants, individuals identifying as bisexual, reporting lower educational qualifications, or being unemployed reported lower uptake across multiple GBMSM-selective vaccinations. Individuals who reported greater levels of sexual behaviour and recent SHS use were more likely to report vaccinations., Conclusion: Eligible participants reported high uptake of vaccinations; however, uptake was lower amongst young GBMSM and self-identifying bisexual men. Awareness of groups with lower vaccination uptake will help inform practice, delivery strategies and health promotion, to improve the reach and impact of vaccinations amongst GBMSM., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: A growing population of patients with chronic kidney disease (CKD) presents with non-ST-segment-elevation myocardial infarction, although little is known about their longer-term mortality., Methods and Results: Using the MINAP (Myocardial Ischaemia National Audit Project) registry, linked to Office for National Statistics mortality data, we analyzed 363 559 UK patients with non-ST-segment-elevation myocardial infarction, with or without CKD. Cox regression models were fitted, adjusting for baseline demographics. Compared with patients without CKD, patients with CKD were less frequently prescribed P2Y12 inhibitors (89% versus 86%, P <0.001) less likely to undergo invasive angiography (67% versus 41%, P <0.001) or percutaneous coronary intervention (41% versus 25%, P <0.001), and were less often referred to cardiac rehabilitation (80% versus 66%, P <0.001). Following non-ST-segment-elevation myocardial infarction, patients with CKD had higher risk of 30-day (adjusted hazard ratio [HR], 1.24 [95% CI, 1.20-1.29], 1-year 1.47 [95% CI, 1.44-1.51]) and 5-year mortality 1.55 (95% CI, 1.53-1.58) than patients without CKD (all P <0.001). Risk of mortality over the entire study period was highest in CKD Stage 5 (HR, 2.98 [95% CI, 2.87-3.10]), even after excluding mortality ≤30 days (HR, 3.03 [95% CI, 2.90-3.17]) ( P <0.001). There was no significant difference in proportion of deaths attributable to cardiovascular disease at 30 days (CKD; 76% versus no CKD; 76%), or 1 -year (CKD; 62% versus no CKD; 62%)., Conclusions: Patients with CKD were significantly less likely to receive invasive investigation or undergo percutaneous coronary intervention and had significantly higher risk of short- and longer-term mortality. Risk of mortality increased with reducing CKD stage. Cardiovascular disease was the main cause of mortality in patients with CKD, but at comparable rates to the general population with non-ST-segment-elevation myocardial infarction.

Background: FebriDx is a single-use, analyser-free, point-of-care test with markers for bacterial (C-reactive protein [CRP]) and viral (myxovirus resistance protein A [MxA]) infection, measured on a finger-prick blood sample., Aim: As part of a larger feasibility study, we explored the views of healthcare professionals (HCPs) and patients on the use of FebriDx to safely reduce antibiotic prescriptions for lower respiratory tract infections (LRTIs) in primary care., Design & Setting: Remote semi-structured qualitative interviews were conducted in South England., Method: In total, 22 individuals (12 patients who underwent FebriDx testing and 10 HCPs from general practices that conducted testing) participated in interviews, which were analysed thematically., Results: Patients and HCPs expressed positive views about use of the test. They felt FebriDx was a useful tool to inform prescribing decisions and provided a visual aid to support shared decision making and appropriate antibiotic use. Most felt it would be feasible to integrate use into routine primary care consultations. Some practical difficulties with blood collection and interpreting results, which impacted on usability, were identified. Some patients' reactions to negative test results suggested the need for better communication alongside use of the test., Conclusion: FebriDx was perceived as a useful tool to guide antibiotic prescribing and support shared decision making. Initial practical problems with testing and communicating results are potential barriers to use. Training and practice on using the test and effective communication are likely to be important elements in ensuring patient understanding and satisfaction, and successful adoption., (Copyright © 2024, The Authors.)

Background: S. pneumoniae (SPN) is the most common cause of pneumonia. The disease can be effectively prevented through immunisation. Since December 2020, the Malaysian Government has included the 10-valent pneumococcal conjugate vaccine (PCV10) for all infants born on or after 1 January 2020 as part of the National Immunisation Programme (NIP). However, the epidemiology of pneumonia remains poorly understood. To fill the knowledge gap, we established a multicentre surveillance study to understand the burden of pneumococcal pneumonia among young children in Peninsular Malaysia., Methods: MY-Pneumo is a multicentre prospective case-control study conducted in three sentinel sites located in three different states of Peninsular Malaysia - Kuala Lumpur, Pahang, and Kelantan. A cohort of at least 500 incident cases and 500 controls is enrolled beginning in October 2021 and matched for age. Cases are hospitalised children < 5 years with radiologically confirmed pneumonia, and the controls are children without any features suggestive of pneumonia. Clinical samples, including nasopharyngeal swabs (NPS) and urine, are collected according to the study protocol. Biological fluids such as blood, cerebrospinal fluid (CSF) and pleural fluid are obtained from invasive pneumonia disease (IPD) patients, if available. All children are tested for SPN using polymerase chain reaction (PCR) and pneumococcal urine antigen test (PUAT) using BinaxNow., Discussion: Surveillance data, including carriage rate, serotype variations and the phylogeny data structure of SPN among young children in Malaysia during PCV implementation, will be generated from this study. Trends and patterns of pneumococcal serotypes by different regions are important for targeted public health strategies. Our data will provide baseline information for estimating the impact of PCV10 implementation and will influence policymakers' decisions regarding the upgrade from PCV10 to a higher-valency conjugate vaccine in Malaysia., Trial Registration: This project was registered at ClinicalTrials.gov (NCT04923035) on 2021, June 11. The study protocol was approved by the International Medical University Joint-Committee on Research & Ethics (4.15/JCM-216/2021) and the Institutional Review Board at sentinel sites (USM/JEPeM/21020190, IREC 2021-114, MREC ID No: 2021128-9769) and University of Southampton's Ethics and Research Governance (ERGo II 64844)., (© 2024. The Author(s).)