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We present a genome assembly from an individual female Andrena bicolor (Gwynne's mining bee; Arthropoda; Insecta; Hymenoptera; Andrenidae). The genome sequence is 351.7 megabases in span. Most of the assembly is scaffolded into 5 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 21.02 kilobases in length.
We study the volume of rigid loop-O(n) quadrangulations with a boundary of length 2p in the non-generic critical regime, for all n ∈ ( 0 , 2 ] . We prove that, as the half-perimeter p goes to infinity, the volume scales in distribution to an explicit random variable. This limiting random variable is described in terms of the multiplicative cascades of Chen et al. (Ann Inst Henri Poincaré D 7(4):535-584, 2020), or alternatively (in the dilute case) as the law of the area of a unit-boundary γ -quantum disc, as determined by Ang and Gwynne (Ann Inst Henri Poincaré D 57(1): 1-53, 2021), for suitable γ . Our arguments go through a classification of the map into several regions, where we rule out the contribution of bad regions to be left with a tractable portion of the map. One key observable for this classification is a Markov chain which explores the nested loops around a size-biased vertex pick in the map, making explicit the spinal structure of the discrete multiplicative cascade. We stress that our techniques enable us to include the boundary case n = 2 , that we define rigorously, and where the nested cascade structure is that of a critical branching random walk. In that case the scaling limit is given by the limit of the derivative martingale and is inverse-exponentially distributed, which answers a conjecture of Aïdékon and Da Silva (Probab Theory Relat Fields 183(1):125-166, 2022).
Bleaney et al 2025 have shown there is widespread variation in UK oesophageal radiotherapy practice (1). This variation is in all stages of the radiotherapy pathway and brings into focus the need for a concise summary of current best practice. An attempt to summarise best practice and priorities for research was published in 2013 by Gwynne et al. (2). In this article, developments in oesophageal radiotherapy in the UK over the past decade are summarised and current best practice is reviewed. The role of radiotherapy in oesophageal cancer management and aspects of radiotherapy planning from target volume delineation to motion management, image-guided radiotherapy, choice of organs at risk dose constraints, and use of protons are examined. This includes the opportunity to discuss potential areas of development that may become standard clinical practice in the next 5-10 years, for example, adaptive radiotherapy, the integration of magnetic resonance imaging (MRI), and the use of moderate hypofractionation. The importance of quality assurance and imaging for response assessment are reviewed, and priorities for future research are determined. With an established track record of high-quality UK oesophageal RT trials, the UK upper gastrointestinal clinical oncology community is well placed to develop new trials and further improve outcomes for oesophageal cancer patients, and this article summarises current best practice and research priorities for oesophageal radiotherapy in the UK.
To determine whether the screening age for atrial fibrillation (AF) should be lowered for Indigenous Australians with the goal of reducing risk of stroke and other health burdens. Systematic review of medical databases identified 24 studies reporting outcome measures: AF incidence/prevalence, age of AF occurrence/diagnosis, cardiovascular risk factors and stroke risk. Risk of bias was evaluated using the Joanna Briggs Institute quality appraisal tools. Meta-analysis of mean age of AF onset was performed. An expert panel reviewed the evidence and formed consensus recommendations regarding screening for AF for Indigenous Australians. MEDLINE, Embase, Scopus, Cochrane, CINAHL, Australian Indigenous HealthInfoNet and grey literature. The review yielded five key findings. Indigenous Australians when compared with non-Indigenous Australians have: (i) higher AF rates at every age group, and meta-analysis showed onset of AF for Indigenous people at 15.9 years (95% CI, 11.5-20.4), younger than for other Australians; (ii) higher prevalence of cardiovascular risk factors; (iii) higher stroke rates (38%-47% vs. 10%-15% of all strokes occur before age of 55 years), higher mortality and other adverse outcomes after stroke and the nationally age standardised risk ratio of death from AF was 1.8 for 1997-2022; (iv) less likelihood of receiving optimal treatment; and (v) greater cost of care for stroke rehabilitation. The evidence supports an amendment to the AF guideline to opportunistically screen Indigenous Australians from at least age 55 years, and when AF is found, follow guideline recommendations for management of rate, rhythm, stroke prevention and concomitant risk factors/comorbidities. Further, the logistics of care should be considered when deciding on the localised care pathway. National implementation of these recommendations should minimise missed diagnoses and ensure timely, accessible and appropriate care/treatment. Prospective registration with PROSPERO (CRD42024514586) on 13 May 2024.
Pain can profoundly impact motor functioning to support self-preservation, yet its influence on the interaction between tactile input and corticospinal excitability (CSE) remains unclear. Across two experiments, a short- and long-latency afferent inhibition (AI) paradigm examined (i) whether tactile AI is modulated in the presence of tonic pain and (ii) the effect of pain on CSE in the presence of tactile afferent stimulation. In experiment 1, a single electrotactile stimulus (0.2- or 0.4-ms duration) was delivered to the index finger at one of six intervals (15 to 160 ms) before transcranial magnetic stimulation (TMS) over the ipsilateral first dorsal interosseous (FDI) hotspot. In experiment 2, the same procedure was tested during moderate, tonic forearm heat pain. Both experiments showed significant AI at 25, 35, and 160 ms delays, with facilitation at 60 ms. This effect was not influenced by the duration of afferent stimulation (experiment 1) nor by tonic heat pain (experiment 2). However, CSE was significantly reduced in painful compared to painless conditions (P = 0.021, η2p = 0.132), indicating that while tonic pain modulates CSE, tactile afferent inhibition is unaffected. These findings show an inhibitory effect of pain on motor output that, in this context, occurs alongside preserved tactile-motor interactions.
The primary somatosensory cortex (S1) has long been implicated in tactile perception, yet its precise role in conscious tactile detection remains uncertain. The current study investigated the causal and time-specific involvement of S1 in tactile detection using single-pulse transcranial magnetic stimulation (spTMS). In two experiments, spTMS was applied over contralateral S1, an active control site (inferior parietal lobe; IPL), or under a sham condition at short (25 and 75 ms; Experiment 1) or longer (130 ms; Experiment 2) intervals following electrotactile stimulation of the finger. Participants performed a go/no-go detection task at sensory threshold. In Experiment 1, tactile sensitivity was significantly reduced following early S1 stimulation compared with both active control and sham conditions. In contrast, no such effect was observed at a later timepoint in Experiment 2. Self-reported TMS-related distraction ratings did not account for the observed sensitivity differences, suggesting sensitivity-specific modulation by early TMS rather than general task disruption. Together, these findings support a causal role for early S1 activity in conscious tactile detection. We propose that disruption at this early stage impairs initial encoding of tactile input, thereby attenuating subsequent perceptual awareness. Overall, the results underscore the critical contribution of S1 in conscious tactile detection and are compatible with recent accounts in which conscious tactile perception emerges from processing within a distributed neural network.
We investigated mechanisms underlying circulating DNA damage across the gastro-oesophageal reflux disease (GORD), Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) spectrum using the lymphocyte micronucleus (MN) assay. MN frequency (MN%) was quantified in lymphocytes from healthy volunteers (HVs), GORD, BO and OAC patients, alongside plasma biomarkers of inflammation and oxidative stress. Ex vivo challenge assays assessed lymphocyte responses to hydrogen peroxide (H2O2), vinblastine and the bile acid deoxycholic acid (DCA). Tissue-based NF-κB expression was also correlated with MN levels. OAC patients exhibited significantly elevated MN% compared with HVs (p < 0.001), GORD (p < 0.001) and BO (p = 0.016). OAC lymphocytes showed increased sensitivity to vinblastine relative to HVs (p = 0.025) and GORD patients (p = 0.033). Higher baseline MN% correlated with reduced inducible MN formation following H2O2 or DCA, suggesting altered oxidative stress responses. MN% also associated with plasma 8-OHdG, IL-8 and 2'3'-cGAMP, and with reduced oesophageal tissue IκB, indicating activation of oxidative and cGAS-STING/NF-κB signalling. These findings highlight systemic aneugenic and oxidative stress processes that contribute to lymphocyte MN formation in OAC and suggest that MN% may serve as a minimally invasive indicator of inflammation-linked genomic instability. Further investigation is needed to determine its relevance to OAC progression.
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Familial hypercholesterolemia (FH) is a common genetic condition that causes hypercholesterolemia and increased risk for premature atherosclerotic cardiovascular disease (ASCVD). The prevalence, management, and consequences of genetically confirmed FH across the US are poorly understood. To identify genotype-positive FH in a national US cohort and describe its prevalence, consequences, and lipid-lowering management. In the All of Us (AoU) cohort study, whole-genome sequencing and phenotypic data from US adult participants enrolled between May 2018 and July 2022 were analyzed to identify and study genotype-positive FH. Data were analyzed between May 2024 and May 2025. FH variants (pathogenic or likely pathogenic) in LDLR, APOB, and PCSK9 genes were manually classified with standard criteria. The primary outcomes were demographic characteristics, lipid measurements, ASCVD, and prevalence of FH and noncarriers in AoU. Lipid management was then characterized among individuals with FH through lipid-lowering therapy (LLT) documentation and guideline-based low-density lipoprotein cholesterol (LDL-C) targets. A total of 245 388 participants were included, with mean (SD) age of 56.5 (16.9) years and 145 563 female participants (59.3%). Genotype-positive FH was identified in 865 participants (prevalence, 0.35%; 95% CI, 0.33%-0.38%; 1 in 287 participants). Among individuals with genotype-positive FH, 349 (40%) were prescribed statins, and 332 (38.4%) had LDL-C measured. Coronary artery disease, peripheral artery disease, and transient ischemic attack or stroke were significantly more common in genotype-positive FH carriers compared to noncarriers (coronary artery disease: odds ratio [OR], 2.91; 95% CI, 2.34-3.58; peripheral artery disease: OR, 1.51; 95% CI, 1.16-1.96; and transient ischemic attack or stroke: OR, 1.54; 95% CI, 1.11-2.09). Only 30.1% of participants positive for FH variants had LDL-C less than 100 mg/dL at their most recent result compared to 48.2% of noncarriers (P < .001). Of the total participants with ASCVD and LLT prescription, significantly fewer individuals with FH met the secondary prevention LDL-C target (<70 mg/dL; 19.33% vs 43.12%; P < .001) compared to noncarriers. This cohort study finds a prevalence of genotype-positive FH in All of Us participants of 0.35% (95% CI, 0.33%-0.38%), with state-level variation. A minority of individuals with genotype-positive FH met guideline-recommended LDL-C targets and had increased rates of ASCVD.
Indigenous Australians experience a disproportionate burden of type 2 diabetes mellitus and cardiovascular disease. While clinician-led, community-based exercise programs are effective in general populations, limited peer-reviewed evidence is available describing culturally adapted exercise interventions with Indigenous Australians that transparently reports governance, cultural adaptation, and theoretical design. This paper reports the co-design and development of tools for the Preventing Indigenous Cardiovascular Disease and Diabetes through Exercise (PrIDE) study, an adaptation of the Beat It program that incorporates wearable technology. Using the Co-design Health Research and Innovation Model, four tools were developed with Indigenous governance through a Consumer Advisory Group and a project-specific Consumer User Panel. Three tools were culturally adapted-the PrIDE Exercise Program, the Strong Spirit Strong Self self-efficacy assessment, and Keep Your Heart Strong educational materials-and a newly developed tool, the Success Plan. Cultural adaptations were prospectively documented using the Model for Adaptation Design and Impact, and all tools were assessed using the Aboriginal and Torres Strait Islander Quality Appraisal Tool. Behavior change mechanisms were mapped using the COM-B model. This paper provides transparent documentation of culturally adapted theory-informed tool development to support reproducibility and knowledge translation. The evaluation of effectiveness, acceptability, and psychometric properties will be reported following PrIDE implementation.
Anchoring is a prominent judgment bias which causes people's estimates of uncertain quantities to assimilate towards recently encountered values. Here, we ask whether items can cause anchoring - will the question "Does a handheld flashlight torch cost more or less than a laptop?" induce anchoring in the same way as "Does a handheld flashlight torch cost more or less than £500"? We present evidence from ten studies suggesting that it can, and that perceptions of the value of the anchor item (e.g., the laptop) are also anchored. In other words, estimates for both items being compared assimilate towards each other. We also find that low value items are anchored more strongly than high value items. Overall, there is evidence for a small anchoring-by-items effect (Hedge's g = 0.25), which we suggest previous studies may have been underpowered to detect. Among existing theories of anchoring, Selective Accessibility would appear to provide the best account of the data.
Clinical trials must ensure the quality of both standard and interventional treatments to rigorously evaluate potential benefits, avoid adverse outcomes, and maintain the integrity of results. Quality assurance (QA) endeavours to achieve this and is fundamental to all clinical trial elements, though variation exists between specialties. For radiotherapy (RT) in the UK, the NIHR-funded national Radiotherapy Trials Quality Assurance (RTTQA) group has centralised trial RTQA processes across the RT pathway enabling a robust, consistent, efficient and multidisciplinary approach, replacing piecemeal, trial-by-trial application for QA funding. Meanwhile, the surgical community are moving towards standardised QA processes but has yet to achieve this universally. For SACT, though the importance of QA is recognised, under-reporting persists, and the increasing number and diversity of agents used pose challenges. QA in pathology and radiology is also growing as the complexity of clinical trials increases. Internationally, the EORTC has developed QA processes across domains, but uncertainty and challenges in QA implementation remain. Additionally, while the benefits of trial QA are now recognised, the potential negative effects of QA need to be recognised. Using illustrative examples from contemporary oesophago-gastric cancer studies, we further explore the current status of clinical trial QA across these specialties.
Auto-contouring systems are rapidly becoming more widely used for radiotherapy treatment planning. There is an acknowledged need for formal guidance to help healthcare professionals understand how to safely adopt this technology. The Royal College of Radiologists Artificial Intelligence in Clinical Oncology working group established a multi-disciplinary group of national experts in artificial intelligence and radiotherapy quality assurance (QA). This group has produced consensus recommendations for the safe use of the technology. These include model selection, clinical commissioning, day-to-day QA, and post-implementation monitoring. Other factors such as the impact on the multi-disciplinary team, education, and training are also considered. The healthcare professional approving auto-contours for use will have overall responsibility, and it is therefore of utmost importance that they have a good understanding of the risks of auto-contouring and how contours should be assessed to mitigate these risks. This guidance aims to enable healthcare professionals acting as operators of a medical device to understand what they need to know about auto-contouring, to facilitate safe adoption of this technology.
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Hand grip strength is an established indicator of individual health status and is used as a biomarker for predicting mortality, disability, and disease risks. GripAble hand grip dynamometer offers a modernized approach to measuring grip strength with its digital and high-accuracy measurement system. This study aimed to (1) assess the interrater reliability of maximum grip strength (MGS) measurement and (2) establish GripAble's own gender-, age group- and hand-stratified normative MGS reference values of the adult UK population. Cross-sectional study design. Interrater reliability among three raters assessing 30 participants across diverse age groups was measured using the intraclass correlation. In the second study, 11 investigators gathered MGS data from 907 participants across diverse age groups and gender. The average, standard deviation, minimum, median, maximum, and percentiles of MGS were computed for each gender, age group, and hand (L/R). The relationship between MGS and age was examined using quantile regression analysis. Additionally, generalized linear model regression analysis was conducted to explore the influence of participants' demographics (gender, hand [L/R], hand length, hand circumference, age, weight, and height) on MGS. MGS measurements between raters showed excellent agreement (ICC(2,1) = 0.991, 95% confidence interval [0.98, 1.0]). The MGS and age relationship follows a curvilinear pattern, reaching a peak median MGS values of up to 20 kg between 30 and 49 years for females and up to 35 kg between 30 and 59 years for males. Subsequently, MGS declined as age advanced. Gender and hand (L/R) emerged as the primary factors influencing MGS, followed by hand length, hand circumference, age, weight, and height. The presented normative MGS reference values can be used for interpreting MGS measurements obtained from adults in the United Kingdom using GripAble. This study, along with previous studies on GripAble devices, confirms GripAble as a reliable and valid tool for measuring MGS.
Resistance to chemotherapy remains a major hurdle to the cure of patients with acute myeloid leukemia (AML). Recent studies indicate that a minority of malignant cells, termed drug-tolerant persisters (DTP), stochastically upregulate stress pathways to evade cell death upon acute exposure to chemotherapy without acquiring new genetic mutations. This chemoresistant state is transient and the cells return to the baseline state after removal of chemotherapy. Nevertheless, the mechanisms employed by DTP to resist chemotherapy are not well understood and it is largely unknown whether these mechanisms are also seen in patients receiving chemotherapy. Here, we used leukemia cell lines, primary AML patients' samples and samples from patients with AML receiving systemic chemotherapy to study the DTP state. We demonstrated that a subset of AML cells transiently increases membrane rigidity to resist killing due to acute exposure to daunorubicin and Ara-C. Upon removal of the chemotherapy, membrane rigidity returned to baseline and the cells regained chemosensitivity. Although resistant to chemotherapy, the increased membrane rigidity rendered AML cells more susceptible to T-cell-mediated killing. Thus, we identified a novel mechanism by which DTP leukemic cells evade chemotherapy and a strategy to eradicate these persistent cells.
There are nearly 500,000 cases of Lyme disease each year in the United States; 10%-20% of them result in the development of a debilitating chronic disease known as post-treatment Lyme disease. Existing standardized and modified two-tier tests (STT/MTT) suffer from poor detection rates in the first weeks of infection, where the antibody response, the basis of diagnosis, is developing but is not robust enough for detection. During this early window, false negative results are common, which leads to delayed treatment and increases the likelihood of developing severe symptoms. The InBios Lyme Detect Multiplex ELISA is a microarray-based assay designed to capture a set of commonly used diagnostic antibodies specific to Borrelia burgdorferi from human serum. The multiplex array captures common diagnostic antibodies, including those to C6, VlsE, and OspC, and has in-line controls. Diagnostic index scores are calculated from the relative abundance of controls and antibodies using a proprietary machine learning algorithm. The assay was evaluated here for reproducibility, accuracy, and performance. It was found to be reproducible using a group of 30 samples run in triplicate. The assay performed well in a blinded panel, correctly identifying all standard two-tier test-positive samples and controls while also detecting 21 of 79 samples that were clinically diagnosed but undetectable by standard Lyme serologic tests. There was one false positive from 66 look-alike disease samples and 146 healthy controls. The InBios assay has the potential to improve diagnostic sensitivity within the early weeks of infection while matching the specificity of current diagnostic tests. During initial Lyme disease infection, existing diagnostic tests have poor sensitivity, resulting in a high number of false-negative tests. This is due to the lag between infection and a robust immune response capable of being detected by such tests. With a multiplexed array of nine unique antibody targets specific for Borrelia burgdorferi, interpreted by a proprietary machine learning algorithm, the InBios Lyme Detect Multiplex ELISA has the potential to increase diagnostic sensitivity within the first few weeks of infection, reducing the number of false-negative tests. Improving diagnostic sensitivity during early infection would reduce the risk of developing severe symptoms, including post-treatment Lyme disease.
The SCOPE2 trial evaluates radiotherapy (RT) dose escalation for oesophageal cancer. We report findings from the accompanying RT quality assurance (RTQA) programme and identify recommendations for PROTIEUS, the next UK trial in oesophageal RT. SCOPE2's RTQA programme consisted of a pre-accrual and on-trial component. RTQA pre-accrual requirements included acceptable submission of 3D ± 4D benchmark contouring exercise(s) and a high-dose planning case. On-trial requirements for contouring and planning included prospective reviews (PRs) of each centre's first 3D ± 4D patient and all high-dose cases prior to formal safety review. Further PRs were at the RTQA team's discretion. Timely retrospective reviews (TRRs) were also undertaken for a random 10%. Submissions were assessed against pre-defined criteria and RT planning guidance document (RPGD). This study includes initial submissions only; subsequent resubmissions are not included in this analysis. For contouring, 30/64 (47%) pre-accrual submissions were approved. 38/64 (59%) contained ≥1 target volume (TV) unacceptable variation from protocol (UV), most commonly in CTVB and ITV. Organ-at-risk (OAR) contour review was undertaken in 28/64 (44%); 6/28 (21%) contained ≥1 UV, most commonly in heart and spinal cord. 82/126 (65%) on-trial submissions were approved. 47/126 (37%) contained ≥1 TV UV, most commonly in CTVB, GTV and ITV. For OARs, 30/126 (24%) contained ≥1 UV, most commonly in heart and lungs. On-trial contour submissions were significantly more likely to be approved than pre-accrual (p = 0.016). For planning, 32/43 (79%) pre-accrual plans were approved, those unacceptable were due to PTV coverage/conformity. 118/120 (98%) on-trial plans were approved, the remaining unacceptable were due to PTV coverage/conformity. No UVs in OAR dose constraints were observed. All on-trial submissions were approved following resubmission where necessary. Despite an RPGD, contouring atlas, and similar contouring protocols from preceding trials, the SCOPE2 RTQA programme demonstrates a high frequency of UVs. Our findings inform recommendations for future oesophageal RT trials.
Oesophageal squamous cell carcinoma is the predominant histopathological subtype of oesophageal cancer across the world, representing as many as 90% of all cases; however, within Western cohorts, it is a low-prevalence disease, and, as such, appropriately powered trials to establish a standard treatment paradigm in this population remain challenging. The aim of this study was to assess current practices and compare outcomes for patients with locally advanced oesophageal squamous cell carcinoma across the UK and Ireland. This was a retrospective multicentre cohort study of patients managed with curative intent for squamous cell carcinoma of the middle or distal oesophagus in 23 hospitals across the UK and Ireland. Consecutive patients diagnosed between 1 January 2012 and 31 December 2016 were included. This study included 1545 patients, of whom 923 (59.7%) received definitive chemoradiotherapy, 286 (18.5%) neoadjuvant chemotherapy + surgery, 218 (14.1%) neoadjuvant chemoradiotherapy + surgery, and 118 (7.6%) surgery alone. Neoadjuvant chemoradiotherapy + surgery was associated with significantly longer survival than neoadjuvant chemotherapy or definitive chemoradiotherapy (median 83.9 versus 27.8 versus 26.5 months). In propensity score-matched analysis of overall survival, patients receiving neoadjuvant chemoradiotherapy + surgery had significantly longer survival than those who had definitive chemoradiotherapy (median 56.8 versus 43.1 months; hazard ratio 0.39, 95% confidence interval 0.20 to 0.78; P < 0.001). This multicentre retrospective cohort study suggests that, despite a majority of patients being treated with definitive chemoradiotherapy, patients undergoing neoadjuvant chemoradiotherapy and surgery have improved survival compared with those receiving definitive chemoradiotherapy or neoadjuvant chemotherapy + surgery. In the absence of robust Western randomized clinical trial data, neoadjuvant chemoradiotherapy + surgery should be considered the standard for well selected patients fit for surgery.
Metformin is a widely used anti-diabetic drug. Several studies have suggested that metformin has anticancer activity in some malignancies, including prostate cancer. Metformin might also mitigate the adverse metabolic effects of androgen-deprivation therapy (ADT). We hypothesised that metformin might improve survival in patients with metastatic hormone-sensitive prostate cancer and reduce metabolic complications associated with ADT. The STAMPEDE multi-arm, multi-stage, randomised phase 3 trial recruited patients with high-risk locally advanced or metastatic adenocarcinoma of the prostate staged by conventional imaging with isotope bone and CT scanning. This publication reports findings for the most recent STAMPEDE research question, testing the addition of metformin to standard of care for non-diabetic (glycated haemoglobin [HbA1c] <48 mmol/mol [equivalent to <6·5%]) patients with metastatic disease with adequate renal function (glomerular filtration rate ≥45 ml/min/1·73 m2) and WHO performance status 0-2. This trial recruited from 112 hospitals in the UK and Switzerland to the STAMPEDE protocol. Patients were randomly allocated (1:1) to standard of care or standard of care plus metformin 850 mg twice daily. Random assignment was by telephone using minimisation with a random element of 20% (developed and maintained by the MRC Clinical Trials Unit at UCL), stratified for randomising hospital, age (<70 years vs ≥70 years), WHO performance status (0 vs 1 or 2), type of ADT, regular long-term use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs; yes vs no), pelvic nodal status (positive vs negative), planned radiotherapy (yes vs no), and planned docetaxel or androgen receptor pathway inhibitor (ARPI) use (docetaxel vs abiraterone, enzalutamide, or apalutamide vs none). Standard of care comprised ADT with or without radiotherapy and with or without docetaxel or ARPI. The primary outcome measure was overall survival, defined as the time to death from any cause, assessed in the intention-to-treat population. Safety was assessed in patients who started treatment. The trial is registered with ClinicalTrials.gov, NCT00268476 and ISRCTN, ISRCTN78818544. Between Sep 5, 2016, and Mar 31, 2023, 1874 patients with metastatic disease were randomly allocated to standard of care (n=938) or standard of care plus metformin (n=936). The median patient age was 69 years (IQR 63-73) and the median PSA was 84 ng/mL (24-352). 1758 (94%) of 1874 patients were newly diagnosed with metastatic disease and 116 (6%) were diagnosed with metachronous relapsing disease. 1543 (82%) of 1874 patients received ADT plus docetaxel and 52 (3%) received abiraterone, enzalutamide, or apalutamide. The median time to most recent case report form follow-up was 60 months (IQR 49-72). 473 deaths were reported in the standard of care group; median survival was 61·8 months (IQR 29·7 to not reached). There were 453 deaths in the metformin group; median survival was 67·4 months (32·5 to not reached; HR 0·91, 95% CI 0·80-1·03; p=0·15). Grade 3 or worse adverse events were reported in 487 (52%) of 938 patients in the standard of care group and 523 (57%) of 921 patients in the standard of care plus metformin group. 61 (7%) patients in the standard of care group and 84 (9%) patients in the standard of care plus metformin group reported at least one grade 3 or worse gastrointestinal adverse event; all other body systems showed no difference in grade 3 adverse events. There were six drug-related deaths in the standard of care group and one in the standard of care plus metformin group. We did not find significant evidence of an overall survival benefit of adding metformin to standard of care in the overall population of patients with metastatic hormone-sensitive prostate cancer. The side-effect profile of metformin was as expected and consisted mainly of diarrhoea. Adverse metabolic side-effects of ADT were significantly reduced in the metformin group compared with the standard of care group. Cancer Research UK, Prostate Cancer UK, and UK Research and Innovation Medical Research Council.