{"gname":"Academia Sinica","grp_id":"38","rels":[{"rel_title":"HIV as a Host Susceptibility State for Severe Drug Hypersensitivity: Disentangling Biological Susceptibility from Drug Exposure in the FAERS Database","rel_doi":"10.64898\/2026.07.07.26356279","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26356279","rel_abs":"Background: HIV infection has long been associated with increased incidence of severe cutaneous adverse reactions (SCAR). It remains unknown whether this increased incidence is a direct biological result of HIV infection, differences in drug exposure, or other demographic factors. Objective: To evaluate the association between HIV and SCAR and determine whether this relationship persists after adjusting for demographic factors and structured drug exposure. Methods: We analyzed reports from the FDA Adverse Event Reporting System (FAERS) from 2013-2023. SCAR outcomes included Stevens-Johnson syndrome\/toxic epidermal necrolysis (SJS\/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed drug eruption (GBFDE). HIV status was determined using antiretroviral exposure, indication text, and machine-learning imputation. Logistic regression models were constructed sequentially: unadjusted, demographic-adjusted, and fully adjusted with drug principal components to account for polypharmacy. Drug-level disproportionality and HIV-drug interaction analyses were also performed. Results: In unadjusted models, HIV was strongly associated with SCAR (OR ~2.0-2.7). Adjustment for demographics attenuated this association, and further adjustment for drug exposure reduced the effect to near null for overall SCAR and DRESS. A modest residual association persisted for SJS\/TEN (OR ~1.3). Disproportionality analyses demonstrated enrichment of specific high-risk drugs in PLWH. Interaction modeling revealed drug-specific amplification of SCAR risk in HIV, notably for carbamazepine and clarithromycin, whereas other drugs showed minimal interaction. Conclusion: The association between HIV and SCAR is largely explained by differences in drug exposure and demographic factors. Residual risk is drug-specific rather than uniform, supporting a model in which HIV modifies susceptibility to select drug triggers rather than acting as a global risk factor. Further prospective and retrospective studies are required to quantify associations.","rel_num_authors":7,"rel_authors":[{"author_name":"Eric M Mukherjee","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Dodie Park","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Amir Asiaee","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew S Krantz","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Cosby A Stone Jr.","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Michelle D Martin-Pozo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Elizabeth Jane Phillips","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"An epigenetic speedometer to measure Pace of Aging: FraminghamPACE","rel_doi":"10.64898\/2026.07.07.26357388","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357388","rel_abs":"Geroscience clinical trials need biomarker surrogate endpoints for healthspan. Leading candidates are omics-based composites developed from machine learning analysis of aging phenotypes including calendar age, survival, functional capacity, and Pace of Aging. Existing Pace of Aging biomarkers were developed in the Dunedin Longitudinal Study, limiting inference about strengths\/weaknesses of the method as distinct from the Study, a unique single-year birth cohort followed through midlife with near-perfect retention and uniform measurement of multi-organ-system function across two decades of follow-up. We adapted our Pace of Aging method for mixed-age cohorts with variable follow-up of organ-function measures and applied it to develop a novel DNA methylation biomarker of Pace of Aging in data from the Framingham Heart Study Offspring Cohort, FraminghamPACE. Validation analyses across four independent cohorts and one clinical trial establish advantages for the Pace of Aging method in developing biomarkers that are both predictive of healthspan and responsive to geroprotective intervention.","rel_num_authors":10,"rel_authors":[{"author_name":"William T Marella","author_inst":"Robert N Butler Columbia Aging Center, Columbia University Mailman School of Public Health"},{"author_name":"Calen P Ryan","author_inst":"Robert N Butler Columbia Aging Center, Columbia University Mailman School of Public Health"},{"author_name":"David Corcoran","author_inst":"Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill"},{"author_name":"Claire Eckstein Indik","author_inst":"Robert N Butler Columbia Aging Center, Columbia University Mailman School of Public Health"},{"author_name":"Alex Furuya","author_inst":"Department of Epidemiology, Columbia University Mailman School of Public Health"},{"author_name":"Michael S Kobor","author_inst":"Edwin S. Leong Centre for Healthy Aging, University of British Columbia"},{"author_name":"Karen Sugden","author_inst":"Department of Psychology and Neuroscience, Duke University"},{"author_name":"Avshalom Caspi","author_inst":"Department of Psychology and Neuroscience, Duke University"},{"author_name":"Terrie Moffitt","author_inst":"Department of Psychology and Neuroscience, Duke University"},{"author_name":"Daniel W Belsky","author_inst":"Robert N Butler Columbia Aging Center, Columbia University Mailman School of Public Health"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Integrated molecular analysis of NSCLC brain metastasis tissue and multimodal ctDNA reveals distinct signatures of patient outcomes","rel_doi":"10.64898\/2026.06.29.26355802","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26355802","rel_abs":"While recent therapeutic advances have extended the survival of patients with non-small cell lung cancer (NSCLC), overcoming metastatic progression in the CNS remains a significant challenge. Some patients with NSCLC may require concurrent management of CNS and extracranial metastases, while others develop isolated brain metastasis or leptomeningeal disease. These heterogenous clinical outcomes are difficult to predict and diagnose for early intervention with current surveillance modalities. Herein, we comprehensively analyzed gene mutations, copy number variations, and DNA methylation of NSCLC brain metastasis tissue collected at the time of craniotomy, combined with ctDNA sequencing of paired plasma and CSF liquid biopsies. We confirmed a high concordance between the molecular features of brain metastasis tissue with ctDNA from CSF which were largely distinct from ctDNA alterations in paired plasma samples. Plasma ctDNA tumor fraction and ctDNA hypermethylation were most significantly associated with extracranial metastasis and overall survival. Alternatively, we identified specific hypermethylated DNA loci in brain metastasis tissue and CSF ctDNA as significant correlates of brain metastasis progression and risk of leptomeningeal disease. Our findings support the utility of integrating ctDNA testing from CSF and plasma, while revealing distinct epigenetic features and biomarkers of brain metastasis or leptomeningeal disease.","rel_num_authors":16,"rel_authors":[{"author_name":"Darin Dolezal","author_inst":"Yale University School of Medicine"},{"author_name":"Sampada Chande","author_inst":"Yale University School of Medicine"},{"author_name":"Giancarlo Bonora","author_inst":"Predicine Inc."},{"author_name":"Yong Huang","author_inst":"Predicine Inc."},{"author_name":"Myles Walsh","author_inst":"Predicine Inc."},{"author_name":"Savannah Kandigian","author_inst":"Yale University School of Medicine"},{"author_name":"Wei Wei","author_inst":"Yale University School of Medicine"},{"author_name":"Anna Arnal-Estape","author_inst":"Yale University School of Medicine"},{"author_name":"Kurt Schalper","author_inst":"Yale University School of Medicine"},{"author_name":"Sarah Goldberg","author_inst":"Yale University School of Medicine"},{"author_name":"Darren Cross","author_inst":"Bioscience, Early Oncology TDE, AstraZeneca"},{"author_name":"Massimo Squatrito","author_inst":"AstraZeneca, Translational Medicine, AstraZeneca"},{"author_name":"Nicholas Blondin","author_inst":"Yale University School of Medicine"},{"author_name":"Shidong Jia","author_inst":"Predicine Inc."},{"author_name":"Veronica Chiang","author_inst":"Yale University School of Medicine"},{"author_name":"Don X Nguyen","author_inst":"Yale University School of Medicine"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"A pan-organ exposomic atlas of human aging for precision environmental health","rel_doi":"10.64898\/2026.06.26.26356646","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356646","rel_abs":"Environmental exposures are major modifiable determinants of human aging, yet the evidence remains fragmented across organ-agnostic summaries and rarely confronts population inequity. Here we present an exposomic atlas of pan-organ aging in ~300,000 UK Biobank adults, mapping 164 environmental and behavioural exposures onto biological aging of the whole body and nine organ subsystems. Comprising 1,476 systematically tested exposure-subsystem associations, the atlas reveals that environmental effects on human aging are pervasively organ-specific, with 65.9% of exposures acting divergently across organ subsystems. This landscape resolves into nine navigable modules that preserve organ selectivity, predict 23 major age-related diseases, and expose distinct dimensions of health inequity. In-silico analyses further show that priorities for ameliorating aging are target-dependent rather than universal, diverge markedly from the whole-body ranking (Kendall's {tau} = 0.52 to 0.39), reorder substantially across population strata, with findings externally validated in an ethnically distinct cohort. The atlas establishes an organ-resolved and target-aware foundation for precision environmental health.","rel_num_authors":3,"rel_authors":[{"author_name":"Shaopeng Yang","author_inst":"Sun Yat-sen University"},{"author_name":"Zhuoyao Xin","author_inst":"Johns Hopkins University"},{"author_name":"Wei Wang","author_inst":"Sun Yat-sen University"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"The Circadian Disruption Index: development, validation, and responsiveness to circadian health education","rel_doi":"10.64898\/2026.07.08.26357517","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357517","rel_abs":"Study Objectives To develop and initially validate the Circadian Disruption Index (CDI), a self-report measure of circadian disruption, and obtain preliminary evidence of its responsiveness to circadian health education. Methods In Study 1, 244 participants completed a 22-item CDI version and external measures. The sample was randomly divided for exploratory and confirmatory factor analyses. Internal consistency, external associations, and discrimination of poor sleep quality were examined. In Study 2, 72 postgraduate students completed the CDI before and 1 week after a 16-hour circadian health education program in an uncontrolled pre-post design. Results Analyses yielded a 15-item, three-factor structure comprising rhythm stability and light exposure, behavioral habits and diet, and sleep quality and subjective complaints. Total-score internal consistency was acceptable (Cronbach's  = 0.871). Confirmatory factor analysis showed a comparative fit index of 0.902 and a root mean square error of approximation of 0.072, although the Tucker-Lewis index was 0.882. CDI scores correlated with sleep quality, chronotype, corrected midsleep on free days, depression, and anxiety, but not social jetlag. The area under the curve for poor sleep quality was 0.807 (95% confidence interval, 0.753-0.862), with an exploratory cutoff of [&le;] 23. In Study 2, CDI scores decreased from 22.26 to 19.88 (p = 0.002; Cohen's dz = 0.36). Conclusions The CDI demonstrated satisfactory internal consistency, a meaningful multidimensional structure, and responsiveness to short-term changes following circadian health education, supporting its potential utility for assessing circadian disruption and monitoring circadian-related behavioral changes.","rel_num_authors":15,"rel_authors":[{"author_name":"Yimei Fan","author_inst":"Guangzhou medical university"},{"author_name":"Mingyu Tian","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Jiaying Xu","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Mingxin Cao","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Nana Zheng","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Yaping Liu","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Sizhi Ai","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Yannis Yan Liang","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Jing Wang","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Xiaoqing Hu","author_inst":"Department of Psychology, The University of Hong Kong, Hong Kong, SAR, China."},{"author_name":"Xiao Tan","author_inst":"Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School"},{"author_name":"Christian Benedict","author_inst":"Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden"},{"author_name":"Yun Kwok Wing","author_inst":"Li Chiu Kong Family Sleep Assessment Unit, Department of Psychiatry, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, SAR, China."},{"author_name":"Jihui Zhang","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Hongliang Feng","author_inst":"The affiliated brain hospital of Guangzhou Medical University"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"A study of sex-specific genetic effects underlying risk of orofacial clefts also highlights the potential impact of sequencing errors due to short read mis-mapping","rel_doi":"10.64898\/2026.07.07.26357463","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357463","rel_abs":"Orofacial clefts (OFCs), including cleft lip (CL), cleft palate (CP), and cleft lip with cleft palate (CLP), are among the most common craniofacial malformations in humans, with a birth prevalence of approximately 1 in 1,000 live births globally. Non-syndromic forms of OFC are predominantly genetic, with significant variability in prevalence across populations. Understanding the genetic underpinnings of OFCs remains a key public health priority, given the substantial medical and societal burden of these conditions. Recent genome-wide association studies (GWAS) have implicated numerous genetic loci, but challenges remain due to genetic heterogeneity and complex gene-environment interactions. This study aimed to identify sex-specific genetic risk factors for cleft lip with or without cleft palate (CL\/P) through a meta-analysis of whole genome sequencing (WGS) data from 1,922 case-parent trios across eight diverse cohorts. Our approach revealed four SNPs in three distinct regions that showed genome-wide significant sex-specific effects. However, despite each of these SNPs passing standard quality control filters, follow-up analyses showed that these signals most likely were technical artifacts caused by sequencing errors, in particular mis-mapped reads due to sequence similarities with the sex chromosomes. These findings highlight the necessity for careful scrutiny when studying differences between the sexes in genetic association studies.","rel_num_authors":16,"rel_authors":[{"author_name":"Kanika Kanchan","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Zeynep ERDO\u011eAN-YILDIRIM","author_inst":"University of Pittsburgh, School of Dental Medicine"},{"author_name":"Seth R Berke","author_inst":"Princeton University"},{"author_name":"Nandita Mukhopadhyay","author_inst":"Univ. of Pittsburgh"},{"author_name":"Debashree Ray","author_inst":"Johns Hopkins University"},{"author_name":"Claire Louise Simpson","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Jacqueline A Bidinger","author_inst":"Johns Hopkins University"},{"author_name":"Sarah W Curtis","author_inst":"Emory University"},{"author_name":"Azeez Butali","author_inst":"University of Iowa"},{"author_name":"Holger Schwender","author_inst":"Heinrich-Heine-Universitaet"},{"author_name":"Alan F Scott","author_inst":"Johns Hopkins University"},{"author_name":"Joan Bailey Wilson","author_inst":"National Human Genome Research Institute"},{"author_name":"Terri  H. Beaty","author_inst":"Johns Hopkins University"},{"author_name":"Elizabeth Leslie","author_inst":"Emory University"},{"author_name":"Mary  L. Marazita","author_inst":"University of Pittsburgh"},{"author_name":"Ingo Ruczinski","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"A study of sex-specific genetic effects underlying risk of orofacial clefts also highlights the potential impact of sequencing errors due to short read mis-mapping","rel_doi":"10.64898\/2026.07.07.26357463","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357463","rel_abs":"Orofacial clefts (OFCs), including cleft lip (CL), cleft palate (CP), and cleft lip with cleft palate (CLP), are among the most common craniofacial malformations in humans, with a birth prevalence of approximately 1 in 1,000 live births globally. Non-syndromic forms of OFC are predominantly genetic, with significant variability in prevalence across populations. Understanding the genetic underpinnings of OFCs remains a key public health priority, given the substantial medical and societal burden of these conditions. Recent genome-wide association studies (GWAS) have implicated numerous genetic loci, but challenges remain due to genetic heterogeneity and complex gene-environment interactions. This study aimed to identify sex-specific genetic risk factors for cleft lip with or without cleft palate (CL\/P) through a meta-analysis of whole genome sequencing (WGS) data from 1,922 case-parent trios across eight diverse cohorts. Our approach revealed four SNPs in three distinct regions that showed genome-wide significant sex-specific effects. However, despite each of these SNPs passing standard quality control filters, follow-up analyses showed that these signals most likely were technical artifacts caused by sequencing errors, in particular mis-mapped reads due to sequence similarities with the sex chromosomes. These findings highlight the necessity for careful scrutiny when studying differences between the sexes in genetic association studies.","rel_num_authors":16,"rel_authors":[{"author_name":"Kanika Kanchan","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Zeynep ERDO\u011eAN-YILDIRIM","author_inst":"University of Pittsburgh, School of Dental Medicine"},{"author_name":"Seth R Berke","author_inst":"Princeton University"},{"author_name":"Nandita Mukhopadhyay","author_inst":"Univ. of Pittsburgh"},{"author_name":"Debashree Ray","author_inst":"Johns Hopkins University"},{"author_name":"Claire Louise Simpson","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Jacqueline A Bidinger","author_inst":"Johns Hopkins University"},{"author_name":"Sarah W Curtis","author_inst":"Emory University"},{"author_name":"Azeez Butali","author_inst":"University of Iowa"},{"author_name":"Holger Schwender","author_inst":"Heinrich-Heine-Universitaet"},{"author_name":"Alan F Scott","author_inst":"Johns Hopkins University"},{"author_name":"Joan Bailey Wilson","author_inst":"National Human Genome Research Institute"},{"author_name":"Terri  H. Beaty","author_inst":"Johns Hopkins University"},{"author_name":"Elizabeth Leslie","author_inst":"Emory University"},{"author_name":"Mary  L. Marazita","author_inst":"University of Pittsburgh"},{"author_name":"Ingo Ruczinski","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Trends in the Incidence of Kaposi Sarcoma among Adults Attending HIV Care Facilities in East Africa and Latin America in the Treat-All Era","rel_doi":"10.64898\/2026.06.26.26356374","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356374","rel_abs":"Abstract Background: In resource-rich regions, such as the U.S. and Europe, the incidence of Kaposi sarcoma (KS) amongst persons living with HIV (PWH) has dramatically declined with the advent of combination antiretroviral therapy (ART). In contrast, in low- and middle-income countries (LMICs), much less is known, particularly since the World Health Organization's recommendation in late 2015 to use ART in all PWH. We take advantage of the coincident electronic clinical data capture at HIV care facilities to estimate the incidence of KS among PWH in care with ready access to ART, piloting a data validation approach to address errors in these routine clinic data. Methods: We evaluated PWH enrolled from January 2010 to December 2019 in 13 HIV care clinics in 8 countries participating in the East Africa (EA-IeDEA) and Caribbean, Central and South America (CCASAnet) regions of the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium. Selected measurements were validated via chart review on a subset of PWH, and we estimated KS incidence in both unvalidated and validated data via generalized raking techniques. Results: A total of 235,474 PWH from EA-IeDEA and 19,683 from CCASAnet gave rise to 719 and 103 incident cases of KS, respectively. A total of 824 eligible records were validated. ART use was substantially lower in EA-IeDEA than CCASAnet in 2010 but equalized by 2019. From 2010 to 2019, KS incidence decreased on average 21% per year (incidence rate ratio [IRR] 0.79; 95% CI 0.75-0.82) in EA-IeDEA but only 6% (IRR=0.94; 95% CI 0.83-1.06) in CCASAnet. Conclusions: Among PWH attending HIV care facilities in East Africa, we observed a trend suggesting a reduction in KS incidence that paralleled increased Treat All era ART use in these clinics. In the Caribbean, Central and South America, there was hardly a change in the incidence, despite high-frequency ART use in the region as well.","rel_num_authors":27,"rel_authors":[{"author_name":"Aggrey Semeere","author_inst":"Infectious Diseases Institute, Makerere University"},{"author_name":"Joshua Slone","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Gustavo Amorim","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Beverly Musick","author_inst":"Indiana University"},{"author_name":"Brenda Crabtree-Ram\u00edrez","author_inst":"Departamento de Infectolog\u00eda, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n"},{"author_name":"Lameck Diero","author_inst":"Moi University"},{"author_name":"Larissa Otero","author_inst":"Instituto de Medicina Tropical Alexander von Humboldt"},{"author_name":"Hilary Vansell Riley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Antony Ngeresa","author_inst":"Moi University"},{"author_name":"Mark Nsumba","author_inst":"Infectious Diseases Institute, Makerere University"},{"author_name":"Haruna Ssemuwemba","author_inst":"Masaka Regional Referral Hospital"},{"author_name":"Paul Enyel","author_inst":"Mbarara Regional Referral Hospital"},{"author_name":"Gertrude Nakigozi","author_inst":"Rakai Health Sciences Program"},{"author_name":"Godloveness Rubega","author_inst":"Morogoro Regional Referral Hospital"},{"author_name":"Jerome Lwali","author_inst":"Tumbi Regional Referral Hospital"},{"author_name":"Guisela Salgado","author_inst":"Instituto Hondure\u00f1o de Seguridad Social"},{"author_name":"Guilherme Calvet","author_inst":"Instituto Nacional de Infectolog\u00eda Evandro Chagas"},{"author_name":"Maria Fernanda Rodriguez","author_inst":"Fundaci\u00f3n Arriar\u00e1n y Universidad de Chile"},{"author_name":"Ana Grana","author_inst":"Instituto de Medicina Tropical Alexander von Humboldt"},{"author_name":"Karen Juarez","author_inst":"Departamento de Infectolog\u00eda, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n"},{"author_name":"Ran Tao","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Stephany Duda","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Constantin Yiannoutsos","author_inst":"City University New York"},{"author_name":"Thomas Lumley","author_inst":"University of Auckland"},{"author_name":"Jeffrey Martin","author_inst":"University of California, San Francisco"},{"author_name":"Pamela A. Shaw","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Bryan E. Shepherd","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Data-driven Prediction of Fifteen-Year All-Cause Mortality among 2.3 Million Individuals in the VA","rel_doi":"10.64898\/2026.06.29.26356460","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356460","rel_abs":"We present a data-driven framework to predict 15-year all-cause mortality using outpatient administrative records for 2.3 million Veterans in the largest integrated U.S. healthcare system. Rather than relying on predefined clinical phenotypes, we used the 1,000 most common outpatient medical codes from each of three data types\/modalities: ICD-9 (Dx), Current Procedural Terminology (CPT), and prescription drugs (Rx), encoded as binary features. Using these features, we trained three machine learning (ML) algorithms (logistic regression with lasso, random forest, and a 3-layered feed-forward neural network) to predict 15-year mortality risk. The features were also mapped to variables for the widely used Charlson Comorbidity Index (CCI), Elixhauser, and Veterans Aging Cohort Study (VACS) indices, refitted for 15-year mortality prediction, for baseline comparison. All our models significantly outperformed the widely used CCI, Elixhauser, and VACS indices, with C-statistics ranging from 0.82 to 0.84 versus 0.739 to 0.804 for the baselines. Relative improvements in C-statistics of our approach over the baselines were consistent across different subgroups (age groups of <65 years, those 65+years, Blacks, Hispanics, etc.) Our approach enabled the identification of high-impact predictors with clinical grounding , without requiring hand-curated phenotypes. Cardiovascular diseases and mental health diagnoses\/treatments emerged as leading long-term mortality indicators. Using unsupervised ML techniques including PCA and K-means clustering, we associated interpretable patterns and complex interactions between diagnoses and treatments, highlighting comorbidities, disease trajectories, and healthcare utilization patterns. The ability to achieve the predictive performance and algorithmically detect such relationships purely from outpatient data supports the scalability and broad applicability of our framework. This framework not only improves mortality risk stratification over existing clinical indices, but also enables better understanding of how medical codes, regardless of category, interact to predict long-term outcomes.","rel_num_authors":15,"rel_authors":[{"author_name":"Sayera Dhaubhadel","author_inst":"Los Alamos National Laboratory"},{"author_name":"Judith D Cohn","author_inst":"Los Alamos National Laboratory"},{"author_name":"Tanmoy Bhattacharya","author_inst":"Los Alamos National Laboratory"},{"author_name":"Ruy M. Ribeiro","author_inst":"Los Alamos National Laboratory"},{"author_name":"Kumkum Ganguly","author_inst":"Los Alamos National Laboratory"},{"author_name":"Nicolas  W Hengartner","author_inst":"Los Alamos National Laboratory"},{"author_name":"Janet P Tate","author_inst":"Yale University"},{"author_name":"Lauren Costa","author_inst":"Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), VA Boston Healthcare System, Boston, USA"},{"author_name":"Yuk-Lam Ho","author_inst":"VA Boston Healthcare System"},{"author_name":"Kelly Cho","author_inst":"VA Boston Healthcare System"},{"author_name":"Lauren Costa","author_inst":"Dept. of Veterans Affairs"},{"author_name":"Jean  C. Beckham","author_inst":"Durham Veterans Affairs (VA) Health Care System; Duke University"},{"author_name":"Nathan A Kimbrel","author_inst":"Durham Veterans Affairs (VA) Health Care System; Duke University"},{"author_name":"Amy C. Justice","author_inst":"VA Connecticut Healthcare System; Yale University"},{"author_name":"Benjamin  H. McMahon","author_inst":"Los Alamos National Laboratory"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Cell-type-specific polygenic risk scores reveal adipocyte-related interactions with lipids in coronary artery disease","rel_doi":"10.64898\/2026.07.07.26357510","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357510","rel_abs":"Background: Genome-wide polygenic risk scores (PRSs) for coronary artery disease (CAD) aggregate genetic effects across the genome and may obscure biologically distinct mechanisms. We aimed to develop cell-type-specific PRSs (csPRSs) using single-cell RNA sequencing (scRNA-seq) data and investigate their interactions with lipids on CAD risk. Methods: Using publicly available scRNA-seq data from human heart tissue, we identified cell-type-specific genes across 13 major cell types and 64 subpopulations and grouped them into 10 cell clusters. Variants from a CAD genome-wide association study (GWAS) were mapped to cluster-specific genes to construct csPRSs for European-ancestry participants from the UK Biobank (UKB). Interactions between csPRSs and lipid-related phenotypes were evaluated using Cox proportional hazards models and stratified analyses, with significant findings further assessed in an internal validation dataset. Results: Distinct interaction patterns with lipid phenotypes were observed across csPRSs. Low-density lipoprotein (LDL)-related lipid traits, including apolipoprotein B (ApoB), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (cholesterol), primarily interacted with adipocytes (Adip), whereas high-density lipoprotein (HDL) traits interacted with endothelial-mesothelial (EC-Meso), fibroblast (FB), and immune-cell csPRSs. Notably, interactions for Adip csPRSs were replicated in internal validation analyses. Conclusions: Cell-type-specific decomposition of genome-wide PRSs for CAD identified biologically distinct lipid interactions that were not captured by the genome-wide PRS. Adipocyte genetic factors may influence how LDL lipids affect CAD risk. These findings highlight the potential of cell-type-informed PRSs to improve the biological interpretation of PRSs and provide insights into the heterogeneous mechanisms underlying CAD.","rel_num_authors":5,"rel_authors":[{"author_name":"Jiaqi Hu","author_inst":"Yale School of Public Health"},{"author_name":"Leqi Xu","author_inst":"Yale School of Public Health"},{"author_name":"Tianyu Liu","author_inst":"Yale School of Public Health"},{"author_name":"Wangjie Zheng","author_inst":"Yale School of Public Health"},{"author_name":"Hong-yu Zhao","author_inst":"Yale School of Public Health"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"SSRI prescription during acute COVID-19 and risk of Long COVID symptoms and conditions among patients with depression","rel_doi":"10.64898\/2026.07.06.26357401","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357401","rel_abs":"Background: Long COVID is a syndrome characterized by symptoms and conditions across all biological systems. This breadth of Long COVID phenotypes impedes efforts to identify the mechanistic pathways of Long COVID. Low serotonin may play a role in long-term sequelae of COVID-19, and selective serotonin reuptake inhibitors (SSRIs) may prevent these sequelae. Evaluation of the relationship between SSRIs and distinct categories of symptoms and conditions associated with Long COVID can highlight the mechanistic pathways that drive these relationships. Methods: We evaluated electronic health record data from a retrospective cohort of patients in the National Clinical Cohort Collaborative with comorbid depression and COVID-19 between October 2021 and February 2024. We estimated the relationship between SSRI prescription (versus no SSRI prescription) during acute COVID-19 and the one-year cumulative incidence of Long COVID-related conditions and symptoms across 14 human phenotype ontology categories. We applied Super Learner and targeted maximum likelihood estimation to estimate risk ratios while adjusting for confounders of interest and correcting for false discoveries from repeated testing. Results: We evaluated EHR data from 542,938 patients. We found that patients who were prescribed SSRIs during COVID-19 had a significantly lower risk of symptoms and conditions related to gastrointestinal factors (adjusted risk ratio (aRR) 0.95, 95% CI 0.92, 0.97), general health (aRR 0.91, 95% CI 0.88, 0.95), headaches (aRR 0.96, 95% CI 0.92, 0.99) and skin (aRR 0.92, 95% CI 0.87, 0.98). Discussion: We found that the prescription of SSRIs during acute COVID-19 was associated with a significantly lower risk of post-COVID sequelae related to gastrointestinal, headache-related, skin-related, and general symptoms and conditions, compared with no SSRI prescription. These findings highlight the role of serotonin in Long COVID and specific sequelae that may be reduced by SSRIs.","rel_num_authors":11,"rel_authors":[{"author_name":"Zachary Butzin-Dozier","author_inst":"Stanford University, Stanford, CA USA"},{"author_name":"Yunwen Ji","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Lin-Chiun Wang","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Manav Kumar","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"A. Jerrod Anzalone","author_inst":"University of Nebraska Medical Center, Omaha, NE, USA"},{"author_name":"Ariana Budhihartanto","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Eric Hurwitz","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Rena C. Patel","author_inst":"University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Alan E. Hubbard","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Jodi Halpern","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"- on behalf of the National Clinical Cohort Collaborative","author_inst":"-"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Metformin and Severe Post-COVID-19 Outcomes Among Individuals with Diabetes Mellitus","rel_doi":"10.64898\/2026.07.06.26357398","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357398","rel_abs":"Background: Metformin is one of the most commonly prescribed medications for individuals with diabetes and may provide protection against long-term sequelae of COVID-19. Methods: We evaluated a retrospective cohort of individuals in the National Clinical Cohort Collaborative with type 2 diabetes mellitus and COVID-19 who were prescribed metformin or a dipeptidyl peptidase-4 inhibitor (DPP4i) at least 30 days before the onset of acute COVID-19 between October 1, 2021, and November 15, 2023. We compared the 12-month cumulative incidence of Long COVID diagnosis (ICD-10 U09.9: Post COVID-19 condition, unspecified), probable Long COVID (based on a model-derived phenotype), and mortality between individuals prescribed metformin vs. DPP4i. We applied Super Learner and targeted maximum likelihood estimation to obtain risk ratios while adjusting for covariates of interest. Results: In our sample of 53,332 individuals with type 2 diabetes and COVID-19, we found that metformin prescription was associated with a lower risk of all-cause mortality after COVID-19 (adjusted risk ratio [aRR] 0.61, 95% CI 0.51, 0.73). We also observed that metformin users, compared to DPP4i users, had a slightly lower risk of probable Long COVID (aRR 0.87, 95% CI 0.81, 0.94) but did not detect a significant relationship with Long COVID diagnosis (aRR 0.90, 95% CI 0.68, 1.20), although we observed similar point estimates across Long COVID outcomes. Conclusions: These findings support the hypothesis that metformin prescription during acute COVID-19 may be associated with lower mortality among adults with diabetes. These analyses also provide modest evidence of a protective association against Long COVID in adults with diabetes, although estimates were imprecise.","rel_num_authors":21,"rel_authors":[{"author_name":"Zachary Butzin-Dozier","author_inst":"Stanford University, Stanford, CA USA"},{"author_name":"Yunwen Ji","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Lin-Chiun Wang","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"A. Jerrod Anzalone","author_inst":"University of Nebraska Medical Center, Omaha, NE, USA"},{"author_name":"Oluwasolape Olawore","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Ryan Hafen","author_inst":"Purdue University, West Lafayette, IN, USA"},{"author_name":"Eric Hurwitz","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Manav Kumar","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Rena C. Patel","author_inst":"University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Ariana Budhihartanto","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Mark van der Laan","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"John M. Colford Jr.","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Alan E. Hubbard","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"John B. Buse","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Steven Johnson","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Jane Reusch","author_inst":"University of Colorado, Anschutz, Aurora, CO, USA"},{"author_name":"Lauren E. Chan","author_inst":"University of Chicago, Chicago, IL, USA"},{"author_name":"Richard Moffitt","author_inst":"Renaissance School of Medicine, Stony Brook University, New York, NY, USA"},{"author_name":"Rachel Wong","author_inst":"Renaissance School of Medicine, Stony Brook University, New York, NY, USA"},{"author_name":"Carolyn Bramante","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"- on behalf of the National Clinical Cohort Collaborative","author_inst":"-"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Metformin and Severe Post-COVID-19 Outcomes Among Individuals with Diabetes Mellitus","rel_doi":"10.64898\/2026.07.06.26357398","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357398","rel_abs":"Background: Metformin is one of the most commonly prescribed medications for individuals with diabetes and may provide protection against long-term sequelae of COVID-19. Methods: We evaluated a retrospective cohort of individuals in the National Clinical Cohort Collaborative with type 2 diabetes mellitus and COVID-19 who were prescribed metformin or a dipeptidyl peptidase-4 inhibitor (DPP4i) at least 30 days before the onset of acute COVID-19 between October 1, 2021, and November 15, 2023. We compared the 12-month cumulative incidence of Long COVID diagnosis (ICD-10 U09.9: Post COVID-19 condition, unspecified), probable Long COVID (based on a model-derived phenotype), and mortality between individuals prescribed metformin vs. DPP4i. We applied Super Learner and targeted maximum likelihood estimation to obtain risk ratios while adjusting for covariates of interest. Results: In our sample of 53,332 individuals with type 2 diabetes and COVID-19, we found that metformin prescription was associated with a lower risk of all-cause mortality after COVID-19 (adjusted risk ratio [aRR] 0.61, 95% CI 0.51, 0.73). We also observed that metformin users, compared to DPP4i users, had a slightly lower risk of probable Long COVID (aRR 0.87, 95% CI 0.81, 0.94) but did not detect a significant relationship with Long COVID diagnosis (aRR 0.90, 95% CI 0.68, 1.20), although we observed similar point estimates across Long COVID outcomes. Conclusions: These findings support the hypothesis that metformin prescription during acute COVID-19 may be associated with lower mortality among adults with diabetes. These analyses also provide modest evidence of a protective association against Long COVID in adults with diabetes, although estimates were imprecise.","rel_num_authors":21,"rel_authors":[{"author_name":"Zachary Butzin-Dozier","author_inst":"Stanford University, Stanford, CA USA"},{"author_name":"Yunwen Ji","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Lin-Chiun Wang","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"A. Jerrod Anzalone","author_inst":"University of Nebraska Medical Center, Omaha, NE, USA"},{"author_name":"Oluwasolape Olawore","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Ryan Hafen","author_inst":"Purdue University, West Lafayette, IN, USA"},{"author_name":"Eric Hurwitz","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Manav Kumar","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Rena C. Patel","author_inst":"University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Ariana Budhihartanto","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Mark van der Laan","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"John M. Colford Jr.","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Alan E. Hubbard","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"John B. Buse","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Steven Johnson","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Jane Reusch","author_inst":"University of Colorado, Anschutz, Aurora, CO, USA"},{"author_name":"Lauren E. Chan","author_inst":"University of Chicago, Chicago, IL, USA"},{"author_name":"Richard Moffitt","author_inst":"Renaissance School of Medicine, Stony Brook University, New York, NY, USA"},{"author_name":"Rachel Wong","author_inst":"Renaissance School of Medicine, Stony Brook University, New York, NY, USA"},{"author_name":"Carolyn Bramante","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"- on behalf of the National Clinical Cohort Collaborative","author_inst":"-"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"A higher polygenic score for peripheral artery disease is associated with younger age at surgery among patients undergoing revascularization","rel_doi":"10.64898\/2026.06.25.26356619","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356619","rel_abs":"We examined whether polygenic risk for peripheral artery disease (PAD) is associated with severity among patients undergoing lower extremity revascularization at Yale New Haven Hospital. Patients were classified into European (EUR) and non-European (non-EUR) ancestry groups. Associations between the 19-variant polygenic score (PGS) and nine severity indicators were evaluated using linear and Cox regression models stratified by ancestry, followed by meta-analysis. Significant findings (p < 0.05) were assessed for replication in the UK Biobank (UKB). After quality control, 68 EUR and 59 non-EUR patients were included. In EUR patients, higher PGS was associated with increased risk for stroke (HR = 2.43, 95% CI 1.06-5.57). Meta-analysis revealed a significant association between higher PGS and younger age at surgery ({beta} = -2.90, SE = 1.28), which was replicated in the UKB ({beta} = -0.58, SE = 0.15). These results suggest genetic risk contributes to PAD severity.","rel_num_authors":8,"rel_authors":[{"author_name":"Jiaqi Hu","author_inst":"Yale School of Public Health"},{"author_name":"Dana Alameddine","author_inst":"Yale School of Medicine"},{"author_name":"Shreef Said","author_inst":"Yale School of Medicine"},{"author_name":"He Wang","author_inst":"Stony Brook University"},{"author_name":"Mingfu Yu","author_inst":"Yale School of Medicine"},{"author_name":"Michael Murray","author_inst":"Icahn Chool of Medicine at Mount Sinai"},{"author_name":"Andrew DeWan","author_inst":"Yale School of Public Health"},{"author_name":"Cassius Iyad Ochoa Chaar","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Sequential Word Properties in Verbal Fluency: Detecting High-Proficiency Cognitive Impairment","rel_doi":"10.64898\/2026.07.06.26357360","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357360","rel_abs":"Verbal fluency (VF) tasks are widely used to differentiate patients with cognitive impairment from healthy controls, but total word count produced during these tasks becomes unreliable when patients and controls exhibit comparable proficiency. This study examined, in detail, whether item-level and sequential properties of words produced during a VF task could reliably differentiate high-proficiency patients indistinguishable from controls by word count alone. Seventy-seven native Mandarin Chinese speakers (38 controls and 39 patients with mild cognitive impairment or mild dementia) completed a semantic VF task. Participants were subdivided by proficiency into four groups: high-proficiency controls (HC), low-proficiency controls (LC), high-proficiency patients (HP), and low-proficiency patients (LP). The LC and HP subgroups were matched on semantic fluency scores and thus provided a key focus for the investigation. We examined item-level properties (word frequency, contextual diversity, semantic diversity, surprisal) and sequential properties (positional frequency variation) of the words produced. Significant group differences emerged across item-level psycholinguistic properties, though these were primarily driven by the LP group, with no reliable differentiation between LC and HP. Crucially, positional frequency variation distinguished LC from HP. LC participants began their lists with high-frequency words followed by a systematic decline, whereas HP patients produced words within a consistently narrow frequency band throughout. These findings indicate that item-level psycholinguistic properties alone are insufficient to differentiate HP from LC, whereas sequential word frequency variation provides a potential index of cognitive impairment, reflecting underlying differences in semantic retrieval and memory organisation. Future work with larger samples is needed to validate generalisability.","rel_num_authors":5,"rel_authors":[{"author_name":"Ya-Ning Chang","author_inst":"Miin Wu School of Computing, National Cheng Kung University, Tainan, Taiwan"},{"author_name":"Yi-Hsuan Wang","author_inst":"College of Medicine, National Cheng Kung University, Tainan, Taiwan"},{"author_name":"Chia-Ju Chou","author_inst":"Cardinal Tien Hospital, New Taipei City, Taiwan"},{"author_name":"Yi-Chien Liu","author_inst":"Cardinal Tien Hospital, New Taipei City, Taiwan"},{"author_name":"Matthew A. Lambon Ralph","author_inst":"MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, United Kingdom"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Heterogeneous Treatment Effects in HFpEF: Distinguishing Drug-Specific Response from Prognostic Phenotypes Across Randomized Trials","rel_doi":"10.64898\/2026.07.06.26357251","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357251","rel_abs":"Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods: We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results: Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti-volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions: The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting.","rel_num_authors":30,"rel_authors":[{"author_name":"Clodomir Santana","author_inst":"University of California, Davis, USA"},{"author_name":"Asuka Katayama","author_inst":"University of California, Davis, USA"},{"author_name":"Aditya Ballal","author_inst":"University of California, Davis, USA"},{"author_name":"Padmini Sirish","author_inst":"University of California, Davis, USA"},{"author_name":"David A. Liem","author_inst":"University of California, Davis, USA"},{"author_name":"Julie T. Bidwell","author_inst":"University of California, Davis, USA"},{"author_name":"Chao-Yin Chen","author_inst":"University of California, Davis, USA"},{"author_name":"Miriam Nuno","author_inst":"University of California, Davis, USA"},{"author_name":"Imo Ebong","author_inst":"University of California, Davis, USA"},{"author_name":"Xiao-Dong Zhang","author_inst":"University of California, Davis, USA"},{"author_name":"Leighton Izu","author_inst":"University of California, Davis, USA"},{"author_name":"Barry A. Borlaug","author_inst":"Mayo Clinic, Rochester, Minnesota, USA"},{"author_name":"Julio A. Chirinos","author_inst":"University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"},{"author_name":"Akshay S. Desai","author_inst":"Brigham and Women's Hospital, Boston, Massachusetts, USA"},{"author_name":"Patrice Desvigne-Nickens","author_inst":"Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA"},{"author_name":"Michael M. Givertz","author_inst":"Brigham and Women's Hospital, Boston, Massachusetts, USA"},{"author_name":"Sadiya S. Khan","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA"},{"author_name":"Dalane W. Kitzman","author_inst":"Wake Forest University School of Medicine, Winston Salem, North Carolina, USA"},{"author_name":"Gregory D. Lewis","author_inst":"Massachusetts General Hospital, Boston, Massachusetts, USA"},{"author_name":"Laura J. Rasmussen-Torvik","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA"},{"author_name":"Margaret M. Redfield","author_inst":"Mayo Clinic, Rochester, Minnesota, USA"},{"author_name":"Vandana Sachdev","author_inst":"Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA"},{"author_name":"Svati H. Shah","author_inst":"Duke Clinical Research Institute, Chapel Hill, North Carolina, USA"},{"author_name":"Kavita Sharma","author_inst":"Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Emily Tinsley","author_inst":"Foundation for the National Institutes of Health, North Bethesda, Maryland, USA"},{"author_name":"Renee Wong","author_inst":"Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA"},{"author_name":"Sanjiv J. Shah","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA"},{"author_name":"Javier E. Lopez","author_inst":"University of California, Davis, USA"},{"author_name":"Nipavan Chiamvimonvat","author_inst":"University of Arizona, Phoenix, Arizona, USA"},{"author_name":"Martin Cadeiras","author_inst":"University of California, Davis, USA"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"In Vivo Spatial Transcriptomics for Bleeding-free Profiling Human Internal Organs","rel_doi":"10.64898\/2026.07.06.26357355","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357355","rel_abs":"Despite the significant technical advancement in spatial transcriptomics, its clinical usage is largely untapped. Here, we develop an integrated system, ENDO-Genome, for minimally invasive in-body transcript sampling to facilitate live spatial transcriptomic analysis of human internal organs. This is achieved by integrating a nanoarrayed biochip with existing endoscope to perform pressure-sensor-calibrated \"Touch & Go\" RNA extraction directly from human internal organs, including the highly vascularized liver or kidney, without the need for tissue biopsy, voiding any bleeding risks. By a demonstration using gastrointestinal endoscopy, multiplexed landscape of 55 mRNA transcripts was obtained from multiple locations of human intestinal tract via a 5-minute operation in routine examinations. Benefiting from a sequencing-free approach, each assay costs less than 10 US dollars. For the clinical study involving 15 Crohn' s disease (CD) patients, no complication case was reported out of 47 ENDO-Genome operations, showcasing the gentle deposition and excellent safety of the technique. The live spatial transcriptomics provides direct in vivo pictures of the heterogenous spatial transcriptional programs underlying CD pathological response at different intestinal locations, revealing distinct ileal phenotypes. This is manifested by unique microscale scattering of inflammation gene clusters, along with the discovery of a tissue-specific cooperative mechanisms between inflammation and RNA methylation regulations at single- or multi-cell scales.","rel_num_authors":20,"rel_authors":[{"author_name":"Hailiang Sun","author_inst":"City University of Hong Kong"},{"author_name":"Feng Guo","author_inst":"City University of Hong Kong"},{"author_name":"Xinzhe Zhao","author_inst":"Sun Yat-sen University"},{"author_name":"Youyang Wan","author_inst":"City University of Hong Kong"},{"author_name":"Xijian Zhang","author_inst":"Sun Yat-sen University"},{"author_name":"Jiachen Sun","author_inst":"Sun Yat-sen University"},{"author_name":"Xingdao He","author_inst":"City University of Hong Kong"},{"author_name":"Baowen Gai","author_inst":"Sun Yat-sen University"},{"author_name":"Chuxiao Xiong","author_inst":"City University of Hong Kong"},{"author_name":"Yutao Ma","author_inst":"City University of Hong Kong"},{"author_name":"Jin Qu","author_inst":"City University of Hong Kong"},{"author_name":"Pengyu Li","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Feng Gao","author_inst":"Sun Yat-sen University"},{"author_name":"Xi Zhao","author_inst":"City University of Hong Kong"},{"author_name":"Xianglin Ji","author_inst":"City University of Hong Kong"},{"author_name":"Zhengbao Yang","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Lung-Yi Mak","author_inst":"The University of Hong Kong"},{"author_name":"Yat Hin Yap","author_inst":"The University of Hong Kong"},{"author_name":"Jia Ke","author_inst":"Sun Yat-sen University"},{"author_name":"Peng Shi","author_inst":"City University of Hong Kong"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Foundation Model RNAGAN Enhances Biomedical Insight of Nasopharyngeal Carcinoma Metastasis","rel_doi":"10.64898\/2026.07.02.736240","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736240","rel_abs":"RNAGAN (version 2.0, https:\/\/github.com\/ZhaozhengHou-HKU\/RNAGAN-2.0.git) is a published foundation model that analyzes single-cell and bulk-level RNA sequencing samples and enables multiple applications that enhance medical insights. Here we applied this model to Nasopharyngeal Carcinoma (NPC) as in-context few-short format (i.e., the model was never trained with any NPC data). We conducted all four supported functions, which include sample stratification, vectorization, pseudo data generation, and marker identification. The results were then used for identifying metastatic NPC and to investigate mechanisms associated with NPC metastasis.\n\nExamination with stratification showed that the accuracy of RNAGAN results for evaluating the metastasis risk in NPC patients are comparable to or outcompeted recently published risk estimation linear prediction model. Vectorization results present consistency across multiple cohorts and RNAGAN model versions. In the task of identifying markers and mechanisms related to NPC metastasis, incorporating pseudo data substantially enhanced the representativeness of single-cohort-based differential expression (DE) analysis. Moreover, RNAGAN identified metastasis-related marker genes based on single cohort, were concordant with the ground truth obtained across multiple cohorts (p=1.05e-9).\n\nRegarding biomedical mechanisms, RNAGAN enabled second-order feature extraction, unveiling a remarkable domination of the protective function of adaptive immune responses (as indicated by IL21R levels) over the hazardous function of chronic, non-resolving innate inflammation (as indicated by S100A8 levels) against NPC metastasis after first-line treatment. This association demonstrates a high degree of consistency with the external cohort.\n\nThis study demonstrates the utility of the foundation model RNAGAN in uncovering therapeutic insights for novel cancer types without extra training. We reveal a critical spatial mechanism preventing distant metastasis via humoral anti-tumor immunity in NPC. High S100A8 expression by innate antigen-presenting cells (APCs) triggers an inflammatory cascade promoting epithelial-mesenchymal transition (EMT) and metastasis. However, when germinal center IL21R+ B cells simultaneously colocalize with these innate signals, they override this suppressive tissue stress. Spatial analysis shows that a high S100A8\/IL21R intersection within tumor regions strictly distinguishes treatment responders, whereas non-responders display spatial mismatch or S100A8+ hyper-infiltration. This coordinated innate-adaptive cross-talk sustains functional tertiary lymphoid structures (TLS) that mature IgG-secreting plasma cells, which opsonize and eliminate emerging EMT tumor cells before systemic escape. Consequently, while S100A8 alone is an unreliable prognosticator, its spatial colocalization with IL21R is a robust protective indicator overlooked by conventional bulk analysis methods.","rel_num_authors":7,"rel_authors":[{"author_name":"Zhaozheng HOU","author_inst":"University of Hong Kong"},{"author_name":"Yijia Qian","author_inst":"University of Hong Kong"},{"author_name":"Victor Ho-Fun Lee","author_inst":"University of Hong Kong"},{"author_name":"Dora Lai-Wan Kwong","author_inst":"University of Hong Kong"},{"author_name":"Xinyuan Guan","author_inst":"University of Hong Kong"},{"author_name":"Zhonghua Liu","author_inst":"Columbia University"},{"author_name":"Wei Dai","author_inst":"University of Hong Kong"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Foundation Model RNAGAN Enhances Biomedical Insight of Nasopharyngeal Carcinoma Metastasis","rel_doi":"10.64898\/2026.07.02.736240","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736240","rel_abs":"RNAGAN (version 2.0, https:\/\/github.com\/ZhaozhengHou-HKU\/RNAGAN-2.0.git) is a published foundation model that analyzes single-cell and bulk-level RNA sequencing samples and enables multiple applications that enhance medical insights. Here we applied this model to Nasopharyngeal Carcinoma (NPC) as in-context few-short format (i.e., the model was never trained with any NPC data). We conducted all four supported functions, which include sample stratification, vectorization, pseudo data generation, and marker identification. The results were then used for identifying metastatic NPC and to investigate mechanisms associated with NPC metastasis.\n\nExamination with stratification showed that the accuracy of RNAGAN results for evaluating the metastasis risk in NPC patients are comparable to or outcompeted recently published risk estimation linear prediction model. Vectorization results present consistency across multiple cohorts and RNAGAN model versions. In the task of identifying markers and mechanisms related to NPC metastasis, incorporating pseudo data substantially enhanced the representativeness of single-cohort-based differential expression (DE) analysis. Moreover, RNAGAN identified metastasis-related marker genes based on single cohort, were concordant with the ground truth obtained across multiple cohorts (p=1.05e-9).\n\nRegarding biomedical mechanisms, RNAGAN enabled second-order feature extraction, unveiling a remarkable domination of the protective function of adaptive immune responses (as indicated by IL21R levels) over the hazardous function of chronic, non-resolving innate inflammation (as indicated by S100A8 levels) against NPC metastasis after first-line treatment. This association demonstrates a high degree of consistency with the external cohort.\n\nThis study demonstrates the utility of the foundation model RNAGAN in uncovering therapeutic insights for novel cancer types without extra training. We reveal a critical spatial mechanism preventing distant metastasis via humoral anti-tumor immunity in NPC. High S100A8 expression by innate antigen-presenting cells (APCs) triggers an inflammatory cascade promoting epithelial-mesenchymal transition (EMT) and metastasis. However, when germinal center IL21R+ B cells simultaneously colocalize with these innate signals, they override this suppressive tissue stress. Spatial analysis shows that a high S100A8\/IL21R intersection within tumor regions strictly distinguishes treatment responders, whereas non-responders display spatial mismatch or S100A8+ hyper-infiltration. This coordinated innate-adaptive cross-talk sustains functional tertiary lymphoid structures (TLS) that mature IgG-secreting plasma cells, which opsonize and eliminate emerging EMT tumor cells before systemic escape. Consequently, while S100A8 alone is an unreliable prognosticator, its spatial colocalization with IL21R is a robust protective indicator overlooked by conventional bulk analysis methods.","rel_num_authors":7,"rel_authors":[{"author_name":"Zhaozheng HOU","author_inst":"University of Hong Kong"},{"author_name":"Yijia Qian","author_inst":"University of Hong Kong"},{"author_name":"Victor Ho-Fun Lee","author_inst":"University of Hong Kong"},{"author_name":"Dora Lai-Wan Kwong","author_inst":"University of Hong Kong"},{"author_name":"Xinyuan Guan","author_inst":"University of Hong Kong"},{"author_name":"Zhonghua Liu","author_inst":"Columbia University"},{"author_name":"Wei Dai","author_inst":"University of Hong Kong"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Telomerase RNA regulates the epigenome primed for human lineage commitment","rel_doi":"10.64898\/2026.07.03.736284","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736284","rel_abs":"Telomerase RNA (TERC) is known as the essential template for telomere elongation. Here, we report an unexpected role for TERC in regulating chromatin accessibility, which is primed for determining the cell fate of human embryonic stem cells (hESCs). TERC-deficient hESCs retain critical markers for pluripotency but fail to undergo lineage differentiation as shown by standard in vivo teratoma formation as well as in vitro differentiation assays, which is consistent with repressed transcription during differentiation into the three germ lineages. Notably, transient re-introduction of TERC into TERC-deficient hESCs rescued lineage differentiation capacity without restoring telomere length. TERC binds to the promoters and enhancers of developmental genes marked by H3K27ac to maintain an open chromatin state. Loss of TERC reduces H3K27ac deposition and decreases chromatin accessibility through the remodelling of three-dimensional genome organization, including TAD boundary insulation and compartment switching. Collectively, our findings reveal that TERC is a chromatin-associated noncoding RNA that regulates the epigenomic architecture that governs cell fate for lineage commitment during development.","rel_num_authors":16,"rel_authors":[{"author_name":"Jie Li","author_inst":"Nankai University"},{"author_name":"Peng Su","author_inst":"Nankai University"},{"author_name":"Mingqi Gao","author_inst":"Peking University"},{"author_name":"Chang Liu","author_inst":"Nankai University"},{"author_name":"Niannian Li","author_inst":"Weifang People's Hospital"},{"author_name":"Guofeng Feng","author_inst":"Nankai University"},{"author_name":"Yongqin Yu","author_inst":"Nankai University"},{"author_name":"Zhifei Chen","author_inst":"Nankai University"},{"author_name":"Guoxing Yin","author_inst":"Nankai University"},{"author_name":"Xiaoying Ye","author_inst":"Nankai University"},{"author_name":"Jiangtao Lu","author_inst":"Nankai University"},{"author_name":"Ziyi Jin","author_inst":"Nankai University"},{"author_name":"Zhengmao Zhu","author_inst":"Nankai University"},{"author_name":"Haiying Liu","author_inst":"Sun Yat-sen University"},{"author_name":"Hua Wang","author_inst":"Peking University"},{"author_name":"Lin Liu","author_inst":"Nankai University"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Environment-dependent landscapes of coding variant impacts on coproporphyrinogen oxidase","rel_doi":"10.64898\/2026.07.02.735896","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.735896","rel_abs":"Hereditary coproporphyria (HCP) -- caused by variants in coproporphyrinogen oxidase (CPOX) -- can be diagnosed via genome sequencing. However, 74% of clinically-reported CPOX missense variants are classified as variants of uncertain significance (VUS) due to lack of evidence. CPOX variant classification is further complicated by environment-dependence: For example, the CPOX variant p.Asn272His (c.814A>C) is classified as benign yet has been associated with HCP-like symptoms in the context of mercury exposure. Here we measured the functional impact of nearly all possible CPOX amino acid substitutions in both the presence and absence of mercury. The resulting CPOX variant effect maps reflect known protein structure and mutational tolerance patterns while also offering new sequence-structure-function insights. Scores from this atlas not only distinguish pathogenic from benign variants but also identify mercury-dependent variant impacts, thus informing our clinical, structural, and functional understanding of CPOX deficiency and illustrating the value of systematic context-dependent multiplexed assays of genetic variant effects.","rel_num_authors":17,"rel_authors":[{"author_name":"Warren van Loggerenberg","author_inst":"University of Pittsburgh"},{"author_name":"Haotian Zhang","author_inst":"University of Pittsburgh"},{"author_name":"Vignesh Senguttuvan","author_inst":"University of Pittsburgh"},{"author_name":"Michael J Chambers","author_inst":"University of Pittsburgh"},{"author_name":"Mailoan Panchalingam","author_inst":"University of Toronto"},{"author_name":"Alireza Rasoulzadeh","author_inst":"University of Pittsburgh"},{"author_name":"Anna Axakova","author_inst":"University of Toronto"},{"author_name":"Marinella Gebbia","author_inst":"University of Toronto"},{"author_name":"Robert J Desnick","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Bruce Wang","author_inst":"University of California San Francisco"},{"author_name":"Caroline Schmitt","author_inst":"French Centre of Porphyrias"},{"author_name":"Laurent Gouya","author_inst":"French Centre of Porphyrias"},{"author_name":"Jordi To-Figueras","author_inst":"University of Barcelona"},{"author_name":"Alexander Wahl","author_inst":"Labcorp Genetics"},{"author_name":"Ivet Bahar","author_inst":"Stony Brook University"},{"author_name":"Pemra Doruker","author_inst":"Allotar Therapeutics"},{"author_name":"Frederick P Roth","author_inst":"University of Pittsburgh"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Environment-dependent landscapes of coding variant impacts on coproporphyrinogen oxidase","rel_doi":"10.64898\/2026.07.02.735896","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.735896","rel_abs":"Hereditary coproporphyria (HCP) -- caused by variants in coproporphyrinogen oxidase (CPOX) -- can be diagnosed via genome sequencing. However, 74% of clinically-reported CPOX missense variants are classified as variants of uncertain significance (VUS) due to lack of evidence. CPOX variant classification is further complicated by environment-dependence: For example, the CPOX variant p.Asn272His (c.814A>C) is classified as benign yet has been associated with HCP-like symptoms in the context of mercury exposure. Here we measured the functional impact of nearly all possible CPOX amino acid substitutions in both the presence and absence of mercury. The resulting CPOX variant effect maps reflect known protein structure and mutational tolerance patterns while also offering new sequence-structure-function insights. Scores from this atlas not only distinguish pathogenic from benign variants but also identify mercury-dependent variant impacts, thus informing our clinical, structural, and functional understanding of CPOX deficiency and illustrating the value of systematic context-dependent multiplexed assays of genetic variant effects.","rel_num_authors":17,"rel_authors":[{"author_name":"Warren van Loggerenberg","author_inst":"University of Pittsburgh"},{"author_name":"Haotian Zhang","author_inst":"University of Pittsburgh"},{"author_name":"Vignesh Senguttuvan","author_inst":"University of Pittsburgh"},{"author_name":"Michael J Chambers","author_inst":"University of Pittsburgh"},{"author_name":"Mailoan Panchalingam","author_inst":"University of Toronto"},{"author_name":"Alireza Rasoulzadeh","author_inst":"University of Pittsburgh"},{"author_name":"Anna Axakova","author_inst":"University of Toronto"},{"author_name":"Marinella Gebbia","author_inst":"University of Toronto"},{"author_name":"Robert J Desnick","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Bruce Wang","author_inst":"University of California San Francisco"},{"author_name":"Caroline Schmitt","author_inst":"French Centre of Porphyrias"},{"author_name":"Laurent Gouya","author_inst":"French Centre of Porphyrias"},{"author_name":"Jordi To-Figueras","author_inst":"University of Barcelona"},{"author_name":"Alexander Wahl","author_inst":"Labcorp Genetics"},{"author_name":"Ivet Bahar","author_inst":"Stony Brook University"},{"author_name":"Pemra Doruker","author_inst":"Allotar Therapeutics"},{"author_name":"Frederick P Roth","author_inst":"University of Pittsburgh"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Living in a metal-rich world: Enhanced growth and reduced metal accumulation in Fusarium fungi from the Kiirunavaara iron ore mine","rel_doi":"10.64898\/2026.07.09.737466","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737466","rel_abs":"Background: Human activities such as mining generally lead to increased heavy metal concentrations in the environment. While traditional remediation techniques are often costly, the use of fungi as bioremediators, known as mycoremediation, is increasingly gaining attention as a sustainable approach for removal of heavy metals. Here, we evaluated heavy metal levels inside the Kiirunavaara iron ore mine in Northern Sweden and analysed fungal responses to various metal concentrations by comparing growth and metal uptake in mine-derived isolates and closely related control isolates. Results: Sediments inside the mine were enriched in heavy metals compared to those from the outlet of the mine to natural lakes. Six Fusarium isolates were recovered from contaminated mining environments: five isolates from inside the mine were identified as Fusarium oxysporum, and one isolate from the outlet was identified as Fusarium tricinctum. Isolates from the mine and outlet showed overall higher survival and biomass production in presence of copper, iron, and zinc across a range of concentrations (up to 1000 mg\/L) compared to control isolates. At the same time, these isolates often exhibited reduced relative metal uptake. As a result, mycoremediation potential, assessed as total uptake in the grown mycelium, was isolate-dependent. Conclusions: Based on these results, we conclude that Fusarium isolates from the Kiirunavaara mine show increased growth in media enriched with heavy metals compared to closely related control isolates. We additionally show that mycoremediation potential is not necessarily associated with environmental origin. Instead, mycoremediation potential should be evaluated on a case-by-case basis for each isolate and based on specific needs for mycoremediation.","rel_num_authors":4,"rel_authors":[{"author_name":"Petter Birger Madsen","author_inst":"Stockholm University"},{"author_name":"Noah Hensen","author_inst":"Stockholm University"},{"author_name":"Marion Orsucci","author_inst":"Stockholm University"},{"author_name":"Hanna Johannesson","author_inst":"The Royal Swedish Academy of Sciences, Stockholm, Sweden."}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Early-life acquisition of Lactobacillaceae protects against experimental cholera","rel_doi":"10.64898\/2026.07.08.737341","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737341","rel_abs":"Cholera causes severe diarrheal illness in young children, but the mechanisms underlying age-dependent susceptibility remain unclear. Experimental cholera in neonatal mice recapitulates age-dependent susceptibility: suckling mice are susceptible to Vibrio cholerae colonization and cholera toxin (CT)-dependent disease, whereas adult mice are not readily colonized and do not develop cholera-like disease. Here, we define a developmental window in which susceptibility declines sharply over the first two postnatal weeks. Maternal antibiotic exposure disrupted vertical transmission of maternal microbiota to offspring and altered distal small intestinal microbiota assembly, extending the window of susceptibility to CT-dependent V. cholerae colonization and disease. Pups born to antibiotic-treated dams exhibited reduced Lactobacillaceae and increased Enterobacteriaceae, and reintroduction of an endogenous Lactobacillus isolate restored offspring lactobacilli levels and reestablished resistance to experimental cholera at two weeks of age. Consistent with a direct protective role, increasing lactobacilli in susceptible neonatal mice reduced experimental cholera burden, and cultures of the endogenous Lactobacillus isolate as well as spent culture media acidified the in vitro growth environment and rapidly eliminated recoverable V. cholerae. Together, these findings identify vertical transmission of maternal microbiota to offspring and lactobacilli-associated antagonism as determinants of early-life resistance to cholera.","rel_num_authors":4,"rel_authors":[{"author_name":"Claire M. L. Chapman","author_inst":"University of California, San Diego"},{"author_name":"Sophia Di Stefano","author_inst":"University of California, San Diego"},{"author_name":"Andrew Kapinos Silva","author_inst":"University of California, San Diego"},{"author_name":"Fabian Rivera-Chavez","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"The anatomical compartment defines distinct immune remodeling within human visceral adipose tissue during aging","rel_doi":"10.64898\/2026.07.06.736672","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736672","rel_abs":"Age-associated inflammation varies across tissues, but whether distinct visceral adipose tissue (VAT) depots undergo inflammatory remodeling in a depot-specific manner remains unclear. Here we profiled human peri-organ VAT, comparing kidney-associated fat (KF, from kidney transplantation donors) and gallbladder-associated fat (GBF, from asymptomatic cholecystectomy patients with incidental polyps), using single-cell RNA sequencing, flow cytometry, intracellular protein profiling and in situ analysis. GBF showed broad tissue-residency and granzyme K-associated remodeling across conventional, regulatory and innate-like lymphocyte compartments, whereas KF showed stronger B cell remodeling, greater myeloid representation and more compartmentalized changes within resident effector-like CD8 T cell states. We further identified age-associated CD20 T cells with features consistent with local B-T cell interaction and an antigen-experienced, granzyme K-associated inflammatory memory phenotype. In situ analysis revealed age-associated myeloid accumulation and crown-like structure remodeling, accompanied by distinct myeloid inflammatory programs in KF and GBF. Finally, depot-specific immune signatures associated with clinical indices of adjacent kidney and liver function. These findings indicate that age-associated distinct immune programs within peri-organ VAT depots track with local tissue context and the state of the adjacent organ.","rel_num_authors":17,"rel_authors":[{"author_name":"Rodrigo Castaneda","author_inst":"Korea Institute of Science and Technology (KIST)"},{"author_name":"Hye-In Sim","author_inst":"Korea Institute of Science and Technology (KIST)"},{"author_name":"Narae Park","author_inst":"Korea Institute of Science and Technology (KIST)"},{"author_name":"Hye-Jin Lee","author_inst":"Korea Institute of Science and Technology (KIST)"},{"author_name":"Minsun Yu","author_inst":"Korea Institute of Science and Technology (KIST)"},{"author_name":"Hyun Yong Jin","author_inst":"Genentech Inc"},{"author_name":"Hyun Jung Kim","author_inst":"Korea University College of Medicine"},{"author_name":"Kye Jin Park","author_inst":"University of Ulsan College of Medicine"},{"author_name":"Bo-Yeong Jin","author_inst":"Seoul National University"},{"author_name":"Hyun Kyu Song","author_inst":"Korea University"},{"author_name":"Heeju Ryu","author_inst":"Sungkyunkwan University"},{"author_name":"Cheolju Lee","author_inst":"Korea Institute of Science and Technology"},{"author_name":"Kanghyun Ryu","author_inst":"Korea Institute of Science and Technology (KIST)"},{"author_name":"Youngmin Ko","author_inst":"University of Ulsan College of Medicine"},{"author_name":"Hye-Sung Jo","author_inst":"Korea University"},{"author_name":"Yoon Park","author_inst":"Korea Institute of Science and Technology (KIST)"},{"author_name":"Rafael Taeho Han","author_inst":"Korea Institute of Science and Technology (KIST)"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Single-molecule imaging reveals cytoplasmic translation of P granule-enriched mRNAs in C. elegans","rel_doi":"10.64898\/2026.07.01.735846","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735846","rel_abs":"Germ granules are condensates in germ plasm, a specialized cytoplasm that segregates to the embryonic germline. In Drosophila, translation of nanos mRNA occurs at the surface of germ granules, suggesting that the granules promote translation. In C. elegans, however, germ (P) granules are not essential for Nanos expression. Using single-molecule imaging in C. elegans embryos, we map the distribution of translating and non-translating molecules of the Nanos homolog nos-2 and two other maternal mRNAs enriched in P granules. In early germline blastomeres, these mRNAs are not translated and distribute between the cytoplasm and P granules. At translation onset, mRNA molecules in the cytoplasm are translated, while most mRNA molecules in the P granules remain non-translating. nos-2 translation requires a rise in the concentration of the RNA-binding protein POS-1, which occurs independently of P granules. Consistent with low translation inside the granules, P granules are depleted of ribosomes and 43S pre-initiation complexes. Our observations suggest that germ granules promote Nanos protein expression by concentrating Nanos mRNA in germline precursors, but do not directly promote translation.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC=\"FIGDIR\/small\/735846v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (22K):\norg.highwire.dtl.DTLVardef@1041f85org.highwire.dtl.DTLVardef@1b15755org.highwire.dtl.DTLVardef@1dcb759org.highwire.dtl.DTLVardef@1895e0b_HPS_FORMAT_FIGEXP  M_FIG C_FIG SynopsisGerm granules are condensates proposed to regulate the translation of mRNAs like Nanos that code for germ cell fate determinants. Using single-molecule imaging in C. elegans embryos, this study shows that P granule scaffolds concentrate mRNAs in germline precursors, but do not control the activity of translational regulators.\n\n- P granules concentrate mRNAs but are depleted of ribosomes and 43S pre-initiation complexes\n- Translation occurs mainly in the cytoplasm where ribosomes are most abundant\n- nanos translation onset is timed by a rise in POS-1, which counteracts the repressor SPN-4; both enrich in P granules but act independently.","rel_num_authors":5,"rel_authors":[{"author_name":"William R Simmons","author_inst":"Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine"},{"author_name":"Qi Geng","author_inst":"Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine"},{"author_name":"Stephanie ITT Miller","author_inst":"Department of Biological Sciences, Dartmouth College"},{"author_name":"Erik E Griffin","author_inst":"School of Life Sciences, University of Warwick"},{"author_name":"Geraldine Seydoux","author_inst":"HHMI, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Distinct transcriptional programs define cranial motor neuron subtypes during vertebrate development","rel_doi":"10.64898\/2026.07.02.731459","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.731459","rel_abs":"Closely related neurons that share core differentiation programs can be difficult to distinguish by gene expression, even when they differ in connectivity and function. Cranial motor neurons (cMNs) exemplify this challenge, forming discrete nuclei that control behaviors as diverse as eye movement, feeding, facial expression, and regulation of visceral organ function. However, the developmental programs that drive cMN target choices and functional specialization have not been comprehensively studied in any vertebrate. Here, we present an integrated single-cell RNA-sequencing atlas of zebrafish cMN development from 18 to 144 hours post-fertilization, combining FACS-purified cMNs with cMNs computationally extracted from published whole-embryo datasets and perform extensive validation by HCR in situ hybridization. We find that each cranial motor nucleus expresses a distinct transcriptional signature, and in many cases, we identify transcriptional correlates to functional subtypes within individual nuclei as determined by retrograde labeling. We find that identity often precedes axon targeting, indicating that cranial motor neuron fate is genetically specified early in development. These distinct identities are shaped by the intersection of shared function, rhombomere origin, and developmental time. A cross-species comparison reveals a largely one-to-one correspondence between zebrafish and mouse cMN nuclei, indicating that these genetic programs are conserved. Together, this atlas provides a nucleus-resolved molecular framework for understanding cranial motor neuron diversification, and for interpreting human cranial dysinnervation disorders.","rel_num_authors":6,"rel_authors":[{"author_name":"Austin Seroka","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Riku Yasutomi","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Italia DiChristina","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Adam J Isabella","author_inst":"University of Minnesota"},{"author_name":"Cole Trapnell","author_inst":"University of Washington"},{"author_name":"Cecilia B Moens","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Room to breathe: Nutrition and developmental oxygen modulate the crowding effect on size in Drosophila melanogaster","rel_doi":"10.64898\/2026.07.02.736161","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736161","rel_abs":"In a wide variety of animals, developmental crowding results in adults with smaller bodies. The crowding effect on body size in Drosophila melanogaster is canonically attributed to heightened competition for nutrition. However, whether other consequences of crowding also contribute to its effect on size remains an open question. We tested the relative contributions of nutritional competition, oxygen availability, and larval-generated metabolites to the crowding effect on size. We found that while nutrition explains most of the variation in body size due to crowding, oxygen also contributes in a sex- and nutrition-dependent manner. We found no evidence that larval-generated chemicals affect body size. These data confirm a widely suspected but untested role of nutrition in producing the crowding effect on size in D. melanogaster, while revealing an unexpected role of oxygen, and raise the possibility that behavior may be a mediator of density-dependent plasticity.\n\nResearch HighlightsWe found that both nutrition and oxygen mediate the crowding effect on size in Drosophila melanogaster.","rel_num_authors":2,"rel_authors":[{"author_name":"Cole M Nicholls","author_inst":"University of Illinois Chicago"},{"author_name":"Alexander Shingleton","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"K63-linked ubiquitin chains mark inactive Smoothened for packaging into ciliary extracellular vesicles","rel_doi":"10.64898\/2026.07.01.735856","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735856","rel_abs":"Signaling receptors can exit cilia either by retrieval back into the cell or by secretion in extracellular vesicles (EVs), a process known as ectocytosis. The mechanisms that govern ectocytosis remain poorly understood. Here, we leverage quantitative proteomic profiling to identify the Hedgehog signaling receptor Smoothened (SMO) as a major cargo of cilia-derived EVs. Surprisingly, ligands that promote ciliary accumulation of SMO strongly suppressed its packaging into EVs, indicating that ectocytosis selectively packages specific conformational states of SMO. We further find that SMO packaged into EVs is extensively modified with K63-linked ubiquitin chains. Preventing SMO ubiquitination or selectively removing K63-linked ubiquitin chains from SMO markedly reduced its secretion into EVs and caused SMO accumulation within cilia. Together, these results identify K63-linked ubiquitin chains as a sorting signal for ciliary ectocytosis and indicate that ubiquitin-dependent packaging of inactive SMO contributes to the dynamic redistribution of SMO during Hedgehog signaling.","rel_num_authors":6,"rel_authors":[{"author_name":"Mingli Zhu","author_inst":"UCSF"},{"author_name":"Yash Raj","author_inst":"UCSF"},{"author_name":"Gary A Bradshaw","author_inst":"Harvard Medical School"},{"author_name":"David U Mick","author_inst":"Saarland University School of Medicine"},{"author_name":"Marian U Kalocsay","author_inst":"MD Anderson Cancer Center"},{"author_name":"Maxence V Nachury","author_inst":"UCSF"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Microfluidic Tissue Array Platform for Personalized Drug Screening Using Tumor Explants or Biopsies","rel_doi":"10.64898\/2026.07.01.735821","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735821","rel_abs":"Despite major improvements in molecular characterization of breast cancer, current biomarkers still fall short in accurate treatment prediction. Interrogating tumor tissue ex-vivo in its native conformation is a direct strategy for guiding treatment of individual patients but presents a challenge. In this study, we developed a microfluidic tissue array (FTA) using small biopsy samples (< 1mm3) mimicking physiological flow for consistent exchange of nutrients and waste, retaining the tumor native stroma. Cell\/patient-derived breast cancer xenograft tissues were maintained over 2 weeks in the array and their response to therapeutic agents, doxorubicin or neratinib, were interrogated. Drug response in the uFTA showed >2-fold reduction in tumor cell viability which corroborated tumor size shrinkage in mice bearing the same tumor load. EdU\/Ki67 assays indicated selective retention of cells with higher proliferative capacity after drug treatment, underscoring in vivo clinical relevance. We have also developed a valved-FTA to increase throughput and variety of treatment conditions on the same chip. Together, this FTA can be staged as a powerful, low-cost benchtop theranostic tool for personalized cancer therapeutics compatible with FDAs New Approach Methods.","rel_num_authors":8,"rel_authors":[{"author_name":"A.H. R Ahmed","author_inst":"The City College of the City University of New York"},{"author_name":"Hong Shao","author_inst":"Memorial Sloan-Kettering Cancer Center"},{"author_name":"Lorraine Col\u00f3n-Cartagena","author_inst":"Memorial Sloan-Kettering Cancer Center"},{"author_name":"Lian Wang","author_inst":"VivoZ Biolabs, LLC"},{"author_name":"Xuejun Jiang","author_inst":"Memorial Sloan-Kettering Cancer Center"},{"author_name":"Fresia Pareja","author_inst":"Memorial Sloan-Kettering Cancer Center"},{"author_name":"Sarat Chandarlapaty","author_inst":"Memorial Sloan-Kettering Cancer Center"},{"author_name":"Sihong Wang","author_inst":"The City College of the City University of New York"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"DDX3 Regulates the Innate Immune Response to Bone Sarcomas","rel_doi":"10.64898\/2026.07.01.735844","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735844","rel_abs":"Osteosarcoma (OS) and Ewing sarcoma (EWS) are the most common malignant bone tumors in children and adolescents, with survival rates around 25% in metastatic disease and few advances in treatment in decades. High DDX3 expression has been reported across various sarcoma subtypes. Depending on the context, DDX3 appears to have opposing roles in regulating the tumor immune microenvironment. Within macrophages, DDX3 promotes inflammatory cytokine expression and supports immune cell function. In contrast, in tumor cells DDX3 suppresses a pro-inflammatory state by unwinding dsRNAs, preventing a Type I interferon response. We show that inhibiting DDX3 with RK-33 leads to dsRNA accumulation, inducing a Type I interferon response and broader inflammatory gene expression changes across multiple sarcoma models, shifting macrophage polarization toward a pro-inflammatory M1-like phenotype. To evaluate whether this innate immune microenvironmental remodeling could translate into clinical benefit, we assessed the therapeutic efficacy of RK-33 alone or in combination with mifamurtide, an immunostimulant, in immune competent mouse models of osteosarcoma, with metastatic burden as the primary outcome. We found that in the absence of MYC over-expression, the combination treatment significantly reduced metastatic spread. These findings support targeting DDX3 as a novel innate immune based therapeutic strategy and highlight that the tumors molecular landscape critically influences therapeutic responsiveness.","rel_num_authors":14,"rel_authors":[{"author_name":"Rachel Weil","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Esteban Uceda Arias-Stella","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Da Peng","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Patrick Cahan","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Natalie ter Hoeve","author_inst":"UMC Utrecht"},{"author_name":"Paul J. van Diest","author_inst":"UMC Utrecht"},{"author_name":"Venu Raman","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Poornima Gourabathini","author_inst":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center"},{"author_name":"Kimberly Q. McKinney","author_inst":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center"},{"author_name":"Kenzie Wells","author_inst":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center"},{"author_name":"Kaitlyn H. Smith","author_inst":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center"},{"author_name":"Jeffrey Huo","author_inst":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center"},{"author_name":"Javier Oesterheld","author_inst":"Atrium Health Levine"},{"author_name":"David Loeb","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"DDX3 Regulates the Innate Immune Response to Bone Sarcomas","rel_doi":"10.64898\/2026.07.01.735844","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735844","rel_abs":"Osteosarcoma (OS) and Ewing sarcoma (EWS) are the most common malignant bone tumors in children and adolescents, with survival rates around 25% in metastatic disease and few advances in treatment in decades. High DDX3 expression has been reported across various sarcoma subtypes. Depending on the context, DDX3 appears to have opposing roles in regulating the tumor immune microenvironment. Within macrophages, DDX3 promotes inflammatory cytokine expression and supports immune cell function. In contrast, in tumor cells DDX3 suppresses a pro-inflammatory state by unwinding dsRNAs, preventing a Type I interferon response. We show that inhibiting DDX3 with RK-33 leads to dsRNA accumulation, inducing a Type I interferon response and broader inflammatory gene expression changes across multiple sarcoma models, shifting macrophage polarization toward a pro-inflammatory M1-like phenotype. To evaluate whether this innate immune microenvironmental remodeling could translate into clinical benefit, we assessed the therapeutic efficacy of RK-33 alone or in combination with mifamurtide, an immunostimulant, in immune competent mouse models of osteosarcoma, with metastatic burden as the primary outcome. We found that in the absence of MYC over-expression, the combination treatment significantly reduced metastatic spread. These findings support targeting DDX3 as a novel innate immune based therapeutic strategy and highlight that the tumors molecular landscape critically influences therapeutic responsiveness.","rel_num_authors":14,"rel_authors":[{"author_name":"Rachel Weil","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Esteban Uceda Arias-Stella","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Da Peng","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Patrick Cahan","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Natalie ter Hoeve","author_inst":"UMC Utrecht"},{"author_name":"Paul J. van Diest","author_inst":"UMC Utrecht"},{"author_name":"Venu Raman","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Poornima Gourabathini","author_inst":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center"},{"author_name":"Kimberly Q. McKinney","author_inst":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center"},{"author_name":"Kenzie Wells","author_inst":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center"},{"author_name":"Kaitlyn H. Smith","author_inst":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center"},{"author_name":"Jeffrey Huo","author_inst":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center"},{"author_name":"Javier Oesterheld","author_inst":"Atrium Health Levine"},{"author_name":"David Loeb","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"The Spatial Landscape of Extracellular Matrix Gene Expression in Healthy and Type 2 Diabetic Human Pancreas","rel_doi":"10.64898\/2026.06.30.733275","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.733275","rel_abs":"The unique peri-islet and double-layered vascular basement membrane (BM) of the human pancreatic islet are critical regulators of beta cell survival and function. While animal models imply that endothelial cells (ECs) are the exclusive source of islet BM, the precise cellular origins and spatial organization of the human islet matrisome remain poorly defined due to overlap in genes that mark non-epithelial cell populations and loss of spatial context during single-cell dissociation. In this study, we combine computational integration of whole-pancreas single-cell transcriptomes using CONCORD with high-resolution MERFISH spatial genomics to map the extracellular matrix (ECM) landscape across 251,477 spatially resolved cells from seven non-diabetic and five type 2 diabetic human donors. Contrary to an endothelial-centric paradigm, our data support a cooperative division of labor in the provision of BM, where pericytes represent the dominant transcriptional source of structural BM collagens (COL4A1, COL4A2) and ECs selectively express complementary matrix factors (HSPG2, LAMA5). Spatial neighborhood analysis further resolves a specialized population of islet-associated fibroblasts enriched at the islet boundary that are characterized by expression of peri-islet laminin genes. In type 2 diabetes, this homeostatic perivascular niche changes composition, marked by a significant increase in the islet fibroblast-to-pericyte ratio. Concurrently, islet pericytes undergo pro-fibrotic reprogramming characterized by the loss of canonical identity markers (PDGFRB), altered expression of ECM genes including COL1A2 and COL18A1, and upregulation of contractile machinery (MYL9). In the non-diabetic pancreas, pericytes constitute the principal vascular BM-expressing population within islets, whereas type 2 diabetes is associated with coordinated, compartment-specific remodeling of vascular-supportive stromal populations.\n\nResearch in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIExtracellular matrix (ECM), and in particular basement membrane (BM), are essential structural and signaling components of the pancreatic islet microenvironment that contribute to beta cell function and survival.\nC_LIO_LIIslet capillaries are closely associated with endocrine cells and are surrounded by specialized BMs; however, the cellular sources of these BM components in the adult human pancreas remain incompletely defined.\nC_LIO_LIType 2 diabetes is associated with islet fibrosis and vascular dysfunction, but cell type-specific alterations in ECM-producing populations have not been comprehensively characterized in situ.\nC_LI\n\nWhat is the key question?O_LIWhich cell populations produce the components of ECM, including BM, within the adult human islet, and how are these populations altered in type 2 diabetes?\nC_LI\n\nWhat are the new findings?O_LISpatial transcriptomics identifies pericytes as the predominant vascular-associated source of ECM, including BM, gene expression in human islets, whereas endothelial cells exhibit complementary but more limited matrix-producing programs.\nC_LIO_LISpatial transcriptomics identifies an islet-associated fibroblast population enriched for fibrillar collagen and BM-associated genes that localizes preferentially to the islet surface niche.\nC_LIO_LIType 2 diabetes is associated with remodeling of perivascular ECM programs, including reduced expression of vascular basement membrane genes, a shift from a pericyte to smooth muscle-like identity, and increased expression of matrix-remodeling and fibrosis-associated genes.\nC_LI\n\nHow might this impact clinical practice in the foreseeable future?O_LIDefining the cellular sources and disease-associated remodeling of the human islet ECM may inform the development of therapies aimed at preserving or restoring the islet microenvironment in type 2 diabetes.\nC_LIO_LIIncluding key subtypes of islet-associated ECM-producing cells may be important in improving current protocols to generate replacement islets from human pluripotent stem cells for cell replacement therapy for diabetes.\nC_LI","rel_num_authors":5,"rel_authors":[{"author_name":"Luisa Kimberly Meneses","author_inst":"UCSF"},{"author_name":"Honesty J Kim","author_inst":"UCSF"},{"author_name":"Gregory L Szot","author_inst":"UCSF"},{"author_name":"Julie B Sneddon","author_inst":"UCSF"},{"author_name":"Zev Jordan Gartner","author_inst":"UCSF"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"NDE1 Localizes to the Subdistal Appendages to Maintain Centrosome Integrity and Microtubule Organization","rel_doi":"10.64898\/2026.07.01.735914","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735914","rel_abs":"Centrosomes organize microtubules, coordinate ciliogenesis, and support accurate cell division. At the mature mother centriole, distal and subdistal appendages confer specialized functions in ciliary docking, microtubule organization, and intracellular trafficking. Nuclear distribution element 1 (NDE1) is a centrosome-associated regulator of dynein-dependent processes and ciliogenesis, but its nanoscale organization and contribution to centrosome architecture remain incompletely understood. Here, using expansion microscopy and STED super-resolution imaging, we show that endogenous NDE1 forms a ring-like structure at the subdistal appendages in mouse embryonic fibroblasts and human RPE-1 cells. NDE1 occupies an intermediate radial position between the more centriole-proximal CEP128 layer and the more peripheral ninein layer. Depletion of ODF2 or CEP128 reduces centrosomal NDE1, whereas CEP170 depletion has little effect, placing NDE1 within an ODF2- and CEP128-dependent branch of the subdistal appendage organization network. NDE1 depletion compromises centrosome integrity, reduces the centrosomal enrichment of core centriolar proteins, increases the separation between paired centrioles, and generates ectopic foci containing multiple centriolar markers. Loss of NDE1 also disrupts pericentriolar material organization and impairs the establishment of focused, centrosome-associated microtubule arrays. Furthermore, NDE1 depletion increases LC3B- and p62-positive structures and reduces autophagic flux. Together, our findings establish NDE1 as a subdistal appendage-associated factor that supports centrosome architecture and microtubule-organizing activity. More broadly, they support an emerging view of subdistal appendages as a molecularly layered platform in which distinct but cooperating components connect mother centriole maturation to microtubule organization, ciliary regulation, and intracellular trafficking.","rel_num_authors":3,"rel_authors":[{"author_name":"Vickie Yang","author_inst":"California Institute of Technology"},{"author_name":"Paula Almeida Coelho","author_inst":"California Instittue of Technology"},{"author_name":"David Moore Glover","author_inst":"California Institute of Technology"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Drinking Motives Synchronize Behavioral and Neural Craving Responses to Alcohol-drinking Videos","rel_doi":"10.64898\/2026.07.05.736452","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.05.736452","rel_abs":"Alcohol drinking motives vary among individuals and shape experiences and beliefs about alcohol, influencing the processing of alcohol-related cues. In real-life settings, these cues are contextually rich, amplifying the role of such individualized drinking motives on cue processing. However, previous literature has primarily relied on images of alcohol, which lack contexts and differ significantly from real-life. Here, aiming to investigate real-life craving, we examined the role of alcohol drinking motives in craving in response to naturalistic alcohol-drinking videos. We asked fifty-three problematic alcohol users to speak about their reasons for drinking alcohol to capture unique alcohol drinking motives of each individual. Participants also underwent functional MRI while watching fifteen alcohol-drinking videos, and reported their subjective level of craving and self-relatedness for each video. Behavioral data analysis revealed that individuals with greater alcohol use severity tended to report greater cue-induced craving, but only when they reported that a video was related to themselves. Inter-subject representational similarity analysis showed that participants with similar alcohol drinking motives, reflected in shared drinking reasons and similar self-relatedness to the videos, exhibited synchronized craving-related neural responses during video-watching. Notably, these shared neural processes mediated the link between similar drinking motives and similar self-reported craving levels across participants. Together, our findings highlight the crucial role of alcohol drinking motives in shaping cue-induced alcohol craving, and provide deeper insights into craving in real-world contexts.","rel_num_authors":8,"rel_authors":[{"author_name":"Mina Kwon","author_inst":"Seoul National University"},{"author_name":"Suyeon Song","author_inst":"Seoul National University"},{"author_name":"Hyeonmin Lee","author_inst":"Seoul National University"},{"author_name":"Manjae Kwon","author_inst":"Yonsei University, Severance Hospital"},{"author_name":"Jung-Seok Choi","author_inst":"Samsung Medical Center"},{"author_name":"Young-Chul Jung","author_inst":"Yonsei University, College of Medicine"},{"author_name":"Monica D. Rosenberg","author_inst":"University of Chicago"},{"author_name":"Woo-Young Ahn","author_inst":"Seoul National University"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Hippocampal ripples are distinguishable from aperiodic activity","rel_doi":"10.64898\/2026.07.05.736595","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.05.736595","rel_abs":"High-frequency \"ripple\" oscillations support learning and memory across species, yet it has been argued that putative ripples in awake human recordings are false positives produced when algorithms misread aperiodic (1\/f) fluctuations as ripple-band oscillations. We show that this conclusion arises from an artifact of evaluating detection algorithms on surrogate data containing only aperiodic activity. Ripple detectors are adaptive, setting their threshold from the amplitude statistics of the signal, so applying them to surrogate data that contains only aperiodic activity lowers the threshold and inflates false positives (median 62%). Adding real ripple-band events back to the surrogate corrects this threshold shift and eliminates most false detections across multiple standard algorithms. Using multivariate classifiers, we show aperiodic fluctuations can reproduce the power of ripples but not their timing or spectral content. These findings indicate care needs to be taken when using surrogates to evaluate ripple detection algorithms. Thus, under realistic signal properties, human hippocampal ripples remain distinguishable from aperiodic activity.","rel_num_authors":1,"rel_authors":[{"author_name":"James E Kragel","author_inst":"The University of Chicago"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Assessing tensor decomposition quality of immune profiling data from a dictionary learning perspective","rel_doi":"10.64898\/2026.07.03.736447","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736447","rel_abs":"Systems-level immune profiling data arising from longitudinal studies of vaccination or infection has an inherent multi-index array structure. While tensor decomposition of such datasets has gained popularity, choosing a rank and trial for a decomposition is not straightforward. We show that taking into account the experimental data model can inspire the development of new metrics to assess the quality of a Non-negative CANDECOMP\/PARAFAC (NCPD) decomposition, and can thus be used to choose a rank and trial for the decomposition. Moreover, we show how framing the results via a dictionary learning framework can better enable interpretation of the components of the decomposition.","rel_num_authors":5,"rel_authors":[{"author_name":"Anna Konstorum","author_inst":"North Carolina State University"},{"author_name":"Jian Xing","author_inst":"Yale School of Medicine"},{"author_name":"Shuchin Aeron","author_inst":"Tufts University"},{"author_name":"Misha Kilmer","author_inst":"Tufts University"},{"author_name":"Steven Kleinstein","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Assessing tensor decomposition quality of immune profiling data from a dictionary learning perspective","rel_doi":"10.64898\/2026.07.03.736447","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736447","rel_abs":"Systems-level immune profiling data arising from longitudinal studies of vaccination or infection has an inherent multi-index array structure. While tensor decomposition of such datasets has gained popularity, choosing a rank and trial for a decomposition is not straightforward. We show that taking into account the experimental data model can inspire the development of new metrics to assess the quality of a Non-negative CANDECOMP\/PARAFAC (NCPD) decomposition, and can thus be used to choose a rank and trial for the decomposition. Moreover, we show how framing the results via a dictionary learning framework can better enable interpretation of the components of the decomposition.","rel_num_authors":5,"rel_authors":[{"author_name":"Anna Konstorum","author_inst":"North Carolina State University"},{"author_name":"Jian Xing","author_inst":"Yale School of Medicine"},{"author_name":"Shuchin Aeron","author_inst":"Tufts University"},{"author_name":"Misha Kilmer","author_inst":"Tufts University"},{"author_name":"Steven Kleinstein","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Genetic Variation in Drosophila melanogaster Aggression","rel_doi":"10.64898\/2026.07.04.736468","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.04.736468","rel_abs":"Animals fight for resources to obtain fitness benefits; most contests are intrasexual, and males tend to fight more than females. Although the genetic basis of male aggression is well studied, we know little about the genetic variation of female aggression. Female aggression varies with reproductive status and is potentially influenced not only by her genotype, but also by the genotype of her mate. Here we measured both male and female aggression in a set of Drosophila melanogaster inbred lines by competing each line against a standard competitor. Aggression varied among lines for both sexes, but male and female aggression were not correlated. Female aggression for many lines increased with mating, as expected, but not all lines changed aggression. However, when females were mated to males of different lines, male genotype did not affect the post-mating change in aggression, suggesting that ejaculate-mediated effects do not vary across these lines. The aggression level of the standard opponent was positively correlated with that of focal individuals indicating that individuals modulate their behavior according to the genotype of their opponent.","rel_num_authors":4,"rel_authors":[{"author_name":"Jennifer  M Gleason","author_inst":"The University of Kansas - Lawrence Campus: The University of Kansas"},{"author_name":"Cailin  M Kessen","author_inst":"The University of Kansas - Lawrence Campus: The University of Kansas"},{"author_name":"Vaishnavi Verma","author_inst":"The University of Kansas - Lawrence Campus: The University of Kansas"},{"author_name":"Eleanor Bath","author_inst":"Durham University"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Elucidating the JNK Signaling Pathway in Neonatal Muscle Growth and Neuromuscular Contractures","rel_doi":"10.64898\/2026.06.30.735638","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735638","rel_abs":"Neuromuscular contractures arising from neonatal brachial plexus injuries (NBPI) are highly disabling and currently incurable. We previously showed that contractures involve impaired longitudinal growth of denervated muscles, a defect mediated through myostatin (MSTN) signaling, a potent negative regulator of muscle size. However, MSTN-mediated contractures occur independent of canonical signaling pathways, including SMAD 2\/3 and AKT\/mTOR. Through a mouse model of NBPI, our present study extended these findings by revealing pharmacologic inhibition of JNK signaling, a noncanonical pathway downstream of MSTN, partially rescues contractures without restoring muscle length. Rather, JNK activation upregulates myofiber expression of the target gene Lmna, which encodes the nuclear envelope proteins Lamin A and Lamin C that are vital for nuclear stability, resulting in pervasive myonuclear displacement. These results suggest that other factors contribute to contracture pathology beyond deficits in longitudinal muscle growth. Further, while JNK inhibition does not restore length of denervated muscles, it impedes size and mass of normally innervated neonatal muscles, suggesting a requirement of JNK signaling for neonatal muscle growth. Our collective findings thereby establish new mechanistic insights into the molecular basis of aberrant muscle growth and neuromuscular contracture formation, potentially leading to novel targets for muscle restorative strategies and medical contracture prevention.","rel_num_authors":9,"rel_authors":[{"author_name":"Kasey Shao","author_inst":"University of Cincinnati"},{"author_name":"Madelyn Shoates","author_inst":"Xavier University"},{"author_name":"Daniela Barrios","author_inst":"University of Cincinnati"},{"author_name":"Sophia Conte","author_inst":"University of Kentucky"},{"author_name":"Albaraa Tarabishi","author_inst":"John Hopkins University"},{"author_name":"Geethika Velaga","author_inst":"University of Cincinnati"},{"author_name":"Kritton Shay-Winkler","author_inst":"Cincinnati Children's Hospital Medical Center"},{"author_name":"Qingnian Goh","author_inst":"Cincinnati Children's Hospital Medical Center"},{"author_name":"Roger Cornwall","author_inst":"Cincinnati Children's Hospital Medical Center"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Restricting Dietary Isoleucine Promotes Foxo3-Dependent Mitochondrial Respiration by Reducing Caloric Intake","rel_doi":"10.64898\/2026.07.01.735791","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735791","rel_abs":"Our prior work demonstrated that lowering dietary branched-chain amino acids (BCAAs) improves cardiac outcomes during pressure overload-induced stress. Here, we identify isoleucine restriction (IleR) as the key driver of this effect. Dietary isoleucine restriction induces hypophagia and weight loss, recapitulating the effects of caloric restriction (CR). Although it does not prevent the initial development of left ventricular hypertrophy, it halts its progression and the decline in ejection fraction compared with controls. This is associated with preservation of electron transport chain (ETC) gene expression, cristae structure, NAD+\/NADH levels, and mitochondrial respiratory capacity in cardiomyocytes, which is recapitulated by CR. Mechanistically, both IleR and CR diets increase Foxo3 expression, thereby blocking the decline in expression of its target ETC and mitochondrial genome-encoded genes. Consequently, this improves mitochondrial respiratory capacity and reduces cardiac fibrosis. We conclude that restricting dietary isoleucine improves cardiac health by increasing Foxo3 expression and mitochondrial function via a cell-autonomous mechanism and by reducing caloric intake.","rel_num_authors":6,"rel_authors":[{"author_name":"Julianne Austin","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Minzhen He","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Zhi Yang","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Dayyan Sayed","author_inst":"Parsippany High School"},{"author_name":"Danish Sayed","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Maha Abdellatif","author_inst":"Rutgers New Jersey Medical School"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Cell Cluster Geometry and Fluidity Control the Transition from Single-Cell Chemorepulsion to Collective Chemotaxis","rel_doi":"10.64898\/2026.07.04.736449","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.04.736449","rel_abs":"Directed migration along chemical gradients controls immune surveillance, development, and cancer invasion. However, the same chemical cue can produce different responses depending on its concentration and whether cells move alone or in groups. For example, in steep gradients, isolated malignant lymphocyte cells migrate away from the chemoattractant source, whereas clusters of the same cells continue to migrate toward it. Here, combining computational modeling and experimental observations, we show that this reversal is governed by coupled mechanisms acting across molecular, cellular, and collective scales. At the single-cell level, our model predicts that receptor endocytosis generates a feedback that produces a nonmonotonic surface receptor density with increasing chemoattractant concentration. Above a critical concentration that depends on the cell's volume-to-sensing-area ratio, receptor depletion reverses cell polarity and drives chemorepulsion. However, in clusters, cell-cell contacts reduce the membrane area exposed to ligand, increasing the volume-to-sensing-area ratio, thus increasing the critical concentration and preserving chemotaxis. An agent-based model incorporating these mechanisms quantitatively reproduces the sign reversal of the migration index across gradient steepness and cluster size. We show that collective rearrangements further stabilize chemoattraction with exchanges between the cluster rim and core helping remove chemorepulsive cells from the leading edge, keeping their fraction below the threshold required to reverse cluster migration. The model further predicts, and experiments confirm, that increasing ambient ligand concentration while keeping the gradient fixed reduces cluster chemoattraction. Our results identify receptor trafficking, cell geometry, and cluster fluidity as physical determinants of collective directional decision-making, with implications for immune cell homing, tissue morphogenesis, and cancer dissemination.","rel_num_authors":5,"rel_authors":[{"author_name":"Monika Sanoria","author_inst":"University of California Merced"},{"author_name":"Gema Malet Engra","author_inst":"IFOM ETS - The AIRC Institute of Molecular Oncology, Via Adamello 16, Milan, 20139, Italy"},{"author_name":"Giorgio Scita","author_inst":"IFOM, the FIRC Institute of Molecular Oncology"},{"author_name":"Nir Gov","author_inst":"Weizmann Institute of Science"},{"author_name":"Ajay Gopinathan","author_inst":"University of California Merced"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"IgGM2: An All-Atom Foundation Model for Adaptive Immune Receptor Design","rel_doi":"10.64898\/2026.07.09.737510","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737510","rel_abs":"Accurate immune receptor design requires modeling the coupled variation of amino-acid sequence, full-atom conformation, and target-binding geometry across antibodies, nanobodies, and T-cell receptors (TCRs). Existing methods often address only part of this problem, either by separating structure generation from sequence design, relying on fixed-backbone inverse folding, or focusing on a single receptor class. We introduce IgGM2, a unified all-atom generative framework for immune receptor structure prediction and CDR sequence-structure co-design. IgGM2 follows a structure-to-design strategy: it first learns how immune receptors are positioned around fixed target structures, and then transfers this target-conditioned structural prior to CDR design. Unlike modular design pipelines, IgGM2 jointly generates CDR residue identities and full-atom receptor structures, allowing framework geometry to adapt to designed CDRs without separate inverse folding or external sidechain packing. Unlike continuous residue encodings based on virtual-atom geometry, IgGM2 keeps sequence prediction explicit while using atom14 placeholders only for full-atom representation. On structure prediction benchmarks, IgGM2 better captures receptor-target spatial relationships than AlphaFold3 on FoldBench and achieves strong performance on TCR-pMHC modeling. On sequence design benchmarks, IgGM2 improves amino-acid recovery and Rosetta-based interface preference metrics, suggesting more favorable generated binding interfaces. These results support IgGM2 as a unified all-atom framework for adaptive immune receptor structure prediction and design.","rel_num_authors":14,"rel_authors":[{"author_name":"Jian Ma","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Fandi Wu","author_inst":"Tencent, AI for Life Sciences Lab, Shenzhen, China"},{"author_name":"Lin Yao","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Jing Gao","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Rubo Wang","author_inst":"University of Chinese Academy of Sciences"},{"author_name":"Qifeng Li","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Nianzu Yang","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Songlin Jiang","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Dawei Huang","author_inst":"Tencent, AI for Life Sciences Lab, Shenzhen, China"},{"author_name":"Xiaoyong Pan","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Yiheng Zhu","author_inst":"Zhongguancun Institute of Artificial Intelligence"},{"author_name":"Tingjun Hou","author_inst":"Zhejiang University"},{"author_name":"Jianhua Yao","author_inst":"Tencent, AI for Life Sciences Lab, Shenzhen, China"},{"author_name":"Junchi Yan","author_inst":"Shanghai Jiao Tong University"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Nox4 Mediates Diastolic Function in a Genetic Model of Pitx2 Haploinsufficiency","rel_doi":"10.64898\/2026.06.30.735639","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735639","rel_abs":"Heart failure with preserved ejection fraction (HFpEF) commonly coexists with atrial fibrillation (AF), but shared mechanisms remain unclear. In this study, we hypothesized that Pitx2, a transcription factor located near the strongest genetic locus associated with AF in humans, increases susceptibility to HFpEF-like remodeling. We also sought to understand pathways that might be central to this increased risk. Male and female Pitx2+\/- mice and wild-type littermates received 3-week subcutaneous osmotic pump infusion of saline or angiotensin II (Ang II; 500 ng\/kg\/min). Cardiac structure and function were assessed by echocardiography and catheterization, and functional capacity by exercise treadmill. RNA transcriptomic profiling was performed to identify candidate pathways. In a separate cohort, Ang II-treated mice were randomized to oral GKT136901 (30 mg\/kg\/day) or vehicle during infusion. After Ang II infusion, Pitx2+\/- mice developed exaggerated HFpEF-like changes, including greater left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, elevated left ventricular end-diastolic pressure, and reduced treadmill performance. RNA-seq showed enrichment of metabolic and stress-response pathways with selective upregulation of Nox4, confirmed by RT-qPCR. GKT136901 attenuated structural remodeling, diastolic dysfunction indices, elevated filling pressures, and cardiomyocyte hypertrophy, but did not improve endurance. These findings implicate redox signaling, including Nox4, in AF genetic susceptibility-HFpEF interactions.","rel_num_authors":7,"rel_authors":[{"author_name":"Sumner L Gardner","author_inst":"Vanderbilt University"},{"author_name":"Anam Fatima","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Faris Abusharkh","author_inst":"Vanderbilt University"},{"author_name":"Elizabeth Kobeck","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Chitra Basu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Francis J Miller","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Vineet Agrawal","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Exposure to P. falciparum and common cold viruses shape vaccine responses in early life","rel_doi":"10.64898\/2026.07.06.736529","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736529","rel_abs":"Vaccine immunogenicity is consistently lower in low-income countries than in high-income settings, yet the factors driving this disparity remain incompletely understood. Using multiplexed electrochemiluminescence serology, we measured IgG and IgA responses to Expanded Program on Immunization (EPI) vaccines and common childhood viral infections in 89 Ugandan infants. We integrated detailed parasitological surveillance and maternal clinical data to examine how P. falciparum infection history, concurrent parasitemia, maternal gravidity, and early-life viral exposures shaped serological profiles. We found that infants mounted robust responses to most EPI vaccines, but critical gaps in protection persisted for diphtheria, measles and rubella. Children born to primigravid mothers had lower antibody levels at 8 weeks of age, independent of placental malaria and only partially explained by maternal age. Contrary to expectation, cumulative P. falciparum exposure was positively associated with antibody concentrations to diphtheria and varicella, and concurrent parasitemia was positively correlated with responses to multiple antigens. Early seroconversion to rhinovirus C was associated with higher polio IgA and rotavirus IgG concentrations at 24 weeks. Together, these findings suggest that common microbial exposures during infancy, including respiratory viruses and P. falciparum may positively modulate vaccine responsiveness.","rel_num_authors":16,"rel_authors":[{"author_name":"Florian Bach","author_inst":"Stanford University School of Medicine"},{"author_name":"George B. Sigal","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Jacob Wohlstadter","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Rayven Brown","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Gaby Dunn","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Teri Ngo","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Brian Ngo","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Cat Demos","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Kenneth Musinguzi","author_inst":"Infectious Diseases Research Collaboration"},{"author_name":"Felistas Nankya","author_inst":"Infectious Diseases Research Collaboration"},{"author_name":"Abel Kakuru","author_inst":"Infectious Diseases Research Collaboration"},{"author_name":"Alyssa Sbarra","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Grant Dorsey","author_inst":"University of California, San Francisco"},{"author_name":"Moses  R. Kamya","author_inst":"Makerere University"},{"author_name":"Saki Takahashi","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Prasanna Jagannathan","author_inst":"Stanford University"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Exposure to P. falciparum and common cold viruses shape vaccine responses in early life","rel_doi":"10.64898\/2026.07.06.736529","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736529","rel_abs":"Vaccine immunogenicity is consistently lower in low-income countries than in high-income settings, yet the factors driving this disparity remain incompletely understood. Using multiplexed electrochemiluminescence serology, we measured IgG and IgA responses to Expanded Program on Immunization (EPI) vaccines and common childhood viral infections in 89 Ugandan infants. We integrated detailed parasitological surveillance and maternal clinical data to examine how P. falciparum infection history, concurrent parasitemia, maternal gravidity, and early-life viral exposures shaped serological profiles. We found that infants mounted robust responses to most EPI vaccines, but critical gaps in protection persisted for diphtheria, measles and rubella. Children born to primigravid mothers had lower antibody levels at 8 weeks of age, independent of placental malaria and only partially explained by maternal age. Contrary to expectation, cumulative P. falciparum exposure was positively associated with antibody concentrations to diphtheria and varicella, and concurrent parasitemia was positively correlated with responses to multiple antigens. Early seroconversion to rhinovirus C was associated with higher polio IgA and rotavirus IgG concentrations at 24 weeks. Together, these findings suggest that common microbial exposures during infancy, including respiratory viruses and P. falciparum may positively modulate vaccine responsiveness.","rel_num_authors":16,"rel_authors":[{"author_name":"Florian Bach","author_inst":"Stanford University School of Medicine"},{"author_name":"George B. Sigal","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Jacob Wohlstadter","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Rayven Brown","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Gaby Dunn","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Teri Ngo","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Brian Ngo","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Cat Demos","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Kenneth Musinguzi","author_inst":"Infectious Diseases Research Collaboration"},{"author_name":"Felistas Nankya","author_inst":"Infectious Diseases Research Collaboration"},{"author_name":"Abel Kakuru","author_inst":"Infectious Diseases Research Collaboration"},{"author_name":"Alyssa Sbarra","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Grant Dorsey","author_inst":"University of California, San Francisco"},{"author_name":"Moses  R. Kamya","author_inst":"Makerere University"},{"author_name":"Saki Takahashi","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Prasanna Jagannathan","author_inst":"Stanford University"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Challenges and Solutions in Quantifying Brain \u03b2-Hydroxybutyrate (BHB) with 1H-MRS Following Oral Keto-Ester Consumption","rel_doi":"10.64898\/2026.07.04.736442","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.04.736442","rel_abs":"Purpose: {beta}-hydroxybutyrate (BHB), a ketone body and alternative cerebral energy substrate, can be measured in vivo using J-difference edited proton magnetic resonance spectroscopy (1H-MRS). Oral ketone supplementation with substrates such as the ketone monoester (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate (KME) and 1,3-butanediol (BD) have gained attention as a mechanism to elevate circulating BHB and induce ketosis without dietary restrictions. Elevated brain ketone availability is of growing therapeutic interest as a strategy to support neuronal energetics in conditions such as epilepsy, neurodegenerative disease, and alcohol use disorder (AUD). However, both pathways introduce BD into the bloodstream, which crosses the blood-brain barrier. Critically, BD exhibits a spectral signature that closely resembles the prominent BHB peak in JDE-MR spectroscopic imaging (MRSI), identified in a pilot AUD study. Methods: Two separate JDE-MRSI acquisitions tailored for BHB and BD editing were implemented, exploiting frequency separation between the BHB (4.14ppm) and BD (3.95ppm) coupling partners of the observed 1.2ppm resonance to independently quantify each metabolite. Results: Brain BD concentrations (0.25-0.58mM) were comparable to or exceeded corresponding BHB concentrations (0.20-0.27mM) in all volunteers after consumption of a single dose of the KME, indicating that BD constitutes a major fraction of the signal conventionally attributed to BHB. Combined BHB+BD concentrations (~0.45-0.85mM) were consistent with brain BHB values reported in prior studies employing similar doses of the KME, indicating that those measurements likely reflect a combined BHB+BD signal. Conclusions: Separate quantification of the two metabolites is important for interpreting brain ketone studies and for understanding the full pharmacology of KME supplementation.","rel_num_authors":14,"rel_authors":[{"author_name":"Mansimran Virk","author_inst":"University of Calgary"},{"author_name":"Kennedy T Conners","author_inst":"University of Calgary"},{"author_name":"Razi Kitaneh","author_inst":"Yale University"},{"author_name":"Marcella M Mignosa","author_inst":"Yale University"},{"author_name":"Scott McIntyre","author_inst":"Yale University"},{"author_name":"Terence W Nixon","author_inst":"Yale University"},{"author_name":"Kelly DeMartini","author_inst":"Yale University"},{"author_name":"Stephanie O'Malley","author_inst":"Yale University"},{"author_name":"John H Krystal","author_inst":"Yale University"},{"author_name":"Henk M. De Feyter","author_inst":"Yale University"},{"author_name":"Gustavo Angarita-Africano","author_inst":"Yale University"},{"author_name":"Graeme F Mason","author_inst":"Yale University"},{"author_name":"Robin A de Graaf","author_inst":"Yale University"},{"author_name":"Chathura Kumaragamage","author_inst":"University of Calgary"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Solid-like PAR protein assemblies encode long-term spatial memory of cell polarity during suspended animation","rel_doi":"10.64898\/2026.06.30.733387","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.733387","rel_abs":"During suspended animation, organisms must preserve cellular organization despite the collapse of the active biochemical processes that normally maintain it. Here we show that anoxia-induced suspended animation drives cell polarity proteins into a poised, memory-like state that preserves spatial information and templates rapid resumption of morphogenesis upon reanimation. In C. elegans embryos, anoxia drives progressive assembly of the polarity protein PAR-3 into solid-like clusters that preserve the polarity axis during metabolic arrest despite inactivation of patterning reactions normally required to maintain PAR asymmetry. Embryos expressing cluster-defective PAR-3 fail to maintain asymmetry during arrest and consequently exhibit polarity axis defects upon reanimation, demonstrating that arrested PAR-3 clusters function as physical templates for re-establishment of polarity. Our data suggest that cells cope with transient metabolic arrest by reversibly converting actively maintained biochemical patterns into stable physical templates that preserve spatial information for later reactivation.","rel_num_authors":7,"rel_authors":[{"author_name":"Joana Borrego-Pinto","author_inst":"The Francis Crick Institute"},{"author_name":"Jake Cornwall Scoones","author_inst":"The Francis Crick Institute"},{"author_name":"Nisha Hirani","author_inst":"The Francis Crick Institute"},{"author_name":"KangBo Ng","author_inst":"The Francis Crick Institute"},{"author_name":"Buzz Baum","author_inst":"MRC Laboratory of Molecular Biology"},{"author_name":"Shiladitya Banerjee","author_inst":"Georgia Institute of Technology"},{"author_name":"Nathan Goehring","author_inst":"The Francis Crick Institute"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Phenotypic CRISPR screening identifies ZBTB10 as a novel regulator of human trophoblast differentiation","rel_doi":"10.64898\/2026.06.29.734890","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.734890","rel_abs":"The human placenta is built by trophoblast cells that fuse together, secrete hormones, and invade the uterus, and defects in these processes contribute to pregnancy disorders such as preeclampsia. Because cell-cell fusion and hormone secretion are inherently non-cell-autonomous processes, their regulators have remained inaccessible to conventional pooled CRISPR screens. Here, we developed an arrayed CRISPR screen in fusogenic BeWo trophoblasts that simultaneously quantifies fusion and hCG secretion across 412 gene perturbations. The screen revealed that these two hallmark functions of trophoblast differentiation are genetically separable. We characterized the strongest novel hit, ZBTB10, in trophoblast stem cells, organoids, and placental tissue and find that ZBTB10 is an essential regulator of human trophoblast differentiation. ZBTB10 is required for invasive extravillous trophoblast differentiation and supports syncytiotrophoblast maturation, establishing it as a cross-lineage regulator that both activates and represses distinct trophoblast fate programs. Together, these findings provide a genetic platform and phenotypic dissection of how regulatory networks control human placental development.","rel_num_authors":14,"rel_authors":[{"author_name":"Meagan N Esbin","author_inst":"University of Washington School of Medicine"},{"author_name":"Rituja Bhowmik","author_inst":"Edward and Pearl Fein Memory and Aging Center, Weill Institute for Neurosciences, University of California San Francisco"},{"author_name":"Hanqin Li","author_inst":"University of California Berkeley"},{"author_name":"Andrew Cearlock","author_inst":"University of Washington School of Medicine"},{"author_name":"Jiayu Chen","author_inst":"University of Washington School of Medicine"},{"author_name":"Tomy Tran","author_inst":"Innovative Genomics Institute"},{"author_name":"Stephen A McCartney","author_inst":"University of Washington School of Medicine"},{"author_name":"Ian A Glass","author_inst":"University of Washington School of Medicine"},{"author_name":"- Birth Defects Research Laboratory (BDRL)","author_inst":"-"},{"author_name":"Dirk Hockemeyer","author_inst":"University of California, Berkeley"},{"author_name":"Xavier Darzacq","author_inst":"University of California Berkeley"},{"author_name":"Fyodor Urnov","author_inst":"University of California Berkeley"},{"author_name":"Robert Tjian","author_inst":"University of California, Berkeley"},{"author_name":"Min Yang","author_inst":"University of Washington School of Medicine"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"High throughput chromatographic ultra-purification of virus-like particles for downstream viromics","rel_doi":"10.64898\/2026.07.09.737491","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737491","rel_abs":"Virus-like particles (VLPs) are an abundant component of microbiomes with critical ecological roles such as population control through viral predation and horizontal gene transfer. Studying the collection of viruses in microbiomes (the virome) through metagenomics has provided important insights into the composition and functions of VLPs in different environments. However, the current gold-standard method for VLP purification, CsCl density gradient ultracentrifugation (CsCl), is low throughput, time consuming and suffers from biases which limits the ability to study viromes in larger sample sets and can interfere with data interpretation. Here we present an anion exchange (AEX) chromatography-based approach for the purification of VLPs from microbiome samples that allows for significant increases in throughput and reproducibility while achieving VLP purity levels similar to or higher than CsCl. We used microbiome samples of known composition to first establish and evaluate the AEX approaches and compare them to CsCl. We implemented the AEX approach both for fast performance liquid chromatography (FPLC) and in multi-well plates. We compared the VLPs purified with CsCl and AEX using shotgun metagenomic sequencing and found that AEX performs similarly to or better than CsCl for purification of VLPs. AEX purified VLP-fractions captured significantly more viral DNA compared to CsCl. We also found that both AEX and CsCl were capable of capturing viruses present at extremely low relative abundances (<0.001%). Additionally, we found that DNase digestion and CsCl may bias against filamentous phage morphologies. Finally, we purified VLPs from conventional murine feces using AEX and CsCl. AEX purified murine fecal VLPs had a much higher viral DNA content (85%) than CsCl (41%). While there were some differences in viral contigs assembled from AEX and CsCl VLP metagenomes, these method unique viral contigs made up only small proportions (<8%) of the relative abundance in the VLP metagenomes. AEX, particularly in the multi-well format, enables the ultrapurification of VLPs from tens to hundreds of samples in a single day thus facilitating virome studies with the large sample numbers needed for translational and clinical research.","rel_num_authors":3,"rel_authors":[{"author_name":"Jessie L. Maier","author_inst":"North Carolina State University"},{"author_name":"Namita Deshmukh","author_inst":"North Carolina State University"},{"author_name":"Manuel Kleiner","author_inst":"North Carolina State University"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Coupling of tubulin acetylation to microtubule stabilization through molecular mimicry","rel_doi":"10.64898\/2026.07.08.736797","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.736797","rel_abs":"Microtubules support diverse cellular functions through regulation by microtubule-associated proteins and tubulin post-translational modification, yet how these two layers are mechanistically integrated remains unclear. -tubulin acetylation marks mechanically resilient microtubules, and its incorporation in defined microtubule sub-populations is not well understood. Here, we identify MTCL1 as a molecular link between microtubule stabilization and post-translational modification installation. We find that MTCL1 stabilizes microtubules and alters the luminal surface when copolymerized with tubulin, remodeling -tubulin and enhancing TAT-mediated tubulin acetylation through molecular mimicry. This effect depends on assembly history and is not observed in pre-assembled microtubules. Targeted deletion of MTCL1 in zebrafish impacts axonal organization, leading to motor defects and increased seizure susceptibility. These findings establish MTCL1 as a licensing factor that couples microtubule stabilization with acetylation to regulate neuronal function.","rel_num_authors":14,"rel_authors":[{"author_name":"Juan M Perez-Bertoldi","author_inst":"Biophysics Graduate Group, University of California, Berkeley"},{"author_name":"Thanh mai Julie Dang","author_inst":"Sorbonne Universite, INSERM, CNRS, Institut de la Vision"},{"author_name":"Mert Golcuk","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh"},{"author_name":"Eva Lanska","author_inst":"Institute of Biotechnology, Czech Academy of Sciences, BIOCEV"},{"author_name":"Danilo Lopes","author_inst":"Institut Curie, Universite PSL"},{"author_name":"Veronique Henriot","author_inst":"Institut Curie, Universite PSL"},{"author_name":"Jingyi Luo","author_inst":"School of Biomedical Sciences, Faculty of Medicine, The University of Hong Kong"},{"author_name":"Rui Zhang","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, School of Medicine"},{"author_name":"Shih-Chieh Ti","author_inst":"School of Biomedical Sciences, Faculty of Medicine, The University of Hong Kong"},{"author_name":"Carsten Janke","author_inst":"Institut Curie, Universite PSL"},{"author_name":"Zdenek Lansky","author_inst":"Institute of Biotechnology, Czech Academy of Sciences, BIOCEV"},{"author_name":"Mert Gur","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh"},{"author_name":"Filippo Del Bene","author_inst":"Sorbonne Universite, INSERM, CNRS, Institut de la Vision"},{"author_name":"Eva Nogales","author_inst":"University of California, Berkeley\/HHMI"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Coupling of tubulin acetylation to microtubule stabilization through molecular mimicry","rel_doi":"10.64898\/2026.07.08.736797","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.736797","rel_abs":"Microtubules support diverse cellular functions through regulation by microtubule-associated proteins and tubulin post-translational modification, yet how these two layers are mechanistically integrated remains unclear. -tubulin acetylation marks mechanically resilient microtubules, and its incorporation in defined microtubule sub-populations is not well understood. Here, we identify MTCL1 as a molecular link between microtubule stabilization and post-translational modification installation. We find that MTCL1 stabilizes microtubules and alters the luminal surface when copolymerized with tubulin, remodeling -tubulin and enhancing TAT-mediated tubulin acetylation through molecular mimicry. This effect depends on assembly history and is not observed in pre-assembled microtubules. Targeted deletion of MTCL1 in zebrafish impacts axonal organization, leading to motor defects and increased seizure susceptibility. These findings establish MTCL1 as a licensing factor that couples microtubule stabilization with acetylation to regulate neuronal function.","rel_num_authors":14,"rel_authors":[{"author_name":"Juan M Perez-Bertoldi","author_inst":"Biophysics Graduate Group, University of California, Berkeley"},{"author_name":"Thanh mai Julie Dang","author_inst":"Sorbonne Universite, INSERM, CNRS, Institut de la Vision"},{"author_name":"Mert Golcuk","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh"},{"author_name":"Eva Lanska","author_inst":"Institute of Biotechnology, Czech Academy of Sciences, BIOCEV"},{"author_name":"Danilo Lopes","author_inst":"Institut Curie, Universite PSL"},{"author_name":"Veronique Henriot","author_inst":"Institut Curie, Universite PSL"},{"author_name":"Jingyi Luo","author_inst":"School of Biomedical Sciences, Faculty of Medicine, The University of Hong Kong"},{"author_name":"Rui Zhang","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, School of Medicine"},{"author_name":"Shih-Chieh Ti","author_inst":"School of Biomedical Sciences, Faculty of Medicine, The University of Hong Kong"},{"author_name":"Carsten Janke","author_inst":"Institut Curie, Universite PSL"},{"author_name":"Zdenek Lansky","author_inst":"Institute of Biotechnology, Czech Academy of Sciences, BIOCEV"},{"author_name":"Mert Gur","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh"},{"author_name":"Filippo Del Bene","author_inst":"Sorbonne Universite, INSERM, CNRS, Institut de la Vision"},{"author_name":"Eva Nogales","author_inst":"University of California, Berkeley\/HHMI"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Coupling of tubulin acetylation to microtubule stabilization through molecular mimicry","rel_doi":"10.64898\/2026.07.08.736797","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.736797","rel_abs":"Microtubules support diverse cellular functions through regulation by microtubule-associated proteins and tubulin post-translational modification, yet how these two layers are mechanistically integrated remains unclear. -tubulin acetylation marks mechanically resilient microtubules, and its incorporation in defined microtubule sub-populations is not well understood. Here, we identify MTCL1 as a molecular link between microtubule stabilization and post-translational modification installation. We find that MTCL1 stabilizes microtubules and alters the luminal surface when copolymerized with tubulin, remodeling -tubulin and enhancing TAT-mediated tubulin acetylation through molecular mimicry. This effect depends on assembly history and is not observed in pre-assembled microtubules. Targeted deletion of MTCL1 in zebrafish impacts axonal organization, leading to motor defects and increased seizure susceptibility. These findings establish MTCL1 as a licensing factor that couples microtubule stabilization with acetylation to regulate neuronal function.","rel_num_authors":14,"rel_authors":[{"author_name":"Juan M Perez-Bertoldi","author_inst":"Biophysics Graduate Group, University of California, Berkeley"},{"author_name":"Thanh mai Julie Dang","author_inst":"Sorbonne Universite, INSERM, CNRS, Institut de la Vision"},{"author_name":"Mert Golcuk","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh"},{"author_name":"Eva Lanska","author_inst":"Institute of Biotechnology, Czech Academy of Sciences, BIOCEV"},{"author_name":"Danilo Lopes","author_inst":"Institut Curie, Universite PSL"},{"author_name":"Veronique Henriot","author_inst":"Institut Curie, Universite PSL"},{"author_name":"Jingyi Luo","author_inst":"School of Biomedical Sciences, Faculty of Medicine, The University of Hong Kong"},{"author_name":"Rui Zhang","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, School of Medicine"},{"author_name":"Shih-Chieh Ti","author_inst":"School of Biomedical Sciences, Faculty of Medicine, The University of Hong Kong"},{"author_name":"Carsten Janke","author_inst":"Institut Curie, Universite PSL"},{"author_name":"Zdenek Lansky","author_inst":"Institute of Biotechnology, Czech Academy of Sciences, BIOCEV"},{"author_name":"Mert Gur","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh"},{"author_name":"Filippo Del Bene","author_inst":"Sorbonne Universite, INSERM, CNRS, Institut de la Vision"},{"author_name":"Eva Nogales","author_inst":"University of California, Berkeley\/HHMI"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Mind the Alignment Gap: A Spatial Transcriptomics Benchmark for Scientific Coding Agents","rel_doi":"10.64898\/2026.07.05.736638","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.05.736638","rel_abs":"Scientific coding agents are difficult to benchmark because many research tasks require executable work yet produce ambiguous or hard-to-verify outputs. Because benchmark construction requires substantial time and resources, automation offers a path to accelerating methods evaluation. We introduce an interactive framework for constructing scientific-agent benchmarks from peer-reviewed papers and diagnosing agent behavior through trace inspection. We apply it as a case study in spatial transcriptomics alignment, constructing 40 tasks from SABench in which agents submit coordinate tables aligning pairs of two-dimensional tissue slices. Across 120 runs and three configurations, we compare a basic prompt, a package-aware prompt, and a full prompt with a prebuilt virtual environment. In this setting, richer package and environment context increased tool exploration but reduced the mean alignment score relative to the basic prompt (0.36 vs. 0.43; 95% CI, [-0.11,-0.03]). Trace inspection showed that added scaffolding often induced unnecessary transformations, fragile package-first workflows, and infrastructure failures. These results illustrate how specialized tooling can alter agent behavior and why scientific-agent benchmarks should evaluate agent traces and the workflows that produce them in addition to the final outputs.","rel_num_authors":2,"rel_authors":[{"author_name":"Yiqun T. Chen","author_inst":"Johns Hopkins University"},{"author_name":"Stephanie C. Hicks","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"LeafRank: A phylodynamic framework for inferring relative fitness from single-cell phylogenies in chromosomally unstable tumors","rel_doi":"10.64898\/2026.07.06.736651","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736651","rel_abs":"Tumors contain cancer cells with diverse growth potentials that shape evolutionary trajectories, yet this fitness diversity remains difficult to quantify in cases of whole-genome duplication (WGD) and chromosomal instability. We present LeafRank, a mathematical framework that leverages single-cell DNA-seq phylogenies to infer the relative fitness of individual cells. Using a multi-type branching process model, LeafRank integrates full tree topology, including branch lengths and bifurcation patterns, to estimate marginal fitness probabilities under punctuated evolutionary regimes driven by rare driver events. To account for elevated aberration rates following WGD, we introduce a tree-rescaling strategy that adjusts for lineage-specific genomic instability. Unlike methods focused on predefined subclones, LeafRank ranks all sampled cells, enabling flexible assessment of growth heterogeneity. Simulations demonstrate high accuracy across spatial and non-spatial virtual tumors. Applied to ovarian cancer, LeafRank reveals directional and parallel selection in WGD tumors and identifies recurrent copy number events enriched in high-fitness lineages. WGD lineages do not show immediate growth advantages but acquire fitness through subsequent alterations.","rel_num_authors":4,"rel_authors":[{"author_name":"Chenyu Wu","author_inst":"Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Kevin Leder","author_inst":"Department of Industrial and Systems Engineering, University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Zicheng Wang","author_inst":"School of Data Science, The Chinese University of Hong Kong (CUHK-Shenzhen), Shenzhen, China"},{"author_name":"Ruping Sun","author_inst":"Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"EZSolver: Template-free prediction of polar enzymatic mechanisms via bidirectional flow matching and search","rel_doi":"10.64898\/2026.07.08.737313","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737313","rel_abs":"Predicting enzymatic reaction mechanisms is critical for understanding enzyme function and for designing and dis-covering new enzymes. Current computational predictors rely on deterministic, rule-based dictionaries, which per-form well on in-distribution tasks but fail to generalize to out-of-distribution (OOD) chemistry. To address this limita-tion, we present EZSolver, a template-free, generative framework for polar enzymatic mechanism prediction. Powered by a flow matching predictor (EZFlow) and navigated by an evaluator-guided bidirectional beam search, EZSolver learns the chemistry of electron redistribution instead of memorizing rigid templates. Evaluated across diverse en-zyme classes, EZSolver achieves a 60.0% accuracy and an 84.6% chemical plausibility rate for full mechanism predic-tion of unseen polar enzymatic reactions. While rule-based models collapse without predefined templates, EZSolver successfully extrapolates chemical knowledge to infer uncatalogued pathways, as demonstrated during rigorous OOD benchmarking. By illuminating enzymatic chemical mechanisms, EZSolver helps pave the way for automated predic-tion of enzyme function and discovery and design of novel biocatalysts for sustainable chemistry.","rel_num_authors":3,"rel_authors":[{"author_name":"Lun-Hsin Kuo","author_inst":"California Institute of Technology"},{"author_name":"Jason Yang","author_inst":"California Institute of Technology"},{"author_name":"Frances Arnold","author_inst":"California Institute of Technology"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Estriol is a Stronger Transcriptional Activator than is either 17beta-Estradiol or Estrone of Hu-man and Elephant Shark Estrogen Receptor-alpha and Estrogen Receptor-beta transfected into COS-7 Cells","rel_doi":"10.64898\/2026.07.03.736429","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736429","rel_abs":"Humans and other vertebrates contain two estrogen receptors (ERs), ER-alpha and ER-beta, which mediate the physiological actions of three estrogens: estrone (E1), estradiol (E2) and estriol (E3). Of these three estrogens, in vivo, E2 is the strongest transcriptional activator of ER-alpha and ER-beta, E1 is next most active, followed by E3. We studied transcriptional activation of human ER-alpha and ER-beta by E2, E1 and E3 in African green monkey kidney (COS-7) cells, which we compared with studies of estrogen stimulation of ER transcription in human em-bryonic kidney (HEK-293) cells. To our surprise, in COS-7 cells, E3 had the lowest half-maximal response (EC50) for human ER-alpha and ER-beta than either E2, which was second most active estrogen, or E1. In contrast, for human ER-alpha and ER-beta transfected into HEK-293 cells, E2 was the most active estrogen, followed by E1 and E3. Similar results were found in COS-7 cells and HEK-293 cells transfected with elephant shark ER-alpha and ER-beta. Thus, under some conditions, E3 is a more active estrogen than either E2 or E1. This suggests that E3 may be a novel physiological ligand for the ER in some mammalian cells.","rel_num_authors":4,"rel_authors":[{"author_name":"Ya Ao","author_inst":"Hokkaido University"},{"author_name":"Ronn Matthew delos Reyes Cabizares","author_inst":"Hokkaido University"},{"author_name":"Michael E. Baker","author_inst":"University of California, San Deigo"},{"author_name":"Yoshinao Katsu","author_inst":"Hokkaido University"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Confined T cell migration controls programmed cell death 1 expression","rel_doi":"10.64898\/2026.07.03.736145","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736145","rel_abs":"T cell immune checkpoint expression and dysfunction are attributed solely to molecular cues. We discover using microphysiological systems and in vivo models that transmigration through confined pores induces acute loss of programmed cell death 1 within minutes of surface immune checkpoint markers on CD8+ T cells through ubiquitin-mediated proteasomal degradation, corresponding with enhanced fitness and function. Such imprints and its underlying mechanism of programmed cell death 1 loss are conserved across species and applicable to human TIL and CAR T cells, and are correlative with disease outcomes in human melanoma. Our findings establish the diverse tissues landscapes that T cells traverse during immunosurveillance, and specifically transmigration, as a form of mechanical immune regulation, and reveal a mechano-modulatory strategy to improve the quality and persistence of engineered or patient-derived T cells for adoptive immunotherapy.","rel_num_authors":14,"rel_authors":[{"author_name":"Yunus Alapan","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jaehoon Kim","author_inst":"Georgia Institute of Technology"},{"author_name":"Kiyoon Min","author_inst":"Georgia Institute of Technology"},{"author_name":"Alexander Shih","author_inst":"Georgia Institute of Technology"},{"author_name":"Samuel N Lucas","author_inst":"Georgia Institute of Technology"},{"author_name":"Taehee Yoon","author_inst":"Georgia Institute of Technology"},{"author_name":"Paul A Archer","author_inst":"Georgia Institute of Technology"},{"author_name":"Heather K Lin","author_inst":"Emory University"},{"author_name":"Ruby Freeman","author_inst":"Emory University"},{"author_name":"Megen C Wittling","author_inst":"Emory University"},{"author_name":"Megan Wyatt","author_inst":"Emory University"},{"author_name":"Chrystal M Paulos","author_inst":"Emory University"},{"author_name":"Sarwish Rafiq","author_inst":"Emory University"},{"author_name":"Susan Napier Thomas","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Enhancement of a STING Agonist Vaccine for Tuberculosis Using Locally Supercharged MS2 Viral Capsids","rel_doi":"10.64898\/2026.07.03.736450","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736450","rel_abs":"Mycobacterium tuberculosis (Mtb) infection kills more people worldwide than any other pathogen. While the Bacille Calmette-Guerin (BCG) vaccine for Mtb has been widely used for over a century, it provides insufficient protection to eradicate this disease. One of our labs has recently established that a protein antigen (H1) can be combined with a STING pathway agonist to achieve strong protection against Mtb in mice, with performance that exceeds that of the BCG vaccine. However, its reliance on a synthetic cyclic dinucleotide (CDN) with relatively poor cell uptake requires higher dosing levels, thus increasing costs. To increase the efficiency of this vaccine and provide a delivery strategy that could also be used in humans, the H1 Mtb antigen and CDN adjuvant were conjugated to genome-free MS2 viral capsids that included cationic mutations to increase cell uptake. Specifically, the H1 antigen was conjugated to the external surface of MS2 using a tyrosinase-mediated oxidative coupling reaction, and the native STING agonist cGAMP was coupled to internal cysteine residues through a reductively cleavable disulfide linker. The resulting MS2-H1 and MS2-cGAMP conjugates were then co-delivered for three doses of vaccination in mice before exposure to Mtb. The MS2-based vaccine platform was observed to have comparable efficacy to the original H1\/CDN formulation, but its enhanced uptake properties enabled 57-fold less CDN and 3-fold less H1 antigen. Additionally, this vaccine elicited immune responses that have been previously demonstrated to correlate with protection. The ability of the capsid shells to protect the CDN cargo during transport allowed enzymatically produced, and thus readily accessible, cGAMP to be used instead of more costly CDNs that require many synthetic steps. This, combined with the reduced overall amount of CDN and H1 that was required, could lower the production costs of future vaccines substantially. Finally, the ability of the capsid-based carriers to bypass the membrane transporters for CDNs suggests that this enhanced vaccination platform is likely to exhibit improved human efficacy in future studies.","rel_num_authors":8,"rel_authors":[{"author_name":"Hannah S Martin","author_inst":"University of California, Berkeley"},{"author_name":"Isabel D amb-Echegaray","author_inst":"University of California Berkeley"},{"author_name":"Paul Huang","author_inst":"University of California Berkeley"},{"author_name":"Lillian Shallow","author_inst":"University of California Berkeley"},{"author_name":"Amir Balakhmet","author_inst":"University of California Berkeley"},{"author_name":"Preeta Pratakshya","author_inst":"University of California Berkeley"},{"author_name":"Sarah Stanley","author_inst":"University of California, Berkeley"},{"author_name":"Matthew B Francis","author_inst":"University of California Berkeley"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate","rel_doi":"10.64898\/2026.07.03.731744","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.731744","rel_abs":"Virtual memory T cells are increasingly recognized as a functionally distinct lineage within the CD8 T cell pool, but when and how commitment to the lineage is enforced remain poorly understood. Here we demonstrate that TVM lineage choice is exceptionally sensitive to dosage and repression competence of the key T cell transcription factor Bcl11b. Three different genetic models of slightly reduced Bcl11b each biased CD8 cell development to TVM generation without deregulating effector differentiation. Timed conditional knockouts and adoptive transfers narrowed the developmental window and showed that Bcl11b levels determine diversion to virtual memory fate uniquely during intrathymic positive selection. Whereas total Bcl11b loss disrupts TCR signalling, a <2-fold dose reduction of Bcl11b enhanced selective responses to TCR stimulation. Chromatin accessibility profiling and single cell RNA-seq indicated that Bcl11b dose reduction redirects cells to the TVM fate, from the late cycling fraction of mature CD8SP thymocytes, by a mechanism independent of previously described cytokine-driven pathways.","rel_num_authors":2,"rel_authors":[{"author_name":"Tom Sidwell","author_inst":"California Institute of Technology"},{"author_name":"Ellen V. Rothenberg","author_inst":"California Institute of Technology"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"The mammalian muscle spindle as a tunable feedback controller in locomotion","rel_doi":"10.64898\/2026.07.03.736206","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736206","rel_abs":"Although muscle spindle sensory signals have been extensively studied, little is known about how and why muscle spindle firing is modulated by the central nervous system during movement. Specialized motor neurons to the muscle spindle, i.e. gamma motor neurons, can profoundly alter spindle firing during behavior, but technological limitations hinder our ability to record gamma motor and muscle spindle sensory signals during most behaviors. We used a biophysical model of a muscle spindle within a muscle-tendon unit to simulate how gamma drive may modulate muscle spindle Ia firing during locomotion. Based on a few available recordings from decerebrate animals, we demonstrate that our model, tuned to passive stretch conditions, can reproduce profound changes in muscle spindle firing in response to identical joint motions in locomotor vs. relaxed stretch conditions. Our model can discover phasic patterns of two types of gamma motor neuron drive based on recorded muscle spindle Ia firing and joint motion. By simulating perturbations, we conclude that: 1) sinusoidal activation of static gamma motor neurons during locomotion, encoding intended movement, modulates muscle spindle signals such that they act as sensorimotor feedback signals based on errors from the intended muscle fascicle length; 2) phasic on\/off activation of dynamic gamma motor neurons during locomotion acts as an event detector, heightening muscle spindle Ia responses to discrete perturbations. As such, their muscle-within-muscle structure allows the muscle spindle to act as a highly tunable physical internal model of muscle state to guide movement. Our model supports proposed but as-yet-untested theories of muscle spindle function and offers a framework for extending the testing of muscle spindle function to active, behavioral conditions.","rel_num_authors":4,"rel_authors":[{"author_name":"Surabhi N Simha","author_inst":"Emory University and Georgia Institute of Technology"},{"author_name":"Gregory  S. Sawicki","author_inst":"Georgia Institute of Technology"},{"author_name":"Timothy C Cope","author_inst":"Georgia Institute of Technology"},{"author_name":"Lena H Ting","author_inst":"Emory University and Georgia Tech"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Hemodynamic Signals Reshape Biological Inference in Widefield Calcium Imaging","rel_doi":"10.64898\/2026.07.03.736453","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736453","rel_abs":"Widefield calcium imaging is widely used to study cortex-wide neural dynamics, yet fluorescence signals are strongly influenced by hemodynamic fluctuations arising from blood volume and oxygenation changes. Although hemodynamic correction is frequently applied, it remains unclear whether vascular contributions represent a modest preprocessing concern or systematically bias biological interpretations of cortical activity. Here, we used dual-wavelength imaging to determine how hemodynamic correction reshapes inference of cortical dynamics across mouse lines expressing GCaMP6s, GCaMP6f, and jGCaMP8m, across multiple analytical domains, and under healthy and glioblastoma conditions. We systematically compared uncorrected and corrected signals using analyses spanning functional parcellation, connectivity, spectral structure, brain-behavior coupling, and low-dimensional network-state dynamics. Hemodynamic correction consistently reduced global functional connectivity, increased network modularity, redistributed spectral power away from slow-frequency dominance, and reorganized multivariate representations of cortical state space. These findings demonstrate that vascular signals do not behave as unstructured measurement noise but instead introduce organized variance that propagates across analytical pipelines and influences inference of cortical dynamics. The consequences of this bias were particularly relevant in glioblastoma, where tumor-associated vascular remodeling amplifies the mismatch between fluorescence signals and underlying neuronal activity. In this disease setting, correction revealed hemispheric asymmetries, reduced network-state entropy, and constrained trajectories within cortical state space that were obscured in uncorrected recordings, demonstrating that vascular remodeling can fundamentally alter interpretation of tumor-associated brain dynamics. More broadly, vascular signals systematically biased estimates of functional organization, network architecture, brain-behavior relationships, and disease-associated phenotypes. Together, these findings establish hemodynamic correction as a critical determinant of biological interpretation in mesoscale calcium imaging rather than a simple preprocessing refinement.","rel_num_authors":9,"rel_authors":[{"author_name":"Tenesha Connor","author_inst":"cleveland clinic research"},{"author_name":"macit emre lacin","author_inst":"cleveland clinic research"},{"author_name":"james hartz","author_inst":"university of buffalo"},{"author_name":"Miguel Maldonado","author_inst":"cleveland clinic research"},{"author_name":"kemal ozdemirli","author_inst":"cleveland clinic research"},{"author_name":"Anthony R Sloan","author_inst":"Cleveland Clinic Lerner Research Institute"},{"author_name":"Justin Lathia","author_inst":"Cleveland Clinic"},{"author_name":"sarah muldoon","author_inst":"university of buffalo"},{"author_name":"Murat Yildirim","author_inst":"Cleveland Clinic Lerner Research Institute"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"The Role of Juvenile Hormone in Midgut Remodeling During Drosophila melanogaster Diapause","rel_doi":"10.64898\/2026.07.03.736443","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736443","rel_abs":"Many insects enter diapause, a programmed state of developmental arrest that enables survival under adverse environmental conditions. In Drosophila melanogaster Meigen, 1830, diapause is characterized by reproductive arrest and reduced intestinal growth, accompanied by suppressed intestinal stem cell (ISC) activity. Juvenile Hormone (JH) promotes ISC proliferation under favorable conditions, but its capacity to modulate stem cell dynamics during cold-induced diapause remains unclear. Here, we investigated whether JH signaling can reactivate midgut remodeling in adult females maintained at 11. At this temperature, flies exhibited pronounced gut atrophy and elevated Phospho-histone H3 (PH3+) cell abundance, consistent with temperature-dependent G2\/M phase arrest JH treatment significantly increased the proportion of Delta-positive progenitor cells in the anterior (R2) and posterior (R5) midgut regions at both 11 and 25, demonstrating that JH acts as a conserved mitogen for the ISC pool irrespective of thermal environment. A trend toward reduced PH3+ accumulation in the posterior midgut following JH treatment (p = 0.061) suggests possible facilitation of mitotic exit, though this effect did not reach statistical significance. Despite cellular-level changes, JH treatment did not restore overall gut size, indicating that the 72-84 hour exposure window was insufficient for subsequent tissue hypertrophy. Additionally, we identified a recurrent cold-induced pathology of gut distension, provisionally termed Lumen Obstruction Syndrome (LOS), which was independent of JH signaling. These findings reveal an uncoupling of JH-driven stem cell expansion from gross organ growth under diapause conditions, highlighting the selective sensitivity of the ISC compartment to endocrine signaling during environmental stress.","rel_num_authors":2,"rel_authors":[{"author_name":"Hlib Burtsev","author_inst":"Brown University"},{"author_name":"Marc Tatar","author_inst":"Brown University"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Aclarubicin disrupts RNA polymerase II progression at replication-coupled histone genes","rel_doi":"10.64898\/2026.07.08.737292","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737292","rel_abs":"Anthracyclines are highly effective chemotherapeutic agents that cause DNA and chromatin damage. One member of the anthracyclines, aclarubicin, has recently gained therapeutic interest due to its ability to kill cancer cells through chromatin-based mechanisms, thus avoiding the off-target effects associated with DNA damage. Despite this, the molecular mechanism of action leading to aclarubicin-induced chromatin damage remains elusive. Here we performed Cleavage Under Targets and Tagmentation (CUT&Tag) of RNA polymerase II (Pol II) and other transcriptional regulators in human cells during aclarubicin treatment. We found that aclarubicin strongly disrupts the replication-coupled histone genes, resulting in a nonproductive accumulation of Pol II-transcription machinery here beyond the levels at other genes. We attribute this sensitivity to the dense Pol II loading and rapid transcription of the histone genes, which intensify the chromatin-disrupting effects of aclarubicin at these loci. Together, our findings support the effectiveness of aclarubicin as an anticancer drug and point to the histone gene cluster as a promising target for therapeutic intervention.","rel_num_authors":4,"rel_authors":[{"author_name":"Kevin K. Nguyen","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Matthew Wooten","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Kami Ahmad","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Steven Henikoff","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Domain-specific proteome remodeling defines mouse myelin aging","rel_doi":"10.64898\/2026.07.05.736479","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.05.736479","rel_abs":"Myelin, once regarded as a static insulating structure, is now recognized as a dynamic component of the nervous system, capable of remodeling in response to experience. Its breakdown is linked to cognitive decline and neurodegenerative diseases, often preceding neuronal dysfunction. While the myelin proteome has been studied, the age- and sex-related changes it undergoes remain poorly understood. In this study, we purified myelin proteins from young, middle-aged, and aged male and female mice. Using mass spectrometry-based proteomics, we identified 4,095 unique proteins in males and 3,931 in females, with roughly 30% showing significant age-related changes in both sexes. We find an age-related increase in compact myelin structural proteins, such as MBP, MOBP, and CLDN11, and a selective vulnerability in non-compact myelin cytoskeletal proteins, such as SEPTIN2, SEPTIN8, and OPALIN. Notably, disease-associated proteins previously characterized in single-cell transcriptomics appear at the protein level in aged myelin. To firmly distinguish between proteins derived from oligodendrocytes and other cell types in vivo, we labeled nascent oligodendrocyte proteins with bio-orthogonal non-canonical amino acid tagging (BONCAT). We discovered a dramatic age-related increase in lysosomal and vesicle-associated proteins, while translation and synaptic proteins decrease in myelin with age in both sexes. This dataset highlights molecular mechanisms underlying the loss of myelin integrity and function with age and provides a novel tool for studying oligodendrocyte-derived nascent proteins in vivo.","rel_num_authors":17,"rel_authors":[{"author_name":"Yarden Freund","author_inst":"The Weizmann Institute of Science"},{"author_name":"Michael Schoof","author_inst":"Stanford University"},{"author_name":"Noa Moreno","author_inst":"The Weizmann Institute of Science"},{"author_name":"Florian Kriegel","author_inst":"Saarland University"},{"author_name":"Heather Shin","author_inst":"Stanford University"},{"author_name":"Vanessa Waelchli","author_inst":"Stanford University"},{"author_name":"Achint Kaur","author_inst":"Stanford University"},{"author_name":"Kevin Abraham","author_inst":"Stanford University"},{"author_name":"Ido Fogel","author_inst":"The Weizmann Institute of Science"},{"author_name":"Sophia M. Shi","author_inst":"Stanford University"},{"author_name":"Ning-Sum To","author_inst":"Hong Kong Center for Neurodegenerative Diseases"},{"author_name":"Ian H. Guldner","author_inst":"Stanford University"},{"author_name":"Tom H. Cheung","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Andrew C. Yang","author_inst":"University of California"},{"author_name":"Andreas H. Keller","author_inst":"Saarland University"},{"author_name":"Tony Wyss-Coray","author_inst":"Stanford University"},{"author_name":"Tal Iram","author_inst":"The Weizmann Institute of Science"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Domain-specific proteome remodeling defines mouse myelin aging","rel_doi":"10.64898\/2026.07.05.736479","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.05.736479","rel_abs":"Myelin, once regarded as a static insulating structure, is now recognized as a dynamic component of the nervous system, capable of remodeling in response to experience. Its breakdown is linked to cognitive decline and neurodegenerative diseases, often preceding neuronal dysfunction. While the myelin proteome has been studied, the age- and sex-related changes it undergoes remain poorly understood. In this study, we purified myelin proteins from young, middle-aged, and aged male and female mice. Using mass spectrometry-based proteomics, we identified 4,095 unique proteins in males and 3,931 in females, with roughly 30% showing significant age-related changes in both sexes. We find an age-related increase in compact myelin structural proteins, such as MBP, MOBP, and CLDN11, and a selective vulnerability in non-compact myelin cytoskeletal proteins, such as SEPTIN2, SEPTIN8, and OPALIN. Notably, disease-associated proteins previously characterized in single-cell transcriptomics appear at the protein level in aged myelin. To firmly distinguish between proteins derived from oligodendrocytes and other cell types in vivo, we labeled nascent oligodendrocyte proteins with bio-orthogonal non-canonical amino acid tagging (BONCAT). We discovered a dramatic age-related increase in lysosomal and vesicle-associated proteins, while translation and synaptic proteins decrease in myelin with age in both sexes. This dataset highlights molecular mechanisms underlying the loss of myelin integrity and function with age and provides a novel tool for studying oligodendrocyte-derived nascent proteins in vivo.","rel_num_authors":17,"rel_authors":[{"author_name":"Yarden Freund","author_inst":"The Weizmann Institute of Science"},{"author_name":"Michael Schoof","author_inst":"Stanford University"},{"author_name":"Noa Moreno","author_inst":"The Weizmann Institute of Science"},{"author_name":"Florian Kriegel","author_inst":"Saarland University"},{"author_name":"Heather Shin","author_inst":"Stanford University"},{"author_name":"Vanessa Waelchli","author_inst":"Stanford University"},{"author_name":"Achint Kaur","author_inst":"Stanford University"},{"author_name":"Kevin Abraham","author_inst":"Stanford University"},{"author_name":"Ido Fogel","author_inst":"The Weizmann Institute of Science"},{"author_name":"Sophia M. Shi","author_inst":"Stanford University"},{"author_name":"Ning-Sum To","author_inst":"Hong Kong Center for Neurodegenerative Diseases"},{"author_name":"Ian H. Guldner","author_inst":"Stanford University"},{"author_name":"Tom H. Cheung","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Andrew C. Yang","author_inst":"University of California"},{"author_name":"Andreas H. Keller","author_inst":"Saarland University"},{"author_name":"Tony Wyss-Coray","author_inst":"Stanford University"},{"author_name":"Tal Iram","author_inst":"The Weizmann Institute of Science"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Leveraging Homologous Recombination Deficiency via the Repositioned Prodrug CB1954","rel_doi":"10.64898\/2026.07.08.737246","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737246","rel_abs":"Homologous recombination deficiency (HRD) is an actionable vulnerability found in a substantial fraction of human cancers, yet current HRD-directed therapies are limited by toxicity, incomplete responses, and acquired resistance. Many DNA-damaging agents were developed before DNA repair biomarkers were available, suggesting that abandoned agents may harbor previously unrecognized genotype-selective activity. Here, through a focused screen of DNA-damaging agents in isogenic homologous recombination-proficient and -deficient models, we identify CB1954, a decades-old nitrobenzamide aziridine prodrug, as highly selective for BRCA2-deficient tumor cells. CB1954 forms DNA interstrand crosslinks independent of HR status, but selectively induces DNA-damage signaling, apoptosis, and loss of clonogenic survival in HR-deficient cells. Targeted DDR CRISPR screening and isogenic validation define a distinct repair dependency for the Fanconi anemia and homologous recombination pathways, with limited dependence on mismatch repair or nucleotide excision repair. Genetic and pharmacologic perturbation of NQO2, the bioactivating enzyme for CB1954, reveals a bifurcated mechanism in which NQO2-dependent activation selectively contributes to HRD cytotoxicity, while aziridine-dependent lesions likely account for residual activity in HR-proficient cells. CB1954 exhibits favorable preclinical pharmacokinetic properties and genotype-dependent antitumor activity in BRCA2-deficient xenografts. These findings reposition CB1954 as a historically overlooked HRD-selective agent and demonstrate that biomarker-guided profiling of DNA-damaging agents can uncover new opportunities for precision oncology.","rel_num_authors":11,"rel_authors":[{"author_name":"James L Elia","author_inst":"Yale University"},{"author_name":"Jarvis Hill","author_inst":"Yale University"},{"author_name":"Collin D Heer","author_inst":"Yale University"},{"author_name":"Siji Smolev","author_inst":"Yale University"},{"author_name":"Abbey M Sykes","author_inst":"Yale University"},{"author_name":"Sofia R Arbelaez","author_inst":"Yale University"},{"author_name":"Karlie N Lucas","author_inst":"Yale University"},{"author_name":"Spenser S Johnson","author_inst":"Yale University"},{"author_name":"Ranjini K Sundaram","author_inst":"Yale University"},{"author_name":"Seth B Herzon","author_inst":"Yale University"},{"author_name":"Ranjit S Bindra","author_inst":"Yale University"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Evaluation of Large Language Models for Post-Cystectomy Sexual Health Counseling in Women: A Pilot Study","rel_doi":"10.64898\/2026.06.25.26356154","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356154","rel_abs":"Abstract Objective To evaluate the adherence to guidelines and readability of large language model-generated sexual health information related to female sexual dysfunction following cystectomy, and to determine whether adherence differs across models and prompt formats. A secondary objective was to introduce an analytic strategy using principal component analysis to examine the dimensions of readability metrics. Methods Three large language models (LLMs), ChatGPT, Gemini, and Perplexity were prompted with six clinical questions related to sexual function after cystectomy. Questions were phrased in long-form and short-form language. Responses were independently graded by two reviewers, derived from guideline recommendations. Linear mixed-effects models predicted adherence as functions of LLM, prompt, and reviewer, with clinical questions as a random intercept. Readability was assessed using five metrics, and principal component analysis (PCA) was used to determine latent structure. Results ChatGPT demonstrated the highest (estimated marginal mean [emm] = 0.769), outperforming Gemini (0.499) and Perplexity (0.457). Shorter, less complex prompts elicited higher adherence than more complex, clinical prompts. All models produced content that exceeded recommended reading levels. PCA demonstrated that a single dominant component accounted for 76.7% of variance across readability indices, indicating a shared underlying construct. Conclusion ChatGPT produced the most guideline-concordant information overall. High linguistic complexity was seen across models, highlighting a barrier to patient comprehension. These findings characterize large language models as variable medical information systems whose outputs rely heavily on prompt structure and model type.","rel_num_authors":7,"rel_authors":[{"author_name":"Faheed Shafau","author_inst":"Michigan State University College of Human Medicine"},{"author_name":"Aakash A Dave","author_inst":"Michigan State University"},{"author_name":"Ibukunoluwa Omole","author_inst":"Michigan State University College of Human Medicine"},{"author_name":"Taeris Guzman","author_inst":"Northeast Ohio Medical University"},{"author_name":"Najibha Rehman","author_inst":"Henry Ford Health System"},{"author_name":"Ekene Enemchukwu","author_inst":"Stanford University School of Medicine"},{"author_name":"Larissa Bresler","author_inst":"Northwestern University Feinberg School of Medicine"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Artificially sweetened beverage intake and risk of liver-related adverse events in individuals with MASLD: A prospective UK Biobank cohort study","rel_doi":"10.64898\/2026.07.04.26357265","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357265","rel_abs":"Purpose Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease and liver-related morbidity worldwide. Although dietary factors may influence MASLD progression, the long-term liver-specific implications of artificially sweetened beverage (ASB) intake remain unclear. We aimed to examine the association between ASB intake and the risk of liver-related adverse events and liver-related death among individuals with MASLD. Methods This prospective cohort study included 50,562 participants with MASLD from the UK Biobank. ASB intake was assessed using 24-hour dietary recalls and categorized as 0, >0-1, and >1 serving\/day. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for liver-related adverse events and liver-related death. Restricted cubic spline models were used to assess dose-response patterns, and competing-risk analyses were performed by treating liver-related death as a competing event for liver-related adverse events. Additional substitution, subgroup and sensitivity analyses were conducted to evaluate the robustness of the findings. Results During a median follow-up of 12.8 years, 292 liver-related adverse events and 91 liver-related deaths occurred. Compared with participants reporting no ASB intake, those consuming >1 serving\/day had a higher risk of liver-related adverse events in the fully adjusted model (HR 1.40, 95% CI 1.02-1.93; P = 0.039), whereas the association for >0-1 serving\/day was not statistically significant (HR 1.26, 95% CI 0.92-1.71; P = 0.149). The risk of liver-related adverse events increased across ASB intake categories (P for trend = 0.023). Restricted cubic spline analysis indicated a positive linear association between ASB intake and liver-related adverse events (P-overall <0.001; P-nonlinearity = 0.72). In competing-risk analysis, the association for >1 serving\/day remained consistent after accounting for liver-related death as a competing event (sub-HR 1.40, 95% CI 1.02-1.93; P = 0.038; Gray test P = 0.006). The association was robust in sensitivity analyses. ASB intake was not significantly associated with liver-related death, and beverage substitution analyses showed no significant associations. Conclusion Among individuals with MASLD, high ASB intake, particularly >1 serving\/day, was associated with an increased risk of liver-related adverse events, but not liver-related death. This association was consistent across dose-response, competing-risk, and sensitivity analyses, suggesting that high ASB intake may represent a potential dietary risk marker for adverse liver outcomes in MASLD.","rel_num_authors":7,"rel_authors":[{"author_name":"ning xu","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Jiaxi Lin","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Lihe Liu","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Shiqi Zhu","author_inst":"Soochow University Affiliated No 1 People\\'s Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Rui Li","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Jinzhou Zhu","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Chunfang Xu","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Exploring the Application of the Observational Medical Outcomes Partnership Common Data Model to Multi-site Stroke Rehabilitation Research Data","rel_doi":"10.64898\/2026.06.28.26356618","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.28.26356618","rel_abs":"Background: Emerging artificial intelligence and machine learning (AI\/ML) tools can help generate robust knowledge to support precision rehabilitation approaches for varied patient populations. There is a large amount of research-generated and clinical rehabilitation data available for this purpose; however, a pronounced lack of interoperability prevents large-scale data aggregation. Common data models (CDMs) such as Observational Medical Outcomes Partnership (OMOP) have improved data interoperability across healthcare settings, and more recently, for clinical rehabilitation data, specifically. However, the application of these CDMs to research-generated data has not yet been explored. Therefore, as a foundational step, our study evaluated the breadth and depth of OMOP CDM coverage for data in a multi-site repository of harmonized rehabilitation research data: the Enhancing NeuroImaging Genetics through Meta-Analysis Stroke Recovery (ENIGMA-SR) database. Methods: Two raters independently mapped data elements representing 46 demographics and medical history (DMH) ENIGMA-SR variables and 95 distinct ENIGMA-SR rehabilitation assessments to OMOP standard concepts. Initial rater agreement was assessed for data element inclusion in OMOP and for specific OMOP concepts used (primary metric: Gwet's agreement coefficient [AC]). Mapping differences were reconciled, and final mappings were descriptively analyzed to examine (1) overall OMOP inclusion, (2) inclusion of more granular levels (subscales, items) of complex assessments, and (3) mapped OMOP concept characteristics. Results: Initial rater agreement was good\/very good for overall OMOP inclusion of DMH and assessment data elements and for OMOP concepts mapped across almost all assessment data elements (Gwet's AC: 0.79-0.89). Initial OMOP concept agreement was more variable for DMH data elements; however, all mapping differences were successfully reconciled to 100%. Overall, DMH data elements had higher OMOP inclusion than rehabilitation assessments: 84.8% (39\/46) vs. 58.9% (56\/95). OMOP coverage was particularly limited for complex assessment subscale- and item-level data elements (9.4% [3\/32]; 19.2% [14\/73]) and did not match the granularity level represented in ENIGMA-SR data for 56.2% (41\/73) of complex assessments. DMH and top-level assessment data elements were frequently mapped to multiple OMOP concepts (median: 6, 2; range: 1-23, 1-8), and for > 50% of these data elements the concepts spanned 2-3 different OMOP domains. Conclusion: For ENIGMA-SR, the OMOP CDM has good coverage of DMH data, moderate top-level coverage of rehabilitation assessments, and very limited coverage of assessment subscales and items. This uneven coverage, combined with variability in OMOP concepts and domains mapped to equivalent data points, presents challenges for aggregating clinical and research-generated rehabilitation data into AI\/ML-ready datasets. Moreover, software tools currently available to facilitate the mapping process do not effectively accommodate content- and structure-related features inherent to research-generated data. Going forward, the utility of the OMOP CDM to aggregate multi-source rehabilitation data may be improved by expanding the catalogue of OMOP rehabilitation-related concepts, building cross-walks to research-oriented data standards, and adapting emerging computational tools to streamline the mapping process.","rel_num_authors":7,"rel_authors":[{"author_name":"Katherine J. Loomis","author_inst":"University of Southern California"},{"author_name":"Amisha Kumar","author_inst":"University of Southern California"},{"author_name":"Octavio Marin-Pardo","author_inst":"University of Southern California"},{"author_name":"Grace C. Bellinger","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Margaret A. French","author_inst":"University of Utah"},{"author_name":"Ryan T. Roemmich","author_inst":"Kennedy Krieger Institute\/Johns Hopkins University School of Medicine"},{"author_name":"Sook-Lei Liew","author_inst":"University of Southern California"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Genomic Evidence Links Inflammation to Residual Pulmonary Vascular Obstruction and Risk of Pulmonary Embolism Recurrence","rel_doi":"10.64898\/2026.06.26.26356642","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356642","rel_abs":"Background and Aims: Residual pulmonary vascular obstruction (RPVO) defined as the persistence of thrombotic material within the pulmonary arteries several months after an acute pulmonary embolism (PE) is associated with an increased risk of severe complications, including recurrent events and chronic pulmonary hypertension. However, the genomic architecture underlying RPVO in unprovoked PE remains poorly understood, and this study aims to address this gap. Method: By leveraging genetic and imaging RPVO data from three independent cohorts totaling 586 unprovoked PE patients, we conducted a meta-analysis of genome wide association study (GWAS) of RPVO using a dedicated statistical method to handle the semi-continuous distribution of RPVO. The meta-GWAS was complemented by haplotype association analyses and transcriptome wide association studies as well as Mendelian Randomization (MR) approaches based on plasma metabolites and proteins. Results: Through meta-GWAS, we identified one locus, OSTN, associated with RPVO (lead variant rs59109356 associated with a ~2-fold increase of RPVO, p=3.92x10-8). A second locus, CCN4, previously reported to associate with pulmonary fibrosis, was also identified, with evidence of association approaching genome-wide significance (p=6.7x10-8). We also identified a common haplotype spanning over AHSG\/HRG\/KNG1 associated with a ~3-fold increase of RPVO (p=2.96x10-8). Using plasma protein-based MR, we demonstrated that one unit increase in genetically determined plasma levels of IL-1 R AcP encoding IL1RAP was associated with a 28% (p=1.32x10-6) reduction in RPVO. We also observed statistical evidence that the CCN4 (p=0.06) and IL1RAP (p=0.02) loci associate with the risk of PE recurrence in a sample of 1,617 unprovoked PE patients. Conclusions: By identifying novel molecular determinants of RPVO that map to loci involved in inflammatory pathways and vascular remodeling, our study provides evidence that inflammation is the predominant, and likely the key mechanism underlying RPVO, whereas impaired fibrinolysis appears to play a more limited role.","rel_num_authors":22,"rel_authors":[{"author_name":"Floriane Samaria","author_inst":"Universite de Bordeaux"},{"author_name":"Gaelle Munsch","author_inst":"Universite de Brest"},{"author_name":"Ohanna C. L Bezerra","author_inst":"University of Toronto"},{"author_name":"Kerri L Wiggins","author_inst":"University of Washington"},{"author_name":"Lenaick Gourhant","author_inst":"Centre Hospitalier Univeristaire de Brest"},{"author_name":"Astrid van Hylckama Vlieg","author_inst":"Leids Universitair Medisch Centrum"},{"author_name":"Marine Germain","author_inst":"Universite de Bordeaux"},{"author_name":"Robert Olaso","author_inst":"Universite Paris-Saclay"},{"author_name":"Ilana Caro","author_inst":"Universite de Bordeaux"},{"author_name":"Noemie Saut","author_inst":"Aix-Marseille University"},{"author_name":"Delphine Bacq","author_inst":"Universite Paris-Saclay"},{"author_name":"Catherine A. Lemarie","author_inst":"Universite de Brest"},{"author_name":"Stephanie Debette","author_inst":"Universite de Bordeaux"},{"author_name":"Nicholas L. Smith","author_inst":"University of Washington"},{"author_name":"Frits Richard Rosendaal","author_inst":"Leiden Universitair Medisch Centrum"},{"author_name":"Pierre-Emmanuel Morange","author_inst":"Aix-Marseille University"},{"author_name":"Gregoire Le Gal","author_inst":"University of Ottawa"},{"author_name":"Jean-Fran\u00e7ois Deleuze","author_inst":"Universite Paris-Saclay"},{"author_name":"France Gagnon","author_inst":"University of Toronto Mississauga"},{"author_name":"Marc A. Rodger","author_inst":"McGill University"},{"author_name":"Francis Couturaud","author_inst":"Centre Hospitalier Universitaire de Brest"},{"author_name":"David-Alexandre Tregouet","author_inst":"Universite de Bordeaux"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Genomic Evidence Links Inflammation to Residual Pulmonary Vascular Obstruction and Risk of Pulmonary Embolism Recurrence","rel_doi":"10.64898\/2026.06.26.26356642","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356642","rel_abs":"Background and Aims: Residual pulmonary vascular obstruction (RPVO) defined as the persistence of thrombotic material within the pulmonary arteries several months after an acute pulmonary embolism (PE) is associated with an increased risk of severe complications, including recurrent events and chronic pulmonary hypertension. However, the genomic architecture underlying RPVO in unprovoked PE remains poorly understood, and this study aims to address this gap. Method: By leveraging genetic and imaging RPVO data from three independent cohorts totaling 586 unprovoked PE patients, we conducted a meta-analysis of genome wide association study (GWAS) of RPVO using a dedicated statistical method to handle the semi-continuous distribution of RPVO. The meta-GWAS was complemented by haplotype association analyses and transcriptome wide association studies as well as Mendelian Randomization (MR) approaches based on plasma metabolites and proteins. Results: Through meta-GWAS, we identified one locus, OSTN, associated with RPVO (lead variant rs59109356 associated with a ~2-fold increase of RPVO, p=3.92x10-8). A second locus, CCN4, previously reported to associate with pulmonary fibrosis, was also identified, with evidence of association approaching genome-wide significance (p=6.7x10-8). We also identified a common haplotype spanning over AHSG\/HRG\/KNG1 associated with a ~3-fold increase of RPVO (p=2.96x10-8). Using plasma protein-based MR, we demonstrated that one unit increase in genetically determined plasma levels of IL-1 R AcP encoding IL1RAP was associated with a 28% (p=1.32x10-6) reduction in RPVO. We also observed statistical evidence that the CCN4 (p=0.06) and IL1RAP (p=0.02) loci associate with the risk of PE recurrence in a sample of 1,617 unprovoked PE patients. Conclusions: By identifying novel molecular determinants of RPVO that map to loci involved in inflammatory pathways and vascular remodeling, our study provides evidence that inflammation is the predominant, and likely the key mechanism underlying RPVO, whereas impaired fibrinolysis appears to play a more limited role.","rel_num_authors":22,"rel_authors":[{"author_name":"Floriane Samaria","author_inst":"Universite de Bordeaux"},{"author_name":"Gaelle Munsch","author_inst":"Universite de Brest"},{"author_name":"Ohanna C. L Bezerra","author_inst":"University of Toronto"},{"author_name":"Kerri L Wiggins","author_inst":"University of Washington"},{"author_name":"Lenaick Gourhant","author_inst":"Centre Hospitalier Univeristaire de Brest"},{"author_name":"Astrid van Hylckama Vlieg","author_inst":"Leids Universitair Medisch Centrum"},{"author_name":"Marine Germain","author_inst":"Universite de Bordeaux"},{"author_name":"Robert Olaso","author_inst":"Universite Paris-Saclay"},{"author_name":"Ilana Caro","author_inst":"Universite de Bordeaux"},{"author_name":"Noemie Saut","author_inst":"Aix-Marseille University"},{"author_name":"Delphine Bacq","author_inst":"Universite Paris-Saclay"},{"author_name":"Catherine A. Lemarie","author_inst":"Universite de Brest"},{"author_name":"Stephanie Debette","author_inst":"Universite de Bordeaux"},{"author_name":"Nicholas L. Smith","author_inst":"University of Washington"},{"author_name":"Frits Richard Rosendaal","author_inst":"Leiden Universitair Medisch Centrum"},{"author_name":"Pierre-Emmanuel Morange","author_inst":"Aix-Marseille University"},{"author_name":"Gregoire Le Gal","author_inst":"University of Ottawa"},{"author_name":"Jean-Fran\u00e7ois Deleuze","author_inst":"Universite Paris-Saclay"},{"author_name":"France Gagnon","author_inst":"University of Toronto Mississauga"},{"author_name":"Marc A. Rodger","author_inst":"McGill University"},{"author_name":"Francis Couturaud","author_inst":"Centre Hospitalier Universitaire de Brest"},{"author_name":"David-Alexandre Tregouet","author_inst":"Universite de Bordeaux"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Effect of initiating an ARB- versus ACEI-based regimen on dementia risk, a target trial emulation of 2.5 million US Veterans","rel_doi":"10.64898\/2026.07.05.26357173","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357173","rel_abs":"Background: Hypertension is a modifiable risk factor for dementia, yet the comparative effectiveness of angiotensin receptor blockers (ARBs) versus angiotensin converting enzyme inhibitors (ACEIs) on dementia risk remains uncertain. Objective: To compare the risk of dementia and dementia-free death of ARB versus ACEI initiation among US Veterans with incident hypertension. Methods: We conducted a retrospective target trial emulation using a new-user, active-comparator design among Veterans with incident hypertension. We analyzed longitudinal electronic health records from 2,577,000 individuals who initiated ARBs or ACEIs between 1\/1\/2000-12\/31\/2017, with up to five years of follow-up. The exposure was initiation of an ARB-based versus ACEI-based antihypertensive regimen. Co-primary outcomes were dementia, identified using natural language processing of clinical notes, and dementia-free death. We used inverse probability of treatment weights based on 66 pretreatment covariates to estimate the cumulative incidence of the outcomes for each treatment group. Weighted risk ratios and absolute risk differences through five years were computed with bootstrapped 95% CIs. Secondary outcomes included all-cause death and a composite of dementia or death, evaluated using a weighted Kaplan-Meier approach. Results: Among 2,577,000 Veterans (mean age, 63 years; 4.5% female; 65% White; 15% Black), 10% initiated ARBs and 90% initiated ACEIs. Over five years of follow up, 6% developed dementia, 12% died without dementia, and 13% died overall. ARB initiation yielded consistently lower risk of dementia (risk ratio, 0.88; 95% CI, 0.83-0.93 at 6 months to 0.92; 95% CI, 0.90-0.94 at 5 years) and dementia-free death (risk ratio, 0.90; 95% CI, 0.86-0.96 at 6 months to 1.00; 95% CI, 0.98-1.01 at 5 years) than ACEI initiation. Effects on secondary outcomes were similar to those for primary outcomes. Greater protective dementia effects were observed in older and male Veterans and non-statin users, with similar effects on dementia-free death. Discussion: Among US Veterans with incident treated hypertension, initiation of ARB versus ACEI antihypertensive regimen conveyed a modestly lower risk of dementia. Given the high prevalence of hypertension, these modest effects may confer meaningful population-level benefits on brain health. Future research estimating per-protocol effects using a more generalizable population is needed to confirm our findings. Key words: antihypertensive medication, dementia, natural language processing, target trial emulation, Veteran","rel_num_authors":14,"rel_authors":[{"author_name":"Yizhe Xu","author_inst":"University of Utah"},{"author_name":"Jianlin Shi","author_inst":"University of Utah"},{"author_name":"Ryan Andrews","author_inst":"Columbia University"},{"author_name":"Catherine G. Derington","author_inst":"University of Utah School of Medicine"},{"author_name":"Tom Greene","author_inst":"University of Utah"},{"author_name":"Daniel Scharfstein","author_inst":"University of Utah"},{"author_name":"Ransmond Berchie","author_inst":"University of Utah"},{"author_name":"Mark Supiano","author_inst":"University of Utah"},{"author_name":"Jeff Williamson","author_inst":"Wake Forest University"},{"author_name":"Nicholas Pajewski","author_inst":"Wake Forest University"},{"author_name":"Jeremy Pruzin","author_inst":"Banner Alzheimer's Institute"},{"author_name":"Jaejin An","author_inst":"Kaiser Permanente Southern California"},{"author_name":"Jordana Cohen","author_inst":"University of Pennsylvania"},{"author_name":"Adam P. Bress","author_inst":"University of Utah, School of Medicine"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Enabled Detection of Vascular Perfusion Defects on Ventilation\/Perfusion (V\/Q) Scintigraphy for Pulmonary Embolism","rel_doi":"10.64898\/2026.06.25.26356599","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356599","rel_abs":"Accurate interpretation of planar ventilation-perfusion (V\/Q) scintigraphy, used for diagnosing pulmonary embolism (PE) based on PIOPED\/EANM guidelines, requires objective assessment of mismatched V\/Q defects. Manual delineation of V\/Q defects is time-consuming, subject to interobserver variability, and rarely performed in practice, limiting standardized reporting and quantification of disease burden. To address these challenges, we evaluated four modern AI models for automated segmentation of vascular perfusion defects in planar V\/Q scans and compared their performance to human annotators. We retrospectively identified 2,118 patients who underwent planar V\/Q scans at The Ottawa Hospital (June 2019-February 2023). Six standard projections (ANT, POST, LAO, RAO, LPO, RPO) were included. Four 2D neural networks (U-Net, nnU-Net, Swin UNETR, and a Bottleneck Transformer U-Net [BTU-Net]) were trained on 1,313 patients (7,878 projections) and validated on 329 (1,974 projections) using physician-annotated defects. A hold-out test set of 46 high probability patients was used to evaluate segmentation quality, and defect detection accuracy using free-response receiver operating characteristic (FROC) analysis, where BTU-Net was the only model performing on par with human readers, showing robust sensitivity across the entire range of segmentation probabilities. At 1.5 false positives per projection rate (FPPR), BTU-Net outperformed other models with a sensitivity of 0.529 {+\/-} 0.026, On a separate hold-out set of low likelihood of disease patients (n=430), the lowest FPPR was 0.08 {+\/-} 0.01 for BTU-Net (P<0.0001). BTU-Net enables rapid, consistent, and accurate interpretation of planar V\/Q scans. Such tools may enhance diagnostic efficiency, standardize reporting, and support non-expert readers in evaluating PE.","rel_num_authors":16,"rel_authors":[{"author_name":"Amir Jabbarpour","author_inst":"Caleton University"},{"author_name":"Eric Moulton","author_inst":"Jubilant DraxImage"},{"author_name":"Sanaz Kaviani","author_inst":"The Ottawa Hospital"},{"author_name":"Wanzhen Zeng","author_inst":"The Ottawa Hospital"},{"author_name":"Siraj Ghassel","author_inst":"University of Ottawa"},{"author_name":"Ramin Akbarian","author_inst":"The Ottawa Hospital"},{"author_name":"Anne Couture","author_inst":"Hopital Maisonneuve-Rosemont"},{"author_name":"Aubert Roy","author_inst":"McGill University Faculty of Medicine"},{"author_name":"Richard Liu","author_inst":"Jewish General Hospital"},{"author_name":"Yousif Al-ali","author_inst":"Hopital Maisonneuve-Rosemont"},{"author_name":"Yasser Foufa","author_inst":"Montreal Heart Institute"},{"author_name":"Nuha Hejji","author_inst":"University of Ottawa"},{"author_name":"Sukainah AlSulaiman","author_inst":"The Ottawa Hospital, Ottawa"},{"author_name":"Zeinab Shirazi","author_inst":"zshir069@uottawa.ca"},{"author_name":"Eugene Leung","author_inst":"The Ottawa Hospital"},{"author_name":"Ran Klein","author_inst":"The Ottawa Hospital"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Enabled Detection of Vascular Perfusion Defects on Ventilation\/Perfusion (V\/Q) Scintigraphy for Pulmonary Embolism","rel_doi":"10.64898\/2026.06.25.26356599","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356599","rel_abs":"Accurate interpretation of planar ventilation-perfusion (V\/Q) scintigraphy, used for diagnosing pulmonary embolism (PE) based on PIOPED\/EANM guidelines, requires objective assessment of mismatched V\/Q defects. Manual delineation of V\/Q defects is time-consuming, subject to interobserver variability, and rarely performed in practice, limiting standardized reporting and quantification of disease burden. To address these challenges, we evaluated four modern AI models for automated segmentation of vascular perfusion defects in planar V\/Q scans and compared their performance to human annotators. We retrospectively identified 2,118 patients who underwent planar V\/Q scans at The Ottawa Hospital (June 2019-February 2023). Six standard projections (ANT, POST, LAO, RAO, LPO, RPO) were included. Four 2D neural networks (U-Net, nnU-Net, Swin UNETR, and a Bottleneck Transformer U-Net [BTU-Net]) were trained on 1,313 patients (7,878 projections) and validated on 329 (1,974 projections) using physician-annotated defects. A hold-out test set of 46 high probability patients was used to evaluate segmentation quality, and defect detection accuracy using free-response receiver operating characteristic (FROC) analysis, where BTU-Net was the only model performing on par with human readers, showing robust sensitivity across the entire range of segmentation probabilities. At 1.5 false positives per projection rate (FPPR), BTU-Net outperformed other models with a sensitivity of 0.529 {+\/-} 0.026, On a separate hold-out set of low likelihood of disease patients (n=430), the lowest FPPR was 0.08 {+\/-} 0.01 for BTU-Net (P<0.0001). BTU-Net enables rapid, consistent, and accurate interpretation of planar V\/Q scans. Such tools may enhance diagnostic efficiency, standardize reporting, and support non-expert readers in evaluating PE.","rel_num_authors":16,"rel_authors":[{"author_name":"Amir Jabbarpour","author_inst":"Caleton University"},{"author_name":"Eric Moulton","author_inst":"Jubilant DraxImage"},{"author_name":"Sanaz Kaviani","author_inst":"The Ottawa Hospital"},{"author_name":"Wanzhen Zeng","author_inst":"The Ottawa Hospital"},{"author_name":"Siraj Ghassel","author_inst":"University of Ottawa"},{"author_name":"Ramin Akbarian","author_inst":"The Ottawa Hospital"},{"author_name":"Anne Couture","author_inst":"Hopital Maisonneuve-Rosemont"},{"author_name":"Aubert Roy","author_inst":"McGill University Faculty of Medicine"},{"author_name":"Richard Liu","author_inst":"Jewish General Hospital"},{"author_name":"Yousif Al-ali","author_inst":"Hopital Maisonneuve-Rosemont"},{"author_name":"Yasser Foufa","author_inst":"Montreal Heart Institute"},{"author_name":"Nuha Hejji","author_inst":"University of Ottawa"},{"author_name":"Sukainah AlSulaiman","author_inst":"The Ottawa Hospital, Ottawa"},{"author_name":"Zeinab Shirazi","author_inst":"zshir069@uottawa.ca"},{"author_name":"Eugene Leung","author_inst":"The Ottawa Hospital"},{"author_name":"Ran Klein","author_inst":"The Ottawa Hospital"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Retina-derived Quantitative Biomarkers of Brain Health","rel_doi":"10.64898\/2026.07.05.26357344","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357344","rel_abs":"Accurate and scalable assessment of quantitative neuroimaging biomarkers, such as white matter hyperintensities (WMH) and hippocampal (HIP) volumes, is essential for understanding and monitoring brain health, preventing neurological diseases and improving healthspan. However, population-level evaluation of these neuroimaging biomarkers relies on inaccessible, costly and time-consuming magnetic resonance imaging (MRI). Here we propose RetiBrain, a cross-modal deep learning framework that predicts these neuroimaging biomarkers from retinal color fundus photography (CFP) images. By distilling latent structural representations from MRI-based models into a CFP-based model, RetiBrain establishes biologically grounded eye-to-brain mapping. In a CFP-MRI paired cohort, RetiBrain accurately estimates six WMH- and HIP-related biomarkers and outperforms the state-of-the-art retinal foundation model RETFound, improving the mean Pearson correlation coefficient by 0.309 (from 0.240 to 0.549) and achieving a coefficient of 0.640 for periventricular WMH prediction. By integrating structural, topological and geometric feature analyses from CFP images, RetiBrain identifies interpretable retinal representations associated with neurodegeneration and cerebrovascular injury, hallmarks of major neurological diseases such as dementia and stroke. In a longitudinal cohort comprising 2,082 participants (4,164 CFP images with up to 15 years of follow-up), RetiBrain-predicted neuroimaging biomarkers robustly estimated neurological disease risk, as illustrated by dementia prediction (AUROC of 0.824, hazard ratio 2.500 per standard deviation increase, 95% CI: 2.201-2.840). RetiBrain provides a robust, scalable, cost-effective and convenient approach for the assessment of neuroimaging biomarkers, and has potential for long-term brain health monitoring in large-scale general population settings.","rel_num_authors":14,"rel_authors":[{"author_name":"Taizhangtian Ma","author_inst":"Department of Automation, Tsinghua University"},{"author_name":"Tao Yan","author_inst":"Department of Automation, Tsinghua University"},{"author_name":"Jing Sun","author_inst":"Department of Radiology, Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Ning Wu","author_inst":"Department of Medical Imaging Technology, School of Medical Technology, Capital Medical University"},{"author_name":"Mingze Xu","author_inst":"Center for MRI Research, Academy for Advanced Interdisciplinary Studies, Peking University"},{"author_name":"Ruiheng Zhang","author_inst":"Beijing Tongren Hospital"},{"author_name":"Na Zeng","author_inst":"Department of Infection Control, Peking University First Hospital"},{"author_name":"Qi Sun","author_inst":"Precision and Intelligence Medical Imaging Lab, Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Ying Hui","author_inst":"Kailuan General Hospital"},{"author_name":"Yuntao Wu","author_inst":"Kailuan General Hospital"},{"author_name":"Zhenchang Wang","author_inst":"Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Tien Yin Wong","author_inst":"Tsinghua University"},{"author_name":"Han Lv","author_inst":"Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China"},{"author_name":"Hui Qiao","author_inst":"Department of Automation, Tsinghua University"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Retina-derived Quantitative Biomarkers of Brain Health","rel_doi":"10.64898\/2026.07.05.26357344","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357344","rel_abs":"Accurate and scalable assessment of quantitative neuroimaging biomarkers, such as white matter hyperintensities (WMH) and hippocampal (HIP) volumes, is essential for understanding and monitoring brain health, preventing neurological diseases and improving healthspan. However, population-level evaluation of these neuroimaging biomarkers relies on inaccessible, costly and time-consuming magnetic resonance imaging (MRI). Here we propose RetiBrain, a cross-modal deep learning framework that predicts these neuroimaging biomarkers from retinal color fundus photography (CFP) images. By distilling latent structural representations from MRI-based models into a CFP-based model, RetiBrain establishes biologically grounded eye-to-brain mapping. In a CFP-MRI paired cohort, RetiBrain accurately estimates six WMH- and HIP-related biomarkers and outperforms the state-of-the-art retinal foundation model RETFound, improving the mean Pearson correlation coefficient by 0.309 (from 0.240 to 0.549) and achieving a coefficient of 0.640 for periventricular WMH prediction. By integrating structural, topological and geometric feature analyses from CFP images, RetiBrain identifies interpretable retinal representations associated with neurodegeneration and cerebrovascular injury, hallmarks of major neurological diseases such as dementia and stroke. In a longitudinal cohort comprising 2,082 participants (4,164 CFP images with up to 15 years of follow-up), RetiBrain-predicted neuroimaging biomarkers robustly estimated neurological disease risk, as illustrated by dementia prediction (AUROC of 0.824, hazard ratio 2.500 per standard deviation increase, 95% CI: 2.201-2.840). RetiBrain provides a robust, scalable, cost-effective and convenient approach for the assessment of neuroimaging biomarkers, and has potential for long-term brain health monitoring in large-scale general population settings.","rel_num_authors":14,"rel_authors":[{"author_name":"Taizhangtian Ma","author_inst":"Department of Automation, Tsinghua University"},{"author_name":"Tao Yan","author_inst":"Department of Automation, Tsinghua University"},{"author_name":"Jing Sun","author_inst":"Department of Radiology, Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Ning Wu","author_inst":"Department of Medical Imaging Technology, School of Medical Technology, Capital Medical University"},{"author_name":"Mingze Xu","author_inst":"Center for MRI Research, Academy for Advanced Interdisciplinary Studies, Peking University"},{"author_name":"Ruiheng Zhang","author_inst":"Beijing Tongren Hospital"},{"author_name":"Na Zeng","author_inst":"Department of Infection Control, Peking University First Hospital"},{"author_name":"Qi Sun","author_inst":"Precision and Intelligence Medical Imaging Lab, Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Ying Hui","author_inst":"Kailuan General Hospital"},{"author_name":"Yuntao Wu","author_inst":"Kailuan General Hospital"},{"author_name":"Zhenchang Wang","author_inst":"Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Tien Yin Wong","author_inst":"Tsinghua University"},{"author_name":"Han Lv","author_inst":"Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China"},{"author_name":"Hui Qiao","author_inst":"Department of Automation, Tsinghua University"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Fine-Tuned Large Language Models for Detecting Social Isolation from Unstructured Clinical Notes","rel_doi":"10.64898\/2026.07.05.26357334","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357334","rel_abs":"ObjectivesThis study aimed to leverage FLAN-T5-Large, BERT, RoBERTa, and Gemma-2-2B, with fine-tuning, to identify instances of social isolation and social support within unstructured clinical notes.\n\nMaterials and MethodsAnnotated clinical note spans containing social context cues were used to fine-tune each model. Performance was evaluated using Accuracy, Precision, Recall, and Macro-F1 score. A structured prompt was used to instruct the model to perform classification task and mitigate overgeneralization. Performance comparisons across the models assessed sensitivity, robustness, and false positive reduction.\n\nResultsFLAN-T5-Large achieved highest performance, with Macro-F1 of 0.92{+\/-}0.04, demonstrating balanced results across classes: social isolation (F1 = 0.91{+\/-}0.03), no social isolation (F1 = 0.94{+\/-}0.05), and social support (F1 = 0.90{+\/-}0.04). Gemma-2-2B produced comparable results, with Macro-F1 score of 0.89{+\/-}0.10. BERT and RoBERTa achieved lower Macro-F1 scores of 0.77{+\/-}0.17 and 0.80{+\/-}0.21 respectively, with variability across categories.\n\nDiscussionA major contribution of this work is precise identification of multiple concepts related to social connectedness. By integrating annotated examples of both true and false positives, including negations and contextually ambiguous terms, the model better distinguished relevant social context cues from noise. Training on both social isolation and support provided a dual framework for comparative analyses and patient stratification.\n\nConclusionTransformer-based NLP models, particularly FLAN-T5-Large, demonstrated potential for identifying social isolation and social support in clinical text. These findings support the use of generative AI techniques to enhance detection of social isolation from EHRs, advancing context-aware healthcare analytics.\n\nLay SummaryHaving strong social connections can help people live longer, while feeling isolated can increase the risk of serious health problems. The signals about if someone is socially isolated are not captured in their Electronic Health Records but are hidden inside clinical notes that are created as part of healthcare visits. Since these notes are long and complex, it is not possible to manually review them for social connections. Hence, advanced Artificial Intelligence models called large language models - LLMs are used to automatically find the signals of social isolation or social support in clinical notes. To train the LLMs in detecting these signals, we first created a large set of examples for three scenarios: social isolation, social support, and situations where the example contained word \"isolation\" but not related to social connection. These examples helped the LLMs to understand the patterns in the examples for each scenario. We trained three LLMs, FLAN-T5, BERT, and Gemma. Among them, FLAN-T5-Large performed better with accurate and consistent results across different patient groups. This automated approach can help healthcare systems identify patients who may lack social support, update their health records and direct them to services that can help them, ultimately improving patient care.","rel_num_authors":7,"rel_authors":[{"author_name":"Lokesh K Chinthala","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Cindy Lemon","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Arash Shaban-Nejad","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Gregory Farage","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Robert L Davis","author_inst":"The University of Tennessee Health Science Center"},{"author_name":"Hua Xu","author_inst":"Yale University"},{"author_name":"Charisse Madlock-Brown","author_inst":"University of Iowa"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Fine-Tuned Large Language Models for Detecting Social Isolation from Unstructured Clinical Notes","rel_doi":"10.64898\/2026.07.05.26357334","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357334","rel_abs":"ObjectivesThis study aimed to leverage FLAN-T5-Large, BERT, RoBERTa, and Gemma-2-2B, with fine-tuning, to identify instances of social isolation and social support within unstructured clinical notes.\n\nMaterials and MethodsAnnotated clinical note spans containing social context cues were used to fine-tune each model. Performance was evaluated using Accuracy, Precision, Recall, and Macro-F1 score. A structured prompt was used to instruct the model to perform classification task and mitigate overgeneralization. Performance comparisons across the models assessed sensitivity, robustness, and false positive reduction.\n\nResultsFLAN-T5-Large achieved highest performance, with Macro-F1 of 0.92{+\/-}0.04, demonstrating balanced results across classes: social isolation (F1 = 0.91{+\/-}0.03), no social isolation (F1 = 0.94{+\/-}0.05), and social support (F1 = 0.90{+\/-}0.04). Gemma-2-2B produced comparable results, with Macro-F1 score of 0.89{+\/-}0.10. BERT and RoBERTa achieved lower Macro-F1 scores of 0.77{+\/-}0.17 and 0.80{+\/-}0.21 respectively, with variability across categories.\n\nDiscussionA major contribution of this work is precise identification of multiple concepts related to social connectedness. By integrating annotated examples of both true and false positives, including negations and contextually ambiguous terms, the model better distinguished relevant social context cues from noise. Training on both social isolation and support provided a dual framework for comparative analyses and patient stratification.\n\nConclusionTransformer-based NLP models, particularly FLAN-T5-Large, demonstrated potential for identifying social isolation and social support in clinical text. These findings support the use of generative AI techniques to enhance detection of social isolation from EHRs, advancing context-aware healthcare analytics.\n\nLay SummaryHaving strong social connections can help people live longer, while feeling isolated can increase the risk of serious health problems. The signals about if someone is socially isolated are not captured in their Electronic Health Records but are hidden inside clinical notes that are created as part of healthcare visits. Since these notes are long and complex, it is not possible to manually review them for social connections. Hence, advanced Artificial Intelligence models called large language models - LLMs are used to automatically find the signals of social isolation or social support in clinical notes. To train the LLMs in detecting these signals, we first created a large set of examples for three scenarios: social isolation, social support, and situations where the example contained word \"isolation\" but not related to social connection. These examples helped the LLMs to understand the patterns in the examples for each scenario. We trained three LLMs, FLAN-T5, BERT, and Gemma. Among them, FLAN-T5-Large performed better with accurate and consistent results across different patient groups. This automated approach can help healthcare systems identify patients who may lack social support, update their health records and direct them to services that can help them, ultimately improving patient care.","rel_num_authors":7,"rel_authors":[{"author_name":"Lokesh K Chinthala","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Cindy Lemon","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Arash Shaban-Nejad","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Gregory Farage","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Robert L Davis","author_inst":"The University of Tennessee Health Science Center"},{"author_name":"Hua Xu","author_inst":"Yale University"},{"author_name":"Charisse Madlock-Brown","author_inst":"University of Iowa"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"In-clinic validation of a smartphone-based finger tapping test for use in neurodegenerative and neurological populations.","rel_doi":"10.64898\/2026.06.25.26356467","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356467","rel_abs":"BackgroundMotor disturbances are common in neurologic and neurodegenerative syndromes. A standard motor speed and dexterity measure is the finger tapping test (FTT). The FTT has traditionally been administered in clinic using a mechanical FTT, limiting accessibility and early motor change quantification. This study assessed the validity of a smartphone app-based FTT, which may expand access and enable more frequent testing.\n\nMethodsThe cohort was diagnostically diverse, including participants with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome, primary progressive aphasia, multiple sclerosis, and clinically unimpaired controls. Participants completed a 20-second ALLFTD Mobile App (mApp)-FTT with each hand. Tapping speed metrics were extracted. Participants completed the gold-standard mechanical FTT, a neurologist-administered finger tapping exam, the PSP Rating Scale (PSPRS) and the Unified Parkinsons Disease Rating Scale (UPDRS). Correlations assessed mApp-FTT and mechanical FTT relationships; regressions evaluated associations with neurologist-rated finger tapping impairment, PSPRS and UPDRS, adjusting for age and sex.\n\nResultsThe mApp-FTT showed moderate-to-strong correlations with the mechanical FTT (dominant: r=0.63, p<0.001; non-dominant: r=0.55, p<0.001). Taps per second were associated with PSPRS motor severity (dominant hand: std. {beta}=-0.59, 95% CI [-0.91, -0.27], p<0.001) and the UPDRS (dominant hand: std. {beta}=-0.41, 95% CI [-0.82, 0.00], p=0.049). Flight time was modestly associated with neurologist-rated finger tapping impairment (dominant hand: std. {beta}=0.15, 95% CI [0.00, 0.29], p=0.044).\n\nConclusionThese findings support mApp-FTT validity as a measure of motor function across neurodegenerative conditions. Validation in longitudinal and unsupervised remote settings is warranted to understand scalability and evaluate change over time.","rel_num_authors":24,"rel_authors":[{"author_name":"Morgan O'Connor","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA"},{"author_name":"Mark Sanderson-Cimino","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Zi Li","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA"},{"author_name":"Sreya Dhanam","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Anjali Sadarangani","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Joshua Downer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Ray Fregly","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Jack Taylor","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Amy B. Wise","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Kaitlin B. Casaletto","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Leah K. Forsberg","author_inst":"Department of Neurology, Mayo Clinic, Rochester, MN, USA"},{"author_name":"Maria Luisa Gorno-Tempini","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Hilary W. Heuer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Joel H. Kramer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"John Kornak","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA"},{"author_name":"Bruce L Miller","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Emily W Paolillo","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Riley Bove","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Gil Rabinovici","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"William W. Seeley","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Brad F. Boeve","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Howie J. Rosen","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Adam L. Boxer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Adam M. Staffaroni","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Association Between Area Deprivation and Dental Provider Density in California: A Cross-Sectional Ecological Study","rel_doi":"10.64898\/2026.07.04.26357261","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357261","rel_abs":"Neighborhood socioeconomic disadvantage may contribute to inequities in access to dental care by influencing the geographic distribution of providers. The Area Deprivation Index (ADI) is a validated measure of neighborhood deprivation, but its association with dental workforce availability has not been examined statewide in California. This study evaluated the relationship between neighborhood deprivation and dental provider density across California ZIP Code Tabulation Areas (ZCTAs). We conducted a cross-sectional ecological study of California ZCTAs using publicly available data from the National Plan and Provider Enumeration System (April 2026), the Neighborhood Atlas 2023 ADI, and 2024 U.S. Census population estimates. Active dental providers were linked to ZCTAs and provider density was calculated per 10,000 residents. ADI was aggregated to the ZCTA level using the median ADI national percentile. Negative binomial regression was used to assess the association between ADI and dental provider density, with population included as an offset. Secondary analyses examined California-specific ADI quartiles, dental deserts, and specialist versus general dentist availability. The final analytic sample included 1,426 California ZCTAs representing 39,016,384 residents and 37,945 active dental providers. Greater neighborhood deprivation was significantly associated with lower dental provider density. Each one-percentile increase in ADI corresponded to a 1.8% reduction in provider density (incidence rate ratio [RR] 0.9823, 95% confidence interval [CI] 0.9799-0.9847; p < 0.001). Compared with the least deprived quartile, the most deprived quartile had 61% fewer dental providers (RR 0.39, 95% CI 0.34-0.45; p < 0.001). Overall, 15.9% of ZCTAs contained no active dental providers, increasing from 6.8% in the least deprived quartile to 31.1% in the most deprived quartile. Specialist availability demonstrated an even steeper deprivation gradient, with specialist density declining by 86% between the least and most deprived quartiles. Neighborhood deprivation was strongly associated with reduced dental provider availability across California. Highly deprived communities had substantially lower provider density, were more likely to be dental deserts, and experienced particularly pronounced shortages of dental specialists. ADI may be a useful tool for identifying communities where workforce shortages and socioeconomic disadvantage intersect and for informing equitable workforce planning and policy interventions.","rel_num_authors":2,"rel_authors":[{"author_name":"Anna-Lena Asiedu","author_inst":"University of California San Francisco, School of Dentistry"},{"author_name":"Collins Gaba","author_inst":"Boston University School of Social Work"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Prevalence of cancer in patients with cardiovascular diseases and risk factors: a systematic review and meta-analysis","rel_doi":"10.64898\/2026.07.04.26357301","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357301","rel_abs":"Background No systematic review has been conducted to pool the existing evidence and quantify cancer prevalence rates in cardiovascular diseases (CVDs). We aimed to estimate pooled cancer prevalence in coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), hypertension, type 2 diabetes mellitus (DM), stroke, peripheral arterial disease (PAD), and valvular heart diseases (VHD). Methods PubMed, Web of Science, and Scopus were searched from 2010 to July 2024. The outcomes were proportions of patients with active, any, previous, blood, solid, and metastatic cancer. The prevalence rates were estimated via one-step generalized linear mixed models. Results Totally, we retrieved 676 studies with enrollment of roughly 180 million participants. The analysis for active cancer included 59 studies with a population of 4,759,695 patients. The pooled prevalence of active cancer was 4.22% (95% confidence interval (CI) 2.18-5.32), 4.43% (95% CI 2.78-6.38), 4.60% (95% CI 1.72-8.13), 4.61% (95% CI, 2.83-6.97), 4.90% (95% CI 3.84-6.37), and 5.55% (95% CI 3.97-7.01) in patients with type 2 DM, chronic HF, any stroke, CAD, VHD, and AF. For any cancer, prevalence rates ranged from 14.10% (95% CI 12.20-15.99) in AF to 7.04% (95% CI 6.05-8.03) in CAD. Conclusion Pooled prevalence rates demonstrate a measurable burden of cancer among patients with a wide range of CVDs, highlighting the need for multidisciplinary management in this population.","rel_num_authors":15,"rel_authors":[{"author_name":"Akhmetzhan Galimzhanov","author_inst":"Astana Medical University"},{"author_name":"Elif Beytekin","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Leh Chuan Lim","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Abdul Basit Ali Zai","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Gemina Doolub","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Mustafa Aljarshawi","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Balamrit Singh Sokhal","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Andrija Matetic","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Rodrigo Bagur","author_inst":"Department of Cardiology, London Health Sciences Centre Western University London Ontario Canada"},{"author_name":"Louise Sun","author_inst":"Division of Cardiothoracic Anesthesiology, Stanford University School of Medicine, Stanford, California, USA"},{"author_name":"Cheng Han Ng","author_inst":"Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore"},{"author_name":"Miguel Nobre Menezes","author_inst":"Structural and Coronary Heart Disease Unit, Cardio-Oncology Unit CHULN Hospital de Santa Maria, Cardiovascular Center of the University of Lisbon, 1649-028 Lisb"},{"author_name":"Sarah Zaman","author_inst":"Westmead Applied Research Centre, University of Sydney, Sydney, Australia."},{"author_name":"Bonnie Ky","author_inst":"Thalheimer Center for Cardio-Oncology, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"},{"author_name":"Mamas Mamas","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Recalibrating Mendelian randomization under winner's curse, sample structure and polygenicity","rel_doi":"10.64898\/2026.06.25.26356593","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356593","rel_abs":"Recently, Hu et al. (2024) conducted a benchmarking study showing that most existing Mendelian randomization (MR) methods exhibit substantial bias and inflated type-I error rates in real data. They attributed these failures to two largely neglected sources of bias: winners curse and polygenicity-induced bias. Although a few methods have been developed to address one or both of these issues, existing approaches either do not fully account for both biases or are restricted to the univariable setting. In this paper, we propose a multivariable Rao-Blackwellization that corrects winners curse while accounting for polygenicity and sample structure in a unified framework. Unlike univariable Rao-Blackwellization, where instrument selection yields a truncated normal statistic amenable to a Mills-ratio correction, multivariable Rao-Blackwellization conditions on a noncentral{chi} 2 statistic, for which no analogous correction is available. We derive closed-form conditional moments under this instrument selection model and use them to construct bias-corrected summary statistics that can be integrated into a wide range of existing MR methods. Simulations and real data analyses show that, when combined with methods such as MR-cML and MR-BEE, the proposed correction substantially improves type-I error control and yields more robust inference.","rel_num_authors":4,"rel_authors":[{"author_name":"Yihe Yang","author_inst":"Case Western Reserve University"},{"author_name":"Zhaotong Lin","author_inst":"Florida State University"},{"author_name":"Haoran Xue","author_inst":"City University of Hong Kong"},{"author_name":"Xiaofeng Zhu","author_inst":"Case Western Reserve university"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Recalibrating Mendelian randomization under winner's curse, sample structure and polygenicity","rel_doi":"10.64898\/2026.06.25.26356593","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356593","rel_abs":"Recently, Hu et al. (2024) conducted a benchmarking study showing that most existing Mendelian randomization (MR) methods exhibit substantial bias and inflated type-I error rates in real data. They attributed these failures to two largely neglected sources of bias: winners curse and polygenicity-induced bias. Although a few methods have been developed to address one or both of these issues, existing approaches either do not fully account for both biases or are restricted to the univariable setting. In this paper, we propose a multivariable Rao-Blackwellization that corrects winners curse while accounting for polygenicity and sample structure in a unified framework. Unlike univariable Rao-Blackwellization, where instrument selection yields a truncated normal statistic amenable to a Mills-ratio correction, multivariable Rao-Blackwellization conditions on a noncentral{chi} 2 statistic, for which no analogous correction is available. We derive closed-form conditional moments under this instrument selection model and use them to construct bias-corrected summary statistics that can be integrated into a wide range of existing MR methods. Simulations and real data analyses show that, when combined with methods such as MR-cML and MR-BEE, the proposed correction substantially improves type-I error control and yields more robust inference.","rel_num_authors":4,"rel_authors":[{"author_name":"Yihe Yang","author_inst":"Case Western Reserve University"},{"author_name":"Zhaotong Lin","author_inst":"Florida State University"},{"author_name":"Haoran Xue","author_inst":"City University of Hong Kong"},{"author_name":"Xiaofeng Zhu","author_inst":"Case Western Reserve university"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Sickle Cell Disease Demographics and Clinical Epidemiology in Gambian Urban and Rural Cohorts Retrospective Analysis","rel_doi":"10.64898\/2026.07.03.26357219","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357219","rel_abs":"Globally, approximately 75% of sickle cell disease (SCD) cases occurs in sub-Saharan Africa, yet empirical data on its natural history, clinical burden, and modifiers remain scarce in the region. This retrospective study describes the demographic characteristics, complications, and routine care and examines how non-genetic factors and blood markers relate to disease severity. We analysed 8402 medical records from 840 SCD patients with confirmed HbSS genotype registered in MRCG Keneba and Fajara clinics (NKeneba=148; NFajara=692). A generalised linear model was employed to estimates association of non-genetic correlates, blood biomarkers, routine care medications with disease severity. Here we showed 67% of patients in Keneba cohort and 92% of those in Fajara cohort had no documented SCD-related chronic complication. Despite no documented evidence of hydroxyurea use, SCD crises (Keneba=0.57, Fajara=0.63) and infections (Keneba=0.53, Fajara=0.35) rates -expressed per patient-year-were low in both cohorts with 99% patients experiencing [&le;]3 SCD crises per patient-year. Age at diagnosis, gender and seasonality were not significantly associated with SCD crises or other clinical outcomes\/events rates. Each additional folic acid prescription was associated with higher haemoglobin(g\/dL) (total folic acid prescriptions: {beta}Fajara=1.31,P=0.005; {beta}Keneba=1.20,P<0.001). Penicillin prophylaxis was associated with reduced rate of infection (total Pen V prescriptions: IRRFajara=0.85,P=0.002; IRRKeneba=0.93,P=0.002) and SCD crises (IRRFajara=0.67,P=0.001; IRRKeneba=0.87,P=0.001). This study found low acute events rates and chronic complications prevalence in the absence hydroxyurea use. No significant associations were observed between non-genetic correlates and clinical events, but the study highlighted the needs for continues folic acid supplementation and penicillin prophylaxis due to their observed beneficial effects.","rel_num_authors":11,"rel_authors":[{"author_name":"Mustapha Dibbasey","author_inst":"Medical Research Council, the Gambia at London School of Hygiene and Tropical Medicine"},{"author_name":"Kevin Esoh","author_inst":"McKusick-Nathans Institute, and Department of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA"},{"author_name":"Bubacarr Susso","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Karen Forrest","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Bakary Sonko","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Lamin Makalo","author_inst":"Department of Paediatrics, Edward Francis Small Teaching Hospital, Banjul, The Gambia"},{"author_name":"Eniyou Oriero","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Ndong Ignatius Cheng","author_inst":"Department of Epidemiology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana"},{"author_name":"Lucas Amenga-Etego","author_inst":"West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, LG 54, Accra, Ghana"},{"author_name":"Carla Cerami","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Alfred Amambua-Ngwa","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Association of anti-Ro-52 positivity with cardiovascular outcomes in patients with anti-synthetase syndrome","rel_doi":"10.64898\/2026.07.04.26357290","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357290","rel_abs":"BackgroundAnti-synthetase syndrome (ASyS) is a subgroup of idiopathic inflammatory myopathies that is increasingly recognized as a distinct entity with features of myositis, interstitial lung disease, inflammatory arthritis, and Raynauds phenomenon. Co-reactivity with anti-Ro-52, an antibody directed against the Ro-52 E3 ubiquitin ligase, has been shown to be associated with progressive interstitial lung disease within this patient population. However, less is known regarding the association of anti-Ro-52 positivity with cardiovascular outcomes.\n\nMethodsA sub-cohort of patients with anti-synthetase antibodies at a large single institution center was retrospectively analyzed to define presence of anti-Ro-52 positivity (defined as anti-Ro-52 titer greater than or equal to 11 utilizing the line immunoblot platform, Euroline Autoimmune Inflammatory Myopathies, EuroImmun Diagnostics, Lubeck, Germany). Patients who did not meet 2017 ACR\/EULAR classification criteria for idiopathic inflammatory myopathies were excluded from the final analysis. Cardiovascular outcomes ascertained via retrospective chart review included atrial fibrillation, left bundle branch block, right bundle branch block, pulmonary hypertension (confirmed via right heart catheterization), heart failure with reduced ejection fraction (HFrEF, defined as ejection fraction less than or equal to 40%), acute coronary syndrome (based on clinical diagnosis and angiography if available), and myocarditis (based on clinician diagnosis and either cardiac MRI or troponin elevation). When a pre-specified cardiac outcome was identified, the date of onset was recorded. Differences in proportions were analyzed via Chi-squared and Fishers exact tests, and time-to-event analyses were performed via Cox Proportional Hazards Models, incorporating a false discovery rate correction for multiple outcomes. All analyses were performed using SAS v9.4.\n\nResults88 patients were included in the final analysis, of whom 69 (78.4%) were categorized as anti-Ro-52 positive. Patients with anti-Ro-52 positivity had a higher maximum recorded serum creatine kinase (median 1297 vs 395 units per liter, p = 0.042). No significant associations between anti-Ro-52 positivity and the pre-defined cardiovascular outcomes were found over median follow up time of 12.5 years.\n\nConclusionsIn a large, single-center cohort of patients with ASyS, anti-Ro-52 positivity was not associated with an increased burden of negative cardiovascular outcomes, including the onset of pulmonary hypertension. Future studies may seek to further elucidate the mechanisms underlying the pleiotropic effects of anti-Ro-52 antibodies on the cardiopulmonary system.","rel_num_authors":7,"rel_authors":[{"author_name":"Archit V. Potharazu","author_inst":"Johns Hopkins Medicine"},{"author_name":"Jae-Hoon Chung","author_inst":"Johns Hopkins Medicine"},{"author_name":"Lisa Yanek","author_inst":"Johns Hopkins Medicine"},{"author_name":"Will Kelly","author_inst":"Johns Hopkins Medicine"},{"author_name":"Nisha Gilotra","author_inst":"Johns Hopkins Medicine"},{"author_name":"Luigi Adamo","author_inst":"Johns Hopkins Medicine"},{"author_name":"Julie Paik","author_inst":"Johns Hopkins Medicine"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Neonatal Hypothermia at and after Admission: Burden and Associations with Outside Air Temperature and Neonatal Ward Temperature in Four Sub Saharan African Countries Implementing with the NEST360 Alliance","rel_doi":"10.64898\/2026.07.04.26357151","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357151","rel_abs":"BackgroundAnnually, 2.3 million newborns die, largely from preventable causes. Neonatal hypothermia is an important contributor to morbidity and mortality, particularly in low-resource settings. This study quantified the burden of hypothermia at and after admission in four NEST360-supported countries and examined associations between outside air temperature, ward temperature, and neonatal hypothermia.\n\nMethodsWe conducted a retrospective analysis of newborn admissions (January 2021 to June 2025) across 66 neonatal units in Kenya, Malawi, Nigeria, and Tanzania. Hypothermia was defined using WHO thresholds (mild: 36.0-36.4{degrees}C; moderate: 32.0-35.9{degrees}C; severe: <32.0{degrees}C). Newborn admission and lowest after admission body temperatures were extracted from routine clinical records. Ward temperatures were captured using the Hadli Monitoring System, and environmental temperatures were obtained from Open-Meteo. Multivariate ordinal logistic regression assessed associations between air temperature, ward temperature, and hypothermia at admission and during admission.\n\nResultsAmong 418,458 newborn admissions with recorded admission temperatures, 47.3% (n=220,684) were hypothermic at admission (country range: 22.8%-61.9%), while 63.5% (n=48,746) experienced hypothermia during hospital stay (country range: 18.5%-74.4%), based on 76,855 admissions (July 2024-June 2025) with temperature data. Based on admission and subsequent temperature, 28.5% had no documented hypothermia, 8.6% improved to non-hypothermic status, 29.4% developed hypothermia after admission, and 33.5% experienced hypothermia at admission and during hospital stay. Across 59 neonatal units, minimum ward temperatures >26{degrees}C were maintained on 92.6% of 365 days. At admission, ward temperatures of 30-33{degrees}C were associated with 9% lower odds of a lower thermal category versus 26-28{degrees}C (p<0.01). After admission, ward temperatures of 28-30{degrees}C reduced odds by 18% (p<0.05). Warmer outside temperatures (>24{degrees}C day, >21{degrees}C night) were protective, corresponding to 19% and 68% lower odds of a lower thermal category after admission, respectively, compared with 19-24{degrees}C and 15-21{degrees}C reference groups. Newborns had 3.6-fold higher odds of hypothermia at night than during the day. Each 1{degrees}C increase in post-admission temperature reduced odds of death by 6%.\n\nConclusionNeonatal hypothermia remains highly prevalent despite most units maintaining ward temperatures above WHO minimum standards (26{degrees}C). Strengthening all components of the warm chain, particularly at night and during colder seasons, is essential to reduce hypothermia and improve survival.\n\nKey Findings\n\nO_TBL View this table:\norg.highwire.dtl.DTLVardef@594cddorg.highwire.dtl.DTLVardef@c54366org.highwire.dtl.DTLVardef@cbdef5org.highwire.dtl.DTLVardef@9ada86org.highwire.dtl.DTLVardef@8095c6_HPS_FORMAT_FIGEXP  M_TBL C_TBL","rel_num_authors":23,"rel_authors":[{"author_name":"Melissa Mar","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Christine A Bohne","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"John Wainaina","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Mariam Thabit Johari","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"George Okello","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Edith Gicheha","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Catherine Paul","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Rebecca Richards-Kortum","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Maria Oden","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Joy E Lawn","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"Lucas Malla","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"Kristina Shemwell","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"William M Macharia","author_inst":"Department of Paediatrics, Aga Khan University, Nairobi, Kenya"},{"author_name":"Hannah Mwaniki","author_inst":"Department of Paediatrics, Aga Khan University, Nairobi, Kenya"},{"author_name":"Nahya Salim Masoud","author_inst":"Department of Paediatrics and Child Health, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania"},{"author_name":"Samuel K Ngwala","author_inst":"School of Global and Public Health, Kamuzu University of Health Sciences, Blantyre, Malawi"},{"author_name":"Msandeni Chiume","author_inst":"Ministry of Health, Malawi - Reproductive Health Department"},{"author_name":"Veronica Chinyere Ezeaka","author_inst":"Department of Paediatrics, College of Medicine, University of Lagos, Lagos, Nigeria"},{"author_name":"Elizabeth M Molyneux","author_inst":"Department of Paediatrics, Kamuzu University of Health Sciences, Blantyre, Malawi"},{"author_name":"Natasha R Rhoda","author_inst":"Children's Institute, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa"},{"author_name":"Vincent Otieno Ochieng","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Opeyemi Odedere","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Lisa R Hirschhorn","author_inst":"Northwestern University Feinberg School of Medicine, Illinois, USA"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Organised cancer screening among women who receive medically assisted reproduction treatments","rel_doi":"10.64898\/2026.07.05.26357336","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357336","rel_abs":"There are no published data on cancer screening by women using medically assisted reproduction (MAR). Such data would aid interpretation of the cancer incidence and risk profiles for this group. Using linked population-based Australian health registries and administrative datasets, we compared organised publicly funded cervical and breast screening episodes for women who received one of three types of MAR and matched women who did not between 1991 and 2016. We modelled the proportion of women screened in the three years before and after first MAR treatment, adjusting for age, remoteness, parity, socio-economic disadvantage, cancer history, and uptake of the other screening program. After adjustment, a greater proportion of women who received MAR than women who did not had cervical screening before MAR (77.3%-84.1% vs 57.5%-62.0%, depending on treatment) and after MAR (77.0%-78.5% vs 68.1%-68.3%). Contrastingly, breast screening estimates were 7.6%-9.6% vs 9.3%-10.5% before MAR and 11.0%-15.0% vs 12.8%-14.9% after MAR.","rel_num_authors":12,"rel_authors":[{"author_name":"Adrian Raymond Walker","author_inst":"UNSW Sydney"},{"author_name":"Signe Odahl","author_inst":"Norwegian University of Science and Technology"},{"author_name":"Christos Venetis","author_inst":"Aristotle University of Thessaloniki"},{"author_name":"Louisa Jorm","author_inst":"UNSW Sydney"},{"author_name":"Neville F Hacker","author_inst":"UNSW Sydney"},{"author_name":"Michael Chapman","author_inst":"UNSW Sydney"},{"author_name":"Antoinette C Anazodo","author_inst":"UNSW Sydney"},{"author_name":"Robert J Norman","author_inst":"Adelaide University"},{"author_name":"Catharyn Stern","author_inst":"University of Melbourne"},{"author_name":"Ursula M Sansom-Daly","author_inst":"UNSW Sydney"},{"author_name":"Georgina Mary Chambers","author_inst":"UNSW Sydney"},{"author_name":"Claire Melissa Vajdic","author_inst":"UNSW Sydney"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Bench-stepping training improves stair-walking dynamics in older women: evidence from an exploratory nonlinear kinematic analysis","rel_doi":"10.64898\/2026.07.02.26357116","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357116","rel_abs":"IntroductionStair walking challenges balance and coordination in older people. Bench-stepping training improves stair climbing speed in healthy older women. This study assessed whether bench-stepping also improves dynamic balance and movement complexity during stair walking.\n\nMethodsStair walking data were obtained from a previous study involving 45 healthy older women (69y{+\/-}4) that assessed the effects of a 12-week bench-stepping intervention with non-training controls. Centre-of-mass acceleration was measured during stair ascent and descent. Linear dynamics included time, acceleration magnitude, and harmonic ratios (HR; indicating symmetry). Movement complexity was quantified using nonlinear dynamics including sample entropy (SE), recurrence quantification analysis (RQA), and fractal dimension (FD).\n\nResultsFor stair ascent, increased speed (p =0.018, R2partial =0.093,) was accompanied by proportional increases in acceleration magnitudes (p[&le;]0.039, R2partial =0.078-0.101). SE decreased more in the intervention group (p [&le;]0.012, R2partial =0.049-0.101), indicating more predictable dynamics. In contrast, for stair descent, no changes in speed or acceleration magnitudes were observed. However, SE (p =0.001, R2partial =0.082) and maximum RQA line length (p= 0.008, R2partial =0.057) of vertical acceleration increased significantly compared to controls, indicating lower predictability and more persistent recurring patterns. No significant changes were found for other outcomes. Exploratory factor analysis revealed distinct differences in motor behaviour between stair ascent and descent.\n\nConclusionBench-stepping training induced measurable changes in stair walking dynamics. Specifically, sample entropy shows potential as a sensitive marker of altered motor complexity, particularly of vertical accelerations. Interestingly, the direction of changes in unpredictability differed between stair ascent and descent, suggesting different underlying control strategies.","rel_num_authors":8,"rel_authors":[{"author_name":"Remco Johan Baggen","author_inst":"Vrije Universiteit Amsterdam\/Neuroscience Research Australia"},{"author_name":"Kimberley Stefanie van Schooten","author_inst":"Neuroscience Research Australia\/University of New South Wales"},{"author_name":"Evelien Van Roie","author_inst":"Hasselt University"},{"author_name":"Sabine Marie Verschueren","author_inst":"KU Leuven"},{"author_name":"Christophe Delecluse","author_inst":"KU Leuven"},{"author_name":"Kim Delbaere","author_inst":"University of New South Wales\/NeuRA"},{"author_name":"Stephen R Lord","author_inst":"Neuroscience Research Australia"},{"author_name":"Jaap H. van Dieen","author_inst":"VU Amsterdam: Vrije Universiteit Amsterdam"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Validation of aEEG-CSA Neonatal Seizure Detection Algorithm on Hypothermia Treated Infants with HIE","rel_doi":"10.64898\/2026.07.02.26356964","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26356964","rel_abs":"ObjectiveTo validate a neonatal seizure detection algorithm that is based on extracted clinical features of the aEEG and CSA on a cohort of cooled neonatal patients with hypoxic ischemic encephalopathy.\n\nMethodsA seizure detection algorithm was designed using aEEG margin features, CSA features, trained on a public dataset of 79 neonatal EEGs with three supervised machine learning classifiers. It was subsequently tested on an inhouse cohort of 23 neonates with asphyxia whose EEGs were collected during cooling therapy.\n\nResultsThe trained Random Forest, Support Vector Machines and Artificial Neural Network classifiers had an AUC of 0.76, 0.77, and 0.77 and an average accuracy of 0.85, 0.86, and 0.85 respectively. Finally, the average AUC across the 10 seizure patients included was 0.85.\n\nConclusionA neonatal seizure detection algorithm that uses a combination of aEEG and CSA clinical features can capture seizures in HIE patients. Performance across seizure patients is not correlated with seizure duration.","rel_num_authors":5,"rel_authors":[{"author_name":"Sylvia Edoigiawerie","author_inst":"Cook County Hospital"},{"author_name":"Julia Henry","author_inst":"AdventHealth for Children"},{"author_name":"Brett Beaulieu-Jones","author_inst":"University of Chicago"},{"author_name":"Henry David","author_inst":"University of Chicago"},{"author_name":"Naoum Issa","author_inst":"University of Chicago"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"GLP Medications and Severe Post-COVID-19 Outcomes Among Individuals with Type 2 Diabetes Mellitus","rel_doi":"10.64898\/2026.07.03.26357246","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357246","rel_abs":"BackgroundGlucagon-like peptide-1 receptor agonist-based therapies (GLP) have recently emerged as promising treatments across a wide range of health conditions. These medications may have protective effects against severe long-term consequences of COVID-19 by promoting weight loss, exerting antihyperglycemic and anti-inflammatory effects, and providing cardiovascular and endothelial protection.\n\nMethodsWe evaluated electronic health record data from a retrospective cohort of individuals in the National Clinical Cohort Collaborative. We included individuals with type 2 diabetes mellitus and comorbid COVID-19 who were prescribed either GLP (treatment) or a sodium-glucose co-transporter 2 inhibitor (SGLT2i) and subsequently developed acute COVID-19 between October 1, 2021, and April 1, 2023. We compared the 12-month cumulative incidence of mortality and Long COVID (Long COVID diagnosis and probable Long COVID via computational phenotype) between groups. We applied targeted maximum likelihood estimation to compare outcome risks by exposure status, controlling for covariates of interest.\n\nResultsWe analyzed data from 14,215 individuals with COVID-19 and comorbid type 2 diabetes (mean age, 60 years; mean BMI, 37). Compared to SGLT2i, a prescription for GLP medication was associated with a lower risk of mortality (adjusted risk ratio [aRR] 0.71; 95% CI 0.53, 0.95), but not Long COVID diagnosis (aRR 1.01; 95% CI 0.80, 1.27) or probable Long COVID (aRR 0.94; 95% CI 0.88, 1.01).\n\nConclusionsWe found that among individuals with type 2 diabetes and comorbid COVID-19, a prescription for GLP vs. SGLT2i medications was associated with a lower risk of mortality, but not Long COVID.","rel_num_authors":14,"rel_authors":[{"author_name":"Zachary Butzin-Dozier","author_inst":"Stanford University, Stanford, CA USA"},{"author_name":"Lin-Chiun Wang","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Yunwen Ji","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Manav Kumar","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"A. Jerrod Anzalone","author_inst":"University of Nebraska Medical Center, Omaha, NE, USA"},{"author_name":"Eric Hurwitz","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Rena C. Patel","author_inst":"University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Ariana Budhihartanto","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"John B. Buse","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Steven Johnson","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Jane Reusch","author_inst":"University of Colorado, Anschutz, Aurora, CO, USA"},{"author_name":"Carolyn Bramante","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Rachel Wong","author_inst":"Renaissance School of Medicine, Stony Brook University, New York, NY, USA"},{"author_name":"- on behalf of the National Clinical Cohort Collaborative","author_inst":"-"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Cardiovascular events in individuals with small\/medium LDL particle discordance","rel_doi":"10.64898\/2026.06.25.26356542","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356542","rel_abs":"AimsDespite similar LDL-C levels, size and composition of LDL particles (LDL-P) varies widely. Among the metabolically perturbed, or those with altered function of lipid regulatory proteins, LDL-C levels mask elevated atherogenic small-medium LDL-P (S\/M LDL-P). We assessed the contribution of such discordance in S\/M LDL-P on major adverse cardiovascular event risk (MACE).\n\nMethods and resultsUK Biobank participants with Nightingale NMR metabolomics (487,521 participants), were classified as high or low cardiometabolic burden. S\/M LDL-P discordance was defined as the difference between LDL-C predicted S\/M LDL-P and observed S\/M LDL-P. Genetic variants encoding cholesterol ester transfer protein (CETP), which regulates cholesterol-triglyceride exchange and the production of small LDL particles, were identified via whole genome sequencing. Adjusted Cox proportional hazard regression was used to estimate MACE associations. S\/M LDL-P discordance showed an LDL-C and Apo-B independent association with MACE (47,935 cases), which differed by cardiometabolic burden group: hazard ratio (HR) per standard deviation 1.09 (95%CI 1.05; 1.13) and HR 1.24 (95%CI 1.21; 1.27) for low\/high burden, respectively. Loss of function (LoF) CETP variants were strongly associated with lower levels of both S\/M LDL-P and S\/M LDL-P discordance. For example, the S\/M LDL-P discordance effect of CETP LoF carriership for low\/high metabolic burden, respectively, was -4.62 nmol\/L (95%CI -8.40; -0.83) compared to -11.10 nmol\/L (95%CI -15.57; -6.63).\n\nConclusionS\/M LDL-P discordance (overabundance) is strongly associated with MACE risk, especially in people with high cardiometabolic burden. S\/M LDL-P discordance is modified by CETP genetic variation, suggesting a role for CETP-mediated lipid remodelling beyond LDL-C changes.\n\nTranslational perspectiveConventional lipid parameters such as LDL-C and apolipoprotein B may underestimate the atherogenic burden conferred by an overabundance of small and medium LDL particles, particularly in patients with diabetes, obesity, or established atherosclerotic disease. We introduce a novel measure of small\/medium LDL particle (S\/M LDL-P) discordance, quantifying the excess of S\/M LDL-P beyond what is predicted by LDL-C alone. S\/M LDL-P discordance is independently associated with time to incident MACE, especially in people with increased cardiometabolic burden. Genetic loss of function in cholesteryl ester transfer protein (CETP), which regulates cholesterol-triglyceride exchange and the production of small LDL particles, reduced S\/M LDL-P discordance, in particular among those with metabolically perturbed states where discordance was otherwise high. Taken together, these findings provide support for the potential role of CETP inhibition, as a therapeutic strategy that may lower cardiovascular risk in part through reduction of S\/M LDL-P discordance. This hypothesis is currently being evaluated with obicetrapib in the PREVAIL trial.","rel_num_authors":10,"rel_authors":[{"author_name":"Amand Floriaan Schmidt","author_inst":"University College London"},{"author_name":"Nikita Hukerikar","author_inst":"University College London"},{"author_name":"Sam Quill","author_inst":"University College London"},{"author_name":"Marion van Vugt","author_inst":"Amsterdam University Medical Centers"},{"author_name":"Mathijs de Kleer","author_inst":"NewAmsterdam Pharma B.V."},{"author_name":"Marc Ditmarsch","author_inst":"NewAmsterdam Pharma B.V."},{"author_name":"Michael Szarek","author_inst":"University of Colorado School of Medicine"},{"author_name":"John J. Kastelein","author_inst":"NewAmsterdam Pharma B.V."},{"author_name":"Kausik K. Ray","author_inst":"Imperial College London"},{"author_name":"Michael H. Davidson","author_inst":"University of Chicago"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Association of Neutrophil-to-Lymphocyte Ratio and Systemic Immune-Inflammation Index With Mortality in Patients With Pericarditis: A Retrospective Dual-Cohort Study Using Two Independent Databases","rel_doi":"10.64898\/2026.06.25.26356550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356550","rel_abs":"BackgroundRisk stratification in pericarditis relies mainly on clinical presentation, suspected etiology, imaging findings, and conventional inflammatory biomarkers. Whether complete blood count-derived inflammatory indices are associated with mortality in pericarditis and reproducible across independent real-world datasets remains unclear.\n\nMethodsWe conducted a retrospective dual-cohort study of hospitalized adults with pericarditis using a Hong Kong cohort from the Clinical Data Analysis and Reporting System (CDARS) as the primary analysis cohort and the Medical Information Mart for Intensive Care IV (MIMIC-IV) cohort as an independent reproducibility cohort. Baseline neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) were analyzed as continuous variables and cohort-specific tertiles. The primary outcome was long-term all-cause mortality in the Hong Kong cohort. Secondary and reproducibility outcomes included 90-day mortality in the Hong Kong cohort and 30-day, 90-day, and observable follow-up mortality in MIMIC-IV. Cox models were adjusted for age, sex, renal disease, diabetes mellitus, hypertension, ischemic heart disease, and malignancy.\n\nResultsAmong 504 patients in the Hong Kong cohort and 464 patients in MIMIC-IV, all-cause mortality occurred in 241 and 113 patients during cohort-specific follow-up, respectively. In the Hong Kong cohort, higher NLR was associated with long-term all-cause mortality after full adjustment. Compared with NLR tertile 1, the adjusted hazard ratio was 1.60 for tertile 3. Higher SII was also associated with long-term mortality, with an adjusted hazard ratio of 1.55 for tertile 3 versus tertile 1. NLR and SII showed directionally consistent associations with 90-day mortality in the Hong Kong cohort and with 30-day, 90-day, and observable follow-up mortality in MIMIC-IV. Sensitivity analyses yielded broadly consistent findings.\n\nConclusionsIn two independent real-world cohorts of hospitalized patients with pericarditis, higher baseline NLR and SII were associated with increased all-cause mortality, with NLR showing the more consistent prognostic signal. These complete blood count-derived indices may provide simple adjunctive information for mortality risk stratification, although prospective validation is needed before incorporation into formal management algorithms.","rel_num_authors":5,"rel_authors":[{"author_name":"Lingyu Mi","author_inst":"Chinese Academy of Medical Sciences & Peking Union Medical College"},{"author_name":"Ishan Lakhani","author_inst":"Chinese University of Hong Kong"},{"author_name":"Wing Tak Wong","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Gary Tse","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Fang Fang","author_inst":"Chinese Academy of Medical Sciences & Peking Union Medical College"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Diagnostic accuracy and acceptability of self- and health worker-collected tongue swabs for Mycobacterium tuberculosis complex detection in adults in South Africa","rel_doi":"10.64898\/2026.07.04.26357275","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357275","rel_abs":"Tongue swabs (TSs) are a non-invasive specimen type for the detection of Mycobacterium tuberculosis complex (MTBC) and can expand access to testing for individuals unable to produce sputum. This study evaluated the diagnostic performance and user acceptability of self-collected and health worker (HW)-collected tongue swabs using the Xpert MTB\/RIF Ultra (Ultra) assay and assessed participant perspectives on self-collection.\n\nIn this prospective, cross-sectional study, symptomatic and asymptomatic adults under investigation for TB were enrolled from a high HIV prevalence setting. Each participant provided both a self-collected and a HW-collected TS, which were tested using Ultra. Ultra TS results were compared to liquid culture as the reference standard and sputum Ultra as a comparator. Participant perspectives on self-collection were captured via questionnaires.\n\nSensitivity on Ultra for both self- and HW-collected TSs was 68% (95% CI:51.9-81.9), compared to liquid culture. This sensitivity was significantly higher than that of sputum smear microscopy (46%, 95% CI: 30.7-62.6; McNemars p = 0.003). Tongue swab sensitivity was lower than sputum Ultra (80.5%; p<0.001) and decreased with low bacillary loads. Importantly, TSs enabled MTBC detection in six participants unable to produce sputum. Most participants (>90%) found self-collection instructions easy to follow, reporting high confidence and comfort, and trust in results from self-collected TSs.\n\nThis study demonstrates that self-collected TSs perform comparably to those collected by health workers for TB detection using Ultra and are both feasible and acceptable in a high TB\/HIV burden setting. To maximize impact, clear training instructions and robust linkage to care remain critical priorities.\n\nImportanceThis study supports the use of tongue swabs (TSs) as a non-invasive alternative for tuberculosis diagnosis, particularly for individuals unable to produce sputum. When tested on the Xpert MTB\/RIF Ultra assay, self-collected TSs performed comparably to health worker-collected swabs, yielding a 68% sensitivity (95% CI: 51.9-81.9) relative to liquid culture. This sensitivity was significantly higher than that of sputum smear microscopy (46%, 95% CI: 30.7-62.6; McNemars p = 0.003). Importantly, TSs successfully detected Mycobacterium tuberculosis complex in six patients who could not provide sputum, underscoring their clinical utility in expanding diagnostic access. Furthermore, high user acceptability (>90%) confirms that self-collection is both feasible and trusted by patients in high TB\/HIV burden settings. To maximize real-world impact, implementing clear training instructions and establishing robust linkage to care, especially following negative results, remain critical programmatic priorities.","rel_num_authors":10,"rel_authors":[{"author_name":"Anura David","author_inst":"University of the Witwatersrand Faculty of Health Sciences"},{"author_name":"Yeonsoo Baik","author_inst":"Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"},{"author_name":"Lesley Scott","author_inst":"University of the Witwatersrand Johannesburg Faculty of Health Sciences"},{"author_name":"Griffiths Kubeka","author_inst":"The Aurum Institute for Health Research, Parktown, Johannesburg, South Africa"},{"author_name":"Adelaide Benoit","author_inst":"Johns Hopkins University School of Public Health, Maryland, USA"},{"author_name":"Lyndel Singh","author_inst":"Wits Diagnostics Innovation Hub, Wits Health Consortium (PTY) Ltd, Johannesburg, South Africa"},{"author_name":"Pedro da Silva","author_inst":"National Priority Programmes, National Health Laboratory Services, Johannesburg, South Africa"},{"author_name":"Wendy Stevens","author_inst":"Wits Diagnostics Innovation Hub, Health Sciences Research Office, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg"},{"author_name":"Gregory P Bisson","author_inst":"Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"},{"author_name":"Salome Charalambous","author_inst":"The Aurum Institute"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"NEXIM: A Nash Equilibrium-Based Framework for Stable Explainable AI in Medical Applications","rel_doi":"10.64898\/2026.06.25.26356568","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356568","rel_abs":"Reliable explanations are important for trustworthy medical applications of artificial intelligence (AI), but attribution-based explanations can vary across model randomization and small analytic changes. We present NEXIM (Nash Equilibrium-based Explainability and Interpretability Model), implemented here as an accuracy-constrained, equilibrium-inspired model-selection framework that jointly evaluates held-out prediction error, explanation stability, and cross-model connectivity. The implementation evaluated ten GradientBoosting Regressor models per prediction horizon, differing only by random seed (0-9), using a fixed 75\/25 patient split. Kernel SHAP attribution vectors were compared using Spearman rank correlation, and graph connectivity summarized whether each model belonged to a dense explanation-similarity region. Candidate models within 0.02 Montreal Cognitive Assessment points of the best root mean squared error (RMSE) were ranked using a multiplicative Explanation Equilibrium Score. In longitudinal Parkinsons Progression Markers Initiative data, NEXIM selected the RMSE-optimal model at the one- and three-year horizons. At the two-year horizon, it selected Model 4 rather than the RMSE-only Model 8, increasing scaled stability from 0.8757 to 0.8847 and normalized graph connectivity from 0.889 to 1.000 while increasing RMSE by only 0.0014. The two models retained the same top-20 feature set but differed modestly in feature order, illustrating that NEXIM primarily acted as a reproducibility screen rather than identifying clinically contradictory explanations. Stability and consensus are treated as reproducibility criteria, not evidence of causal faithfulness, clinical usefulness, or improved patient outcomes. NEXIM may therefore serve as a governance checkpoint for model refresh and documentation, but external validation, stronger model-family baselines, and prospective clinical evaluation remain necessary.","rel_num_authors":4,"rel_authors":[{"author_name":"Dipak P Upadhyaya","author_inst":"Case Western Reserve University"},{"author_name":"Satya S Sahoo","author_inst":"Case Western Reserve University"},{"author_name":"Katrina Prantzalos","author_inst":"Case Western Reserve University"},{"author_name":"Pedram Golnari","author_inst":"Case Western Reserve University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Tacrolimus variability and creatinine predict readmission after liver transplantation","rel_doi":"10.64898\/2026.07.02.26357106","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357106","rel_abs":"Unplanned readmissions after liver transplantation occur in over 30% of recipients, yet no validated prediction models exist, and prior observational studies suffer from immortal time bias. The optimal readmission window for outcome prediction and the feasibility of early risk stratification remain undefined. This study is a retrospective analysis of 922 adult liver transplant recipients (August 2018-August 2025) at a single center. Time-varying Cox regression evaluated 14-, 30-, and 90-day readmission windows as predictors of 1-year mortality, correcting for immortal time bias. Gradient-boosted machine learning models leveraging 528,400 laboratory measurements (28 analytes) predicted 90-day readmission using either complete hospitalization data or data restricted to postoperative day 7. Feature importance was quantified by gain, and clinical utility was assessed through risk stratification. Among 902 hospital survivors, 342 (37.9%) experienced an unplanned readmission within 90 days of initial discharge. Only the 90-day readmission window predicted 1-year mortality in time-varying analysis (HR 1.73, 95% CI 1.17-2.57, p=0.006). The model for readmission using complete data achieved AUC 0.614 (95% CI 0.576-0.652); the postoperative day 7 restricted model achieved AUC 0.615 (95% CI 0.577-0.652), with no meaningful performance difference. The tacrolimus coefficient of variation x peak creatinine interaction was the dominant predictor in both the complete model (17.3% importance, rank 1) and the day 7 restricted model (20.4% importance, rank 2). This interaction stratified patients into high-risk (tacrolimus CV >0.3 and creatinine >2.0 mg\/dL; 49.8% readmission) versus low-risk (24.8% readmission) groups (risk ratio 2.01, p<0.001). These results identify a modifiable biological determinant of readmission and establish a framework for targeted interventions to reduce unplanned readmission and improve post-transplant outcomes.","rel_num_authors":1,"rel_authors":[{"author_name":"Kevin  Marc Korenblat","author_inst":"Washington University School of Medicine in Saint Louis: Washington University in St Louis School of Medicine"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Expanding the Pediatric Heart Donor Pool: National Outcomes of Donation After Circulatory Death Versus Donation After Brain Death Heart Transplantation","rel_doi":"10.64898\/2026.07.03.26357254","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357254","rel_abs":"BackgroundDonation after circulatory death (DCD) is an increasingly accepted strategy to expand the adult heart donor pool, but its use in children remains limited and incompletely characterized. We compared national characteristics and post-transplant outcomes of pediatric DCD versus donation after brain death (DBD) heart transplantation.\n\nMethodsWe performed a retrospective cohort study of the Organ Procurement and Transplantation Network (OPTN) registry, including patients younger than 18 years who underwent primary isolated heart transplantation between January 1993 and March 2025. Recipients were stratified by donor type (DCD vs DBD). Continuous variables were compared with the Mann-Whitney U test and categorical variables with the {chi}2 or Fisher exact test. Survival was estimated by the Kaplan-Meier method and compared using the log-rank test and Cox proportional hazards regression.\n\nResultsOf 10,671 pediatric heart transplant recipients, 33 (approximately 0.3%) received DCD allografts. The first DCD transplant was recorded in 2004, with a marked increase in 2023-2024. Compared with DBD recipients, DCD recipients were more frequently infants (<1 year, 51.5% vs 28.4%) and more often had congenital heart disease (69.7% vs 47.6%; P=0.033); DCD donors were younger (median 0 vs 6 years; P=0.038) and more frequently died of anoxia (72.7% vs 37.0%; P<0.001). Donor and recipient left ventricular mass were lower in the DCD group (P<0.05), but predicted left ventricular mass matching was similar. DCD recipients had longer hospital stays (median 31.5 vs 19 days; P=0.023); rates of treated rejection, dialysis, stroke, and pacemaker implantation were comparable. Early survival did not differ (30-day, 90-day, and 1-year), and Kaplan-Meier survival through 5 years was not significantly different (hazard ratio 1.17; 95% CI 0.49-2.81; log-rank P=0.73). More than 90% of DCD transplants were performed in four UNOS regions (11, 4, 5, and 8).\n\nConclusionsIn this national analysis, pediatric DCD heart transplantation was uncommon but expanding rapidly, concentrated in a few regions, and used preferentially in infants and children with congenital heart disease. Early post-transplant outcomes were not significantly different from DBD, supporting cautious expansion of DCD as a means of enlarging the pediatric donor pool. The small number of DCD recipients and limited follow-up warrant confirmation in larger, longer-term studies.","rel_num_authors":9,"rel_authors":[{"author_name":"Bilal Khan Mohammed","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Rohit Ganduboina","author_inst":"NRI Institute of Medical Sciences"},{"author_name":"Omar Abdel Kerim","author_inst":"University of Miami Miller School of Medicine, Miami"},{"author_name":"Gayatri Muley","author_inst":"Grant Medical College and Sir J.J. Group of Hospitals"},{"author_name":"Palak Dutta","author_inst":"University of Illinois College of Medicine"},{"author_name":"Nitya Krishna Arumugam","author_inst":"Kasturba Medical College, Manipal"},{"author_name":"John Karamichalis","author_inst":", Columbia University Irving Medical Center"},{"author_name":"Yahiya Pasha Quadri Syed","author_inst":"UW Health Swedish American Hospital"},{"author_name":"Sandeep Sainathan","author_inst":"University of Miami Miller School of Medicine"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Saliva cell-free mitochondrial DNA (cf-mtDNA) response during physical and cognitive stress","rel_doi":"10.64898\/2026.07.02.26356953","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26356953","rel_abs":"Emerging evidence suggests that saliva cell-free mitochondrial DNA (cf-mtDNA) increases in response to psychosocial and physical stress. Here, we quantified saliva cf-mtDNA changes in response to acute physical and cognitive stressors as well as identifying potential predictors of these responses, while also exploring the potential modulatory effects of transcranial infrared laser stimulation (TILS). In a crossover design, a total of 47 participants (53% female, ages 18-30) underwent up to three experimental sessions, including an exercise stress task and two cognitive stress tasks. Repeated saliva samples were collected for cf-mtDNA and cell-free nuclear DNA (cf-nDNA) quantification, alongside continuous measurement of heart rate, oxygen consumption, and blood pressure. Our results show that average cf-mtDNA levels increased by 90% after baseline during exercise experiments, and in cognitive stress experiments peaked 160% above average baseline levels during the stress task. Inter-individual differences in response trajectories were associated with differences in factors such as fitness, sleep quality, and stress perception. Notably, participants with higher cf-mtDNA elevations during the exercise experiment reported fewer recent stressful incidents, drank alcohol less frequently, had higher maximum VO2 during exercise, and had lower BMI. More dynamic responses to cognitive stress were observed in participants with poorer sleep quality and greater blood pressure reactivity. These findings provide a foundation for larger studies by highlighting the dynamic behavior of saliva cf-mtDNA following physical and cognitive stressors, and by suggesting potential drivers of individual differences in saliva cf-mtDNA stress reactivity.","rel_num_authors":7,"rel_authors":[{"author_name":"Caroline Trumpff","author_inst":"Columbia University"},{"author_name":"David Shire","author_inst":"Columbia University"},{"author_name":"Tian Wang","author_inst":"Columbia University"},{"author_name":"Shuang Wang","author_inst":"Columbia University"},{"author_name":"Temmie Yu","author_inst":"Columbia University"},{"author_name":"Martin Picard","author_inst":"Columbia University"},{"author_name":"Annie T. Ginty","author_inst":"Baylor University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Maternal Extracellular Vesicles During Pregnancy and Autism Risk in Children","rel_doi":"10.64898\/2026.06.25.26355526","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26355526","rel_abs":"BackgroundDifferences in extracellular vesicles (EVs), bioactive nanoparticles involved in intercellular signaling, have been reported in those with autism. However, little is known about the association between maternal EVs during pregnancy and the likelihood of autism in offspring. This study evaluated the association of the concentration and cargo material of EVs in prenatal maternal plasma with childhood autism likelihood.\n\nMethodsParticipants in the Nulliparous Pregnancy Outcomes Study provided maternal plasma at 15-23 weeks gestational age. EVs were isolated by ultracentrifugation, and concentration, mean size, CD63 levels, and RNA cargo were assessed by nanoparticle tracking analysis, ELISA, and small RNA sequencing. At 4.5-6 years of age, parents completed the Social Communication Questionnaire. Thirty-one children at high-risk for autism were matched to 31 low-risk children on sex, age, and gestational age. Differential RNA transcript analysis and over representation analysis were performed.\n\nResultsThere were no group differences in CD63 levels, mean particle size, or EV concentration (p>0.1). Nominal bin-level differences were observed at 280-290 nm and 430-440 nm before multiple-comparison correction. One hundred forty-five RNAs, including protein-coding RNAs, piRNAs, lncRNAs, miRNAs, snoRNAs, snRNAs, and tRNAs, were differentially contained, most of them downregulated in those at high risk of autism. These RNAs mapped to pathways involved in immune\/inflammatory signaling, intracellular trafficking, protein turnover, and neurodevelopment. Six of the 62 (9.7%) differentially contained protein-coding RNAs overlapped with genes in the SFARI Gene database.\n\nLimitationsLarge studies involving individuals diagnosed with autism are needed to evaluate the role of prenatal EVs in the pathogenesis of the condition. Additionally, prenatal sampling of EVs across multiple timepoints and subsequent deconvolution to determine the source of the EVs will strengthen interpretability and veracity of our findings.\n\nConclusionsThese findings provide preliminary evidence that maternal prenatal EV RNA cargo is associated with childhood autism likelihood.","rel_num_authors":13,"rel_authors":[{"author_name":"Delia McGowan","author_inst":"Barnard College, Columbia University, New York, NY, United States"},{"author_name":"Serena Nencini","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"William Yakah","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Claire-Marie Vacher","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Helene Lacaille","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"David M Haas","author_inst":"Department of Obstetrics and Gynecology, School of Medicine, Indiana University, Indianapolis, IN, United States"},{"author_name":"William A Grobman","author_inst":"Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH, United States"},{"author_name":"Robert M Silver","author_inst":"Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, United States"},{"author_name":"Uma M Reddy","author_inst":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States"},{"author_name":"Ronald J Wapner","author_inst":"Department of Obstetrics and Gynecology, Columbia University Irving Medical Center New York, NY, United States"},{"author_name":"William P Fifer","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States; Department of Psychiatry, Columbia University Irving Medical C"},{"author_name":"Anna A Penn","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Morgan R Firestein","author_inst":"Department of Pediatrics, Child Health Institute of New Jersey, Brain Health Institute, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United St"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Maternal Extracellular Vesicles During Pregnancy and Autism Risk in Children","rel_doi":"10.64898\/2026.06.25.26355526","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26355526","rel_abs":"BackgroundDifferences in extracellular vesicles (EVs), bioactive nanoparticles involved in intercellular signaling, have been reported in those with autism. However, little is known about the association between maternal EVs during pregnancy and the likelihood of autism in offspring. This study evaluated the association of the concentration and cargo material of EVs in prenatal maternal plasma with childhood autism likelihood.\n\nMethodsParticipants in the Nulliparous Pregnancy Outcomes Study provided maternal plasma at 15-23 weeks gestational age. EVs were isolated by ultracentrifugation, and concentration, mean size, CD63 levels, and RNA cargo were assessed by nanoparticle tracking analysis, ELISA, and small RNA sequencing. At 4.5-6 years of age, parents completed the Social Communication Questionnaire. Thirty-one children at high-risk for autism were matched to 31 low-risk children on sex, age, and gestational age. Differential RNA transcript analysis and over representation analysis were performed.\n\nResultsThere were no group differences in CD63 levels, mean particle size, or EV concentration (p>0.1). Nominal bin-level differences were observed at 280-290 nm and 430-440 nm before multiple-comparison correction. One hundred forty-five RNAs, including protein-coding RNAs, piRNAs, lncRNAs, miRNAs, snoRNAs, snRNAs, and tRNAs, were differentially contained, most of them downregulated in those at high risk of autism. These RNAs mapped to pathways involved in immune\/inflammatory signaling, intracellular trafficking, protein turnover, and neurodevelopment. Six of the 62 (9.7%) differentially contained protein-coding RNAs overlapped with genes in the SFARI Gene database.\n\nLimitationsLarge studies involving individuals diagnosed with autism are needed to evaluate the role of prenatal EVs in the pathogenesis of the condition. Additionally, prenatal sampling of EVs across multiple timepoints and subsequent deconvolution to determine the source of the EVs will strengthen interpretability and veracity of our findings.\n\nConclusionsThese findings provide preliminary evidence that maternal prenatal EV RNA cargo is associated with childhood autism likelihood.","rel_num_authors":13,"rel_authors":[{"author_name":"Delia McGowan","author_inst":"Barnard College, Columbia University, New York, NY, United States"},{"author_name":"Serena Nencini","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"William Yakah","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Claire-Marie Vacher","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Helene Lacaille","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"David M Haas","author_inst":"Department of Obstetrics and Gynecology, School of Medicine, Indiana University, Indianapolis, IN, United States"},{"author_name":"William A Grobman","author_inst":"Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH, United States"},{"author_name":"Robert M Silver","author_inst":"Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, United States"},{"author_name":"Uma M Reddy","author_inst":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States"},{"author_name":"Ronald J Wapner","author_inst":"Department of Obstetrics and Gynecology, Columbia University Irving Medical Center New York, NY, United States"},{"author_name":"William P Fifer","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States; Department of Psychiatry, Columbia University Irving Medical C"},{"author_name":"Anna A Penn","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Morgan R Firestein","author_inst":"Department of Pediatrics, Child Health Institute of New Jersey, Brain Health Institute, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United St"}],"rel_date":"2026-07-06","rel_site":"medrxiv"}]}