medRxiv : the preprint server for health sciences最新文献

{"title":"A precision health approach to medication management in neurodevelopmental conditions: a model development and validation study using four international cohorts.","authors":"Marlee M Vandewouw, Kamran Niroomand, Harshit Bokadia, Sophia Lenz, Jesiqua Rapley, Alfredo Arias, Jennifer Crosbie, Elisabetta Trinari, Elizabeth Kelley, Robert Nicolson, Russell J Schachar, Paul D Arnold, Alana Iaboni, Jason P Lerch, Melanie Penner, Danielle Baribeau, Evdokia Anagnostou, Azadeh Kushki","doi":"10.1101/2025.03.12.25323683","DOIUrl":"10.1101/2025.03.12.25323683","url":null,"abstract":"<p><strong>Background: </strong>Psychotropic medications are commonly used for children with neurodevelopmental conditions, but their effectiveness varies, making prescribing challenging and potentially exposing individuals to multiple medication trials. We developed artificial intelligence (AI) models to predict medication success for stimulants, anti-depressants, and anti-psychotics. We first demonstrate feasibility using cross-sectional data from three research cohorts, then use a cohort of patients from a pharmacology clinic to predict medication choice by class, longitudinally, from electronic medical records (EMRs).</p><p><strong>Methods: </strong>Models were built to predict cross-sectional medication usage from the Child Behaviour Checklist. Data from the Province of Ontario Neurodevelopmental (POND) network ( <i>N</i> =598) trained and tested the models, while data from the Healthy Brain Network (HBN; <i>N</i> =1,764) and Adolescent Brain Cognitive Development (ABCD; <i>N</i> =2,396) studies were used for external validation. For the EMR cohort, data from the Psychopharmacology Program (PPP; <i>N</i> =312) at Holland Bloorview Kids Rehabilitation Hospital were used to predict longitudinal success. Stacked ensemble models were built separately for each medication class, and area under the receiving operating characteristic curve (AU-ROC) evaluated performance.</p><p><strong>Findings: </strong>The research cohorts demonstrated feasibility, with internal testing (POND) achieving an AU-ROC (median [IQR]) of 0.75 [0.73,0.80] for stimulants, 0.83 [0.78,0.87] for anti-depressants, and 0.79 [0.72,0.86] for anti-psychotics. Performance in external testing sets (HBN and ABCD) confirmed generalizability. In the EMR cohort (PPP), AU-ROCs were high: 0.87 [0.83,0.91] for anti-psychotics, 0.84 [0.81,0.88] for stimulants and 0.82 [0.77,0.87] for anti-depressants.</p><p><strong>Interpretation: </strong>This study demonstrates the feasibility of using AI to enhance medication management for children with neurodevelopmental conditions, with expert clinician decisions learned with high accuracy. These findings support the potential for AI decision aids in community settings, promoting faster access to personalized care while highlighting the complexity of clinical and sociodemographic factors influencing medication decisions.</p><p><strong>Funding: </strong>Funding was provided by the Canadian Institutes of Health Research (Operating Grant #527447) and Ontario Brain Institute.</p><p><strong>Research in context: </strong><b>Evidence before this study:</b> Current medication management practices for neurodevelopmental conditions, particularly for children who have not responded to first-line options, are based clinical best guess approaches that can have negative effects on children, their caregivers, and the health system. Precision health tools using artificial intelligence, which are suitable for community use, have the potential to improve the health syst","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757118","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":"Evaluating Modes of Influenza Transmission (EMIT-2): Insights from a Controlled Human Influenza Virus Infection Transmission Trial (CHIVITT).","authors":"Jianyu Lai, Hamed Sobhani, Kristen K Coleman, S-H Sheldon Tai, Filbert Hong, Isabel Sierra Maldonado, Yi Esparza, Kathleen M McPhaul, Shengwei Zhu, Don L DeVoe, Justin R Ortiz, Shuo Chen, Temima Yellin, Juan Manuel Carreno, Florian Krammer, Benjamin J Cowling, Aubree Gordon, Wilbur H Chen, Jelena Srebric, Donald K Milton","doi":"10.1101/2025.04.28.25326458","DOIUrl":"10.1101/2025.04.28.25326458","url":null,"abstract":"<p><p>A previous controlled human influenza transmission trial produced minimal transmission using nasal inoculation of an egg adapted virus. Therefore, we implemented a new trial with naturally infected Donors. We recruited healthy Recipients for four, two-week hotel quarantine cohorts and naturally infected, qRT-PCR confirmed Donors for two cohorts. Five Donors (mean age: 21; 80% female; two H1N1, three H3N2, one for cohort 24b and 4 for 24c, Jan-Feb 2024) exposed Recipients (mean age: 36; 55% female, eight in cohort 24b and 3 in 24c) in a hotel room with limited ventilation but a high air recirculation rate. We collected exhaled breath, ambient and personal bioaerosols, fomite swabs, and sera, and analyzed samples using dPCR and fluorescent focus assays, hemagglutination inhibition (HAI) assay, and enzyme-linked immunosorbent assay (ELISA). Compared with previously studied community-acquired influenza cases, we detected viral RNA (44%) and culturable virus (6%) less frequently and measured fewer viral RNA copies (79 - 8.9×10 <sup>3</sup> copies/30-min) in Donors' exhaled fine aerosols. One of 23 surface swab samples was culture positive. At admission, 8 of 11 Recipients had HAI titers ≤10 but 9 of 11 had stronger binding antibody responses than Donors against vaccine strains corresponding to Donor viruses. No Recipient developed influenza-like illness, PCR-positive respiratory samples, or serological evidence of infection. Potential explanations and insights regarding lack of transmission include importance of cough and seasonal variation in viral aerosol shedding by Donors, of potential cross-reactive immunity in middle-aged Recipients with decades of exposure, and of exposure to concentrated exhaled breath plumes limited by rapid air mixing from environmental controls that distributed aerosols evenly. Future trials over multiple seasons, Donors that cough, younger recipients, and environments that preserve normal exhaled breath plumes will be required to observe transmission from naturally infected Donors under controlled conditions and generate new insights into influenza transmission dynamics.</p><p><strong>Author summary: </strong>Human-to-human influenza virus transmission under controlled conditions could provide insights leading to better control of epidemics and pandemics. However, a previous study using laboratory adapted viruses produced minimal transmission. Therefore, we aimed to study transmission from people naturally infected with circulating viruses. We recruited four cohorts of healthy volunteer Recipients to stay in a quarantine hotel for two weeks. We could not recruit Donors for the first two cohorts. In the last two cohorts, one Donor exposed eight Recipients in the first and four Donors exposed three Recipients in the second. The Donors coughed infrequently and shed less virus into the air than we had observed during previous influenza seasons. No Recipients became infected. Possible explanations include that people infe","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12248172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144628471","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":"Tracking a decade of structural changes in preclinical and prodromal Alzheimer's disease: insights from amyloid-β pathology.","authors":"Ting Qiu, Zhen-Qi Liu, Jonathan Gallego-Rudolf, Manon Edde, Alex Valcourt Caron, Yuanchao Zhang, M Mallar Chakravarty, Jean-Paul Soucy, D Louis Collins, Judes Poirier, John Breitner, Gemma Salvadó, Alexa Pichet Binette, Maxime Descoteaux, Sylvia Villeneuve","doi":"10.1101/2025.09.25.25336640","DOIUrl":"https://doi.org/10.1101/2025.09.25.25336640","url":null,"abstract":"<p><p>Alzheimer's disease (AD) pathology is typically associated with reduced brain volume and cortical thickness, interpreted as neurodegeneration. However, several cross-sectional studies in cognitively unimpaired individuals have paradoxically reported larger brain volume and thicker cortex in the presence of amyloid-β (Aβ), suggesting that Aβ-brain structure associations may not follow a simple linear pattern early in the disease. We leveraged over a decade of longitudinal data from the PREVENT-AD cohort (N=367, mean follow-up 7.17 years, range 0-11.27 years) to investigate how Aβ burden related to both cross-sectional levels and longitudinal changes in brain volume, cortical thickness, and cortical tissue mean diffusivity (MD _T ) derived from free-water corrected diffusion tensor imaging. We examined associations separately in individuals below (Aβ-) and above (Aβ+) the Aβ-positivity threshold, tested for nonlinearity across all participants, and aligned structural trajectories to the estimated years from Aβ-positivity onset. We found that higher Aβ was associated with larger brain volume, higher cortical thickness and lower MD _T in regions such as the fusiform gyrus, supramarginal gyrus, hippocampal volume, inferior parietal and middle temporal cortex in the Aβ- group. The opposite associations were found in the Aβ+ group. Across all participants, volume and thickness showed an inverse U-shaped relationship with Aβ, while MD _T followed a U-shaped pattern. Longitudinally, the rate of cortical thickness change showed an inverse U-shaped association with Aβ, whereas Aβ burden was associated with faster volume loss and greater MD _T increase. When structural measures were aligned to the estimated time of Aβ positivity onset, volume and thickness increased years before the expected Aβ positivity onset and declined thereafter, while MD _T showed no association with time relative to Aβ positivity onset. Our results help reconcile inconsistencies across prior studies and suggest that brain structural changes related to Aβ pathology start years before Aβ positivity onset and follow nonlinear trajectories. These early structural changes might be due to pathological processes such as neuroinflammatory swelling early in the course of the disease.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214806","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":"Brain Health Loss Mediates the Effect of Infarct Volume on Functional Outcome in Ischemic Stroke.","authors":"Erik Lindgren, Luca Angeleri, Kenda Alhadid, Christina Jern, Arne G Lindgren, Jane Maguire, Robert W Regenhardt, Natalia S Rost, Markus D Schirmer","doi":"10.1101/2025.09.26.25335406","DOIUrl":"https://doi.org/10.1101/2025.09.26.25335406","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Brain health may facilitate resilience to detrimental consequences from neurological diseases. Infarct volume is associated with poor functional outcome after acute ischemic stroke (AIS), but potential mediating effects through stroke-related brain health loss have not been investigated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To determine whether stroke-related brain health loss, quantified by change in MRI derived effective Reserve (eR), mediates the effect of acute infarct volume on functional outcome after AIS.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design: &lt;/strong&gt;Observational multicenter cohort study.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Setting: &lt;/strong&gt;We analyzed data from the GASROS (n=488) and MRI-GENIE (n=560) cohorts, collected 2003-2011.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants: &lt;/strong&gt;Adult patients consecutively diagnosed with AIS, with available admission MRI.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Exposure: &lt;/strong&gt;At admission, white matter hyperintensity (WMH) and normal-appearing brain volumes were assessed on T2-FLAIR, and acute infarct volume on diffusion weighted imaging. WMH was normalized by brain volume, creating WMH load. We quantified brain health using eR, a latent variable incorporating age, WMH load, and normal-appearing brain volume. ΔeR reflected the change in eR when acute infarct volume was included, representing stroke-related brain health decline. Mediation analysis was used to determine if ΔeR mediates the effect of infarct volume on functional outcome (modified Rankin Scale [mRS] at 90 days).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main outcome measure: &lt;/strong&gt;Proportion of mediating effect.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We included 1,048 patients (median age 67y, 38% females). At baseline, median NIHSS score was 3 (IQR 1-7), median infarct volume 3.1mL (IQR 0.9-15.5). At 90 days, median mRS score was 1 (IQR 1-3) and 51 (5%) patients had died. In mediation analysis, ΔeR significantly mediated 36% (95% CI 16-56%) of the total effect of infarct volume on functional outcome (direct effect (ß=0.15 [95% CI 0.09-0.22], p&lt;0.001; indirect effect mediated through ΔeR: ß=0.09 [95% CI 0.04 to 0.14], p=0.001). In subgroup-analyses, the mediative effect was apparent among female but not male, and among patients aged &gt;67y but not ≤67y.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions and relevance: &lt;/strong&gt;Stroke-related structural brain health loss mediates about one third of the effect of acute infarct volume on functional outcome after ischemic stroke, with important sex and age differences. Brain health significantly influences outcome and recovery potential, and may be considered a key biomarker when modeling outcome after AIS.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Key points: &lt;/strong&gt;&lt;b&gt;Question:&lt;/b&gt; Does brain health loss associated with acute ischemic stroke mediate the relationship between acute infarct volume and functional outcome?&lt;b&gt;Findings:&lt;/b&gt; In this observational multicenter cohort study of 1,048 patients, mediation analysis suggests that reduction of the brain health MRI marker effective Reserve mediates 36% (95% CI 16-56%","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214838","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":"Privacy-Enhancing Sequential Learning under Heterogeneous Selection Bias in Multi-Site EHR Data.","authors":"Ritoban Kundu, Xu Shi, Kumar Kshitij Patel, Lucila Ohno-Machado, Maxwell Salvatore, Peter X K Song, Bhramar Mukherjee","doi":"10.1101/2025.09.26.25336642","DOIUrl":"https://doi.org/10.1101/2025.09.26.25336642","url":null,"abstract":"<p><strong>Objective: </strong>To develop privacy-enhancing statistical methods for estimation of binary disease risk model association parameters across multiple electronic health record (EHR) sites with heterogeneous selection mechanisms, without sharing raw individual-level data. We illustrate their utility through a cross-biobank analysis of smoking and 97 cancer subtypes using data from the NIH All of Us (AOU) and the Michigan Genomics Initiative (MGI).</p><p><strong>Materials and methods: </strong>Large-scale biobanks often follow heterogeneous recruitment strategies and store data in separate cloud-based platforms, making centralized algorithms infeasible. To address this, we propose two decentralized sequential estimators namely, Sequential Pseudo-likelihood (SPL) and Sequential Augmented Inverse Probability Weighting (SAIPW) that leverage external population-level information to adjust for selection bias, with valid variance estimation. SAIPW additionally protects against misspecification of the selection model using flexible machine learning based auxiliary outcome models. We compare SPL and SAIPW with the existing Sequential Unweighted (SUW) estimator and with centralized and meta learning extensions of IPW and AIPW in simulations under both correctly specified and misspecified selection mechanisms. We apply the methods to harmonized data from MGI ( <i>n</i> = 50,935) and AOU ( <i>n</i> = 241,563) to estimate smoking-cancer associations.</p><p><strong>Results: </strong>In simulations, SUW exhibited substantial bias and poor coverage. SPL and SAIPW yielded unbiased estimates with valid coverage probabilities under correct model specification, with SAIPW remaining robust under selection model misspecification. Both approaches showed no notable efficiency loss relative to centralized methods. Meta-learning methods were efficient for large sites but failed in settings with small cohort sizes and rare outcome prevalence. In real-data analysis, strong associations were consistently identified between smoking and cancers of the lung, bladder, and larynx, aligning with established epidemiological evidence.</p><p><strong>Conclusion: </strong>Our framework enables valid, privacy-enhancing inference across EHR cohorts with heterogeneous selection, supporting scalable, decentralized research using real-world data.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214934","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 Travel Burden with Definitive Prostate Cancer Treatment: A United States Registry Cohort Study.","authors":"Filippo Dagnino, Stephan Korn, Danesha Daniels, Zhiyu Qian, Daniel Stelzl, Hanna Zurl, Klara Pohl, Mei-Chin Hsieh, Brenda Y Hernandez, Andrea Piccolini, Giovanni Lughezzani, Nicolò M Buffi, Stuart R Lipsitz, Amanda Reich, Joel S Weissman, Alexander P Cole, Quoc-Dien Trinh, Hari S Iyer","doi":"10.1101/2025.09.26.25336503","DOIUrl":"https://doi.org/10.1101/2025.09.26.25336503","url":null,"abstract":"<p><strong>Purpose: </strong>Prostate cancer (PCa) mortality disparities are partly driven by unequal access to care. Transportation barriers may limit access to definitive treatment. We studied how driving travel time affects receipt of definitive PCa treatment.</p><p><strong>Materials and methods: </strong>We conducted a cohort study of men with non-metastatic PCa (2000 - 2015; follow-up through 2018) across the metropolitan area cancer registries of seven US states. Travel burden was estimated using Google Maps isochrones representing driving time thresholds to reach the hospital appended to geomasked residential addresses. Outcomes were \"no treatment, \" \"radical surgery,\" or \"radiotherapy\". Covariate-adjusted multinomial logistic regression with interaction terms assessed modification by sociodemographic factors.</p><p><strong>Results: </strong>The study included 132,939 men, of whom 37.0% received no treatment, 41.0% underwent surgery, and 22.0% received radiotherapy. Longer driving time (≥90 min vs <30 min) was associated with higher radical prostatectomy (aOR: 1.07, 95% CI: 1.03, 1.12), but lower radiotherapy (0.72, 95% CI: 0.69 - 0.76). Subgroup analyses revealed higher surgery associated with longer driving times among those in nSES Q1 (aOR: 1.33, 95% CI: 1.21-1.45) vs Q5 (aOR: 0.94, 95% CI: 0.86-1.04), those in low (aOR: 1.16, 95% CI: 1.09-1.24) vs high (aOR: 1.03, 95% CI: 0.98-1.09) population density areas, and those with regional (aOR: 1.30, 95% CI: 1.14-1.48) vs localized (aOR: 1.05, 95% CI: 1.00 -1.09) disease. Longer driving time was mostly associated with lower odds of radiotherapy across sociodemographic subgroups.</p><p><strong>Conclusions: </strong>Higher travel burden was associated with lower radiotherapy receipt, but greater surgery use in deprived and rural patients, which warrants further investigation.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214823","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":"Longitudinal Enrichment of Eosinophilic Esophagitis in Children with AD: The MPAACH Cohort.","authors":"Wan Chi Chang, Lisa J Martin, Latha Satish, Lindsey Williams, Mindy Hammonds, Seth Jenkins, Garrett Osswald, Julie Caldwell, Marc E Rothenberg, Gurjit K Khurana Hershey, Jocelyn M Biagini","doi":"10.1101/2025.09.22.25336085","DOIUrl":"https://doi.org/10.1101/2025.09.22.25336085","url":null,"abstract":"<p><strong>Introduction: </strong>The atopic march refers to the natural history of the sequential development of atopic dermatitis (AD), food allergy (FA), asthma and allergic rhinitis (AR) in childhood, but there is significant heterogeneity in the timing and order of disease presentation. Eosinophilic esophagitis (EoE) is an emerging food-induced inflammatory disease of the esophagus that shares clinical and immunologic features, genetic susceptibility and comorbidities with other march members. We sought to investigate the incidence and prevalence of EoE in a cohort of children with AD and elucidate the individual trajectories of sensitization and allergic comorbidity development.</p><p><strong>Methods: </strong>We evaluated 700 children participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort. FA was defined as parental report of a physician diagnosis. AR was defined by a positive skin prick test to ≥1 aeroallergen and symptoms. Asthma was defined by pulmonary function testing and symptoms according to ATS criteria. Participants were classified as having EoE if they had ≥15 eosinophils per high-power field in at least one esophageal biopsy.</p><p><strong>Results: </strong>Of the 700 children in MPAACH, 10 developed EoE, all after AD onset. The cumulative incidence of EoE in MPAACH was 0.7% by age 2, 0.7% between ages 2 and 5, and 1.6% between ages 5 and 8. The prevalence of EoE in MPAACH is 1.4% (95%CI 0.5-2.3%) and the median age at EoE diagnosis was 3.7 years (interquartile range (IQR): 1.8-6.5). Despite no difference in skin barrier quality or AD severity, children with EoE were more likely to have food sensitization (60% vs. 28%, p=0.039) and FA (70% vs. 13%, p<0.001). 90% of children with EoE had ≥1 allergic comorbidity compared to 49% of the MPAACH cohort (p=0.009). Of these 9, 6 developed FA and/or AR prior to their EoE diagnosis and 3 children developed FA, AR, and/or asthma after EoE onset.</p><p><strong>Conclusions: </strong>Our data support the inclusion of EoE as a fifth member of the march, with new incidence estimates showing enrichment in children with AD, underscoring early-life AD as a risk factor for EoE. The higher prevalence of food sensitization and FA despite no difference in skin barrier quality or AD severity suggests the esophagus as the site of allergen penetration independent of the skin. These data support screening for EoE symptoms in children with early allergic manifestations.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214865","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":"Identification and Validation of Novel Combinatorial Genetic Risk Factors for Endometriosis across Multiple UK and US Patient Cohorts.","authors":"Jason Sardell, Sayoni Das, Gert Lykke Moeller, Marianna Sanna, Karolina Chocian, Krystyna Taylor, Andy Malinowski, Colin Stubberfield, Amy Rochlin, Steve Gardner","doi":"10.1101/2025.08.13.25333595","DOIUrl":"10.1101/2025.08.13.25333595","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Background Endometriosis affects about 10% of women usually of reproductive age. It often has severe negative impacts on patients' quality of life, but the average time to a definitive diagnosis remains 7-9 years, and there are few effective therapeutic options. Relatively little is known about the genetic drivers of the disease even though its heritability is fairly high. A recent large genome wide association study (GWAS) meta-analysis identified 42 genomic loci associated with risk of endometriosis, but together these explain only 5% of disease variance. Methods We used the PrecisionLife combinatorial analytics platform to identify multi-SNP disease signatures significantly associated with endometriosis in a white European UK Biobank (UKB) cohort. We assessed the reproducibility of these multi-SNP disease signatures as well as 35 of the 42 meta-GWAS SNPs in a multi-ancestry American endometriosis cohort from All of Us (AoU) after controlling for population structure. Results We identified 1,709 disease signatures, comprising 2,957 unique SNPs in combinations of 2-5 SNPs, that were associated with increased prevalence of endometriosis in UKB. Pathways enriched in the disease signatures included cell adhesion, proliferation and migration, cytoskeleton remodeling, angiogenesis as well as biological processes involved in fibrosis and neuropathic pain. We observed a significant enrichment of these signatures (58-88%, p&lt;0.04) that are also positively associated with endometriosis in the AoU cohort, including one 2-SNP signature that is individually significant. Reproducibility rates were greatest for higher frequency signatures, ranging from 80-88% for signatures with greater than 9% frequency (p&lt;0.01) in AoU. Encouragingly, the disease signatures also show high reproducibility rates in non-white European AoU sub-cohorts (66-76%, p&lt;0.04 for signatures with greater than 4% frequency). A total of 195 unique SNPs mapping to 98 genes were identified in the high frequency reproducing signatures (&gt;9%). Of these, 7 genes were previously identified in the endometriosis meta-GWAS study and 16 genes have a previous association with endometriosis. 75 novel genes were identified in this study. We characterized 9 novel genes that occur at the highest frequency in reproducing signatures and that do not contain any SNPs linked to known GWAS genes, providing new evidence for links between endometriosis and autophagy and macrophage biology. Reproducibility rates, ranging between 73% to 85%. are especially strong for the signatures that contain these 9 genes independently of any SNPs mapping to the meta-GWAS genes. Conclusion Although using much smaller, less well-characterized datasets than the previous whole genome meta-GWAS study, combinatorial analysis has provided important new insights into the genetics and biology of endometriosis including reproducible biologically relevant genes that are overlooked by GWAS approaches. The 75 novel gene associations pro","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884702","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":"Gaps in the Type 1 Diabetes Mellitus care cascade: a national perspective using South Africa's National Health Laboratory Service (NHLS) database.","authors":"Alana T Brennan, Evelyn Lauren, Jacob Bor, Jaya A George, Siyabonga Khoza, Koleka Mlisana, Emma M Kileel, Sydney Rosen, Frederick Raal, Patricia Hibberd, Matthew P Fox, Nigel J Crowther","doi":"10.1101/2025.09.26.25336712","DOIUrl":"https://doi.org/10.1101/2025.09.26.25336712","url":null,"abstract":"<p><strong>Objective: </strong>Type 1 diabetes mellitus (T1DM) requires lifelong management, yet access to insulin, specialized care, and education is limited in low- and middle-income countries (LMICs). While cascade-of-care analyses are well documented for type 2 diabetes (T2DM), to our knowledge no population-level estimates of the T1DM care cascade exist from LMICs. We therefore evaluated the T1DM care cascade nationally in South Africa and compared outcomes between youth living with HIV (YLWH) and youth living without HIV (YLWOH).</p><p><strong>Research design and methods: </strong>We analyzed South Africa's National Health Laboratory Service (NHLS) data for patients <20 years with a first glycated hemoglobin A1c (HbA1c) or plasma glucose [fasting (FPG), random (RPG)] between April 2004 and March 2015. Laboratory-diagnosed T1DM was defined as HbA1c ≥6.5%, FPG ≥7.0 mmol/L, or RPG ≥11.1 mmol/L. Cascade stages over 24 months were remaining in care and achieving glycemic control (HbA1c <7.0%, FPG <8.0 mmol/L, or RPG <10.0 mmol/L).</p><p><strong>Results: </strong>Of 256,449 youth tested for diabetes, 12.1% met criteria for laboratory-diagnosed T1DM. Among these, 15.9% remained in care and 7.2% achieved glycemic control by 24 months. Retention was similar between YLWH and YLWOH (16.8% vs. 15.8%), but glycemic control was higher among YLWH (72.5% vs. 43.4%).</p><p><strong>Conclusions: </strong>Four of five South African youth with T1DM lacked consistent care, and fewer than 10% achieved glycemic control within two years. Higher control rates among YLWH suggest lessons from HIV care models may strengthen T1DM services. These findings provide the first national estimates of the T1DM care cascade from sub-Saharan Africa and highlight the urgent need for targeted strategies to improve outcomes.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215136","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":"A phase I window-of-opportunity study of neoadjuvant avelumab and hypofractionated radiation therapy in radiation-relapsed meningioma.","authors":"Jiayi Huang, Tanner M Johanns, Jian L Campian, Michael Chicoine, Gregory Zipfel, Milan Chheda, Omar Butt, Danil Ivanov, Konstantin Chernyshov, Basim Salem, Arina Tkachuk, Alena Frank, Daria Klimova, Dmitry Tabakov, Akdes S Harmanci, William C Chen, Akash J Patel, David R Raleigh, Albert H Kim, Chun-Kan Chen","doi":"10.1101/2025.09.26.25336740","DOIUrl":"https://doi.org/10.1101/2025.09.26.25336740","url":null,"abstract":"<p><p>Effective treatments for recurrent, radiation-relapsed meningiomas (RR-meningiomas) following surgery and radiation therapy (RT) are limited. Inhibitors of the programmed-death-1 (PD-1) or programmed-death ligand-1 (PD-L1) pathway have shown modest activity in single-arm phase II studies of RR-meningiomas. This study aimed to evaluate the immunological effects of combining avelumab, a PD-L1 inhibitory antibody, with proton beam therapy (PBT) in RR-meningiomas. Patients with grade 1-3 RR-meningiomas were treated with neoadjuvant avelumab plus hypofractionated PBT, followed by surgery and adjuvant avelumab. Correlative analyses included RNA-sequencing (RNA-seq), whole exome sequencing (WES), multiplex immunofluorescence (MxIF), single-nucleus RNA-seq (snRNA-seq) of pre- and post-treatment tumor tissues, and flow cytometry (FC) of serial blood samples. Nine patients were enrolled: three achieved an immunologic response and prolonged progression-free survival (PFS > 36 months). At a median follow-up of 47.2 months, the median PFS was 19.1 months (95% CI: 15.2-23.0). RNA-seq showed a dynamic change of tumor microenvironment (TME) signatures. MxIF revealed marked infiltration of T cells and CD68+CD206- (M1-phenotype) macrophages in the post-treatment tissues of responders, a pattern absent in non-responders, whose pre- and post-treatment tissues predominantly featured CD206+ (M2-phenotype) macrophages. These findings were supported by snRNA-seq, which identified FN1-associated immunosuppressive macrophage subtype enriched in non-responders. Additionally, FC revealed elevated peripheral primed T-cell signatures one-month after treatment initiation in responders, suggesting a potential predictive biomarker. Avelumab combined with RT may elicit an immune response in a subset of RR-meningiomas, leading to prolonged remission. Further investigations are warranted to validate these findings and to develop predictive biomarkers in larger prospective studies.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214771","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}