Search

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the UK Medical Research Council, Norwegian Research Council, NIH/NHLBI, Measey Foundation, and Doris Duke Foundation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work; TF has received funding from Pfizer, Takeda, Acadia, and iHeed for unrelated consulting work, and receives funds from The BMJ for editorial work; NMD receives funds from The BMJ for editorial work; SMD receives research support from RenalytixAI and Novo Nordisk, outside the scope of the current research.

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes., (© 2024. The Author(s).)

Objectives: There has been limited evidence synthesis examining treatment of ketamine use disorder. We aimed to conduct a systematic review to assess the efficacy and tolerability of pharmacological interventions in the management of ketamine use disorder., Methods: We searched MEDLINE, EMBASE, PsychINFO, and CENTRAL (Cochrane Central Register of Controlled Trials) from database inception to November 14, 2023, for studies of any design that reported on any pharmacological intervention in the management of ketamine use disorder. We extracted any reported measure of efficacy or tolerability and assessed outcome quality using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. We planned to combine outcomes using random-effects meta-analysis, where this was not possible results were reported narratively., Results: Twelve studies met the inclusion criteria reporting on 368 participants. These comprised 1 controlled trial, 2 retrospective case series, and 9 case reports. Two studies reported on ketamine intoxication, 6 on withdrawal, and 4 on craving/relapse prevention. All studies reported only descriptive outcomes, and all evidence was of very low quality. Benzodiazepine regimens and haloperidol were reported to have potential utility in intoxication and withdrawal, whereas naltrexone, lamotrigine, and a combination of paliperidone palmitate and bupropion were reported to have potential utility in craving/relapse prevention., Conclusions: There is a paucity of research into pharmacological management of ketamine use disorder. The limited very low-quality evidence suggests benzodiazepine regimens may be most salient for future exploration in management of ketamine intoxication and withdrawal, whereas case reports suggest naltrexone, lamotrigine, and paliperidone palmitate plus bupropion may potentially merit further investigation with regard to craving/relapse prevention., Competing Interests: All individual authors have completed the International Committee of Medical Journal Editors conflict of interest form. The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine.)

This chapter of the New York City Panel on Climate Change 4 (NPCC4) report provides a comprehensive description of the different types of flood hazards (pluvial, fluvial, coastal, groundwater, and compound) facing New York City and provides climatological context that can be utilized, along with climate change projections, to support flood risk management (FRM). Previous NPCC reports documented coastal flood hazards and presented trends in historical and future precipitation and sea level but did not comprehensively assess all the city's flood hazards. Previous NPCC reports also discussed the implications of floods on infrastructure and the city's residents but did not review the impacts of flooding on the city's natural and nature-based systems (NNBSs). This-the NPCC's first report focused on all drivers of flooding-describes and profiles historical examples of each type of flood and summarizes previous and ongoing research regarding exposure, vulnerability, and risk management, including with NNBS and nonstructural measures., (© 2024 The Author(s). Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

Obesity is a common comorbidity among patients with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF), with the strongest pathophysiologic link of obesity being seen for HFpEF. Lifestyle measures are the cornerstone of weight loss management, but sustainability is a challenge, and there are limited efficacy data in the heart failure (HF) population. Bariatric surgery has moderate efficacy and safety data for patients with preoperative HF or left ventricular dysfunction and has been associated with reductions in HF hospitalizations and medium-term mortality. Antiobesity medications historically carried concerns for cardiovascular adverse effects, but the safety and weight loss efficacy seen in general population trials of glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide/GLP-1 agonists are highly encouraging. Although there are safety concerns regarding GLP-1 agonists in advanced HFrEF, trials of the GLP-1 agonist semaglutide for treatment of obesity have confirmed safety and efficacy in patients with HFpEF., Competing Interests: Funding Support and Author Disclosures Dr Schauer has consultancy agreements with GI Dynamics; Keyron; Persona; Mediflix, Metabolic Health International, Lilly, Ethicon, Medtronic, Novo Nordisk, and Heron; ownership interest in SE Healthcare, Mediflix, and Metabolic Health International; and has received research funding from Ethicon and Medtronic. Dr Lavie has been a speaker and consultant for AstraZeneca on an SGLT2i; and has served on a data and safety monitoring board for Novo Nordisk. Dr Mandras has been a consultant and has served on the Speakers Bureaus for Bayer, CVRX, and United Therapeutics. Dr Tang has served as a consultant for Sequana Medical, Cardiol Therapeutics, Genomics, Zehna Therapeutics, Renovacor, WhiteSwell, Kiniksa Pharmaceuticals, Boston Scientific, CardiaTec Biosciences, and Intellia; and has received honoraria from Springer Nature and American Board of Internal Medicine. Dr daSilva-deAbreu owns stocks of TransMedics Group. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Genetic variants used as instruments for exposures in Mendelian randomisation (MR) analyses may have horizontal pleiotropic effects (i.e., influence outcomes via pathways other than through the exposure), which can undermine the validity of results. We examined the extent of this using smoking behaviours as an example. We first ran a phenome-wide association study in UK Biobank, using a smoking initiation genetic instrument. From the most strongly associated phenotypes, we selected those we considered could either plausibly or not plausibly be caused by smoking. We examined associations between genetic instruments for smoking initiation, smoking heaviness and lifetime smoking and these phenotypes in UK Biobank and the Avon Longitudinal Study of Parents and Children (ALSPAC). We conducted negative control analyses among never smokers, including children. We found evidence that smoking-related genetic instruments were associated with phenotypes not plausibly caused by smoking in UK Biobank and (to a lesser extent) ALSPAC. We observed associations with phenotypes among never smokers. Our results demonstrate that smoking-related genetic risk scores are associated with unexpected phenotypes that are less plausibly downstream of smoking. This may reflect horizontal pleiotropy in these genetic risk scores, and we would encourage researchers to exercise caution this when using these and genetic risk scores for other complex behavioural exposures. We outline approaches that could be taken to consider this and overcome issues caused by potential horizontal pleiotropy, for example, in genetically informed causal inference analyses (e.g., MR) it is important to consider negative control outcomes and triangulation approaches, to avoid arriving at incorrect conclusions., (© 2024 The Author(s). Genetic Epidemiology published by Wiley Periodicals LLC.)

Colorectal cancer is one of the most common cancers in the world. While colonoscopy is an effective screening technique, navigating an endoscope through the colon to detect polyps is challenging. A 3D map of the observed surfaces could enhance the identification of unscreened colon tissue and serve as a training platform. However, reconstructing the colon from video footage remains difficult. Learning-based approaches hold promise as robust alternatives, but necessitate extensive datasets. Establishing a benchmark dataset, the 2022 EndoVis sub-challenge SimCol3D aimed to facilitate data-driven depth and pose prediction during colonoscopy. The challenge was hosted as part of MICCAI 2022 in Singapore. Six teams from around the world and representatives from academia and industry participated in the three sub-challenges: synthetic depth prediction, synthetic pose prediction, and real pose prediction. This paper describes the challenge, the submitted methods, and their results. We show that depth prediction from synthetic colonoscopy images is robustly solvable, while pose estimation remains an open research question., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Danail Stoyanov reports financial support was provided by Medtronic plc. Danail Stoyanov reports a relationship with Odin Medical Ltd. that includes: equity or stocks. Laurence Lovat and Rawen Kader report a relationship with Olympus Corporation that includes: consulting or advisory., (Copyright © 2024. Published by Elsevier B.V.)

Limited studies have triangulated the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and systolic blood pressure (SBP), diastolic blood pressure (DBP) or hypertension risk utilizing both observational and Mendelian randomization (MR) approaches. We employed data from the Norwegian Trøndelag Health Study (HUNT) to conduct cross-sectional (n = 5854) and prospective (n = 3592) analyses, as well as one-sample MR (n = 86,324). We also used largest publicly available data for two-sample MR. Our cross-sectional analyses showed a 25 nmol/L increase in 25(OH)D was associated with a 1.73 mmHg decrease in SBP (95% CI - 2.46 to - 1.01), a 0.91 mmHg decrease in DBP (95% CI - 1.35 to - 0.47) and 19% lower prevalence of hypertension (OR 0.81, 95% CI 0.74 to 0.90) after adjusting for important confounders. However, these associations disappeared in prospective analyses. One-sample and two-sample MR results further suggested no causal relationship between serum vitamin D levels and blood pressure or hypertension risk in the general population., (© 2024. The Author(s).)

Mental state language (MSL) is an important mechanism through which children learn about their social world and place within it. Previous research has suggested that parents may use MSL differently towards children based on their child's gender. However, findings are inconsistent. This scoping review explores the consistency of reported differences in parents' MSL use as a function of children's gender while exploring the methodological variables that may provide insights into these differences. Based on a review of the 27 studies included, 12 found a significant relationship between child gender and parents' MSL, while the remaining did not. The included studies used a range of methodological approaches to elicit MSL. This scoping review allows researchers and practitioners to reflect upon assumptions regarding the associations between child gender and parents' MSL. Further, we call for the use of diverse and informed approaches when studying these associations from a developmental perspective in the future., (© 2024 The Author(s). British Journal of Developmental Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Aims: The aim of this study was to describe the prevalence and patterns of neuropathic pain over one year in a cohort of patients with chronic post-surgical pain at three months following total knee arthroplasty (TKA)., Methods: Between 2016 and 2019, 363 patients with troublesome pain, defined as a score of ≤ 14 on the Oxford Knee Score pain subscale, three months after TKA from eight UK NHS hospitals, were recruited into the Support and Treatment After Replacement (STAR) clinical trial. Self-reported neuropathic pain and postoperative pain was assessed at three, nine, and 15 months after surgery using the painDETECT and Douleur Neuropathique 4 (DN4) questionnaires collected by postal survey., Results: Symptoms of neuropathic pain were common among patients reporting chronic pain at three months post-TKA, with half reporting neuropathic pain on painDETECT (191/363; 53%) and 74% (267/359) on DN4. Of those with neuropathic pain at three months, half continued to have symptoms over the next 12 months (148/262; 56%), one-quarter had improved (67/262; 26%), and for one-tenth their neuropathic symptoms fluctuated over time (24/262; 9%). However, a subgroup of participants reported new, late onset neuropathic symptoms (23/262; 9%). Prevalence of neuropathic symptoms was similar between the screening tools when the lower cut-off painDETECT score (≥ 13) was applied. Overall, mean neuropathic pain scores improved between three and 15 months after TKA., Conclusion: Neuropathic pain is common in patients with chronic pain at three months after TKA. Although neuropathic symptoms improved over time, up to half continued to report painful neuropathic symptoms at 15 months after TKA. Postoperative care should include screening, assessment, and treatment of neuropathic pain in patients with early chronic postoperative pain after TKA., Competing Interests: This study is funded by the National Institute for Health Research (NIHR) (Programme Grant for Applied Research (Grant Reference Number RP-PG-0613-20001)). The study was also supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. J. Bruce is supported by NIHR Research Capability Funding via University Hospitals Coventry and Warwickshire. R. Gooberman-Hill is Co-Chair of the UK Committee on Research Integrity. N. Howells reports payment from Smith & Nephew for lectures related to knee surgery, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Joint Operations, all of which are unrelated to this study. E. Lenguerrand reports institutional payments from NIHR PGfAR, HQIP, NIHR AI, NIHR RfPB, CeramTec, and Tommy's National Centre for Improving Maternity Care, all of which are unrelated to this study. E. Lenguerrand is also an unfunded member of the NIHR Steering Committee, an unfunded College of Experts member for Versus Arthritis, Bone and Joint Infection Registry Scientific Committee Member, SouthWest-Frenchay Research Ethics Committee member, and NIHR Grant Committee member. V. Wylde is Chair of trial steering committees, unrelated to this study., (© 2024 Bertram et al.)

The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%-79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets., (© 2024. The Author(s).)

Diseases diagnosed in adulthood may have antecedents throughout (including prenatal) life. Gaining a better understanding of how exposures at different stages in the lifecourse influence health outcomes is key to elucidating the potential benefits of disease prevention strategies. Mendelian randomisation (MR) is increasingly used to estimate causal effects of exposures across the lifecourse on later life outcomes. This systematic literature review explores MR methods used to perform lifecourse investigations and reviews previous work that has utilised MR to elucidate the effects of factors acting at different stages of the lifecourse. We conducted searches in PubMed, Embase, Medline and MedRXiv databases. Thirteen methodological studies were identified. Four studies focused on the impact of time-varying exposures in the interpretation of "standard" MR techniques, five presented methods for repeat measures of the same exposure, and four described methodological approaches to handling multigenerational exposures. A further 127 studies presented the results of an applied research question. Over half of these estimated effects in a single generation and were largely confined to the exploration of questions regarding body composition. The remaining mostly estimated maternal effects. There is a growing body of research focused on the development and application of MR methods to address lifecourse research questions. The underlying assumptions require careful consideration and the interpretation of results rely on select conditions. Whilst we do not advocate for a particular strategy, we encourage practitioners to make informed decisions on how to approach a research question in this field with a solid understanding of the limitations present and how these may be affected by the research question, modelling approach, instrument selection, and data availability., (© 2023. The Author(s).)

Background: Conservative therapies are recommended as initial treatment for male lower urinary tract symptoms. However, there is a lack of evidence on effectiveness and uncertainty regarding approaches to delivery., Objective: The objective was to determine whether or not a standardised and manualised care intervention delivered in primary care achieves superior symptomatic outcome for lower urinary tract symptoms to usual care., Design: This was a two-arm cluster randomised controlled trial., Setting: The trial was set in 30 NHS general practice sites in England., Participants: Participants were adult men (aged ≥ 18 years) with bothersome lower urinary tract symptoms., Interventions: Sites were randomised 1 : 1 to deliver the TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions trial intervention or usual care to all participants. The TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions intervention comprised a standardised advice booklet developed for the trial from the British Association of Urological Surgeons' patient information sheets, with patient and expert input. Patients were directed to relevant sections by general practice or research nurses/healthcare assistants following urinary symptom assessment, providing the manualised element. The healthcare professional provided follow-up contacts over 12 weeks to support adherence to the intervention., Main Outcome Measures: The primary outcome was the validated patient-reported International Prostate Symptom Score 12 months post consent. Rather than the minimal clinically important difference of 3.0 points for overall International Prostate Symptom Score, the sample size aimed to detect a difference of 2.0 points, owing to the recognised clinical impact of individual symptoms., Results: A total of 1077 men consented to the study: 524 in sites randomised to the intervention arm ( n = 17) and 553 in sites randomised to the control arm ( n = 13). A difference in mean International Prostate Symptom Score at 12 months was found (adjusted mean difference of -1.81 points, 95% confidence interval -2.66 to -0.95 points), with a lower score in the intervention arm, indicating less severe symptoms. Secondary outcomes of patient-reported urinary symptoms, quality of life specific to lower urinary tract symptoms and perception of lower urinary tract symptoms all showed evidence of a difference between the arms favouring the intervention. No difference was seen between the arms in the proportion of urology referrals or adverse events. In qualitative interviews, participants welcomed the intervention, describing positive effects on their symptoms, as well as on their understanding of conservative care and their attitude towards the experience of lower urinary tract symptoms. The interviews highlighted that structured, in-depth self-management is insufficiently embedded within general practitioner consultations. From an NHS perspective, mean costs and quality-adjusted life-years were similar between trial arms. The intervention arm had slightly lower mean costs (adjusted mean difference of -£29.99, 95% confidence interval -£109.84 to £22.63) than the usual-care arm, and a small gain in quality-adjusted life-years (adjusted mean difference of 0.001, 95% confidence interval -0.011 to 0.014)., Conclusions: The intervention showed a small, sustained benefit for men's lower urinary tract symptoms and quality of life across a range of outcome measures in a UK primary care setting. Qualitative data showed that men highly valued the intervention. Intervention costs were marginally lower than usual-care costs. Limitations of the study included that trial participants were unmasked, with limited diversity in ethnicity and deprivation level. Additional research is needed to assess the applicability of the intervention for a more ethnically diverse population.., Trial Registration: This trial is registered as ISRCTN11669964., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/90/03) and is published in full in Health Technology Assessment ; Vol. 28, No. 13. See the NIHR Funding and Awards website for further award information.

The detrimental health effects of smoking are well-known, but the impact of regular nicotine use without exposure to the other constituents of tobacco is less clear. Given the increasing daily use of alternative nicotine delivery systems, such as e-cigarettes, it is increasingly important to understand and separate the effects of nicotine use from the impact of tobacco smoke exposure. Using a multivariable Mendelian randomisation framework, we explored the direct effects of nicotine compared with the non-nicotine constituents of tobacco smoke on health outcomes (lung cancer, chronic obstructive pulmonary disease [COPD], forced expiratory volume in one second [FEV-1], forced vital capacity [FVC], coronary heart disease [CHD], and heart rate [HR]). We used Genome-Wide Association Study (GWAS) summary statistics from Buchwald and colleagues, the GWAS and Sequencing Consortium of Alcohol and Nicotine, the International Lung Cancer Consortium, and UK Biobank. Increased nicotine metabolism increased the risk of COPD, lung cancer, and lung function in the univariable analysis. However, when accounting for smoking heaviness in the multivariable analysis, we found that increased nicotine metabolite ratio (indicative of decreased nicotine exposure per cigarette smoked) decreases heart rate (b = -0.30, 95% CI -0.50 to -0.10) and lung function (b = -33.33, 95% CI -41.76 to -24.90). There was no clear evidence of an effect on the remaining outcomes. The results suggest that these smoking-related outcomes are not due to nicotine exposure but are caused by the other components of tobacco smoke; however, there are multiple potential sources of bias, and the results should be triangulated using evidence from a range of methodologies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Khouja 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.)

Objectives: To estimate the cost-effectiveness of a primary care intervention for male lower urinary tract symptoms (LUTS) compared with usual care., Design: Economic evaluation alongside a cluster randomised controlled trial from a UK National Health Service (NHS) perspective with a 12-month time horizon., Setting: Thirty NHS general practice sites in England., Participants: 1077 men aged 18 or older identified in primary care with bothersome LUTS., Interventions: A standardised and manualised intervention for the treatment of bothersome LUTS was compared with usual care. The intervention group (n=524) received a standardised information booklet with guidance on conservative treatment for LUTS, urinary symptom assessment and follow-up contacts for 12 weeks. The usual care group (n=553) followed local guidelines between general practice sites., Measures: Resource use was obtained from electronic health records, trial staff and participants, and valued using UK reference costs. Quality-adjusted life-years (QALYs) were calculated from the EQ-5D-5L questionnaire. Adjusted mean differences in costs and QALYs and incremental net monetary benefit were estimated., Results: 866 of 1077 (80.4%) participants had complete data and were included in the base-case analysis. Over the 12-month follow-up period, intervention and usual care arms had similar mean adjusted costs and QALYs. Mean differences were lower in the intervention arm for adjusted costs -£29.99 (95% CI -£109.84 to £22.63) while higher in the intervention arm for adjusted QALYs 0.001 (95% CI -0.011 to 0.014). The incremental net monetary benefit statistic was £48.01 (95% CI -£225.83 to £321.85) at the National Institute for Health and Care Excellence UK threshold of £20 000 per QALY. The cost-effectiveness acceptability curve showed a 63% probability of the intervention arm being cost-effective at this threshold., Conclusions: Costs and QALYs were similar between the two arms at 12 months follow-up. This indicates that the intervention can be implemented in general practice at neutral cost., Trial Registration Number: ISRCTN11669964., Competing Interests: Competing interests: Prof Marcus Drake reports personal fees from Astellas and Pfizer, outside the submitted work. Dr Jonathan Rees is chair of the Primary Care Urology Society which has received non-promotional sponsorship for annual meetings from Ferring, Astellas, Neotract and IMedicare. He has also received speaker fees from Astellas Pharmaceuticals. Prof Hashim Hashim reports personal fees from Medtronic, Astellas, Allergan and Boston Scientific, outside the submitted work. Prof Athene Lane reports receiving funding for the clinical trials unit (CTU) of which she was co-director, and is currently an active member on the NIHR CTU Standing Advisory Committee. Dr Matthew Ridd has been on several NIHR committees including the Systematic Reviews NIHR Cochrane Incentive Awards, HTA General Committee, Evidence Synthesis Programme Grants Committee, NIHR Incentive Awards Committee and is currently on the Evidence Synthesis Programme Advisory Group. Stephanie MacNeill is an active member of the HTA General Committee., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objective: To determine whether a standardised and manualised care intervention in men in primary care could achieve superior improvement of lower urinary tract symptoms (LUTS) compared with usual care., Design: Cluster randomised controlled trial., Setting: 30 National Health Service general practice sites in England., Participants: Sites were randomised 1:1 to the intervention and control arms. 1077 men (≥18 years) with bothersome LUTS recruited between June 2018 and August 2019: 524 were assigned to the intervention arm (n=17 sites) and 553 were assigned to the usual care arm (n=13 sites)., Intervention: Standardised information booklet developed with patient and expert input, providing guidance on conservative and lifestyle interventions for LUTS in men. After assessment of urinary symptoms (manualised element), general practice nurses and healthcare assistants or research nurses directed participants to relevant sections of the manual and provided contact over 12 weeks to assist with adherence., Main Outcome Measures: The primary outcome was patient reported International Prostate Symptom Score (IPSS) measured 12 months after participants had consented to take part in the study. The target reduction of 2.0 points on which the study was powered reflects the minimal clinically important difference where baseline IPSS is <20. Secondary outcomes were patient reported quality of life, urinary symptoms and perception of LUTS, hospital referrals, and adverse events. The primary intention-to-treat analysis included 887 participants (82% of those recruited) and used a mixed effects multilevel linear regression model adjusted for site level variables used in the randomisation and baseline scores., Results: Participants in the intervention arm had a lower mean IPSS at 12 months (adjusted mean difference -1.81 points, 95% confidence interval -2.66 to -0.95) indicating less severe urinary symptoms than those in the usual care arm. LUTS specific quality of life, incontinence, and perception of LUTS also improved more in the intervention arm than usual care arm at 12 months. The proportion of urology referrals (intervention 7.3%, usual care 7.9%) and adverse events (intervention seven events, usual care eight events) were comparable between the arms., Conclusions: A standardised and manualised intervention in primary care showed a sustained reduction in LUTS in men at 12 months. The mean difference of -1.81 points (95% confidence interval -0.95 to -2.66) on the IPSS was less than the predefined target reduction of 2.0 points., Trial Registration: ISRCTN Registry ISRCTN11669964., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the UK National Institute for Health and Care Research Health Technology Assessment (HTA) programme for the submitted work; MJD reports personal fees from Astellas and Pfizer, outside the submitted work. JR is chair of the Primary Care Urology Society, which has received non-promotional sponsorship for annual meetings from Ferring, Astellas, Neotract, and IMedicare. He has also received speaker fees from Astellas Pharmaceuticals. HH reports personal fees from Medtronic, Astellas, Allergan, and Boston Scientific, outside the submitted work. JAL reports receiving funding for the clinical trials unit (CTU) of which she was codirector, and she was a member on the National Institute for Health and Care Research (NIHR) CTU Standing Advisory Committee. MJR has been on several NIHR committees, including the Systematic Reviews NIHR Cochrane Incentive Awards, HTA General Committee, Evidence Synthesis Programme Grants Committee, and NIHR Incentive Awards Committee, and is currently on the Evidence Synthesis Programme Advisory Group. SJM is an active member of the HTA General Committee., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

The relationship between adiposity and grip strength (GS) is complex. We investigated whether one pathway through which adiposity affects GS was via chronic inflammation. 367,583 UK Biobank participants had body mass index (BMI), waist-hip-ratio (WHR), C-reactive protein (CRP) and GS data. Univariable Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) analyses (using inverse variance weighted (IVW) weighted median estimates (WME) and MR-Egger models) estimated total, direct and indirect effects of adiposity traits on GS using genetic instruments for BMI and WHR (exposures) and CRP (mediator). Observational findings suggested higher BMI was associated with stronger grip, e.g., in males, per standard deviation (SD) higher BMI, GS was higher by 0.48 kg (95% confidence interval(CI):0.44,0.51), independent of CRP. For males MR estimates were directionally consistent; for females, estimates were consistent with the null. Observational findings for WHR suggested that higher WHR was associated with weaker grip. In multivariable MR-IVW analyses, effects in males were consistent with the null. In females, there were consistent effects such that higher WHR was associated with stronger grip, e.g., 1-SD higher WHR was associated with 1.25 kg (MVMR-Egger; 95% CI:0.72,1.78) stronger grip, independent of CRP. Across sexes and adiposity indicators, CRP's mediating role was minor. Greater adiposity may increase GS in early old age, but effects vary by sex and adiposity location. There was no evidence that inflammation mediated these effects., (© 2023. Springer Nature Limited.)