Search results
Found 9838 matches for
Alcohol Use and Risk of Dementia in Diverse Populations: Evidence from Cohort, Case-control and Mendelian randomization Approaches
Objectives To investigate the relationship between alcohol consumption and dementia. Design Prospective cohort and case-control analyses combined with linear and nonlinear Mendelian randomization. Setting Two large-scale population-based cohorts: the US Million Veteran Program and UK Biobank. Genetic analyses used summary statistics from genome-wide association studies (GWAS). Participants 559,559 adults aged 56–72 years at baseline were included in observational analyses (mean follow-up: 4 years in the US cohort; 12 years in the UK cohort). Genetic analyses used summary data from multiple large GWAS consortia (2.4 million participants). Main outcome measures Incident all-cause dementia, determined through health record linkage, and genetic proxies. Results During follow-up, 14,540 participants developed dementia and 48,034 died. Observational phenotype-only analyses revealed U-shaped associations between alcohol and dementia risk: higher risk was observed among non-drinkers, heavy drinkers (>40 drinks per week; hazard ratio [HR]=1.41, 95% confidence interval[CI] 1.15-1.74), and those with alcohol use disorder (AUD) (HR=1.51[CI 1.42-1.60]) compared with light drinkers. In contrast, Mendelian randomization genetic analysis identified a monotonic increase in dementia risk with greater alcohol consumption. A one standard deviation increase in log-transformed drinks per week was associated with a 15% dementia increase (IVW OR=1.15[1.03-1.27]). A two-fold increase in AUD prevalence was associated with a 16% increase in dementia risk (inverse-variance weighted [IVW] OR=1.16[1.03-1.30]). Alcohol intake increased dementia, but individuals who developed dementia also experienced a decline in alcohol intake over time, suggesting reverse causation—where early cognitive decline leads to reduced alcohol consumption— underlies the supposed protective alcohol effects in observational studies. Conclusions These findings provide evidence for a relationship between all types of alcohol use and increased dementia risk. While correlational observational data suggested a protective effect of light drinking, this could be in part attributable to reduced drinking seen in early dementia; genetic analyses did not support this, suggesting that any level of alcohol consumption may contribute to dementia risk. Public health strategies that reduce the prevalence of alcohol use disorder could potentially lower the incidence of dementia by up to 16%.
Summary of taxonomy changes ratified by the International Committee on Taxonomy of Viruses from the Plant Viruses Subcommittee, 2025.
In March 2025, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote, newly proposed taxa were added to those under the mandate of the Plant Viruses Subcommittee. In brief, 1 new order, 3 new families, 6 new genera, 2 new subgenera and 206 new species were created. Some taxa were reorganized. Genus Cytorhabdovirus in the family Rhabdoviridae was abolished and its taxa were redistributed into three new genera Alphacytorhabdovirus, Betacytorhabdovirus and Gammacytorhabdovirus. Genus Waikavirus in the family Secoviridae was reorganized into two subgenera (Actinidivirus and Ritunrivirus). One family and four previously unaffiliated genera were moved to the newly established order Tombendovirales. Twelve species not assigned to a genus were abolished. To comply with the ICTV mandate of a binomial format for virus species, eight species were renamed. Demarcation criteria in the absence of biological information were defined in the genus Ilarvirus (family Bromoviridae). This article presents the updated taxonomy put forth by the Plant Viruses Subcommittee and ratified by the ICTV.
Substituting sitting with standing and walking in free-living conditions improves daily glucose concentrations in South Asian adults living with overweight/obesity.
BackgroundControlled laboratory studies have demonstrated that breaking up sitting can reduce postprandial glucose in South Asian adults. This study examined the effects of substituting sitting with standing and walking on interstitial glucose in South Asian individuals under free-living conditions.MethodsSouth Asian adults (n = 14 [50% male]; body mass index 26.5 ± 0.8 kg·m-2) aged 41 ± 3 years completed two, 4-day regimens in a counter-balanced order: (1) SIT (restrict walking and standing to ≤ 1 h/day each) and (2) SITless (substitute ≥ 5 h/day of sitting with ≥ 3 h of standing and ≥ 2 h of walking, and interrupt sitting every 30 min). Interstitial glucose was measured using Flash glucose monitoring. Sitting and physical activity were measured with the activPAL3. Outcomes were compared between regimens using linear mixed models.ResultsInterstitial glucose net incremental area under the curve (iAUC) for waking hours was lower by - 9.2 mmol L-1·16 h-1 (95% Confidence Interval [CI]: - 18.1, - 0.3) in SITless than SIT (p = 0.04), while lunch postprandial glucose iAUC was significantly lower by -1.0 mmol L-1.2 h-1 (95% CI - 1.8, 0.2) in SITless (p = 0.02). There were no significant differences in other 24 h or 16 h glucose metrics (p ≥ 0.06). Compared to SIT, sitting was lower by - 3.6 h/day (95% CI - 4.9, - 2.3) in SITless (p ConclusionsSubstituting sitting with standing and walking under free-living conditions can be used to effectively attenuate glycaemia during waking hours, but not across 24 h, in South Asian adults.Clinical trial registrationNCT04645875..
Active Monitoring for AtriaL FIbrillation (AMALFI): rationale, protocol, and pilot for a pragmatic, randomized, controlled trial of remote screening for asymptomatic atrial fibrillation.
ObjectivesScreening for asymptomatic atrial fibrillation (AF) might reduce cardioembolic strokes and screening for asymptomatic AF is recommended by some international guidelines. However, any impact of AF screening on clinical outcomes depends on a sustained increase in AF detection and anticoagulation use over time than would have occurred with routine care alone, highlighting the importance of long-term studies to generate the evidence needed to justify establishing formal screening programs. AMALFI aims to establish the long-term efficacy and cost-effectiveness of remote screening for asymptomatic AF in older individuals at increased risk of stroke using a non-invasive 14-day continuous ECG monitoring patch in UK primary care. This paper describes the study protocol and baseline characteristics of included participants.MethodsAMALFI (ISCRTN 15544176) recruited individuals aged ≥65 years with CHA2DS2-VASc score ≥3 (men) or ≥4 (women) with no previous diagnosis of AF/atrial flutter from 27 UK primary care practices. Participants were randomized to ECG monitoring (Zio XT, iRhythm Technologies; intervention) or usual care (control). Those allocated to ECG monitoring were sent and returned the patch by mail. After wear, participants returned the patch to the device manufacturer where ECG data were analysed via a deep-learned AI algorithm and confirmed by qualified cardiographic technicians. A final report was sent to study investigators, and those indicating AF or other arrhythmias considered by the study team to be clinically actionable were communicated to general practitioners (GPs) immediately by secure email. Additionally, GPs were notified by mail of the presence or absence of AF episodes ≥30 seconds, and of the burden of AF for each of their participants who wore a patch. The letter included signposting to relevant guidelines and findings were managed at the GP's discretion. Participants allocated to the control group were not required to undertake any action. The primary study outcome is the rate of new AF detection at 2.5 years, with secondary outcomes including time spent with a known AF diagnosis at 5 years of follow-up, and analyses of these outcomes by pre-defined age and sex sub-groups. Exploratory outcomes will assess randomized assessments of time to AF detection within 2.5 and 5 years after randomization, time spent with a known AF diagnosis up to 2.5 years from randomization, and anticoagulation exposure within 2.5 and 5 years after randomization. Other exploratory long-term assessments include randomized comparisons of numbers and proportions of hospitalisations (total and cardiovascular), ischaemic stroke, major bleed, and death (all-cause and cardiovascular) in both groups.ResultsBetween 2019 and 2022, AMALFI randomized 5,040 people in England to screening versus usual care using mail-based invitations. Participant mean age was 77±6 years, with 2360 (46.8%) female; median CHA2DS2-VASc score was 4 (IQR 3-5). Follow-up data on AF diagnosis, other clinical diagnoses, prescription of oral anticoagulation and other medications, primary care encounters, referrals for secondary care, and clinical events are currently being collected from primary care practices, complemented via linkage to national-level databases including dispensing data, hospital admissions, and death records. AF detection rates will be assessed at 2.5 and 5 years after randomization, and long-term cost-effectiveness will be analysed.ConclusionAMALFI will provide randomized evidence on the actionable time window of opportunity for intervention generated by remote screening for asymptomatic AF in the UK using a non-invasive long-term continuous monitoring ECG patch, and the cost-effectiveness of this approach. Such data may further elucidate existing patterns of routine AF diagnosis and management, and provide important insights to guide future discussions into nationwide AF screening in the UK. AMALFI results will be reported in 2025 and 2027.
Molnupiravir or nirmatrelvir-ritonavir plus usual care versus usual care alone in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
BackgroundMolnupiravir and nirmatrelvir-ritonavir are oral antivirals that have shown efficacy in preventing disease progression in outpatients with COVID-19. We aimed to evaluate these treatments for patients hospitalised with COVID-19 pneumonia, for whom data on these antivirals are scarce.MethodsThe RECOVERY trial is a randomised, controlled, open-label, adaptive platform trial testing treatments for COVID-19. In this study we report the molnupiravir and nirmatrelvir-ritonavir comparisons from the RECOVERY trial. In each comparison, participants aged 18 years and older were randomly allocated (1:1) to the relevant antiviral (5 days of molnupiravir 800 mg twice daily or 300 mg nirmatrelvir and 100 mg ritonavir twice daily) in addition to usual care, or to usual care alone. The molnupiravir comparison was conducted at 75 hospitals in the UK, two in Nepal, and two in Indonesia; the nirmatrelvir-ritonavir comparison was conducted at 32 hospitals in the UK. Participants could take part in both comparisons. The primary outcome was 28-day mortality, and secondary outcomes were time to discharge alive from hospital and progression to invasive ventilation or death. Analysis was by intention to treat. Both comparisons were stopped because of low recruitment. This study is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.FindingsFrom Jan 24, 2022, to May 24, 2023, 923 participants were recruited to the molnupiravir comparison (445 allocated to molnupiravir and 478 to usual care), and from March 31, 2022, to May 24, 2023, 137 participants were recruited to the nirmatrelvir-ritonavir comparison (68 allocated to nirmatrelvir-ritonavir and 69 to usual care). More than three-quarters of participants were vaccinated and had antispike antibodies at randomisation, and more than two-thirds were receiving other SARS-CoV-2 antivirals. In the molnupiravir comparison, 74 (17%) participants allocated to molnupiravir and 79 (17%) allocated to usual care died within 28 days (hazard ratio [HR] 0·93 [95% CI 0·68-1·28], p=0·66). In the nirmatrelvir-ritonavir comparison, 13 (19%) participants allocated to nirmatrelvir-ritonavir and 13 (19%) allocated to usual care died within 28 days (HR 1·02 [0·47-2·23], p=0·96). In neither comparison was there evidence of any difference in the duration of hospitalisation or the proportion of participants progressing to invasive ventilation or death.InterpretationAdding molnupiravir or nirmatrelvir-ritonavir to usual care was not associated with improvements in clinical outcomes. However, low recruitment meant a clinically meaningful benefit of treatment could not be ruled out, particularly for nirmatrelvir-ritonavir.FundingUK Research and Innovation (UK Medical Research Council), the National Institute for Health and Care Research, and the Wellcome Trust.
ACES: AUTOMATIC COHORT EXTRACTION SYSTEM FOR EVENT-STREAM DATASETS
Reproducibility remains a significant challenge in machine learning (ML) for healthcare. Datasets, model pipelines, and even task or cohort definitions are often private in this field, leading to a significant barrier in sharing, iterating, and understanding ML results on electronic health record (EHR) datasets. We address a significant part of this problem by introducing the Automatic Cohort Extraction System (ACES) for event-stream data. This library is designed to simultaneously simplify the development of tasks and cohorts for ML in healthcare and also enable their reproduction, both at an exact level for single datasets and at a conceptual level across datasets. To accomplish this, ACES provides: (1) a highly intuitive and expressive domain-specific configuration language for defining both dataset-specific concepts and dataset-agnostic inclusion or exclusion criteria, and (2) a pipeline to automatically extract patient records that meet these defined criteria from real-world data. ACES can be automatically applied to any dataset in either the Medical Event Data Standard (MEDS) or Event Stream GPT (ESGPT) formats, or to any dataset in which the necessary task-specific predicates can be extracted in an event-stream form. ACES has the potential to significantly lower the barrier to entry for defining ML tasks in representation learning, redefine the way researchers interact with EHR datasets, and significantly improve the state of reproducibility for ML studies using this modality. ACES is available at: https://github.com/justin13601/aces.
Large-scale epidemiology of opisthorchiasis in 21 provinces in Thailand based on diagnosis by fecal egg examination and urine antigen assay and analysis of risk factors for infection
Introduction Infection with the carcinogenic fish-borne trematode Opisthorchis viverrini, known as opisthorchiasis, is a major cause of biliary cancer (cholangiocarcinoma). Despite decades of disease prevention and control in Thailand, the parasite remains endemic. Here we apply a novel antigen assay for mass screening of opisthorchiasis and compare the prevalence against the conventional examination and analyze risk factors associated with current O. viverrini infection. Materials and methods We conducted a large-scale cross-sectional survey to assess transmission of O. viverrini in the North, Northeast, and Eastern regions of Thailand. We screened randomly selected people (age 15 years and over) in 23 sub-districts, within 21 provinces, with a target sample size of 1,000 per sub-district. Each participant was screened for multiple helminth infection by fecal examination (quantitative formalin-ethyl acetate concentration technique; FECT), and the antigen assay by monoclonal antibody-based enzyme-linked immunosorbent assay (ELISA) was applied to urine samples to detect O. viverrini. We collected risk factors for O. viverrini infection using standardized questionnaire surveys. The data were analyzed with regression models which correlated individual-level explanatory variables against i) infection status with O. viverrini and ii) the intensity of infection, as measured by the antigen assay or FECT. Findings Of the 20,322 individuals enrolled, 19,465 provided urine samples for antigen detection by ELISA and 18,929 provided fecal samples for examination by FECT. The urine antigen assay revealed an overall opisthorchiasis prevalence of 50.3%, a fourfold increase over the 12.2% prevalence detected by FECT. Marked spatial heterogeneity was observed, with antigen‐based prevalence estimates ranging from 22.2% to 71.4% and several localities exceeding 60%. When assessed against a composite reference standard (combined ELISA and FECT), the urine ELISA yielded a diagnostic sensitivity of 91.6%, compared with 21.9% for FECT. We found a positive correlation between fecal egg counts and the concentration of worm antigen in urine across study sites. The ratio between the prevalence of O. viverrini observed by the antigen assay and FECT was high in provinces with a low mean number of O. viverrini eggs, and the ratio approached unity as the mean eggs per gram of stool (EPG) increased. Similar aggregate distribution patterns of fecal egg counts (EPG) and urine antigen concentrations suggest that the urine assay has potential for quantitative diagnostic evaluations. When analyzing individual-level risk factors, we further identified age, sex, occupation, a history of prior treatment with praziquantel, history of O. viverrini examination, and raw fish consumption as predictive of infection with O. viverrini, while a higher education level and certain occupations emerged as protective factors. Conclusions and recommendations Application of the antigen assay to diagnose O. viverrini infection yielded a four-fold higher prevalence than the fecal egg examination, with the highest difference in low endemicity regions, which suggests that previous surveys may have underestimated the extent of opisthorchiasis in Thailand. Given the ease of urine sample collection, our study highlights the potential for application of the antigen assay as a new tool in the control of opisthorchiasis.
Extensive transmission and variation in a functional receptor for praziquantel resistance in endemic Schistosoma mansoni.
Mass-drug administration (MDA) of human populations using praziquantel monotherapy has become the primary strategy for controlling and potentially eliminating the major neglected tropical disease schistosomiasis. To understand how long-term MDA impacts schistosome populations, we analysed whole-genome sequence data of 570 Schistosoma mansoni samples (and the closely related outgroup species, S. rodhaini) from eight countries incorporating both publicly-available sequence data and new parasite material. This revealed broad-scale genetic structure across countries but with extensive transmission over hundreds of kilometres. We characterised variation across the transient receptor potential melastatin ion channel, TRPMPZQ, a target of praziquantel, which has recently been found to influence praziquantel susceptibility. Functional profiling of TRPMPZQ variants found in endemic populations identified four mutations that reduced channel sensitivity to praziquantel, indicating standing variation for resistance. Analysis of parasite infrapopulations sampled from individuals pre- and post-treatment identified instances of treatment failure, further indicative of potential praziquantel resistance. As schistosomiasis is targeted for elimination as a public health problem by 2030 in all currently endemic countries, and even interruption of transmission in selected African regions, we provide an in-depth genomic characterisation of endemic populations and an approach to identify emerging praziquantel resistance alleles.
Pathfinder studies: a novel tool for process mapping data-driven health research to build global research capacity.
BackgroundThere is vast global inequality regarding where health research happens, who leads the research, and who benefits from the evidence. Globally, wealthier nations drive and influence data-driven research and how it is structured institutionally. Key barriers to high-quality research being undertaken in and led by low-resource settings are well reported. These barriers persist, thereby perpetuating a lack of locally generated data and/or evidence to tackle diseases that bring the greatest burden. Our aim was to design a tool to capture best practices in the production of data-driven health research, to advance both quality and quantity of research being conducted where it is needed most.MethodsAn expert group of senior global health researchers from Asia, Africa, Europe, and Latin America and the Caribbean (LAC) convened to discuss potential solutions to addressing this imbalance in both quality and quantity of global health research. This study documents how a novel approach was developed, informed by this discussion, to support research teams in low-resource settings. The new approach, called "Pathfinder", is a process-mapping tool wherein teams document key steps of their research projects flow to produce quality data and subsequent studies.ResultsThe Pathfinder methodology is a novel tool to be used alongside planned studies to guide teams through each step of their research, from setting their research question, to identifying the best methods needed to complete each step, to translating research outputs into impactful policy and practice. It is a standardized framework, which can be applied or adapted to specific settings for research teams track to key steps, challenges, solutions, and tools throughout their planned study's process. Pathfinders can also be applied to studies that have already been completed, retroactively documenting their key components. Several global research institutes are piloting the Pathfinder methodology.ConclusionsPathfinders can help inform future studies by capturing best practices, thereby removing barriers to research, and addressing global inequality in this domain. Specifically, Pathfinders can help identify the methods and skills needed for teams to produce safe, ethical, and accurate data-driven health research.
Heart Rate Profiles During Exercise and Incident Parkinson's Disease.
ObjectiveTo determine whether established heart rate parameters of exercise, related to cardiac autonomic function, are associated with incident Parkinson's disease, independent of both clinical and autonomic prodromal features.MethodsA study of UK Biobank participants who performed a standardized bicycle exercise test (2009-2013), followed until November 2022, and analyzed in January 2024, was carried out. Heart rate increase from rest to exercise, and heart rate decrease from peak exercise to recovery were associated with incident Parkinson's disease. Multivariable adjustment was performed both for clinical characteristics and for prodromal non-cardiac autonomic features.ResultsA total of 69,288 eligible participants (men 48%, mean age 56.8 years [SD 8.2 years]) were followed for 12.5 years: among the 319 (0.5%) who developed Parkinson's disease, recognized prodromal markers (constipation, bladder dysfunction) were more common at baseline. The median lag time to diagnosis was 9.3 years (interquartile range 4.4). Both heart rate increase (37.5 [SD 11.5] vs 40.8 [SD 12.4] b.p.m., p InterpretationCollectively, this suggests that cardiac autonomic involvement precedes clinically manifest Parkinson's disease, and that heart rate recovery might serve as a quantitative prodromal marker. ANN NEUROL 2025.
Characterising ongoing brain aging and baseline effects from cross-sectional data
“Brain age delta” is the difference between age estimated from brain imaging data and actual age. Positive delta in adults is normally interpreted as implying that an individual is aging (or has aged) faster than the population norm, an indicator of unhealthy aging. Unfortunately, from cross-sectional (single timepoint) imaging data, it is impossible to know whether a single individual’s positive delta reflects a state of faster ongoing aging, or an unvarying trait (in other words, a “historical baseline effect” in the context of the population being studied). However, for a cross-sectional dataset comprising many individuals, one could attempt to disambiguate varying aging rates from fixed baseline effects. We present a method for doing this, and show that for the common approach of estimating a single delta per subject, baseline effects are likely to dominate. If instead one estimates multiple biologically distinct modes of brain aging, we find that some modes do reflect aging rates varying strongly across subjects. We demonstrate this, and verify our modelling, using longitudinal (two timepoint) data from 4,400 participants in UK Biobank. In addition, whereas previous work found incompatibility between cross-sectional and longitudinal brain aging, we show that careful data processing does show consistency between cross-sectional and longitudinal results.
A Primer on Inference and Prediction With Epidemic Renewal Models and Sequential Monte Carlo.
Renewal models are widely used in statistical epidemiology as semi-mechanistic models of disease transmission. While primarily used for estimating the instantaneous reproduction number, they can also be used for generating projections, estimating elimination probabilities, modeling the effect of interventions, and more. We demonstrate how simple sequential Monte Carlo methods (also known as particle filters) can be used to perform inference on these models. Our goal is to acquaint a reader who has a working knowledge of statistical inference with these methods and models and to provide a practical guide to their implementation. We focus on these methods' flexibility and their ability to handle multiple statistical and other biases simultaneously. We leverage this flexibility to unify existing methods for estimating the instantaneous reproduction number and generating projections. A companion website SMC and epidemic renewal models provides additional worked examples, self-contained code to reproduce the examples presented here, and additional materials.
Perturbations in the blood metabolome up to a decade before prostate cancer diagnosis in 4387 matched case-control sets from the European Prospective Investigation into Cancer and Nutrition.
Measuring pre-diagnostic blood metabolites may help identify novel risk factors for prostate cancer. Using data from 4387 matched case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we investigated the associations of 148 individual metabolites and three previously defined metabolite patterns with prostate cancer risk. Metabolites were measured by liquid chromatography-mass spectrometry. Multivariable-adjusted conditional logistic regression was used to estimate the odds ratio per standard deviation increase in log metabolite concentration and metabolite patterns (OR1SD) for prostate cancer overall, and for advanced, high-grade, aggressive. We corrected for multiple testing using the Benjamini-Hochberg method. Overall, there were no associations between specific metabolites or metabolite patterns and overall, aggressive, or high-grade prostate cancer that passed the multiple testing threshold (padj <0.05). Six phosphatidylcholines (PCs) were inversely associated with advanced prostate cancer diagnosed at or within 10 years of blood collection. metabolite patterns 1 (64 PCs and three hydroxysphingomyelins) and 2 (two acylcarnitines, glutamate, ornithine, and taurine) were also inversely associated with advanced prostate cancer; when stratified by follow-up time, these associations were observed for diagnoses at or within 10 years of recruitment (OR1SD 0.80, 95% CI 0.66-0.96 and 0.76, 0.59-0.97, respectively) but were weaker after longer follow-up (0.95, 0.82-1.10 and 0.85, 0.67-1.06). Pattern 3 (8 lyso PCs) was associated with prostate cancer death (0.82, 0.68-0.98). Our results suggest that the plasma metabolite profile changes in response to the presence of prostate cancer up to a decade before detection of advanced-stage disease.