medRxiv : the preprint server for health sciences最新文献

{"title":"A Pan-Organ Vision-Language Model for Generalizable 3D CT Representations.","authors":"Cameron Beeche, Joonghyun Kim, Hamed Tavolinejad, Bingxin Zhao, Rakesh Sharma, Jeffrey Duda, James Gee, Farouk Dako, Anurag Verma, Colleen Morse, Bojian Hou, Li Shen, Hersh Sagreiya, Christos Davatzikos, Scott Damrauer, Marylyn D Ritchie, Daniel Rader, Qi Long, Tianlong Chen, Charles E Kahn, Julio Chirinos, Walter R Witschey","doi":"10.1101/2025.07.03.25330654","DOIUrl":"10.1101/2025.07.03.25330654","url":null,"abstract":"<p><p>Generalizable foundation models for computed tomographic (CT) medical imaging data are emerging AI tools anticipated to vastly improve clinical workflow efficiency. However, existing models are typically trained within narrow imaging contexts, including limited anatomical coverage, contrast settings, and clinical indications. These constraints reduce their ability to generalize across the broad spectrum of real-world presentations encountered in volumetric CT imaging data. We introduce Percival, a vision-language foundation model trained on over 400,000 CT volumes and paired radiology reports from more than 50,000 participants enrolled in the Penn Medicine BioBank. Percival employs a dual-encoder architecture with a transformer-based image encoder and a BERT-style language encoder, aligned via symmetric contrastive learning. Percival was validated on over 20,000 participants imaging data encompassing over 100,000 CT volumes. In image-text recall tasks, Percival outperforms models trained on limited anatomical windows. To assess Percival's clinical knowledge, we evaluated the biologic, phenotypic and prognostic relevance using laboratory-wide, phenome-wide association studies and survival analyses, uncovering a rich latent structure aligned with physiological measurements and disease phenotypes.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine on sexually transmitted and reproductive tract infections: results from a randomised trial in Uganda.","authors":"Harriet Adrama, Erin J Dela Cruz, Nida Ozarslan, Abel Kakuru, Bakar Odongo, Stephanie L Gaw, Jade Benjamin-Chung, Jimmy Kizza, Miriam Aguti, John Ategeka, Peter Olwoch, Miriam Nakalembe, Bishop Opira, Tamara D Clark, Moses R Kamya, Philip J Rosenthal, Grant Dorsey, Michelle E Roh","doi":"10.1101/2025.07.02.25330769","DOIUrl":"10.1101/2025.07.02.25330769","url":null,"abstract":"<p><strong>Background: </strong>In sub-Saharan Africa, sexually transmitted and reproductive tract infections (STIs/RTIs) are important, but underdiagnosed risk factors for adverse pregnancy outcomes. Sulfadoxine-pyrimethamine (SP), used for intermittent preventive treatment of malaria in pregnancy (IPTp), may reduce STI/RTI burden due to its antibacterial activity. We assessed the impact of IPTp regimens on STI/RTI prevalence at delivery and associations between these infections and adverse birth outcomes.</p><p><strong>Methods: </strong>We conducted a secondary analysis of a randomized controlled trial comparing monthly IPTp with SP, dihydroartemisinin-piperaquine (DP), or DP+SP among pregnant women in Uganda. Vaginal swabs collected at or near delivery were tested for <i>Chlamydia trachomatis</i>, <i>Neisseria gonorrhoeae</i>, <i>Trichomonas vaginalis</i>, and Group B <i>Streptococcus</i> (GBS) using GeneXpert; bacterial vaginosis was assessed using Nugent scoring. Log-binomial regression was used to compare STI/RTI prevalence by IPTp arm, using IPTp-DP as the reference arm. Multivariable Poisson regression with robust standard errors was used to evaluate associations between infections and preterm delivery, term low birthweight (LBW), overall LBW, and small-for-gestational age.</p><p><strong>Results: </strong>Among the 2265 participants assessed, IPTp-SP reduced prevalence of <i>C. trachomatis</i> by 80% (2.5% vs. 12.4%; RR=0.20, 95% CI: 0.12-0.33) and of GBS by 35% (7.7% vs 11.7%; RR=0.65, 95% CI: 0.43-0.99) compared to IPTp-DP. <i>C. trachomatis</i> was associated with increased preterm delivery risk (RR=1.86, 95% CI: 1.07-3.25) and GBS was associated with increased term LBW risk (RR=2.08, 95% CI: 1.06-4.08).</p><p><strong>Conclusions: </strong>Monthly IPTp-SP reduced the prevalence of <i>C. trachomatis</i> and GBS. These infections were associated with adverse birth outcomes, highlighting the potential non-malarial benefits of IPTp-SP.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a consensus extension of the estimands framework for cluster randomised trials (CRT-estimands): results from an international Delphi study.","authors":"Brennan C Kahan, Melanie Bahti, Dongquan Bi, Frank Bretz, Gary S Collins, Andrew Copas, Michael O Harhay, Fan Li, Catherine L Auriemma","doi":"10.1101/2025.07.03.25330799","DOIUrl":"10.1101/2025.07.03.25330799","url":null,"abstract":"<p><strong>Background: </strong>Estimands are increasingly used in randomised trials to clarify research objectives. The ICH E9(R1) addendum sets out five attributes necessary to describe a well-defined estimand. However, the addendum was primarily developed for individually randomised trials. There is growing recognition that estimand descriptions for cluster randomised trials, where groups of individuals are randomised, may require specification of additional considerations. We conducted a Delphi study to assess stakeholder views on additional items for inclusion in a consensus extension of the ICH E9(R1) for cluster randomised trials.</p><p><strong>Methods: </strong>We invited experts in estimands and cluster randomised trials to participate in a modified Delphi process to identify critical items for describing estimands in cluster randomised trials. The research team generated an initial list of eight items and definitions. Across three Delphi rounds, panellists scored items, suggested additional items, and provided open-ended rationales for responses. The consensus threshold was set as ≥70% of respondents rating an attribute as \"essential\" (i.e., score of ≥7 on a 9-point Likert scale) and <15% of respondents rating the item as \"not important\" (i.e., a score of ≤3).</p><p><strong>Results: </strong>Seventy-three (52%) invited individuals participated in Round 1. Response rates were 85% in Round 2 and 95% in Round 3. Panellists included largely statisticians (62, 85%) and clinical trialists (18, 25%). After Round 1, one additional item was added for Round 2 inclusion. After Round 3, five items met consensus criteria: how individuals and clusters are weighted, population of clusters, exposure time of clusters and individuals to the intervention, whether treatment effects are marginal or cluster-specific, and handling of cluster-level intercurrent events.</p><p><strong>Conclusions: </strong>This Delphi identified expert consensus around the importance of several key items for defining estimands in cluster randomised trials. These results can inform the development of consensus guidance outlining the set of attributes to describe when defining estimands for cluster randomised trials.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functionality and phenotype of T cells in patients with varying severity of acute dengue and metabolic status.","authors":"Heshan Kuruppu, Malithi De Silva, Chathumini Dissanayake, Radandee Rathnapriya, Ananda Wijewickrama, Damayanthi Idampitiya, Chandima Jeewandara, Graham Ogg, Gathsaurie Neelika Malavige","doi":"10.1101/2025.07.02.25330735","DOIUrl":"10.1101/2025.07.02.25330735","url":null,"abstract":"<p><strong>Background: </strong>Currently the role of dengue virus (DENV) specific T cell responses in disease pathogenesis and protection are not well understood, including potential differences in those who have obesity. We sought to investigate the functionality and phenotype of T cells in patients with acute dengue fever (DF) or dengue haemorrhagic fever (DHF).</p><p><strong>Methods: </strong>T cell function was assessed in patients with DF (n=50) and DHF (n=12), recruited within ≤4 days of illness and again on day 5 to 7, using 109 peptides representing CD8+ epitopes and 90 peptides targeting CD4+ T cell epitopes. Phenotypic analysis was in DF (n=21) and DHF patients (n=21), recruited between days 6-8 since onset of illness, by multicolor flow cytometry.</p><p><strong>Results: </strong>The frequency of ex vivo IFNγ ELISpot responses to both the CD4+ and CD8+ peptides pools significantly increased from the first to second time point in patients with DF (p<0.0001) but not with DHF. The frequency of ex vivo IFNγ ELISpot responses to CD4+ (p=0.001) and CD8+ peptides pools (p=0.0002) also significantly increased from the first to second time point in lean patients compared obese patients. Cutaneous lymphocyte associated antigen (CLA) expression was significantly higher in the CD8+ T cell subset in patients with DF and DHF compared to HC and these differences were most significant in CD8+CD45RA- T cells. CD8+CD45RA-CLA+ T cells consisted of >50% of the T cells in 9/21 patients with DHF, with 92.7% expressing CD38. CLA expression was highest in the CD8+CD45RA- of obese individuals, which was significantly higher compared to lean individuals (p=0.01). CD27 and CD127 were both significantly downregulated in patients with DHF compared to DF, with ICOS expression being significantly higher in CD8+ T cells in DHF.</p><p><strong>Discussion: </strong>Patients with DHF and obese individuals had impaired T cell functionality. Activated and skin homing CD8+ T cells were associated with DHF, with downregulation of CD27 and CD127. Therefore, the role of skin homing T cells, which have impaired functionality in disease pathogenesis, should be further investigated.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene-environment interactions contribute to blood pressure variation across global populations.","authors":"Khushi Goda, Noah Klimkowski Arango, Francesco Tiezzi, Trudy F C Mackay, Fabio Morgante","doi":"10.1101/2025.07.02.25330727","DOIUrl":"10.1101/2025.07.02.25330727","url":null,"abstract":"<p><p>Understanding the interplay between genetic architecture and environmental exposures is essential for elucidating the biological basis of complex traits such as blood pressure (BP). Although gene-by-environment interactions (G×E) have been previously shown to contribute to BP variation, their role in multi-ancestry cohorts remains underexplored. We hypothesize that G×E effects may explain additional variance in BP traits across diverse populations, where environmental exposures and genetic backgrounds are more heterogeneous. Here, we present an evaluation of the importance of G×E on systolic (SP), diastolic (DP), and pulse pressure (PP) in a multi-ancestry subset of 25,000 individuals from the UK Biobank. We considered 23 lifestyle variables as the environmental exposures, and estimated variance components attributed to demographics, population structure, genetic effects, environmental effects and gene-by-environment interactions. Our results revealed that G×E accounts for 7% of variance in DP, 4% in SP, and 3% in PP. Notably, these estimates exceed those previously reported (2% for all BP traits) in a UK Biobank analysis restricted to White British individuals using similar lifestyle variables and methodology. However, accounting for G×E did not improve prediction accuracy in two cross-validation schemes. We also tried to uncover individual interactions affecting each trait by conducting G×E-GWAS. Although no interaction surpassed genome-wide significance, we annotated suggestive hits and uncovered genes enriched in blood pressure-relevant pathways. Our study suggests that environmental heterogeneity and diverse genetic backgrounds in multi-ancestry cohorts may amplify the role of G×E, underscoring the importance of diverse populations in capturing the full spectrum of trait architecture.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal and cord-blood inflammatory markers and BDNF in diabetic vs non-diabetic pregnancies.","authors":"Michael P Wendel, Heather L Moody, Eric R Siegel, Hari Eswaran, Shannon Rose","doi":"10.1101/2025.07.02.25330741","DOIUrl":"10.1101/2025.07.02.25330741","url":null,"abstract":"<p><strong>Background: </strong>Maternal diabetes is associated with increased systemic inflammation and has been linked to adverse neonatal outcomes, including developmental delays that persist into early childhood. In this study we sought to characterize and compare the maternal levels and fetal cord-blood levels of the inflammatory markers C-reactive protein (CRP) and IL-6, as well as the neurotrophin brain-derived neurotrophic factor (BDNF) between mothers with pre-gestational Type-1 diabetes (T1DM) or Type-2 diabetes (T2DM), and non-diabetic controls (nonDM).</p><p><strong>Methods: </strong>A prospective cohort design was employed, analyzing biomarker concentrations during the third trimester in 98 pregnant women ages 18-40 years of age including 16 participants with T1DM, 49 participants with T2DM and 33 control participants matched for gestational age and body mass index (BMI) to control for confounding factors such as obesity. Plasma samples were collected at 28-30 weeks, 34-36 weeks, delivery, and from cord blood. The biomarkers CRP, IL-6, and BDNF were measured using standardized assays, and concentrations were compared among groups using including ANOVA.</p><p><strong>Results: </strong>In T2DM mothers, CRP levels were 2x higher in the third trimester as compared to nonDM controls. In T1DM mothers, IL6 levels were 3x lower than nonDM controls and 3.4x lower than T2DM. While not reaching statistical significance, cord-blood levels of IL6 were higher in T2DMs than other groups (p=0.052). When examining BDNF levels, no differences were observed between groups.</p><p><strong>Conclusions: </strong>This study emphasizes the importance of addressing inflammation-related risks in pregnancies affected by diabetes. Targeted interventions may mitigate adverse neonatal outcomes and improve health trajectories. Future research should explore direct pathways linking maternal inflammation to fetal neural function to inform clinical strategies.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accelerated frontal grey matter atrophy in relapsing remitting multiple sclerosis.","authors":"Max Korbmacher, Ingrid Anne Lie, Kristin Wesnes, Eric Westman, Thomas Espeseth, Ole Andreas Andreassen, Hanne Harbo, Gro Owren Nygaard, Lars Tjelta Westlye, Stig Wergeland, Kjell-Morten Myhr, Einar August Høgestøl, Øivind Torkildsen","doi":"10.1101/2025.07.01.25330635","DOIUrl":"10.1101/2025.07.01.25330635","url":null,"abstract":"<p><strong>Background: </strong>Grey matter (GM) atrophy has been suggested as the most accurate marker of neurodegeneration in multiple sclerosis (MS) progression. At the same time, few studies have examined regional atrophy longitudinally and how it correlates to different clinical domains.</p><p><strong>Methods: </strong>We used two relapsing remitting MS (RRMS) cohorts (N=250, T₁w-scans=940) sampled for up to 12 years to map grey matter atrophy localisation, compare the examined patterns with six age-matched healthy control (HC) cohorts (N=31,427, T₁w-scans=32,793), and associate the observed atrophy pattern with disability, cognitive decline and fatigue, measured with the Expanded Disability Status Scale (EDSS), Paced Auditory Serial Addition Test (PASAT), and Fatigue Severity Scale (FSS).</p><p><strong>Results: </strong>The strongest, replicable significant brain atrophy patterns in RRMS were found in the frontal lobes, specifically, in the superior frontal cortices (β_age≤-0.27), pars orbitalis (β_age≤-0.25), and thalami (β_age≤-0.20). Across samples, such atrophy patterns were more pronounced than in a sample of more 20-year older HCs in the right superior frontal cortex (Z>2.41, p<0.009), right caudal middle frontal cortex (Z>2.08, p<0.019), right caudate (Z>2.09, p<0.019), and the left frontal pole (Z>2.42, p<0.008). The replicability of associations between volumetrics and clinical outcomes was limited to EDSS and the left superior frontal cortex (β_EDSS≤-0.09) and the pars orbitalis (β_EDSS≤-0.09).</p><p><strong>Conclusion: </strong>Our findings indicate accelerated, early GM atrophy in people with RRMS, specific to the frontal lobes, which is more pronounced than in older HCs and uniquely related to disability-progression. These results suggest frontal lobe atrophy as an imaging biomarker in future MS-trials.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two weeks of cumulative tendon load monitored by insole sensors is associated with plantar flexor function in Achilles tendinopathy.","authors":"Ke Song, Michelle P Kwon, Andy K Smith, Ryan T Pohlig, Karin Grävare Silbernagel, Josh R Baxter","doi":"10.1101/2025.07.01.25330442","DOIUrl":"10.1101/2025.07.01.25330442","url":null,"abstract":"<p><p>Tendon loading dictates rehabilitation outcomes in Achilles tendinopathy but is difficult to track in the real world. In this study, we used instrumented insole sensors to monitor Achilles tendon load for two weeks in fifteen individuals with Achilles tendinopathy, who also completed assessments of their plantar flexor strength, dynamic function, and survey-based outcomes. We used insole data to estimate two types of cumulative Achilles tendon load: overall (≥0.3×body weight) and high-level load (≥3×body weight). We determined Pearson correlations between (1) overall and high-level tendon loads, (2) plantar flexor moment, power, work, (3) heel raise height, repetitions, countermovement jump height, and (4) self-reported symptoms and activity. Overall cumulative tendon load moderately correlated to isometric plantar flexor moment (r = 0.543) and weakly to isokinetic and dynamic functions (0.128-0.413). Cumulative high-level tendon load strongly correlated to heel raise height (0.687) and fast isokinetic moment (0.625), and moderately to other functional measures (0.470-0.592). Symptoms weakly correlated to overall (0.392) and moderately to high-level load (0.436). Self-reported activity weakly correlated to overall (0.297) and strongly to high-level load (0.617). Stronger associations with the high-level Achilles tendon load than the overall load suggest that clinical function assessments provide insight into the real-world performance of high-loading activities. In contrast, the disconnect between overall tendon loading and plantar flexor function may explain the variability in recovery outcomes. Self-reported activity and standard heel raises represent high-level tendon load well, yet they do not always suggest functional deficit. Sensor-monitored tendon load shows promise as a new biomarker for real-world plantar flexor function in Achilles tendinopathy.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomics reveals eleven obesity endotypes with distinct biological and phenotypic signatures.","authors":"Min Seo Kim, Minku Song, Hoyoung Kim, Sanghyeon Park, Injeong Shim, Soohyun Lim, Beomsu Kim, Xingyu Chen, Yang Sui, So Mi Jemma Cho, Satoshi Koyama, Jae-Seung Yun, Pradeep Natarajan, Patrick T Ellinor, Akl C Fahed, Hong-Hee Won","doi":"10.1101/2025.06.30.25330607","DOIUrl":"10.1101/2025.06.30.25330607","url":null,"abstract":"<p><p>Obesity, a leading global risk factor for cardiometabolic conditions, arises from multifaceted and biologically complex mechanisms^1,2. To elucidate the full-dimensional genetic architecture underlying obesity, we conducted a multi-trait, multi-ancestry, genome-wide association study (GWAS) by combining genetic data on anthropometric traits (body mass index, waist circumference, waist-to-hip ratio, and hip circumference) from >2 million ancestrally diverse participants. We identified 743 significant loci, including 86 previously unreported loci, representing a 13% increase in locus discovery. We leveraged machine learning and multimodal data integration to identify the likely effector genes at obesity-associated loci. We performed genetic clustering on biologically enriched multi-trait GWAS data based on Bayesian non-negative matrix factorisation³ in the UK Biobank (<i>n</i> = 408,816) and identified 11 obesity clusters (endotypes). In addition to recapitulating the endotypes that drive classical metabolically healthy and unhealthy obesity phenotypes, we identified nine additional obesity endotypes driven by insulin physiology, beta cell compensation, immune dysregulation, neuroendocrine regulation, and lipid metabolism. Each cluster not only was characterised by unique biomarker features and clinical trajectories but also showed cluster-specific enrichment in tissue and single-cell regulatory regions. To facilitate the clinical and research adoption of obesity endotyping, we created partitioned polygenic scores for the 11 obesity endotypes, which we externally validated their performance using the Mass General Brigham Biobank (<i>n</i> = 48,377), and made publicly available in the PGS Catalog. This study marks a step forward in both the biological resolution and clinical translation of heterogeneity in obesity, implicating that obesity prevention and management should be as diverse as the condition itself.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of bile acids, amino acids, and glycerophospholipid metabolites with food-allergic outcomes in children on peanut oral immunotherapy.","authors":"Jennifer N Styles, Justin K Wang, Ananya Raman, Michael Lu, Jessica A Lasky-Su, Brian P Vickery, Wesley A Burks, Tim Moran, Mike Kulis, Wayne Shreffler, Edwin H Kim, Yamini V Virkud","doi":"10.1101/2025.07.01.25330651","DOIUrl":"https://doi.org/10.1101/2025.07.01.25330651","url":null,"abstract":"<p><strong>Background: </strong>Food allergen immunotherapy can induce remission of food allergies in certain individuals, but the mechanisms underlying this remission are largely unknown. Prior work has identified differences in immunomodulatory metabolites between older children who develop remission versus non-remission on oral immunotherapy (OIT). Here we aim to characterize metabolomic changes during OIT in young children to and validate patterns of immunomodulatory metabolites previously observed.</p><p><strong>Methods: </strong>Untargeted plasma metabolomic profiling was performed on samples from the DEVIL peanut OIT trial (n=41, ages 9-36 months). Remission status was determined by oral food challenges conducted at the end-of-therapy and the end of a 1-month avoidance period. Linear and logistic regression models were used to detect differences in individual metabolites over time on OIT and by remission status. Pathway analyses were used to determine enrichment of chemical subclasses and biological pathways. These pathways were then compared to prior findings generated from similar profiling performed from the PNOIT peanut OIT trial (n=20, ages 7-13).</p><p><strong>Results: </strong>During OIT, glycerophospholipid metabolites (q=3.8×10 ^-5 ) increased over time and most amino acid metabolites (q=6.1×10 ^-45 ) decreased over time. Participants who went on to develop remission, had higher levels of amino acids (q=4.3×10 ^-8 ) and bile acids (q=0.00014), whereas children who developed non-remission had higher levels of glycerophospholipids (q=4.3×10 ^-10 ). Comparison of these findings with our second cohort of OIT in older children, showed replication of the enrichment of glycerophosphocholines (q=1.0×10 ^-13 ) and amino acids (q=2.1×10 ^-5 ) among metabolites that changed over time on OIT and replication of glycerophospholipids(q=5.7×10 ^-16 ), amino acids ( <i>PNOIT</i> q=7.2×10 ^- ⁷ ), and bile acids ( <i>PNOIT</i> q=3.8×10 ^-8 ) among metabolites that varied by remission status.</p><p><strong>Conclusions: </strong>Metabolomic profiles on OIT differed both over time on OIT and by OIT remission status in young children. Between two independent OIT cohorts of different ages we observed replication of significantly enriched chemical subclasses of glycerophospholipids, amino acids, and bile acids. Given the potentially immunomodulatory roles of some of these metabolites, our results suggest that glycerophospholipids, amino acids, and bile acids may be involved in the mechanisms of remission on OIT.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}