{"gname":"University of California, San Francisco","grp_id":"10","rels":[{"rel_title":"Supporting Underrepresented Undergraduate Entry into Aging and Neurosciences Research and Clinical Careers: Student-rated Mentor Behaviors, Relationship Quality and Research Training Satisfaction","rel_doi":"10.64898\/2026.04.15.26350982","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350982","rel_abs":"Improving diversity in U.S. Alzheimers disease (AD) research is a pressing need. By 2050, Hispanic and Latino Americans will comprise 30% of the population. Hispanics are 1.5 times more likely and Blacks are twice as likely to develop AD compared to Whites, yet both remain vastly underrepresented in clinical trials research. Aging and AD research mentorship of underrepresented STEM undergraduates is designed to promote entry into related professions by students committed to decreasing disparities in AD research participation and clinical care. The NIA-funded MADURA program recruited 93 students from backgrounds historically underrepresented in STEM majors and\/or from NIH-defined disadvantaged backgrounds. Trainees were placed in aging\/AD research labs and received weekly training and mentorship from faculty research PIs and other types of supervisors (postdoctoral researchers, graduate students, research assistant staff...) Our study examined student ratings of the program and mentor behaviors, using a program-specific survey and the Mentoring Competency Assessment-21 (MCA-21). Trainees were highly satisfied with both mentoring relationships and the overall program. Student rated MCA-21 competency areas were quite high for both P.I.s and other types of research mentors. However, there were striking differences in associations between competencies and relationship and program satisfaction, by mentor type. For PI mentors, no MCA-21 competencies were associated with relationship satisfaction, but five of six competencies were associated with relationship satisfaction for other mentor types. Similarly, no PI mentor competencies were significantly correlated with overall placement satisfaction, but all six competencies were correlated with overall placement satisfaction for other mentor types. The authors discuss the likelihood of differing student expectations of faculty PI versus other types of research mentors, recommendations for assessing role-specific student expectations (including functions primarily possible only for senior faculty PIs), and utilizing nearer-peer plus PI faculty mentors to comprehensively address the gamut of mentee needs.","rel_num_authors":6,"rel_authors":[{"author_name":"Sharon Thompson","author_inst":"UC San Diego: University of California San Diego"},{"author_name":"Lawrence Ong","author_inst":"University of California San Diego"},{"author_name":"Becky Marquez","author_inst":"University of California San Diego"},{"author_name":"Anthony  J.A. Molina","author_inst":"University of California San Diego"},{"author_name":"Dennis  R. Trinidad","author_inst":"University of California San Diego"},{"author_name":"Steven  D. Edland","author_inst":"University of California San Diego"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Detection and Measurement of Hypopyon on Slit Lamp Examination Versus Anterior Segment Optical Coherence Tomography","rel_doi":"10.64898\/2026.04.15.26350185","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350185","rel_abs":"Purpose: To compare hypopyon detection using anterior segment optical coherence tomography (ASOCT) versus slit lamp examination (SLE) in microbial keratitis, and to evaluate intra-and inter-grader agreement for ASOCT hypopyon measurement. Methods: Two masked graders independently evaluated ASOCT images for hypopyon presence or absence in eyes with microbial keratitis, with disagreements resolved by consensus. A subset of hypopyon eyes underwent triplicate height measurement using two methods (endothelial length, vertical height). Cohen's kappa, intraclass correlation coefficients (ICC), sensitivity, and specificity were calculated comparing diagnostic performance of ASOCT versus SLE. Results: Inter-grader agreement for hypopyon detection on ASOCT was excellent (k=0.94; 95% CI 0.84-1.00) and intra-grader agreement was excellent (k=0.89-1.00). ASOCT detected hypopyon in 67.1% of eyes versus 57.0% by SLE (sensitivity 83.0%, specificity 96.2% using ASOCT as reference). Intra-grader reproducibility was excellent for both endothelial length and vertical height measurements (ICC 0.977-0.996). Inter-grader agreement was good for endothelial length (ICC 0.831) and vertical height (ICC 0.827), though a statistically significant inter-grader bias was identified for vertical height only (Wilcoxon p=0.008). Conclusions: ASOCT detected hypopyon with greater sensitivity than SLE and demonstrated excellent intra-grader and good inter-grader measurement reproducibility. Endothelial length showed slightly superior inter-grader concordance to vertical height measurement.","rel_num_authors":8,"rel_authors":[{"author_name":"Kamini Narendra Reddy","author_inst":"Wilmer Eye Institute, Johns Hopkins University School of Medicine"},{"author_name":"Folahan Ibukun","author_inst":"Wilmer Eye Institute, Johns Hopkins University School of Medicine"},{"author_name":"Kaiyang Huang","author_inst":"Wilmer Eye Institute, Johns Hopkins University School of Medicine; Whiting School of Engineering, Johns Hopkins University"},{"author_name":"Ji Yi","author_inst":"Wilmer Eye Institute, Johns Hopkins University School of Medicine; Whiting School of Engineering, Johns Hopkins University"},{"author_name":"Elesh Jain","author_inst":"SNC Chitrakoot"},{"author_name":"Subeesh Kuyyadiyil","author_inst":"SNC Chitrakoot"},{"author_name":"Gautam S Parmar","author_inst":"SNC Chitrakoot"},{"author_name":"Nakul S Shekhawat","author_inst":"Wilmer Eye Institute, Johns Hopkins University School of Medicine"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Motor-tasks fMRI BOLD activations in chronic stroke with residual hemiparesis in the upper extremity: a pre-neurofeedback baseline characterization","rel_doi":"10.64898\/2026.04.15.26350962","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350962","rel_abs":"Stroke is the third leading cause of death and disability combined worldwide and often results in hemiparesis. Functional magnetic resonance imaging (fMRI) is a non-invasive technique used to investigate changes in brain activations during tasks aimed at restoring the lost motor function. Participants with chronic stroke and residual hemiparesis in the upper extremity were recruited for a clinical intervention that included neurofeedback training and fMRI sessions with motor-execution and motor-imagery tasks. The present study provides a baseline characterization of brain activations prior to neurofeedback training. Since lesion site and volume varied across participants, two fMRI preprocessing pipelines were applied. The first one was used for twelve participants with lesions restricted to a single hemisphere and for one participant with small secondary lesions in the contralesional hemisphere, whereas the second one was used for two participants with large bilateral lesions. These were followed by quality control measures and statistical analysis. First-level (i.e., single-participant) analysis returned the strongest and most extensive activation across participants during motor-execution tasks, with clusters identified in the ipsilesional parietal lobe, bilateral occipital lobes, and cerebellum after Family-Wise Error correction. Second-level (i.e., group-level) analysis involving participants who underwent the first fMRI preprocessing pipeline revealed a significant cluster in the cerebellum after False Discovery Rate correction. These results are consistent with previous studies involving participants with chronic stroke performing motor-tasks. Cerebellar recruitment observed consistently across participants could reflect compensatory mechanisms supporting motor control after stroke.","rel_num_authors":5,"rel_authors":[{"author_name":"Gabriele Varisco","author_inst":"Malardalen University"},{"author_name":"Jeanette Plantin","author_inst":"Danderyd Hospital Division of Rehabilitation Medicine, Karolinska Institutet"},{"author_name":"Rita Almeida","author_inst":"Stockholm University Brain Imaging Centre, Stockholm University"},{"author_name":"Susanne Palmcrantz","author_inst":"Danderyd Hospital Division of Rehabilitation Medicine, Karolinska Institutet"},{"author_name":"Elaine Astrand","author_inst":"Malardalen University"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Transmission dynamics of the COVID-19 pandemic across the emerging variants in mainland China: a hypergraph-based spatiotemporal modeling study","rel_doi":"10.64898\/2026.04.16.26351004","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26351004","rel_abs":"Mainland China experienced multiple waves of COVID19 pandemic during 2020 2022, driven by emerging variants and changes in public health and social measures (PHSMs). We developed a hypergraph-based Susceptible Vaccinated Exposed Infectious Recovered Susceptible (SVEIRS) model to reconstruct epidemic dynamics across 31 provinces, capturing transmission heterogeneity associated with clustered contacts. We assessed key characteristics of transmission at national and provincial levels during four outbreak periods: initial, localized predelta, Delta, and widespread Omicron, which accounted for 96.7% of all infections. We found significant diversity in transmission contributions across cluster sizes, with a small fraction of larger clusters responsible for a disproportionate share of infections. Counterfactual analyses showed that reducing clustersize heterogeneity, while holding overall exposure constant, could have lowered national infections by 11.70 to 30.79%, with the largest effects during Omicron period. Ascertainment rates increased over time but remained spatially heterogeneous with a range: (14.40, 71.93)%. Population susceptibility declined following mass vaccination (to 42.49% in Aug 2021, nationally) and rebounded (to 89.89% in Nov 2022) due to waning immunity with variations across the provinces. Effective reproduction numbers displayed marked temporal and spatial variability, with higher estimates during Omicron. Overall, these results highlight critical role of group contact heterogeneity in shaping epidemic dynamics.","rel_num_authors":7,"rel_authors":[{"author_name":"Yi Wang","author_inst":"School of Science, Harbin Institute of Technology, Shenzhen, China"},{"author_name":"DONG WANG","author_inst":"University of Hong Kong"},{"author_name":"Yiu Chung Lau","author_inst":"WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong,"},{"author_name":"Zhanwei Du","author_inst":"1 WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kon"},{"author_name":"Benjamin J Cowling","author_inst":"The University of Hong Kong"},{"author_name":"Yi Zhao","author_inst":"School of Science, Harbin Institute of Technology, Shenzhen, China"},{"author_name":"Sheikh Taslim Ali","author_inst":"School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Cardiovascular Health at Midlife and Alzheimer Disease Biomarkers","rel_doi":"10.64898\/2026.04.15.26350968","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350968","rel_abs":"Background: Cardiovascular health factors are associated with cognitive decline and risk of dementia, including Alzheimer disease (AD); however, this has been mostly studied in late life. We investigated whether vascular and lifestyle factors are associated with AD plasma and imaging biomarkers in midlife. Methods: We investigated 1,406 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study with information on vascular and lifestyle factors framed from the American Heart Association (AHA) life's essential 8 (LE8) guidelines for cardiovascular health at early midlife (mean age 45.0 SD 3.6) and AD biomarkers in late midlife (mean age 60 SD 3.5). LE8 was calculated and categorized into poor (0-49), intermediate (50-79), and ideal (80-100) cardiovascular health, based on 8 components including smoking, diet, body mass index (BMI), sleep, fasting glucose, blood pressure, cholesterol, and physical activity. We assessed the AD plasma biomarkers phosphorylated tau 217 (ptau-217) and amyloid beta 42\/40 ratio (A{beta}42\/40) and the Spatial Pattern of Abnormality for Recognition of Early AD (SPARE-AD), an algorithm that characterizes AD-like brain atrophy on brain MRI. We used linear regression to examine the association between LE8 and log-transformed and standardized AD biomarker measures adjusting for age, sex, race, education, and kidney function. Results: Compared to ideal LE8, intermediate (67.9% of participants) and poor (12.6%) LE8 was associated with lower A {beta}42\/40 (adjusted mean difference: -2.37, 95% CI: -2.38 to -2.36 and -2.38, 95% CI: -2.40 to -2.36, respectively). There was no association between the LE8 group and ptau-217 level. Moreover, compared to ideal LE8 participants, those with poor LE8 had higher SPARE-AD atrophy pattern (adjusted mean difference: -0.71, 95% CI: -0.81 to -0.62). Conclusion: These findings indicate that poor cardiovascular health in midlife, as defined by the AHA LE8, is linked to less favorable early AD biomarker profiles, particularly reflecting greater amyloid burden and structural brain changes.","rel_num_authors":5,"rel_authors":[{"author_name":"Christina Dintica","author_inst":"University of California, San Francisco"},{"author_name":"Xiaqing Jiang","author_inst":"University of California, San Francisco"},{"author_name":"Leslie M Shaw","author_inst":"University of Pennsylvania"},{"author_name":"R. Nick Bryan","author_inst":"University of Pennsylvania"},{"author_name":"Kristine Yaffe","author_inst":"University of California San Francisco"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Diastolic Age: A Cardiac Biological Clock Derived from Echocardiography and the PREVENT Heart Failure Risk Score","rel_doi":"10.64898\/2026.04.15.26350995","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350995","rel_abs":"Background: Among cardiac measures, diastolic parameters demonstrate the earliest and most consistent age-related changes. This can be leveraged to develop a continuous left ventricular (LV) Diastolic Age from routine echocardiographic parameters. Analogous to how epigenetic clocks weight molecular markers against mortality risk, we calibrated Diastolic Age by weighting echocardiographic features against the validated PREVENT-Heart Failure (HF) risk score. Methods: We analyzed 1,952 participants from the Project Baseline Health Study (median age 50 [36-64] years, 54% female). The measure was derived using partial least-squares regression anchored on PREVENT-HF and calibrated within a healthy reference subgroup. External validation was performed in the WASE (n=1,708) and Stanford Cardiovascular Aging (n=313) cohorts. Associations with ASE-defined LV diastolic dysfunction (LVDD), epigenetic clocks, and major adverse cardiovascular events (MACE) were examined. Results: Diastolic Age correlated strongly with chronological age (r=0.78) with robust external validation (WASE r=0.76; Stanford r=0.82; calibration slopes {approx}1.0). It increased progressively across grades of diastolic dysfunction and discriminated LVDD with an AUC of 0.89 (95% CI 0.87-0.92), and was independently associated with hypertension, diabetes, and elevated C-reactive protein. While correlated with the Levine (r=0.76) and Horvath (r=0.41) epigenetic clocks, residual analyses indicated that Diastolic Age captures a distinct cardiac-specific dimension of biological aging. Over median follow-up of 4.2 years, it independently predicted MACE (HR 2.30, 95% CI 1.70-3.18), with accelerated diastolic aging across all age groups among those with events. Discrimination was comparable to ASE-defined LVDD (C-index 0.83 vs. 0.82). Conclusion: Diastolic Age provides a continuous, echocardiography-derived measure of cardiac biological aging that complements categorical diastolic grading and epigenetic aging clocks, and independently predicts cardiovascular outcomes.","rel_num_authors":20,"rel_authors":[{"author_name":"Gracia Fahed","author_inst":"Stanford University Division of Cardiovascular Medicine"},{"author_name":"Nicholas Cauwenberghs","author_inst":"KU Leuven - University of Leuven"},{"author_name":"Everton Jose Santana","author_inst":"Katholieke Universiteit Leuven"},{"author_name":"Rongrong Chen","author_inst":"Stanford University; Zhangzhou Affiliated Hospital of Fujian Medical University"},{"author_name":"Bettia Edith Celestin","author_inst":"Stanford University"},{"author_name":"Bruna Filipa Gomes Botelho Quintas","author_inst":"Stanford University"},{"author_name":"Sarah Short","author_inst":"Verily"},{"author_name":"Megan Carroll","author_inst":"Verily Life Sciences"},{"author_name":"Tatsuya Miyoshi","author_inst":"MedStar Health Research Institute"},{"author_name":"Kevin Michael Alexander","author_inst":"Stanford University"},{"author_name":"Svati H. Shah","author_inst":"Duke Clinical Research Institute and Duke University Medical Center"},{"author_name":"Shai Shen Orr","author_inst":"Israel Institute of Technology Technion"},{"author_name":"Attila Kovacs","author_inst":"Gottsegen National Cardiovascular Center, Budapest, Hungary"},{"author_name":"Melissa A Daubert","author_inst":"Duke University Medical Center, Duke Clinical Research Institute"},{"author_name":"Tatiana Kuznetsova","author_inst":"University of Leuven"},{"author_name":"Karima Addetia","author_inst":"University of Chicago"},{"author_name":"Federico M. Asch","author_inst":"MedStar Health Research Institute"},{"author_name":"Kenneth W. Mahaffey","author_inst":"Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine"},{"author_name":"Pamela S. Douglas","author_inst":"Duke Clinical Research Institute, Duke University, Durham, NC"},{"author_name":"Francois Haddad","author_inst":"Stanford University"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Uncertainty Aware Decision Support with Computationally Expensive Simulation Models: A Case Study of HIV Intervention Scenarios","rel_doi":"10.64898\/2026.04.15.26350970","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350970","rel_abs":"Detailed agent-based simulations are increasingly used to support policy decisions, but their computational cost and complex uncertainty structure make systematic scenario analysis challenging. We present a data-driven, uncertainty-aware decision support (DDUADS) workflow for using stochastic simulation models as decision-support tools under limited computational budgets. The approach combines several established techniques-sensitivity screening, Bayesian calibration using simulation-based inference, and multi-surrogate model integration for translational efficiency-into a coherent pipeline that enables uncertainty-aware policy analysis. Rather than producing a single baseline, the calibration stage yields a posterior distribution over plausible model parameterizations, allowing flexible, uncertainty-aware forward projections. We demonstrate the DDUADS workflow on the INFORM-HIV agent-based model of HIV transmission in Chicago to evaluate potential disruptions in antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) use. While the specific application is HIV modeling, the challenges and techniques described here arise in other simulation studies and can be applied to decision support in other domains.","rel_num_authors":10,"rel_authors":[{"author_name":"arindam fadikar","author_inst":"Argonne National Laboratory"},{"author_name":"Anna Hotton","author_inst":"University of Chicago"},{"author_name":"Pedro Nascimento de Lima","author_inst":"Rand"},{"author_name":"Raffaele Vardavas","author_inst":"CausalPaths Analytics LLC"},{"author_name":"Nicholson Collier","author_inst":"Argonne National Laboratory"},{"author_name":"Kara Jia","author_inst":"Rand"},{"author_name":"Sara Rimer","author_inst":"Argonne National Laboratory"},{"author_name":"Aditya Khanna","author_inst":"Brown University"},{"author_name":"John Schneider","author_inst":"University of Chicago"},{"author_name":"Jonathan Ozik","author_inst":"Argonne National Laboratory"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Uncertainty Aware Decision Support with Computationally Expensive Simulation Models: A Case Study of HIV Intervention Scenarios","rel_doi":"10.64898\/2026.04.15.26350970","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350970","rel_abs":"Detailed agent-based simulations are increasingly used to support policy decisions, but their computational cost and complex uncertainty structure make systematic scenario analysis challenging. We present a data-driven, uncertainty-aware decision support (DDUADS) workflow for using stochastic simulation models as decision-support tools under limited computational budgets. The approach combines several established techniques-sensitivity screening, Bayesian calibration using simulation-based inference, and multi-surrogate model integration for translational efficiency-into a coherent pipeline that enables uncertainty-aware policy analysis. Rather than producing a single baseline, the calibration stage yields a posterior distribution over plausible model parameterizations, allowing flexible, uncertainty-aware forward projections. We demonstrate the DDUADS workflow on the INFORM-HIV agent-based model of HIV transmission in Chicago to evaluate potential disruptions in antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) use. While the specific application is HIV modeling, the challenges and techniques described here arise in other simulation studies and can be applied to decision support in other domains.","rel_num_authors":10,"rel_authors":[{"author_name":"arindam fadikar","author_inst":"Argonne National Laboratory"},{"author_name":"Anna Hotton","author_inst":"University of Chicago"},{"author_name":"Pedro Nascimento de Lima","author_inst":"Rand"},{"author_name":"Raffaele Vardavas","author_inst":"CausalPaths Analytics LLC"},{"author_name":"Nicholson Collier","author_inst":"Argonne National Laboratory"},{"author_name":"Kara Jia","author_inst":"Rand"},{"author_name":"Sara Rimer","author_inst":"Argonne National Laboratory"},{"author_name":"Aditya Khanna","author_inst":"Brown University"},{"author_name":"John Schneider","author_inst":"University of Chicago"},{"author_name":"Jonathan Ozik","author_inst":"Argonne National Laboratory"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Analysis Of Augmentation Techniques for Spine X-Ray Images","rel_doi":"10.64898\/2026.04.15.26350121","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350121","rel_abs":"Computer vision and deep learning techniques, including convolutional neural networks (CNNs) and transformers, have increased the performance of medical image classification systems. However, training deep learning models using medical images is a challenging task that necessitates a substantial amount of annotated data. In this paper, we implement data augmentation strategies to tackle dataset imbalance in the VinDr-SpineXR dataset, which has a lower number of spine abnormality X-ray images compared to normal spine X-ray images. Geometric transformations and synthetic image generation using Generative Adversarial Networks are explored and applied to the abnormal classes of the dataset, and classifier performance is validated using VGG-16 and InceptionNet to identify the most effective augmentation technique. Additionally, we introduce a hybrid augmentation technique that addresses class imbalance, reduces computational overhead relative to a GAN-only approach, and achieves ~99% validation accuracy with both classifiers across all three case studies. Keywords: Data augmentation, Generative Adversarial Network, VGG-16, InceptionNet, Class imbalance, Computer vision, Spine X-ray, Radiology.","rel_num_authors":2,"rel_authors":[{"author_name":"Elakiya Sivakumar","author_inst":"Independent"},{"author_name":"Anjana Anand","author_inst":"Independent"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Association of coronary artery bypass with cognitive impairment in coronary artery disease across APO (\u03b5) genotypes in AllofUS","rel_doi":"10.64898\/2026.04.12.26350734","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.12.26350734","rel_abs":"STRUCTERED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSCoronary artery bypass graft (CABG) is a widely performed procedure for coronary artery disease (CAD), yet its association with Impaired Cognition (IC), i.e., mild-cognitive impairment or all-cause dementia, while accounting for APO ({varepsilon}) genotype, remains unclear.\n\nMETHODSWe analyzed AllofUS participants with CAD (Age[&ge;]60 yrs) from 2017-2023. We defined CAD as a history of angina\/myocardial infarction\/chronic ischemic heart disease or having percutaneous coronary intervention\/CABG, and IC as mild cognitive impairment or all-cause dementia using ICD\/SNOMED codes. We performed logistic regression analyses to assess the association between CABG and IC, adjusting for clinical factors (age, sex, hypertension, diabetes, hyperlipidemia, depression, stroke, smoking, alcohol use, statin\/antihypertensive\/antidiabetic use), social determinants (self-reported race\/ethnicity, income, employment), and APO ({varepsilon}) genotypes. We further performed stratified analyses across APO ({varepsilon}) genotypes ({varepsilon}2\/{varepsilon}2, {varepsilon}2\/{varepsilon}3 {varepsilon}3\/{varepsilon}3, {varepsilon}2\/{varepsilon}4, {varepsilon}3\/{varepsilon}4, {varepsilon}4\/{varepsilon}4). We defined significance at p [&le;] 0.05.\n\nRESULTSWe included 22,349 with CAD and identified 908 with IC after CAD till 2023. 40% were females, 70% were White, 12% were Black, and 9% were Hispanic. The proportion of IC was higher (5.1% vs 3.5%, p=1e-08) in CABG (n=8,135) vs non-CABG (n=14,214). After adjusting for clinical factors, social determinants, and APO ({varepsilon}) genotypes, CABG (1.23;1.06-1.41, p = 0.005) was associated with IC. In APO ({varepsilon}) stratified analysis, the association of CABG with IC was strongest in the APO {varepsilon}2\/{varepsilon}3 group (1.91;1.21-3.02, p = 0.005).\n\nCONCLUSIONIn the AllofUS cohort, we observed an association between CABG and IC in CAD participants, with the strongest association in the APO {varepsilon}2\/{varepsilon}3 group.\n\nKey MessageO_ST_ABSWhat is already known on this topicC_ST_ABSCoronary artery disease (CAD) and Impaired Cognitive (IC) disease, i.e., mild cognitive impairment and all-cause dementia, share genetic, sociodemographic, and clinical factors, including cardiovascular conditions like coronary artery bypass grafting (CABG) procedure.\n\nWhat this study addsWe observed an association between CABG and IC in CAD participants after adjusting for sociodemographic, clinical factors, and APO ({varepsilon}) effects. Further, when CAD participants were stratified across APO ({varepsilon}) groups, CABG was significantly associated with IC in the APO {varepsilon}2\/{varepsilon}3 group.\n\nHow this study might affect research, practice or policyOur observations highlight the role of APO ({varepsilon}) genotype evaluation in CAD patients for IC risk assessment.","rel_num_authors":7,"rel_authors":[{"author_name":"Praveen Hariharan","author_inst":"Brown university"},{"author_name":"Minoo Bagheri","author_inst":"Vanderbilt University"},{"author_name":"Emeliah Asamoah","author_inst":"Morgan State University School of Community Health and Policy"},{"author_name":"Ioana Voiculescu","author_inst":"City College of New York"},{"author_name":"Purnima Singh","author_inst":"University of Tennessee, Memphis"},{"author_name":"Tafadzwa Machipisa","author_inst":"University of Pennsylvania"},{"author_name":"Tess D Pottinger","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Association of coronary artery bypass with cognitive impairment in coronary artery disease across APO (\u03b5) genotypes in AllofUS","rel_doi":"10.64898\/2026.04.12.26350734","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.12.26350734","rel_abs":"STRUCTERED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSCoronary artery bypass graft (CABG) is a widely performed procedure for coronary artery disease (CAD), yet its association with Impaired Cognition (IC), i.e., mild-cognitive impairment or all-cause dementia, while accounting for APO ({varepsilon}) genotype, remains unclear.\n\nMETHODSWe analyzed AllofUS participants with CAD (Age[&ge;]60 yrs) from 2017-2023. We defined CAD as a history of angina\/myocardial infarction\/chronic ischemic heart disease or having percutaneous coronary intervention\/CABG, and IC as mild cognitive impairment or all-cause dementia using ICD\/SNOMED codes. We performed logistic regression analyses to assess the association between CABG and IC, adjusting for clinical factors (age, sex, hypertension, diabetes, hyperlipidemia, depression, stroke, smoking, alcohol use, statin\/antihypertensive\/antidiabetic use), social determinants (self-reported race\/ethnicity, income, employment), and APO ({varepsilon}) genotypes. We further performed stratified analyses across APO ({varepsilon}) genotypes ({varepsilon}2\/{varepsilon}2, {varepsilon}2\/{varepsilon}3 {varepsilon}3\/{varepsilon}3, {varepsilon}2\/{varepsilon}4, {varepsilon}3\/{varepsilon}4, {varepsilon}4\/{varepsilon}4). We defined significance at p [&le;] 0.05.\n\nRESULTSWe included 22,349 with CAD and identified 908 with IC after CAD till 2023. 40% were females, 70% were White, 12% were Black, and 9% were Hispanic. The proportion of IC was higher (5.1% vs 3.5%, p=1e-08) in CABG (n=8,135) vs non-CABG (n=14,214). After adjusting for clinical factors, social determinants, and APO ({varepsilon}) genotypes, CABG (1.23;1.06-1.41, p = 0.005) was associated with IC. In APO ({varepsilon}) stratified analysis, the association of CABG with IC was strongest in the APO {varepsilon}2\/{varepsilon}3 group (1.91;1.21-3.02, p = 0.005).\n\nCONCLUSIONIn the AllofUS cohort, we observed an association between CABG and IC in CAD participants, with the strongest association in the APO {varepsilon}2\/{varepsilon}3 group.\n\nKey MessageO_ST_ABSWhat is already known on this topicC_ST_ABSCoronary artery disease (CAD) and Impaired Cognitive (IC) disease, i.e., mild cognitive impairment and all-cause dementia, share genetic, sociodemographic, and clinical factors, including cardiovascular conditions like coronary artery bypass grafting (CABG) procedure.\n\nWhat this study addsWe observed an association between CABG and IC in CAD participants after adjusting for sociodemographic, clinical factors, and APO ({varepsilon}) effects. Further, when CAD participants were stratified across APO ({varepsilon}) groups, CABG was significantly associated with IC in the APO {varepsilon}2\/{varepsilon}3 group.\n\nHow this study might affect research, practice or policyOur observations highlight the role of APO ({varepsilon}) genotype evaluation in CAD patients for IC risk assessment.","rel_num_authors":7,"rel_authors":[{"author_name":"Praveen Hariharan","author_inst":"Brown university"},{"author_name":"Minoo Bagheri","author_inst":"Vanderbilt University"},{"author_name":"Emeliah Asamoah","author_inst":"Morgan State University School of Community Health and Policy"},{"author_name":"Ioana Voiculescu","author_inst":"City College of New York"},{"author_name":"Purnima Singh","author_inst":"University of Tennessee, Memphis"},{"author_name":"Tafadzwa Machipisa","author_inst":"University of Pennsylvania"},{"author_name":"Tess D Pottinger","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Association of coronary artery bypass with cognitive impairment in coronary artery disease across APO (\u03b5) genotypes in AllofUS","rel_doi":"10.64898\/2026.04.12.26350734","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.12.26350734","rel_abs":"STRUCTERED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSCoronary artery bypass graft (CABG) is a widely performed procedure for coronary artery disease (CAD), yet its association with Impaired Cognition (IC), i.e., mild-cognitive impairment or all-cause dementia, while accounting for APO ({varepsilon}) genotype, remains unclear.\n\nMETHODSWe analyzed AllofUS participants with CAD (Age[&ge;]60 yrs) from 2017-2023. We defined CAD as a history of angina\/myocardial infarction\/chronic ischemic heart disease or having percutaneous coronary intervention\/CABG, and IC as mild cognitive impairment or all-cause dementia using ICD\/SNOMED codes. We performed logistic regression analyses to assess the association between CABG and IC, adjusting for clinical factors (age, sex, hypertension, diabetes, hyperlipidemia, depression, stroke, smoking, alcohol use, statin\/antihypertensive\/antidiabetic use), social determinants (self-reported race\/ethnicity, income, employment), and APO ({varepsilon}) genotypes. We further performed stratified analyses across APO ({varepsilon}) genotypes ({varepsilon}2\/{varepsilon}2, {varepsilon}2\/{varepsilon}3 {varepsilon}3\/{varepsilon}3, {varepsilon}2\/{varepsilon}4, {varepsilon}3\/{varepsilon}4, {varepsilon}4\/{varepsilon}4). We defined significance at p [&le;] 0.05.\n\nRESULTSWe included 22,349 with CAD and identified 908 with IC after CAD till 2023. 40% were females, 70% were White, 12% were Black, and 9% were Hispanic. The proportion of IC was higher (5.1% vs 3.5%, p=1e-08) in CABG (n=8,135) vs non-CABG (n=14,214). After adjusting for clinical factors, social determinants, and APO ({varepsilon}) genotypes, CABG (1.23;1.06-1.41, p = 0.005) was associated with IC. In APO ({varepsilon}) stratified analysis, the association of CABG with IC was strongest in the APO {varepsilon}2\/{varepsilon}3 group (1.91;1.21-3.02, p = 0.005).\n\nCONCLUSIONIn the AllofUS cohort, we observed an association between CABG and IC in CAD participants, with the strongest association in the APO {varepsilon}2\/{varepsilon}3 group.\n\nKey MessageO_ST_ABSWhat is already known on this topicC_ST_ABSCoronary artery disease (CAD) and Impaired Cognitive (IC) disease, i.e., mild cognitive impairment and all-cause dementia, share genetic, sociodemographic, and clinical factors, including cardiovascular conditions like coronary artery bypass grafting (CABG) procedure.\n\nWhat this study addsWe observed an association between CABG and IC in CAD participants after adjusting for sociodemographic, clinical factors, and APO ({varepsilon}) effects. Further, when CAD participants were stratified across APO ({varepsilon}) groups, CABG was significantly associated with IC in the APO {varepsilon}2\/{varepsilon}3 group.\n\nHow this study might affect research, practice or policyOur observations highlight the role of APO ({varepsilon}) genotype evaluation in CAD patients for IC risk assessment.","rel_num_authors":7,"rel_authors":[{"author_name":"Praveen Hariharan","author_inst":"Brown university"},{"author_name":"Minoo Bagheri","author_inst":"Vanderbilt University"},{"author_name":"Emeliah Asamoah","author_inst":"Morgan State University School of Community Health and Policy"},{"author_name":"Ioana Voiculescu","author_inst":"City College of New York"},{"author_name":"Purnima Singh","author_inst":"University of Tennessee, Memphis"},{"author_name":"Tafadzwa Machipisa","author_inst":"University of Pennsylvania"},{"author_name":"Tess D Pottinger","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Leveraging State-of-the-Art LLMs for the De-identification of Sensitive Health Information in Clinical Speech","rel_doi":"10.64898\/2026.04.13.26349911","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.13.26349911","rel_abs":"Accurate recognition and deidentification of sensitive health information (SHI) in spoken dialogues requires multimodal algorithms that can understand medical language and contextual nuance. However, the recognition and deidentification risks expose sensitive health information (SHI). Additionally, the variability and complexity of medical terminology, along with the inherent biases in medical datasets, further complicate this task. This study introduces the SREDH\/AI-Cup 2025 Medical Speech Sensitive Information Recognition Challenge, which focuses on two tasks: Task-1: Speech transcription systems must accurately transcribe speech into text; and Task-2: Medical speech de-identification to detect and appropriately classify mentions of SHI. The competition attracted 246 teams; top-performing systems achieved a mixed error rate (MER) of 0.1147 and a macro F1-score of 0.7103, with average MER and macro F1-score of 0.3539 and 0.2696, respectively. Results were presented at the IW-DMRN workshop in 2025. Notably, the results reveal that LLMs were prevalent across both tasks: 97.5% of teams adopted LLMs for Task 1 and 100% for Task 2. Highlighting their growing role in healthcare. Furthermore, we finetuned six models, demonstrating strong precision ([~]0.885-0.889) with slightly lower recall ([~]0.830-0.847), resulting in F1-scores of 0.857-0.867.","rel_num_authors":14,"rel_authors":[{"author_name":"Hong-Jie Dai","author_inst":"Intelligent System Laboratory, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Kaohsiung University of Sc"},{"author_name":"Tatheer Hussain Mir","author_inst":"Intelligent System Laboratory, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Kaohsiung University of Sc"},{"author_name":"Liang-Chun Fang","author_inst":"Intelligent System Laboratory, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Kaohsiung University of Sc"},{"author_name":"Ching-Tai Chen","author_inst":"Machine Learning and Bioinformatics Lab, Department of Computer Science, University of Taipei, Taipei, Taiwan"},{"author_name":"Hui-Hsien Feng","author_inst":"Department of English, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan"},{"author_name":"Jiunn-Ru Lai","author_inst":"Wireless Networking and Mobile Computing Research Lab, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Ka"},{"author_name":"Hsieh-Chih Hsu","author_inst":"Intelligent System Laboratory, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Kaohsiung University of Sc"},{"author_name":"Pratham Nandy","author_inst":"CGD Health Pvt. Ltd. Mumbai, India"},{"author_name":"Omkar Panchal","author_inst":"CGD Health Pvt. Ltd. Mumbai, India"},{"author_name":"Wei-Hsiang Liao","author_inst":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan"},{"author_name":"You-Zhen Tien","author_inst":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan"},{"author_name":"Pin-Zhen Chen","author_inst":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan"},{"author_name":"Yun-Ru Lin","author_inst":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan"},{"author_name":"Jitendra Jonnagaddala","author_inst":"UNSW Sydney"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"In silico structural analysis of EthA substitutions for ranking priority mutations leading to ethionamide resistance in Mycobacterium tuberculosis","rel_doi":"10.64898\/2026.04.16.718980","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.718980","rel_abs":"Background: Tuberculosis (TB) is the second-leading cause of deaths from infectious agents and remains a global health threat. Ethionamide (ETH) is a prodrug used in regimens for multidrug-resistant TB, and, partly due to side effects that can lead to low treatment adhesion, resistance arises. Changes in EthA, the monooxygenase that activates ETH, are the main mechanism of resistance. Yet, of hundreds of EthA substitutions found in resistant isolates, only a handful have been annotated as resistance determinants. Results: An in silico analysis was carried out on a previously described panel of Mycobacterium tuberculosis clinical isolates for which genomes and ETH susceptibility testing results were available. EthA substitutions were mapped, revealing the existence of hotspots in its sequence. Visualization of the hotspots in the EthA structural model shows that they cluster in three regions, including ligand binding pockets. Models were built of twenty-three variants found in resistant isolates and changes in local configuration was mapped to identify investigate impact on ETH activation. Information from these models contributed to establishing five criteria for scoring whether substitutions are most likely to lead to resistance. Using these criteria, EthA D58G was selected and its expression is shown to increase growth in high ETH concentrations. Conclusion: Functionally relevant regions of EthA are revealed and point out priority substitutions for functional studies, enhancing identification and detection of substitutions not been previously associated with resistance.","rel_num_authors":7,"rel_authors":[{"author_name":"Rodrigo Fernandes Machado","author_inst":"Instituto Oswaldo Cruz"},{"author_name":"Sophia Lincoln Cardoso","author_inst":"Universidade de Sao Paulo"},{"author_name":"Isabela Cordeiro Pinheiro","author_inst":"Instituto Oswaldo Cruz"},{"author_name":"Jesus Paes Ramos","author_inst":"ENSP-Fiocruz"},{"author_name":"Caetano Antunes","author_inst":"The University of Kansas"},{"author_name":"Priscila Capriles","author_inst":"Universidade Federal de Juiz de Fora"},{"author_name":"Teca C Galvao","author_inst":"Instituto Oswaldo Cruz"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Functional Genomics Reveals TNT Bioremediation Strategies in Pantoea sp. MT58 and Pseudomonas putida KT2440","rel_doi":"10.64898\/2026.04.16.711451","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.711451","rel_abs":"2,4,6-Trinitrotoluene (TNT) is a recalcitrant and pervasive environmental pollutant. Although different environmental microbes have demonstrated their ability to degrade or transform TNT, the underlying genetic basis and cellular machinery remain unclear. In this study, we investigated bacterial strategies in response to TNT exposure in Pantoea sp. MT58 and P. putida KT2440 using proteomics and random barcode transposon-site sequencing (RB-TnSeq). Pantoea sp. MT58 was found to utilize TNT as a sole nitrogen source, whereas P. putida KT2440 exhibited only stress tolerance without assimilation. Pantoea sp. MT58 encodes multiple putative nitroreductases that were upregulated, yet deletion of these genes did not affect growth on TNT, revealing pathway redundancy. Furthermore, fitness profiling provided no evidence for genes involved in the canonical Meisenheimer-complex pathway associated with nitrite release. Instead, the data are most consistent with a sequential nitro-group reduction route in which nitrogen is ultimately recovered as ammonium, with nitrogen routed through the GS-GOGAT pathway with purine and urea pools as the candidate buffering architecture for TNT mineralization. Conversely, P. putida KT2440 relied on Ttg\/RND efflux pumps and toluene tolerance proteins for survival without nitrogen assimilation from TNT. This work distinguishes routes for productive nitrogen assimilation from those involved in nitroaromatic tolerance, expanding the mechanistic understanding of anthropogenic compound metabolism to inform future bioremediation efforts.","rel_num_authors":11,"rel_authors":[{"author_name":"Li-Wen (Audrey) Wang","author_inst":"University of California, Berkeley"},{"author_name":"Thomas Eng","author_inst":"Lawrence Berkeley National Lab"},{"author_name":"Alex Rivier","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Saad Naseem","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Alex Codik","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Yan Chen","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Aparajitha Srinivasan","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Christopher J Petzold","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Kara L Nelson","author_inst":"University of California, Berkeley"},{"author_name":"Adam M. Deutschbauer","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Aindrila Mukhopadhyay","author_inst":"Lawrence Berkeley National Laboratory"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Redox-Triggered Coupling Network Mediates Long-Range Energy Trans-duction in Respiratory Complex I","rel_doi":"10.64898\/2026.04.14.716442","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.716442","rel_abs":"Complex I is a gigantic redox-driven proton pump that powers oxidative phosphorylation by a unique long-range (>200 [A]) proton-coupled electron transfer process. To elucidate the molecular principles underlying this intricate action-at-a-distance effect, we combine here multiscale quantum\/classical (QM\/MM) simulations with site-directed mutagenesis, proteoliposome experiments, and cryo-electron microscopy (cryo-EM). We find that quinol binding at a distinct site within a local membrane cavity, triggers a long-range protonation cascade over water-mediated proton wires along a conserved carboxylate pathway (E-channel). We identify a central mechanical switch point, comprising the conserved Tyr156^H, the mutation of which impedes conformational changes along conserved loops, but not the proton transfer reaction itself. Using our integrative multi-disciplinary approach, we reveal central coupling sites along the redox-driven proton transport process mediating energy conversion in Complex I, and illustrate the power of theory-guided experiments.","rel_num_authors":9,"rel_authors":[{"author_name":"Niklas Hoja","author_inst":"Department of Biochemistry and Biophysics, Stockholm University, 10691, Stockholm, Sweden."},{"author_name":"Jonas Hentschel","author_inst":"Institut fur Biochemie, Albert-Ludwigs-Universitat Freiburg, Germany"},{"author_name":"Hyunho Kim","author_inst":"Department of Biochemistry and Biophysics, Stockholm University, 10691, Stockholm, Sweden."},{"author_name":"Thilo Seifermann","author_inst":"Institut fur Biochemie, Albert-Ludwigs-Universitat Freiburg, Germany"},{"author_name":"Adel Beghiah","author_inst":"Department of Biochemistry and Biophysics, Stockholm University, 10691, Stockholm, Sweden."},{"author_name":"Tim Schlosser","author_inst":"Institut fur Biochemie, Albert-Ludwigs-Universitat Freiburg, Germany"},{"author_name":"Patricia Saura","author_inst":"Stockholm University"},{"author_name":"Thorsten Friedrich","author_inst":"Institut fur Biochemie, Albert-Ludwigs-Universitat Freiburg, Germany"},{"author_name":"Ville R. I. Kaila","author_inst":"Stockholm University"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Host background shapes the portability of a non-canonical translation initiation system across Escherichia coli strains","rel_doi":"10.64898\/2026.04.16.719103","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.719103","rel_abs":"Translation initiation has become an attractive target for engineering orthogonal translation systems, yet the extent to which these systems retain functionality across distinct host backgrounds remains poorly defined. In bacteria, start codon recognition depends on pairing between the initiator tRNA anticodon and a suitable start codon within the appropriate distance from the Shine-Dalgarno sequence. These sequence-specific interactions enable translation initiation to be reprogrammed through anticodon engineering. What is currently missing is an understanding of how anticodon mutants of initiator tRNAs function across different bacterial strains. Here, we systematically evaluated the portability of a library of twelve i-tRNA anticodon mutants paired with their complementary non-canonical start codons. Most i-tRNA-start codon pairs supported detectable translation initiation across multiple strains, demonstrating broad functional portability. However, initiation efficiency, absolute system output, and fitness effects varied substantially between strains. Comparative genomic analyses revealed host-specific gene differences broadly, and endogenous tRNA gene sequence and copy number specifically, was associated with this variability. While most i-tRNA variants were well tolerated, a subset produced strain-dependent growth defects that primarily affected growth rate rather than final culture density. Together, these findings show that translation initiation efficacy of engineered i-tRNAs is partially strain-dependent and that host background must be considered a key design variable when deploying these translation systems. Looking forward, this study provides a framework for host-aware selection of microbial chassis for orthogonal translation applications in synthetic biology.","rel_num_authors":3,"rel_authors":[{"author_name":"Dominic Scopelliti","author_inst":"Washington University in St. Louis"},{"author_name":"Andras Hutvagner","author_inst":"Macquarie University"},{"author_name":"Paul R Jaschke","author_inst":"Macquarie University"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Robust MR-AIV: A Systematic Study of Robustness Improvement and Sensitivity Analysis of MR-AIV","rel_doi":"10.64898\/2026.04.14.718498","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718498","rel_abs":"Cerebrospinal and interstitial fluid transport play a central role in brain metabolic waste clearance, yet non-invasive quantification of deep-brain flow dynamics remains challenging. Magnetic Resonance Artificial Intelligence Velocimetry (MR-AIV) is a physics-informed neural network framework that infers three-dimensional velocity, pressure, and permeability fields from dynamic contrast-enhanced MRI by embedding porous-media flow physics into the learning process. Here, we present a methodological refinement and systematic evaluation of MR-AIV. We introduce a universal, anatomically informed, region-of-interest-based permeability initialization that improves anatomical alignment and physical consistency across subjects. We quantify the sensitivity of inferred fields to key modelling choices, including initialization strategies, permeability bounds, diffusivity assumptions, signal-concentration relationships, and measurement noise. Across these conditions, MR-AIV yields stable velocity and permeability estimates with preserved spatial structure. Together, these results establish practical guidelines and identify stable operating regimes for reliable deployment of MR-AIV. By improving robustness and reproducibility, this work strengthens MR-AIV as a minimally invasive approach for mapping brain-wide porous fluid transport and supports its application to studies of neurological health and disease.","rel_num_authors":7,"rel_authors":[{"author_name":"Mohammad Vaezi","author_inst":"Department of Mechanical Engineering, University of Rochester, Rochester, 14627, NY, USA"},{"author_name":"Juan Diego Toscano","author_inst":"Division of Applied Mathematics, Brown University, Providence, 02912, RI, USA"},{"author_name":"Yisen Guo","author_inst":"Department of Mechanical Engineering, University of Rochester, Rochester, 14627, NY, USA"},{"author_name":"Ryszard Stefan Gomolka","author_inst":"Center for Translational Neuromedicine, University of Copenhagen, 2200 Copenhagen N, Denmark"},{"author_name":"George Em. Karniadakis","author_inst":"Division of Applied Mathematics, Brown University, Providence, 02912, RI, USA"},{"author_name":"Douglas H. Kelley","author_inst":"Department of Mechanical Engineering, University of Rochester, Rochester, 14627, NY, USA"},{"author_name":"Kimberly A. S. Boster","author_inst":"Department of Mechanical Engineering, University of Rochester, Rochester, 14627, NY, USA"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Reduced flexibility in predictive tuning and contextual adaptation in autism: an EEG and behavioral study.","rel_doi":"10.64898\/2026.04.14.718519","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718519","rel_abs":"The brain generates predictions to prepare for upcoming events. Because the environment is not perfectly predictable, the brain also estimates the certainty of these predictions and adjusts preparatory processes accordingly. Given that autistic individuals often resist even small changes to everyday routines, we hypothesized altered tuning of prediction certainty in autism. To test this, EEG was recorded from adolescents and young autistic adults (n = 20) and from age- and IQ-matched non-autistic adults (n = 19) during a probabilistic cued target identification task during which cue validity was systematically varied across four levels: 100%, 84%, 67%, and 33%. Participants were not informed of the cue-target validity nor when it changed. We focused on two neural signatures of anticipatory readiness, contingent negative variation (CNV) and alpha-band event-related desynchronization (-ERD), and one of cognitive updating: the P3 to targets and to invalid (e.g., a non-target in place of the target) stimuli. Across groups, preparatory activity increased as contextual certainty decreased, with larger CNV amplitudes and stronger -ERD preceding targets in lower-probability contexts, suggesting enhanced preparatory engagement under greater uncertainty. Furthermore, larger CNV amplitudes predicted faster reaction times, indicating functionally significant anticipatory dynamics. However, modulation of both neural preparation and response times as a function of cue-target probability was significantly reduced in the autistic group. In addition, autistic participants showed diminished probability-dependent modulation of the P3b to both targets and invalid stimuli, and coupling between anticipatory activity (CNV) and subsequent updating (P3b) was observed in non-autistic participants whereas it was absent in autism. Together, these findings suggest that while predictive mechanisms are present in autism, anticipatory processes are less flexibly tuned to contextual uncertainty and less effectively linked to subsequent cognitive updating. This reduced adaptability may reflect difficulty adjusting internal predictive models to changing environmental contingencies, potentially contributing to core features of autism such as resistance to change and insistence on sameness.","rel_num_authors":5,"rel_authors":[{"author_name":"Theo Vanneau","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Seydanur Reisli","author_inst":"Bristol Myers Squibb"},{"author_name":"Chloe Brittenham","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Michael J Crosse","author_inst":"SEGOTIA"},{"author_name":"Sophie Molholm","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"An Endocytic Checkpoint Controls Macrophage PD-1 Function and Immunotherapy Fate","rel_doi":"10.64898\/2026.04.14.718292","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718292","rel_abs":"Responses to PD1 blockade span durable tumor control to hyperprogressive disease (HPD), yet innate immune mechanisms governing these extremes remain undefined. Here we integrate a macrophage systems atlas (>12,500 transcriptomes) with single-cell profiles from >1,000 anti PD1 treated patients, to identify CCDC88A (GIV) as a macrophage-intrinsic determinant of durable response versus HPD. GIV loss increases PD1 surface retention, suppresses phagocytosis, and accelerates tumor growth across murine models, human macrophages, and patient-derived organoids. Myeloid-specific GIV deletion converts PD1 blockade from tumor-restraining to tumor-accelerating by reprogramming macrophages toward HPD-like states. Mechanistically, GIV engages a conserved TIR-like [TILL] motif within the PD1 cytoplasmic tail to drive dynamin-dependent endocytosis, coupling innate immune signaling logic to checkpoint receptor trafficking. Pharmacologic disruption of this axis phenocopies GIV loss, revealing an endocytic vulnerability that undermines checkpoint efficacy and triggers accelerated growth at relapse. These findings define PD1 routing, rather than ligand-binding, as a macrophage-encoded checkpoint governing antitumor immunity.","rel_num_authors":13,"rel_authors":[{"author_name":"Madhubanti Mullick","author_inst":"University of California, San Diego"},{"author_name":"Ella McLaren","author_inst":"University of California, San Diego"},{"author_name":"Suchismita Roy","author_inst":"University of California, San Diego"},{"author_name":"Brandon Biagas","author_inst":"University of California, San Diego"},{"author_name":"Mahitha Shree Anandachar","author_inst":"University of California, San Diego"},{"author_name":"Vanessa Castillo","author_inst":"University of California, San Diego"},{"author_name":"Samuel Williams","author_inst":"University of California, San Diego"},{"author_name":"Celia R. Espinoza","author_inst":"University of California, San Diego"},{"author_name":"Courtney Tindle","author_inst":"University of California, San Diego"},{"author_name":"Gajanan D. Katkar","author_inst":"University of California, San Diego"},{"author_name":"Patricia A. Thistlethwaite","author_inst":"University of California, San Diego"},{"author_name":"Saptarshi Sinha","author_inst":"University of California, San Diego"},{"author_name":"Pradipta Ghosh","author_inst":"University of California, San Diego"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Multiomic screening platform uncovers the impact of histone mutations on chromatin and cell fate","rel_doi":"10.64898\/2026.04.14.718582","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718582","rel_abs":"Somatic missense mutations in histone genes, often referred to as \"oncohistones\", have been identified in diverse types of human cancers. The functional and mechanistic impact of most oncohistones remains unknown. To address this gap, we developed CHANCLA, a modular platform for high-throughput functional screening of oncohistones using multiomic phenotypic readouts. We used CHANCLA to systematically measure the impact of 303 human oncohistones on cellular proliferation, differentiation, histone-specific post-translational modifications, and chromatin accessibility. Integrative multiomic analyses revealed discrete oncohistone molecular classes that promote proliferation, block lineage-specific differentiation, and physically remodel the chromatin landscape by altering specific histone modifications and reducing nucleosome stability. Structural mapping and computational modeling studies uncovered that functionally convergent mutations are clustered at key nucleosome interfaces, particularly H2B-H4, and that chromatin accessibility-promoting mutations are linked to mono-nucleosome destabilization. Leveraging this multiomic resource, we discovered that the H3.3-Q5H mutant histone is a bona fide human oncohistone that accelerates lung adenocarcinoma growth in vivo. Mechanistically, we found that H3.3-Q5H expression leads to suppression of promoter-associated H3K4me3 and expansion of repressive H3K27me3 domains, resulting in increased KRAS signaling and gene expression programs associated with epithelial-to-mesenchymal transition. Together, this work provides a multiomic functional atlas of cancer-associated histone mutations, identifies structural and mechanistic principles governing chromatin reprogramming by oncohistones, and establishes CHANCLA as a modular platform for systematic discovery of mechanisms and vulnerabilities associated with these genetic lesions.","rel_num_authors":14,"rel_authors":[{"author_name":"Ziyang Ye","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Alireza Khademi","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Ren\u00e9e L. Barbosa","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Foster Birnbaum","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Margaret R. Brown","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Colin E. Fowler","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Arianna Arroyo-Ortega","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Daniel Lee","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Lijuan Feng","author_inst":"WashU Medicine"},{"author_name":"Leah A. Gates","author_inst":"Case Western Reserve University"},{"author_name":"Agata L. Patriotis","author_inst":"Massachussets Institute of Technology"},{"author_name":"Amy E. Keating","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Francisco J. S\u00e1nchez-Rivera","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Yadira M. Soto-Feliciano","author_inst":"Massachusetts Institute of Technology"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Multiomic screening platform uncovers the impact of histone mutations on chromatin and cell fate","rel_doi":"10.64898\/2026.04.14.718582","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718582","rel_abs":"Somatic missense mutations in histone genes, often referred to as \"oncohistones\", have been identified in diverse types of human cancers. The functional and mechanistic impact of most oncohistones remains unknown. To address this gap, we developed CHANCLA, a modular platform for high-throughput functional screening of oncohistones using multiomic phenotypic readouts. We used CHANCLA to systematically measure the impact of 303 human oncohistones on cellular proliferation, differentiation, histone-specific post-translational modifications, and chromatin accessibility. Integrative multiomic analyses revealed discrete oncohistone molecular classes that promote proliferation, block lineage-specific differentiation, and physically remodel the chromatin landscape by altering specific histone modifications and reducing nucleosome stability. Structural mapping and computational modeling studies uncovered that functionally convergent mutations are clustered at key nucleosome interfaces, particularly H2B-H4, and that chromatin accessibility-promoting mutations are linked to mono-nucleosome destabilization. Leveraging this multiomic resource, we discovered that the H3.3-Q5H mutant histone is a bona fide human oncohistone that accelerates lung adenocarcinoma growth in vivo. Mechanistically, we found that H3.3-Q5H expression leads to suppression of promoter-associated H3K4me3 and expansion of repressive H3K27me3 domains, resulting in increased KRAS signaling and gene expression programs associated with epithelial-to-mesenchymal transition. Together, this work provides a multiomic functional atlas of cancer-associated histone mutations, identifies structural and mechanistic principles governing chromatin reprogramming by oncohistones, and establishes CHANCLA as a modular platform for systematic discovery of mechanisms and vulnerabilities associated with these genetic lesions.","rel_num_authors":14,"rel_authors":[{"author_name":"Ziyang Ye","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Alireza Khademi","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Ren\u00e9e L. Barbosa","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Foster Birnbaum","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Margaret R. Brown","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Colin E. Fowler","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Arianna Arroyo-Ortega","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Daniel Lee","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Lijuan Feng","author_inst":"WashU Medicine"},{"author_name":"Leah A. Gates","author_inst":"Case Western Reserve University"},{"author_name":"Agata L. Patriotis","author_inst":"Massachussets Institute of Technology"},{"author_name":"Amy E. Keating","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Francisco J. S\u00e1nchez-Rivera","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Yadira M. Soto-Feliciano","author_inst":"Massachusetts Institute of Technology"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Metabolic Salvage and Acyl-chain Remodeling Support Glycosphingolipid Synthesis with the PDAC Tumor Microenvironment","rel_doi":"10.64898\/2026.04.14.718544","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718544","rel_abs":"Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy where metabolic homeostasis is maintained by tumor and stromal cells within the tumor microenvironment (TME). To better assess pathways supporting macromolecule biosynthesis in PDAC tumors, we apply 13C metabolic flux analysis (MFA) to slice cultures of treatment-naive human tumors and mouse models that retain the native TME. Glycans, lipid headgroups, and very long-chain fatty acids are the most dynamic metabolic pools, while long chain fatty acids, purines, and pyrimidines are predominantly salvaged locally in situ. We use targeted pharmacological modulators to highlight the importance of recycling pathways and metabolic redundancies which mitigate changes in lipid abundances. Finally, we leverage targeted lipid fluxomics and the distinct ganglioside and globoside profiles of tumor and stromal cells, respectively, to demonstrate the role of the lipid kinase PIKfyve in supporting ganglioside homeostasis via sialic acid and ceramide salvage. These data establish application of MFA to slice cultures of PDAC tumors as an effective approach for assessing metabolic mechanisms and therapeutic responses within an intact TME.","rel_num_authors":14,"rel_authors":[{"author_name":"Anna S Trimble","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Casie S Kubota","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Elaine Zhao","author_inst":"University of California San Diego"},{"author_name":"Maureen L Ruchhoeft","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Jonathan R Weitz","author_inst":"Moores Cancer Center, UC San Diego"},{"author_name":"Woncheol Jung","author_inst":"Stephenson Cancer Center, University of Oklahoma Health"},{"author_name":"Kristina L Peck","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Satoshi Ogawa","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Ethan L Ashley","author_inst":"University of California San Diego"},{"author_name":"Herv\u00e9 Tiriac","author_inst":"Moores Cancer Center, UCSD"},{"author_name":"Tae Gyu Oh","author_inst":"Stephenson Cancer Center, University of Oklahoma Health"},{"author_name":"Andrew M Lowy","author_inst":"Moores Cancer Center, UCSD"},{"author_name":"Dannielle D Engle","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Christian M Metallo","author_inst":"The Salk Institute for Biological Studies"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Virtual multiplex staining of the pancreatic islets across type 1 diabetes progression using a Schroedinger bridge","rel_doi":"10.64898\/2026.04.14.718559","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718559","rel_abs":"Classical hematoxylin and eosin (H&E) staining enables review of tissue morphology but lacks information regarding the molecular state of cells. Immunohistochemical (IHC) techniques label specific proteins in tissue, allowing differentiation of relevant structures that may go undetectable in H&E. However, the IHC process is complex, expensive, and time-consuming, especially for multiplex IHC (mIHC) limiting its use in large cohorts. Stain conversion of H&E to IHC using generative artificial intelligence models such as generative adversarial networks (GANs) represent one solution to this problem. However, GANs are unstable during out of distribution sampling and are prone to hallucinations or mode collapse, limiting their accuracy in challenging image conversion tasks. To address this, the field has recently turned to diffusion models. Here, we introduce Schroedinger-bridge for Multiplex ImmunoLabel Estimation (SMILE). Unlike conventional diffusion models that map from source to target through an intermediate Gaussian noise, Schroedinger-bridge diffusion models skip this step and have been shown to better preserve structures during image translation. To test the performance of SMILE, we generated a large cohort of high-fidelity H&E-mIHC image pairs from pancreatic organ donors, targeting insulin, glucagon, and CD3. Our dataset well-sampled across type-1 diabetes status, pancreas anatomical location, age, and sex. Using this cohort, we demonstrate the superiority of SMILE compared to GANs via a comprehensive evaluation framework incorporating texture, distribution, and antibody-specific metrics, as well as blinded pathologist reviews. We further confirmed the ability of SMILE to generate accurate mIHC images from H&Es generated at an external site, to perform whole slide image conversion, and to generate realistic three-dimensional maps of the pancreatic islets in non-diabetic, auto-antibody positive, and type-1 diabetic donor tissue. Finally, we performed stain conversion of paired H&E to HER2 and Ki67 images in breast cancer, confirming the superiority of SMILE in diverse stain conversion applications. Collectively, this framework provides a scalable pipeline for high-throughput proteomic inference from archival H&Es, providing transformative potential for pancreatic research and digital pathology.","rel_num_authors":22,"rel_authors":[{"author_name":"Yu Shen","author_inst":"Johns Hopkins University"},{"author_name":"Won June Cho","author_inst":"Johns Hopkins University"},{"author_name":"Saurabh Joshi","author_inst":"Johns Hopkins University"},{"author_name":"Benjamin Wen","author_inst":"Johns Hopkins University"},{"author_name":"Swarnagouri Naganathanhalli","author_inst":"Johns Hopkins University"},{"author_name":"Maria Beery","author_inst":"University of Florida"},{"author_name":"Casey R Grubel","author_inst":"University of Florida"},{"author_name":"Arrun Sivasubramanian","author_inst":"Johns Hopkins University"},{"author_name":"Andr\u00e9 Forjaz","author_inst":"Johns Hopkins University"},{"author_name":"Mia P Grahn","author_inst":"Johns Hopkins University"},{"author_name":"Lucie Dequiedt","author_inst":"Johns Hopkins University"},{"author_name":"Yichen Huang","author_inst":"Johns Hopkins University"},{"author_name":"Kyu Sang Han","author_inst":"Johns Hopkins University"},{"author_name":"Fan Wu","author_inst":"Johns Hopkins University"},{"author_name":"Brian A Pedro","author_inst":"Johns Hopkins University"},{"author_name":"Laura D Wood","author_inst":"Johns Hopkins University"},{"author_name":"Tiane Chen","author_inst":"Johns Hopkins University"},{"author_name":"Ralph H Hruban","author_inst":"Johns Hopkins University"},{"author_name":"Irina Kusmartseva","author_inst":"University of Florida"},{"author_name":"Mark A Atkinson","author_inst":"University of Florida"},{"author_name":"Denis Wirtz","author_inst":"Johns Hopkins University"},{"author_name":"Ashley L Kiemen","author_inst":"Johns Hopkins University"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Coordinate-Based fMRI Meta-Analyses of Episodic Memory Encoding and Retrieval in Depression","rel_doi":"10.64898\/2026.04.14.718401","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718401","rel_abs":"Background Depression is a mood disorder frequently associated with episodic memory impairment. However, it remains unclear whether functional brain activity differs between depressed and non-depressed individuals during encoding or retrieval of autobiographical or non-autobiographical memories. Clarifying these differences is important for refining theoretical models of memory impairment in depression and, potentially, for developing targeted interventions. Methods We conducted three coordinate-based meta-analyses examining encoding and retrieval of autobiographical and non-autobiographical memory in control participants and individuals with current, remitted, or subthreshold depression, or those at risk for depression. Studies were identified via database searches and analysed using Seed-based d Mapping. Results We included coordinates from 21 fMRI studies. During encoding, depression was associated with reduced activity in the thalamus, the caudate, the salience network, the frontoparietal executive control network, and motor-related areas (ten studies, N = 506). During non-autobiographical retrieval, depression was associated with higher activity in the right inferior frontal gyrus (six studies, N = 332). During autobiographical retrieval, depression was associated with reduced activity in the right insula and fusiform gyrus, alongside increased activity in the left anterior cingulate cortex and the left middle frontal gyrus (ten studies, N = 423). Between-study heterogeneity was low and no evidence for publication bias was found. Discussion Our results indicate that depression may be associated with impaired salience integration during encoding and autobiographical retrieval. In contrast, during non-autobiographical retrieval, increased frontal activity suggests a more vigilant or self-monitoring retrieval mode. Functional brain activity changes in depression therefore appear stage- and content-specific.","rel_num_authors":7,"rel_authors":[{"author_name":"Raphaela Schoepfer","author_inst":"University of Bern"},{"author_name":"Reut Zabag","author_inst":"Yale University"},{"author_name":"Florian Wuethrich","author_inst":"University of Bern"},{"author_name":"Romy Lorenz","author_inst":"Max Planck Institut for Biological Cybernetics"},{"author_name":"Jutta Joormann","author_inst":"Yale University"},{"author_name":"Sina Straub","author_inst":"University of Bern"},{"author_name":"Jessica Peter","author_inst":"University of Bern"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Dynamic-Structure Redesign of Calmodulin Reveals Mechanistic Constraints on Ryr2 Regulation","rel_doi":"10.64898\/2026.04.14.717973","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.717973","rel_abs":"Calmodulin (CaM) is a highly conserved Ca2+ sensor that regulates hundreds of cellular targets through Ca2+ -dependent conformational dynamics. Despite its central role in Ca2+ signaling and disease, its evolutionary conservation and structural flexibility have suggested that CaM is resistant to rational redesign. Here, using the cardiac Ca2+ release channel Ryanodine receptor 2 (RyR2) as a model system, we tested whether incorporating conformational dynamics into computational protein design enables functional reengineering of CaM. We first applied a static structure-based redesign to increase CaM-RyR2 affinity. Although the resulting variant bound more tightly to both the RyR2 peptide and the intact channel in vitro, it distorted peptide geometry and worsened Ca2+ leak in cardiomyocytes ex vivo. Guided by molecular dynamics simulations, we then developed a dynamic-structure redesign strategy that preserves conformational integrity while strengthening binding. The resulting CaM variant exhibited increased RyR2 affinity and reduced pathological Ca2+ leak in a disease-relevant model. These findings show that improved binding affinity alone is insufficient to enhance physiological regulation and that successful CaM redesign requires preservation of conformational dynamics. More broadly, they demonstrate that integrating conformational dynamics into protein redesign can enable functionally predictive engineering of flexible regulatory protein-protein interactions.","rel_num_authors":15,"rel_authors":[{"author_name":"Vladimir Bogdanov","author_inst":"The Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohi"},{"author_name":"Svetlana Tikunova","author_inst":"The Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohi"},{"author_name":"Nicolas Fadell","author_inst":"The Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohi"},{"author_name":"Robyn T. Rebbeck","author_inst":"Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minnesota, Minneapolis, 55455"},{"author_name":"Melanie L. Aprahamian","author_inst":"Department of Chemistry and Biochemistry, Ohio State University, Columbus, Ohio 43210, United States"},{"author_name":"Md Nure Alam Afsar","author_inst":"Department of Chemistry, Mississippi State University, Starkville, Mississippi, 39759"},{"author_name":"Aleksei Chekodanov","author_inst":"Independent Software Developer, Moscow, Russia, 119049."},{"author_name":"Daniel J Blackwell","author_inst":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, 37212"},{"author_name":"Bjorn C Knollmann","author_inst":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, 37212"},{"author_name":"Razvan L. Cornea","author_inst":"Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minnesota, Minneapolis, 55455"},{"author_name":"Pete M Kekenes-Huskey","author_inst":"Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, 60153"},{"author_name":"Steffen Lindert","author_inst":"Department of Chemistry and Biochemistry, The University of California, Los Angeles, California, 90095"},{"author_name":"Christopher N. Johnson","author_inst":"Department of Chemistry, Mississippi State University, Starkville, Mississippi, 39759"},{"author_name":"Sandor Gyorke","author_inst":"The Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohi"},{"author_name":"Jonathan P Davis","author_inst":"The Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohi"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Modeling Synthetic Audience Reactions to Social-Cognitive Narratives: A Generative GSR Model to Predict Real-World Autonomic Alignment during Film Viewing","rel_doi":"10.64898\/2026.04.13.716763","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.13.716763","rel_abs":"While media consumption can be a solitary act, it produces a shared, socially coordinated experience where audiences bodies align in response to shared narrative events that are often social-affective in nature. Despite this recognition, traditional descriptive models of Galvanic skin response (GSR) have existed for decades, yet the socially coordinated aspect remains to be fully reflected in physiological models with the field of communication often treating the underlying generators of autonomic activity as a black box. To bridge this gap, we introduce a computational framework that models the underlying neural driver and its convolution to sweat gland physiology to explain how narrative events translate into measurable conductance. By leveraging multimodal AI models to interpret the social-cognitive content of a film, we generated a predictor timeline for a synthetic audience comprised of digital agents (i.e. artificial body systems responding to the film events with GSR responses). We then test this computational audience model by comparing its predictions against an empirical dataset collected as audience members (N = 96) processed the same stimulus, finding that AI-identified social triggers, like moments of comedic violence or shared emotional shifts, significantly predict the GSR time-course of audience engagement. In sum, this paper moves beyond simple and often retrospective labels like arousal to offer a computational account of how shared social narratives grip the human nervous system. We provide a scalable and expandable framework and a set of tools to predict media impact and understanding the psychophysiological basis of media.","rel_num_authors":4,"rel_authors":[{"author_name":"Ben A Bartling","author_inst":"Michigan State University"},{"author_name":"Ralf Schmaelzle","author_inst":"Michigan State University"},{"author_name":"Hee Jung Cho","author_inst":"Michigan State University"},{"author_name":"Yuetong Du","author_inst":"Michigan State University"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Multi-omic profiling of human antibody-secreting cells reveals diverse subsets sustain durable humoral immunity","rel_doi":"10.64898\/2026.04.13.717827","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.13.717827","rel_abs":"Antibody-secreting cells (ASCs) provide humoral immunity that can mediate lifelong protection against pathogens. Current classifications cannot delineate the heterogenous functionalities, tissue residencies, and lifespans of human ASC subsets, impeding clinical translation. We applied multi-omic sequencing, spatial proteomics, and functional assays to discover and characterize human bone marrow (BM) ASC subsets. We identified two peripheral subsets (ASCp) also present in blood and three BM-resident subsets (ASCr), comprising a maturation continuum associated with increased mitochondrial networking, diminished antibody secretion, differential transcription factor motif accessibility, and preferential co-localization in homotypic niches. CD19+9+ASCr and CD19-ASCr exhibited poor recovery years after BM transplantation, indicating a strong dependence on supportive niches. Childhood vaccine antigens were recognized by long-lived ASCr subsets in adults, as well as by immature HLA DR+ASCp, implying ASCs can differentiate without recent antigen exposure. Our results provide new insights into ASC identity, maturation, and longevity and a generalizable framework for study and manipulation of human ASCs.","rel_num_authors":43,"rel_authors":[{"author_name":"David R. Glass","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Elisabeth M. Dornisch","author_inst":"Allen Institute for Immunology"},{"author_name":"Hang Yin","author_inst":"Allen Institute for Immunology"},{"author_name":"Susan A Ludmann","author_inst":"Allen Institute for Immunology"},{"author_name":"Ashwin Samudre","author_inst":"Allen Institute for Cell Science"},{"author_name":"Sydney Kuhl","author_inst":"Allen Institute for Immunology"},{"author_name":"Jocelin Malone","author_inst":"Allen Institute for Immunology"},{"author_name":"Aishwarya Chander","author_inst":"Allen Institute for Immunology"},{"author_name":"Saransh N. Kaul","author_inst":"Allen Institute for Immunology"},{"author_name":"Cole G. Phalen","author_inst":"Allen Institute for Immunology"},{"author_name":"Vaishnavi Parthasarathy","author_inst":"Allen Institute for Immunology"},{"author_name":"Mebdh A. Dillon","author_inst":"Allen Institute for Immunology"},{"author_name":"Palak C. Genge","author_inst":"Allen Institute for Immunology"},{"author_name":"Tyanna J. Stuckey","author_inst":"Allen Institute for Immunology"},{"author_name":"Stephanie D. Anover-Sombke","author_inst":"Allen Institute for Immunology"},{"author_name":"Peter J. Wittig","author_inst":"Allen Institute for Immunology"},{"author_name":"Mark-Phillip Pebworth","author_inst":"Allen Institute for Immunology"},{"author_name":"Ziyuan He","author_inst":"Allen Institute for Immunology"},{"author_name":"Katherine E. Henderson","author_inst":"Allen Institute for Immunology"},{"author_name":"Priya Ravisankar","author_inst":"Allen Institute for Immunology"},{"author_name":"Veronica Hernandez","author_inst":"Allen Institute for Immunology"},{"author_name":"Blessing Musgrove","author_inst":"Allen Institute for Immunology"},{"author_name":"Suraj Mishra","author_inst":"Allen Institute for  Cell Science"},{"author_name":"Upaasana Krishnan","author_inst":"Allen Institute for Immunology"},{"author_name":"Zachary J. Thomson","author_inst":"Allen Institute for Immunology"},{"author_name":"Morgan Weiss","author_inst":"Allen Institute for Immunology"},{"author_name":"Nina Estep","author_inst":"Allen Institute for Immunology"},{"author_name":"Lucas T. Graybuck","author_inst":"Allen Institute for Immunology"},{"author_name":"Melinda L. Angus-Hill","author_inst":"Allen Institute for Immunology"},{"author_name":"Claire E. Gustafson","author_inst":"Allen Institute for Immunology"},{"author_name":"Mackenzie S. Kopp","author_inst":"Allen Institute for Immunology"},{"author_name":"Julian Reading","author_inst":"Allen Institute for Immunology"},{"author_name":"Xiao-jun Li","author_inst":"Allen Institute for Immunology"},{"author_name":"Matheus P. Viana","author_inst":"Allen Institute for  Cell Science"},{"author_name":"Thomas F. Bumol","author_inst":"Allen Institute for Immunology"},{"author_name":"Ananda W. Goldrath","author_inst":"Allen Institute for Immunology"},{"author_name":"Mikael Sigvardsson","author_inst":"Allen Institute for Immunology"},{"author_name":"Sean C. Bendall","author_inst":"Stanford University"},{"author_name":"Peter J. Skene","author_inst":"Allen Institute for Immunology"},{"author_name":"Damian J. Green","author_inst":"Sylvester Comprehensive Cancer Center"},{"author_name":"Evan W. Newell","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Troy R. Torgerson","author_inst":"Allen Institute for Immunology"},{"author_name":"Marla C. Glass","author_inst":"Allen Institute for Immunology"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Discovering Novel Circuit Mechanisms in Higher Cognition through Factor-Centric Recurrent Neural Network Modeling","rel_doi":"10.64898\/2026.04.16.718933","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.718933","rel_abs":"Recurrent neural networks (RNNs) have transformed how systems neuroscientists generate hypotheses about circuit mechanisms in higher cognition. Yet their promise has been constrained by a fundamental limitation: conventional RNNs are neuron-centric and therefore often difficult to interpret mechanistically. Here we introduce Restricted-RNN, a factor-centric RNN modeling framework developed to uncover interpretable circuit mechanisms. By formalizing factor communication through subpopulations, the dual of neuron communication through subspaces, Restricted-RNN departs fundamentally from standard neuron-centric RNN models and provides a distinct framework for describing circuit mechanisms. Using this approach, we identify novel circuit mechanisms underlying sequence working memory control and the counterintuitive firing-rate reversal observed in perceptual decision-making, with key predictions supported by neurophysiological recordings from monkey frontal and parietal cortex. More importantly, factor-centric RNN modeling reveals a unified low-dimensional neural control state space that links seemingly disparate phenomena across tasks, providing a geometric framework for understanding the pervasive role of control in higher cognition.","rel_num_authors":8,"rel_authors":[{"author_name":"Yiteng Zhang","author_inst":"Lingang Laboratory"},{"author_name":"Xingyu Li","author_inst":"Lingang Laboratory, Shanghai, China"},{"author_name":"Xuewen Shen","author_inst":"School of Physics, Center for Quantitative Biology, Peking  University, China"},{"author_name":"Fangting Li","author_inst":"Peking University"},{"author_name":"Gouki Okazawa","author_inst":"Institute of Neuroscience, Chinese Academy of Sciences"},{"author_name":"Liping Wang","author_inst":"Institute of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sc"},{"author_name":"Jianfeng Feng","author_inst":"Institute of Science and Technology for Brain-inspired Intelligence"},{"author_name":"Bin Min","author_inst":"Lin Gang Laboratory"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"An inhibitory circuit motif governs oscillation-dependent coupling between aperiodic activity and neural spiking","rel_doi":"10.64898\/2026.04.16.719083","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.719083","rel_abs":"Behavior arises from coordinated neural population activity, yet how spiking and synaptic interactions give rise to extracellular population signals, including local field potentials (LFPs), remains unresolved. Beyond oscillations, aperiodic LFP activity has emerged as a putative marker of neural excitability, but its neurophysiological basis and relationship to neural spiking are unclear. Here we employed optogenetics and simultaneous single-unit and LFP recordings in mouse visual cortex to quantify how spiking relates to oscillatory and aperiodic dynamics across cortical states and behavioral contexts. To test circuit mechanisms, we optogenetically suppressed the activity of somatostatin (SST), vasoactive intestinal peptide (VIP), or parvalbumin (PV) interneurons to causally manipulate inhibitory drive, thereby dissociating spiking, aperiodic activity, and gamma oscillations. Across conditions, aperiodic activity tracked neural spiking in a manner consistent with computational predictions, but this coupling was strongly context- and state-dependent: high oscillatory synchrony attenuated the relationship between aperiodic activity and spiking. These results demonstrate that state-dependent changes in neural excitability shift circuit activity between oscillation- and aperiodic-dominated regimes, placing principled limits on interpreting neural mass signals at synaptic or cellular scales.","rel_num_authors":3,"rel_authors":[{"author_name":"Janna D Helfrich","author_inst":"Yale University"},{"author_name":"Julia Veit","author_inst":"Bremen University"},{"author_name":"Randolph F Helfrich","author_inst":"Yale University"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Evolutionary landscapes of zygotic genome activation across animals","rel_doi":"10.64898\/2026.04.16.718233","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.718233","rel_abs":"During early animal embryogenesis, control over gene expression transitions from maternally deposited products to newly transcribed zygotic RNA. This process, termed zygotic genome activation (ZGA), is universal and essential but remains poorly characterized beyond a handful of model species. Here, we generated a comprehensive transcriptomic atlas of early embryogenesis from 61 animal species, spanning 13 phyla. By applying a unified computational framework, we systematically inferred the timing of ZGA across species. We uncover a large variation in ZGA timing, but find that a proxy for nuclear-to-cytoplasmic (N\/C) ratio robustly predicts the onset of genome activation. Comparative analyses of the properties of zygotic genes showed that they are shorter and with fewer introns, enriched in functions related to RNA processing and gene expression, and phylogenetically younger than maternal genes. Altogether, our findings suggest that ZGA is universally timed by the stoichiometry between DNA content and specific maternally deposited factors, and this activation involves a highly flexible transcriptomic program that follows a deeply conserved molecular logic.","rel_num_authors":43,"rel_authors":[{"author_name":"Israel Campo-Bes","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Federica Mantica","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Jon Permanyer","author_inst":"Centre for Genomic Regulation (CRG)"},{"author_name":"Cristina Rodriguez-Marin","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Kero Guynes","author_inst":"Institute of Molecular Biotechnology (IMBA)"},{"author_name":"Tot Senar-Serra","author_inst":"Universitat de Barcelona"},{"author_name":"Gonzalo Quiroga-Artigas","author_inst":"Universite de Montpellier"},{"author_name":"Yan Liang","author_inst":"Queen Mary University of London"},{"author_name":"Allan M. Carrillo-Baltodano","author_inst":"Queen Mary University of London"},{"author_name":"Josefa Cruz","author_inst":"Institute of Evolutionary Biology (IBE)"},{"author_name":"Rossella Annunziata","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Sandra Chevalier","author_inst":"Sorbonne Universite"},{"author_name":"Marta Iglesias","author_inst":"Centre for Genomic Regulation (CRG)"},{"author_name":"Fumiaki Sugahara","author_inst":"Hyogo Medical University"},{"author_name":"Yi-Jyun Luo","author_inst":"Biodiversity Research Center, Academia Sinica"},{"author_name":"Anna Schoenauer","author_inst":"Oxford Brookes University"},{"author_name":"Jorge Corbacho","author_inst":"Centro Andaluz de Biologia del Desarrollo"},{"author_name":"Periklis Paganos","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Filomena Caccavale","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Rosa Maria Sepe","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Luis P. Iniguez","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Mette Handberg-Thorsager","author_inst":"University of Goettingen"},{"author_name":"Christina Zakas","author_inst":"North Carolina State University"},{"author_name":"Ralf J. Sommer","author_inst":"Max Planck Institute for Biology"},{"author_name":"Maria Ina Arnone","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Alistair P. McGregor","author_inst":"Durham University"},{"author_name":"Juan R. Martinez-Morales","author_inst":"Centro Andaluz de Biologia del Desarrollo"},{"author_name":"Noriyuki Satoh","author_inst":"Okinawa Institute of Science and Technology"},{"author_name":"Hector Escriva","author_inst":"Sorbonne Universite"},{"author_name":"Stephanie Bertrand","author_inst":"Sorbonne Universite"},{"author_name":"Arnau Sebe-Pedros","author_inst":"Centre for Genomic Regulation (CRG)"},{"author_name":"Enrico D'Aniello","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Juan Pascual-Anaya","author_inst":"University of Malaga (UMA)"},{"author_name":"Evelyn Houliston","author_inst":"Sorbonne Universite"},{"author_name":"Xavier Franch-Marro","author_inst":"Institute of Evolutionary Biology (IBE)"},{"author_name":"David Martin","author_inst":"Institute of Evolutionary Biology (IBE)"},{"author_name":"Ildiko M.L. Somorjai","author_inst":"University of Saint Andrews"},{"author_name":"Isabel Almudi","author_inst":"Universitat de Barcelona"},{"author_name":"Jose M. Martin-Duran","author_inst":"Queen Mary University of London"},{"author_name":"Yi-Hsien Su","author_inst":"Institute of Cellular and Organismic Biology"},{"author_name":"Alejandro Burga","author_inst":"Institute of Molecular Biotechnology (IMBA)"},{"author_name":"Salvatore D'Aniello","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Manuel Irimia","author_inst":"Universitat Pompeu Fabra"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Evolutionary landscapes of zygotic genome activation across animals","rel_doi":"10.64898\/2026.04.16.718233","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.718233","rel_abs":"During early animal embryogenesis, control over gene expression transitions from maternally deposited products to newly transcribed zygotic RNA. This process, termed zygotic genome activation (ZGA), is universal and essential but remains poorly characterized beyond a handful of model species. Here, we generated a comprehensive transcriptomic atlas of early embryogenesis from 61 animal species, spanning 13 phyla. By applying a unified computational framework, we systematically inferred the timing of ZGA across species. We uncover a large variation in ZGA timing, but find that a proxy for nuclear-to-cytoplasmic (N\/C) ratio robustly predicts the onset of genome activation. Comparative analyses of the properties of zygotic genes showed that they are shorter and with fewer introns, enriched in functions related to RNA processing and gene expression, and phylogenetically younger than maternal genes. Altogether, our findings suggest that ZGA is universally timed by the stoichiometry between DNA content and specific maternally deposited factors, and this activation involves a highly flexible transcriptomic program that follows a deeply conserved molecular logic.","rel_num_authors":43,"rel_authors":[{"author_name":"Israel Campo-Bes","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Federica Mantica","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Jon Permanyer","author_inst":"Centre for Genomic Regulation (CRG)"},{"author_name":"Cristina Rodriguez-Marin","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Kero Guynes","author_inst":"Institute of Molecular Biotechnology (IMBA)"},{"author_name":"Tot Senar-Serra","author_inst":"Universitat de Barcelona"},{"author_name":"Gonzalo Quiroga-Artigas","author_inst":"Universite de Montpellier"},{"author_name":"Yan Liang","author_inst":"Queen Mary University of London"},{"author_name":"Allan M. Carrillo-Baltodano","author_inst":"Queen Mary University of London"},{"author_name":"Josefa Cruz","author_inst":"Institute of Evolutionary Biology (IBE)"},{"author_name":"Rossella Annunziata","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Sandra Chevalier","author_inst":"Sorbonne Universite"},{"author_name":"Marta Iglesias","author_inst":"Centre for Genomic Regulation (CRG)"},{"author_name":"Fumiaki Sugahara","author_inst":"Hyogo Medical University"},{"author_name":"Yi-Jyun Luo","author_inst":"Biodiversity Research Center, Academia Sinica"},{"author_name":"Anna Schoenauer","author_inst":"Oxford Brookes University"},{"author_name":"Jorge Corbacho","author_inst":"Centro Andaluz de Biologia del Desarrollo"},{"author_name":"Periklis Paganos","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Filomena Caccavale","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Rosa Maria Sepe","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Luis P. Iniguez","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Mette Handberg-Thorsager","author_inst":"University of Goettingen"},{"author_name":"Christina Zakas","author_inst":"North Carolina State University"},{"author_name":"Ralf J. Sommer","author_inst":"Max Planck Institute for Biology"},{"author_name":"Maria Ina Arnone","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Alistair P. McGregor","author_inst":"Durham University"},{"author_name":"Juan R. Martinez-Morales","author_inst":"Centro Andaluz de Biologia del Desarrollo"},{"author_name":"Noriyuki Satoh","author_inst":"Okinawa Institute of Science and Technology"},{"author_name":"Hector Escriva","author_inst":"Sorbonne Universite"},{"author_name":"Stephanie Bertrand","author_inst":"Sorbonne Universite"},{"author_name":"Arnau Sebe-Pedros","author_inst":"Centre for Genomic Regulation (CRG)"},{"author_name":"Enrico D'Aniello","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Juan Pascual-Anaya","author_inst":"University of Malaga (UMA)"},{"author_name":"Evelyn Houliston","author_inst":"Sorbonne Universite"},{"author_name":"Xavier Franch-Marro","author_inst":"Institute of Evolutionary Biology (IBE)"},{"author_name":"David Martin","author_inst":"Institute of Evolutionary Biology (IBE)"},{"author_name":"Ildiko M.L. Somorjai","author_inst":"University of Saint Andrews"},{"author_name":"Isabel Almudi","author_inst":"Universitat de Barcelona"},{"author_name":"Jose M. Martin-Duran","author_inst":"Queen Mary University of London"},{"author_name":"Yi-Hsien Su","author_inst":"Institute of Cellular and Organismic Biology"},{"author_name":"Alejandro Burga","author_inst":"Institute of Molecular Biotechnology (IMBA)"},{"author_name":"Salvatore D'Aniello","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Manuel Irimia","author_inst":"Universitat Pompeu Fabra"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Hippocampal and Midbrain Function in Superagers Relates to Memory for Novelty and Expectation Violation","rel_doi":"10.64898\/2026.04.16.718970","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.718970","rel_abs":"Memory performance typically declines with age, but the underlying neurobiological mechanisms remain unclear. Superagers, people over 80 years of age with episodic memory performance comparable to individuals 30 years younger, appear to resist this decline. Novelty and expectation violations are known to engage the hippocampus-midbrain system to enhance memory formation. Here, we examined whether superagers' superior memory performance is supported by preserved hippocampal-midbrain function during novelty and expectation processing. We manipulated item and contextual novelty (i.e., expectation violations) during encoding to test whether superagers show greater mnemonic benefits than their age-matched peers, whether these benefits reflect enhanced hippocampal and midbrain functioning as measured by fMRI, and whether they are associated with preserved dopaminergic integrity measured with neuromelanin-sensitive MRI. Our results show that, although superagers demonstrated overall superior memory performance, both groups exhibited superior recognition of contextually unexpected items. Nevertheless, differences emerged in the processing of expectation during encoding. Superagers exhibited stronger hippocampal responses to expectation violations and habituation to expected events, irrespective of item novelty. Conversely, typical older adults exhibited reduced midbrain response when expected novelty was absent. Neuromelanin accumulation did not account for group differences in midbrain activity or memory performance. Taken together, these findings suggest superagers benefit from adaptive responses to expectation and its violation, which is therefore a candidate mechanism distinguishing exceptional from typical cognitive ageing.","rel_num_authors":4,"rel_authors":[{"author_name":"Marta Garcia Huescar","author_inst":"Laboratory for Clinical Neuroscience"},{"author_name":"Linda Zhang","author_inst":"Reina Sofia Alzheimer Centre, CIEN Foundation, ISCIII, Madrid, Spain"},{"author_name":"Bryan Strange","author_inst":"Laboratory for Clinical Neuroscience, Centre for Biomedical Technology, Universidad Politecnica de Madrid, IdISSC, Madrid 28223, Spain"},{"author_name":"Darya Frank","author_inst":"Andrew Mayes Centre for Cognitive Neuroscience, University of Manchester, Manchester, UK"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Psilocybin reshapes cortical inhibition through selective interneuron recruitment","rel_doi":"10.64898\/2026.04.16.718963","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.718963","rel_abs":"Psychedelics show therapeutic potential for treating psychiatric disorders. While studies have emphasized the roles of cortical pyramidal cells, GABAergic neurons also express serotonin receptors and are therefore likely targets of psychedelics. In this study, we determine the effect of psilocybin on the activity dynamics of major GABAergic cell types in the mouse medial frontal cortex. Psilocybin reduces the firing of somatostatin-expressing interneurons, but increases the activity of parvalbumin-expressing interneurons. This cell type-specific response is unlikely to involve vasoactive intestinal peptide-expressing interneurons. Instead, pharmacological blockade and conditional knockout experiments demonstrate that psilocybin acts on the 5-HT1A receptor at SST interneurons, which contributes to the drug's long-term behavioral effects. Collectively, the results reveal that the classic psychedelic psilocybin alters cortical inhibition in a cell type-specific manner.","rel_num_authors":12,"rel_authors":[{"author_name":"Pasha A Davoudian","author_inst":"Yale University"},{"author_name":"Quan Jiang","author_inst":"Cornell University"},{"author_name":"Cory A Knox","author_inst":"Cornell University"},{"author_name":"Neil K Savalia","author_inst":"Yale University"},{"author_name":"Ling-Xiao Shao","author_inst":"Cornell University"},{"author_name":"Joshua Wilson","author_inst":"Cornell University"},{"author_name":"Amanda M Weiner","author_inst":"Cornell University"},{"author_name":"Catherine W Chong","author_inst":"Cornell University"},{"author_name":"Clara Liao","author_inst":"Yale University"},{"author_name":"Jack D Nothnagel","author_inst":"Cornell University"},{"author_name":"Takeshi Sakurai","author_inst":"University of Tsukuba"},{"author_name":"Alex C Kwan","author_inst":"Cornell University"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Discovery of the rosalexin pathway expands the modular network of maize diterpenoid chemical defenses.","rel_doi":"10.64898\/2026.04.15.718773","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718773","rel_abs":"The evolutionary expansion of specialized metabolism has shaped the ability of plants to adapt to combined pathogen, pest, and other environmental pressures. For instance, the duplication and divergence of ancestral gibberellin pathway genes have given rise to specialized kauralexin and dolabralexin diterpenoids in maize (Zea mays) that serve as core components of disease resistance and stress adaptation. Here, we describe the biosynthesis and elicited production of rosalexins as a previously unrecognized component of the maize chemical defense network. By integrating genomics-enabled gene discovery, combinatorial enzyme assays, and AI-assisted enzyme mechanistic studies we show that maize rosalexin biosynthesis proceeds via a distinct 5-rosanol scaffold formed by the pairwise activity of two diterpene synthases, ZmTPS38\/CPS2\/AN2 and ZmTPS42\/KSL1, recruited from gibberellin metabolism. Further oxygenation by the promiscuous P450 enzyme, ZmCYP71Z18, yields epoxyrosanol that, in turn, can undergo epoxide ring opening to form trihydroxyrosanol. Epoxyrosanol, but not 5-rosanol or trihydroxyrosanol, display strong inhibitory activity on fungal pathogen growth in vitro, highlighting the contribution of the epoxide group to antibiotic efficacy. Large variation in rosalexin presence and abundance exists across maize genotypes due to expansive ZmTPS42\/KSL1 gene sequence variation and pseudogenization. Transcriptomics and targeted metabolomics demonstrated the pathogen-elicited accumulation of rosalexins in maize lines featuring functional ZmTPS42\/KSL1 genes. However, no dominant pathogen resistance phenotype was observed in association with rosalexin abundance. These collective findings expand our knowledge of how multiple interconnected diterpenoid pathways arose in maize via duplication of hormone-metabolic genes and enable the utilization of a common precursor to form modular chemical defense layers.","rel_num_authors":16,"rel_authors":[{"author_name":"Anna E Cowie","author_inst":"University of California, Davis"},{"author_name":"Gabrielle Wyatt","author_inst":"University of Califronia, Davis"},{"author_name":"Siena S Schumaker","author_inst":"University of California, Davis"},{"author_name":"Ahmed Khalil","author_inst":"University of California, San Diego"},{"author_name":"Alicia Sylvia Ross","author_inst":"University of California, Davis"},{"author_name":"Shamita Bhattacharjee","author_inst":"University of California, Davis"},{"author_name":"Jishnu Narayanan","author_inst":"Bar Ilan University"},{"author_name":"Yezhang Ding","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"David Hurd","author_inst":"University of California, Davis"},{"author_name":"Jedidiah O Peek","author_inst":"University of California, Davis"},{"author_name":"Elly Poretsky","author_inst":"University of California, Davis"},{"author_name":"Alisa Huffaker","author_inst":"UC San Diego"},{"author_name":"Dean J Tantillo","author_inst":"University of California, Davis"},{"author_name":"Dan Thomas Major","author_inst":"Bar Ilan University"},{"author_name":"Eric A Schmelz","author_inst":"UC San Diego"},{"author_name":"Philipp Zerbe","author_inst":"University of California, Davis"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Minimizing co-growth as a broad predictor of community robustness","rel_doi":"10.64898\/2026.04.14.717098","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.717098","rel_abs":"Microbial communities rarely remain in a fixed physiological state. Instead, they progress through internal life cycles in which changing metabolites, spatial organization, and physiological states reshape ecological interactions over time. Despite extensive theory on coexistence with fixed interactions, we lack simple quantitative predictors of robustness for communities undergoing repeated growth and dispersal cycles. Here we show that a single quantity, the temporal co-growth of community members, predicts robustness across several models of community maturation, including chemotactic spatial patterning, cross-feeding with toxicity, and a phenomenological many-species model with prescribed growth trajectories. Communities in which different species grow at distinct times persist far longer under stochastic reseeding than communities with overlapping growth, with average community lifetime increasing approximately exponentially as co-growth decreases. Across the systems studied here, diverse mechanisms such as spatial organization, metabolic cascades, and physiological programs promote robustness insofar as they reduce the temporal overlap of rapid growth across species. These results identify co-growth as a common quantitative feature of robust dynamically maturing communities and suggest that minimizing co-growth may provide a broader organizing principle for ecological robustness.","rel_num_authors":6,"rel_authors":[{"author_name":"Milena S Chakraverti-Wuerthwein","author_inst":"Graduate Program in Biophysical Sciences, University of Chicago"},{"author_name":"Yoshiya J Matsubara","author_inst":"Department of Physics, University of Chicago"},{"author_name":"Finnegan D Roach","author_inst":"Department of Physics, University of Chicago"},{"author_name":"Avaneesh V Narla","author_inst":"Kravis Department of Integrated Sciences, Claremont McKenna College"},{"author_name":"Terence Hwa","author_inst":"Department of Physics, University of California, San Diego"},{"author_name":"Arvind S Murugan","author_inst":"Department of Physics, University of Chicago"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Minimizing co-growth as a broad predictor of community robustness","rel_doi":"10.64898\/2026.04.14.717098","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.717098","rel_abs":"Microbial communities rarely remain in a fixed physiological state. Instead, they progress through internal life cycles in which changing metabolites, spatial organization, and physiological states reshape ecological interactions over time. Despite extensive theory on coexistence with fixed interactions, we lack simple quantitative predictors of robustness for communities undergoing repeated growth and dispersal cycles. Here we show that a single quantity, the temporal co-growth of community members, predicts robustness across several models of community maturation, including chemotactic spatial patterning, cross-feeding with toxicity, and a phenomenological many-species model with prescribed growth trajectories. Communities in which different species grow at distinct times persist far longer under stochastic reseeding than communities with overlapping growth, with average community lifetime increasing approximately exponentially as co-growth decreases. Across the systems studied here, diverse mechanisms such as spatial organization, metabolic cascades, and physiological programs promote robustness insofar as they reduce the temporal overlap of rapid growth across species. These results identify co-growth as a common quantitative feature of robust dynamically maturing communities and suggest that minimizing co-growth may provide a broader organizing principle for ecological robustness.","rel_num_authors":6,"rel_authors":[{"author_name":"Milena S Chakraverti-Wuerthwein","author_inst":"Graduate Program in Biophysical Sciences, University of Chicago"},{"author_name":"Yoshiya J Matsubara","author_inst":"Department of Physics, University of Chicago"},{"author_name":"Finnegan D Roach","author_inst":"Department of Physics, University of Chicago"},{"author_name":"Avaneesh V Narla","author_inst":"Kravis Department of Integrated Sciences, Claremont McKenna College"},{"author_name":"Terence Hwa","author_inst":"Department of Physics, University of California, San Diego"},{"author_name":"Arvind S Murugan","author_inst":"Department of Physics, University of Chicago"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Co-occurrence networks can preserve emergent properties of ecological communities","rel_doi":"10.64898\/2026.04.15.718781","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718781","rel_abs":"Interaction networks, in which nodes represent species and edges represent direct interactions between species, have a long and impactful history in community ecology. However, co-occurrence networks, where edges represent statistical relationships among species presences or abundances, are often easier to construct from lab and field data. It is clear that co-occurrence edges often do not represent direct interactions, but frameworks for the interpretation of co-occurrence networks have not kept pace with their generation. It is therefore unclear when and how these networks can be used to gain insight into community dynamics. Here, we use a Generalized Lotka-Volterra-based model to explore the contexts in which emergent properties of species interaction networks are identifiable in their resulting co-occurrence networks. We find that, in spite of many differences in direct edges, key features of the true interaction network, such as unipartite modularity, high-degree nodes (hubs), and bipartite modularity and nestedness, can be preserved in co-occurrence networks. In contrast, node degree distributions are not preserved even in the most idealized scenarios. We propose that networks derived from large co-occurrence datasets could therefore be used in future empirical work to test existing hypotheses of how emergent network structures drive ecological community dynamics.","rel_num_authors":2,"rel_authors":[{"author_name":"Fiona Margaret Callahan","author_inst":"University of California, Berkeley"},{"author_name":"Claire Evensen","author_inst":"University of California, Berkeley"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Adaptation of white adipocytes to cooler temperatures: impacts on energy metabolism and protein acetylation","rel_doi":"10.64898\/2026.04.14.718465","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718465","rel_abs":"Adipocytes throughout the body reside in distinct thermal environments. Visceral adipocytes within the body core are maintained near 37 {degrees}C, whereas those in bone marrow, subcutaneous, and dermal depots occupy cooler regions within the peripheral shell. While brown and beige adipocyte responses to cold stress are well characterized, much less is known about how white adipocytes adapt to moderately reduced temperatures below 37 {degrees}C. Our recent work revealed that cultured adipocytes exposed to 31{degrees}C, a temperature representative of distal adipose regions, exhibit enhanced mitochondrial function, including increased substrate oxidation and ATP turnover, yet the mechanisms underlying this upregulation remain unclear. Here we show that adaptation to cool temperatures leads to a widespread decrease in protein acetylation in both undifferentiated and differentiated adipocytes, independent of nutrient status, and that this change is readily reversible upon rewarming. Subcellular fractionation and immunoblotting demonstrate that the hypoacetylation coincides with a compartment-specific enrichment of acetylated proteins within mitochondria, indicating selective remodeling of the mitochondrial acetylome. Transcriptomic and biochemical analyses reveal that these temperature-dependent changes occur without alterations in acetyltransferase or deacetylase expression, NAD+ concentration, or acetyl-CoA availability, suggesting regulation through alternative mechanisms affecting acetyl-CoA flux or enzyme activity. Integrative acetyl-proteomic and metabolomic profiling identifies mitochondrial enzymes, including serine hydroxymethyltransferase 2 (SHMT2) and propionyl-CoA carboxylase  (PCCA), whose acetylation correlates closely with changes in associated metabolite pools. Together, these findings establish physiologically relevant cooling as a cell-autonomous regulator of mitochondrial protein acetylation and metabolic adaptation in adipocytes.","rel_num_authors":12,"rel_authors":[{"author_name":"Hiroyuki Mori","author_inst":"University of Michigan"},{"author_name":"Hadla Hariri","author_inst":"University of Michigan"},{"author_name":"William Moe","author_inst":"University of Michigan"},{"author_name":"Sophia Durham","author_inst":"University of Michigan"},{"author_name":"Yuridia Guzman","author_inst":"University of Michigan"},{"author_name":"Emma Paulsson","author_inst":"University of Michigan"},{"author_name":"Rachel Simmermon","author_inst":"University of Michigan"},{"author_name":"Parth Bhanderi","author_inst":"University of Michigan"},{"author_name":"Sydney Peterson","author_inst":"University of Michigan"},{"author_name":"Mia Dickson","author_inst":"University of Michigan"},{"author_name":"Charles Evans","author_inst":"University of Michigan"},{"author_name":"Ormond A. MacDougald","author_inst":"University of Michigan"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Dynamic dissociation of the IFT complex drives ciliary dysfunction during C. elegans ageing","rel_doi":"10.64898\/2026.04.15.718672","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718672","rel_abs":"Intraflagellar transport (IFT) is essential for cilia, and its dysfunction drives ciliopathies and systemic ageing. However, the in vivo dynamics of individual components in the IFT complexes remain obscured, leaving the mechanisms of age-dependent IFT failure largely unknown. Here, we report a dual-color super-resolution imaging strategy to dissect the structural integrity and kinetics of IFT trains in the sensory cilia of young and aged Caenorhabditis elegans. We show that IFT complexes are not static entities. Instead, distinct components undergo dynamic dissociation within IFT trains. This intra-complex dissociation causes a remarkable reduction in IFT velocity and is significantly exacerbated in the cilia of aged worms. Mechanistically, we identify the conserved TRiC\/CCT chaperonin complex and daf-19\/RFX, the master transcription factor driving IFT genes, as critical regulators of IFT stability. We demonstrate that their age-dependent downregulation drives the progressive IFT component dissociation. Our findings re-frame the IFT complex as a highly dynamic assembly, uncover a new dimension of IFT regulation, and identify the progressive uncoupling of IFT components as a key driver of ciliary dysfunction during ageing.","rel_num_authors":11,"rel_authors":[{"author_name":"Yidong Shen","author_inst":"Shanghai Institute of Biochemistry and Cell Biology, CAS"},{"author_name":"Jiayi Li","author_inst":"The First Affiliated Hospital of Chongqing Medical University"},{"author_name":"Songyue Wang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Shengzhi Xie","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Meng Chen","author_inst":"Shanghai Jiao Tong University School of Medicine"},{"author_name":"Mengjiao Song","author_inst":"Shanghai Institute of Biochemistry and Cell Biology"},{"author_name":"Xiaona Zhang","author_inst":"Shanghai Institute of Biochemistry and Cell Biology"},{"author_name":"Ji Tang","author_inst":"Shanghai Gonzales Turing Software Co., Ltd."},{"author_name":"Qifu Li","author_inst":"the First Affiliated Hospital of Chongqing Medical University"},{"author_name":"Dong Li","author_inst":"Tsinghua University"},{"author_name":"Xiumin Yan","author_inst":"Shanghai Xinhua Hospital, Shanghai Jiao Tong University School of Medicine"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Disturbed ATP and AMPK homeostasis in an AnkF377del mouse model for craniometaphyseal dysplasia","rel_doi":"10.64898\/2026.04.15.717889","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.717889","rel_abs":"Craniometaphyseal dysplasia (CMD) is a rare genetic disorder characterized by hyperostosis of craniofacial bones and flared metaphyses of long bones. Mutations in ANKH (mouse orthologue ANK), a transmembrane protein mediating ATP and citrate efflux, cause the autosomal dominant form of CMD. How ANK mutations in CMD affect ATP\/citrate homeostasis and downstream targets remains unknown. We determined that cellular ATP export, intracellular ATP levels, and plasma citric acid were significantly reduced in ANKF377del knock-in (AnkKI\/KI) mice. Enrichment and pathway analyses of the plasma metabolome suggested the involvement of the citric acid cycle. It is known that AMPK is phosphorylated and activated when ATP is low. Phospho-AMPK was significantly upregulated in fusing AnkKI\/KI osteoclasts, major contributors to CMD. AMPK inhibitor treatment only during the fusion stage of osteoclasts significantly restored dysfunctional AnkKI\/KI osteoclasts, partly by modulating actin structures. Systemic administration of the AMPK inhibitor SBI-0206965 improved the positioning of cervical loops of incisors but failed to correct other skeletal abnormalities in AnkKI\/KI mice. Limitations of systemic administration of SBI-0206965 include its off-target effects on other cell types and the inability to inhibit AMPK only on fusing osteoclasts. Nonetheless, this proof-of-principle study reveals an important role of the ATP-AMPK axis in CMD pathogenesis.","rel_num_authors":5,"rel_authors":[{"author_name":"Ayano Hatori","author_inst":"1Department of Endodontics, School of Dental Medicine, University of Connecticut, Farmington, CT, United States; 2Center for Regenerative Medicine and Skeletal "},{"author_name":"Shyam Kishor Sah","author_inst":"1Department of Endodontics, School of Dental Medicine, University of Connecticut Health, Farmington, CT, United States; 2Center for Regenerative Medicine and Sk"},{"author_name":"Koen van de Wetering","author_inst":"3Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecule Medicine and PXE International Center of Excellence in Research and Clinical C"},{"author_name":"Ernst J Reichenberger","author_inst":"2Center for Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut"},{"author_name":"I-Ping Chen","author_inst":"1Department of Endodontics, School of Dental Medicine, University of Connecticut Health, Farmington, CT, United States; 2Center for Regenerative Medicine and Sk"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function","rel_doi":"10.64898\/2026.04.14.718012","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718012","rel_abs":"Cardiolipin (CL) is a four-chained, mitochondrial-specific phospholipid crucial for maintenance of inner mitochondrial membrane (IMM) structure and function. In healthy tissues, CL acyl chains are highly unsaturated and maintained by a conserved remodeling pathway. However, dysregulation of CL acyl chain composition can arise from mutations in the CL transacylase, Tafazzin (TAZ), resulting in Barth syndrome (BTHS), where patients exhibit heightened mitochondrial dysfunction. Cells lacking TAZ accumulate three-chained monolysocardiolipin (MLCL) as well as CL species with saturated acyl chains (CLsat). While the presence of MLCL destabilizes electron transport chain (ETC) complexes and IMM-shaping proteins, the contributions of CLsat to mitochondrial dysfunction have not been elucidated. Here, we find that treatment of TAZ knockout cells with exogenous saturated fatty acids causes accumulation of CLsat and loss of mitochondrial inner membrane structure despite only minimal changes in MLCL composition. Imaging of cells with elevated CLsat showed reduced fluidity of the inner membrane. Biophysical measurements and molecular dynamics analyses showed that di-saturated (C16:0 18:1)2 CL species order and rigidify membranes, while also losing the intrinsic lipid curvature characteristic of tetra-unsaturated CL. These results implicate CLsat as a potential driver of mitochondrial dysfunction and an additional therapeutic target in mitigating BTHS pathology.","rel_num_authors":11,"rel_authors":[{"author_name":"Kailash Venkatraman","author_inst":"UC San Diego"},{"author_name":"Daniel Milshteyn","author_inst":"UC San Diego"},{"author_name":"Carolina Sarto","author_inst":"UC San Diego"},{"author_name":"Elida Kocharian","author_inst":"UC San Diego"},{"author_name":"Cailyn M. Sakurai","author_inst":"UC San Diego"},{"author_name":"Aaron M. Armando","author_inst":"UC San Diego"},{"author_name":"Adrian M. Wong","author_inst":"UC San Diego"},{"author_name":"Edward A. Dennis","author_inst":"UC San Diego"},{"author_name":"Xi Fang","author_inst":"UC San Diego"},{"author_name":"Christopher T Lee","author_inst":"UC San Diego"},{"author_name":"Itay Budin","author_inst":"UC San Diego"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Arachidonic acid availability controls neutrophil swarm initiation and scaling","rel_doi":"10.64898\/2026.04.15.718800","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718800","rel_abs":"Neutrophils are first responders of the vertebrate immune system. To efficiently converge on sites of injury and infection, neutrophils engage in a collective migration process known as swarming, in which a small number of activated cells generate amplified recruitment of hundreds to thousands of additional neutrophils. How neutrophils initiate, scale, and terminate these swarms is not well understood. Here we define key roles for the mechanosensitive phospholipase cPLA2 and its product, arachidonic acid (AA), in swarm initiation and scaling. We observe that swarm-initiating neutrophils satisfy the conditions for cPLA2 activation through two coincident inputs: yeast-contact-mediated Ca2+ influx and nuclear stretch following cell spreading along fungal hyphae and clusters. This co-requirement for both chemical and physical features of pathogens may explain how neutrophils restrict swarming to insults that require collective action. We further demonstrate that AA release is necessary and sufficient for swarming and that AA levels regulate swarm magnitude. We propose that neutrophils share AA across multiple yeast-engaged cells to collectively assess infection magnitude. Because calcium influx, nuclear deformation, and cPLA2-mediated AA generation are also features of sterile-injury inflammatory responses, our findings suggest a unifying circuit for swarm regulation across injury and infection contexts.","rel_num_authors":7,"rel_authors":[{"author_name":"Evelyn D Strickland","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Rosheni Kandaswamy","author_inst":"University of California, San Francisco"},{"author_name":"Patrick J Zager","author_inst":"University of California, San Francisco"},{"author_name":"Henry De Belly","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Tasha K Phillips","author_inst":"East Tennessee State University"},{"author_name":"Alex Hopke","author_inst":"East Tennessee State University"},{"author_name":"Orion D. Weiner","author_inst":"University of California, San Francisco"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Cooperative molecular mimicry drives prolonged autoinflammation in multisystem inflammatory syndrome in children","rel_doi":"10.64898\/2026.04.03.26350001","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26350001","rel_abs":"Multisystem inflammatory syndrome in children (MIS-C) is a pediatric hyperinflammatory disease manifesting 4-6 weeks after SARS-CoV-2 infection. While the immunological hallmarks of MIS-C have been defined, few details regarding the underlying disease pathology have been resolved. To address this, we used a multiomics approach to profile the plasma and peripheral immune cells of 13 acute MIS-C patients, 18 recovered MIS-C follow-ups resampled over multiple time points (1-18 months), and 15 healthy pediatric controls. Despite rapid clinical disease resolution, circulating pro-inflammatory (IL-8, IL-6, IL-1, IL-1{beta}, TNF-{beta}) and TH2-type cytokines (IL-4, IL-5, IL-13) remained elevated up to three months post-MIS-C onset, revealing a subclinical inflammatory state that endures in recovered children. Surprisingly, the majority of patient-expanded TCRs recognizing SARS-CoV-2 epitopes were cross-reactive (75%, 12\/16 SARS-CoV-2 TCRs) for autoantigens related to prostaglandin biology and insulin metabolism, suggesting a breakdown of self-tolerance via SARS-CoV-2 molecular mimicry. Indeed, autoantibody screening confirmed that 13 gene targets with self-antigen peptides also exhibited elevated autoantibodies in MIS-C patients. Further, autoreactive TCR expansions lasted over time and correlated with cytokines involved in allergic inflammation. Together, our findings point to a mechanism of sustained autoimmunity wherein promiscuous TCRs recognize both viral and self-antigens that are activated during primary SARS-CoV-2 infection in children who develop MIS-C. Upon onset, these circulating cross-reactive T cells drive clinically apparent sterile autoinflammation that persists subclinically into convalescence.","rel_num_authors":9,"rel_authors":[{"author_name":"Haley E Randolph","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Ashley Richardson","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sofija Buta","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Julie Samuels","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Nina N Brodsky","author_inst":"Yale University School of Medicine"},{"author_name":"Seunghee Kim-Schulze","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Carrie L Lucas","author_inst":"Yale University School of Medicine"},{"author_name":"Rebecca Trachtman","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Dusan Bogunovic","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-04-08","rel_site":"medrxiv"},{"rel_title":"Cooperative molecular mimicry drives prolonged autoinflammation in multisystem inflammatory syndrome in children","rel_doi":"10.64898\/2026.04.03.26350001","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26350001","rel_abs":"Multisystem inflammatory syndrome in children (MIS-C) is a pediatric hyperinflammatory disease manifesting 4-6 weeks after SARS-CoV-2 infection. While the immunological hallmarks of MIS-C have been defined, few details regarding the underlying disease pathology have been resolved. To address this, we used a multiomics approach to profile the plasma and peripheral immune cells of 13 acute MIS-C patients, 18 recovered MIS-C follow-ups resampled over multiple time points (1-18 months), and 15 healthy pediatric controls. Despite rapid clinical disease resolution, circulating pro-inflammatory (IL-8, IL-6, IL-1, IL-1{beta}, TNF-{beta}) and TH2-type cytokines (IL-4, IL-5, IL-13) remained elevated up to three months post-MIS-C onset, revealing a subclinical inflammatory state that endures in recovered children. Surprisingly, the majority of patient-expanded TCRs recognizing SARS-CoV-2 epitopes were cross-reactive (75%, 12\/16 SARS-CoV-2 TCRs) for autoantigens related to prostaglandin biology and insulin metabolism, suggesting a breakdown of self-tolerance via SARS-CoV-2 molecular mimicry. Indeed, autoantibody screening confirmed that 13 gene targets with self-antigen peptides also exhibited elevated autoantibodies in MIS-C patients. Further, autoreactive TCR expansions lasted over time and correlated with cytokines involved in allergic inflammation. Together, our findings point to a mechanism of sustained autoimmunity wherein promiscuous TCRs recognize both viral and self-antigens that are activated during primary SARS-CoV-2 infection in children who develop MIS-C. Upon onset, these circulating cross-reactive T cells drive clinically apparent sterile autoinflammation that persists subclinically into convalescence.","rel_num_authors":9,"rel_authors":[{"author_name":"Haley E Randolph","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Ashley Richardson","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sofija Buta","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Julie Samuels","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Nina N Brodsky","author_inst":"Yale University School of Medicine"},{"author_name":"Seunghee Kim-Schulze","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Carrie L Lucas","author_inst":"Yale University School of Medicine"},{"author_name":"Rebecca Trachtman","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Dusan Bogunovic","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-04-08","rel_site":"medrxiv"},{"rel_title":"Imaging solute transportation along the posterior lymphatic pathway in the ocular glymphatic system in healthy human participants","rel_doi":"10.64898\/2026.04.03.26349283","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26349283","rel_abs":"BackgroundRecently, a posterior pathway for fluid drainage from the retina to the meningeal lymphatics in the optic nerve (ON) sheath was identified in rodents using intravitreal imaging tracers directly injected into the ocular-globe. Fluid and solute clearance along this pathway may be associated with many diseases. However, intravitreal tracers are rarely used in clinical imaging. As intravenous Gadolinium-based-contrast-agent (GBCA) can enter the globe via the blood-ocular-barriers, it may provide an alternative approach to image this pathway.\n\nPurposeTo establish a clinically feasible intravenous GBCA-based MRI approach for tracking fluid and solute transport along the posterior lymphatic pathway in the ocular glymphatic system.\n\nMaterials&MethodsThis prospective study was conducted from March 2021 to September 2022 in healthy participants. Dynamic-susceptibility-contrast-in-the-CSF (cDSC) MRI was performed before, immediately and 4 hours after intravenous-GBCA administration to track GBCA distribution in aqueous humor (AH) and cerebrospinal fluid (CSF) in regions-of-interest (ROIs) in the globe (anterior-cavity, vitreous-body), in the intraorbital and extraorbital ON, and in the intracranial CSF space proximal to the ON (chiasmatic-cistern, interpeduncular-cistern). Kruskal-Wallis tests with post-hoc Dunns tests were used for group comparisons.\n\nResultsSixteen healthy participants (mean age{+\/-}SD: 51{+\/-}21 years, 5 men) were recruited. Intravenous-GBCA enhancement was observed in all ROIs immediately after injection. At 4-hour-post-GBCA, the vitreous body showed a trend of smaller enhancement area (55{+\/-}11% versus 49{+\/-}11%, P=.14) and lower GBCA-concentration (0.044{+\/-}0.014 versus 0.028{+\/-}0.010 mmol\/L, P=.07) compared to immediate-post-GBCA. The intraorbital ON showed more widespread enhancement (39{+\/-}5% versus 59{+\/-}6%, P=.01) and significantly higher GBCA-concentration (0.023{+\/-}0.009 versus 0.059{+\/-}0.015 mmol\/L, P<.001) at 4-hour-post-GBCA.\n\nConclusionDynamic fluid and solute transportation along the posterior lymphatic pathway in the ocular glymphatic system in healthy participants was measured by tracking intravenous-GBCAs entering the globe via the blood-ocular-barriers using cDSC-MRI.\n\nSummary StatementDynamic fluid and solute transportation along the posterior lymphatic pathway in the ocular glymphatic system in healthy participants was measured by tracking intravenous-Gadolinium-based-contrast-agents entering ocular-globe via blood-ocular-barriers using dynamic-susceptibility-contrast-in-the-CSF (cDSC)-MRI.\n\nKey ResultsO_LIIn this prospective study of sixteen participants, Gadolinium-based-contrast-agent (GBCA)-induced signal changes were detected in the aqueous-humor and cerebrospinal fluid immediately following intravenous administration using dynamic-susceptibility-contrast-in-the-CSF (cDSC)-MRI.\nC_LIO_LIAt 4-hour-post-GBCA, the vitreous-body showed a trend of smaller enhancement area (55{+\/-}11% versus 49{+\/-}11%, P=.14) and lower GBCA-concentration (0.044{+\/-}0.014 versus 0.028{+\/-}0.010 mmol\/L, P=.07) compared to immediate-post-GBCA.\nC_LIO_LIThe intraorbital-optic-nerve showed more widespread enhancement (39{+\/-}5% versus 59{+\/-}6%, P=.01) and higher GBCA-concentration (0.023{+\/-}0.009 versus 0.059{+\/-}0.015 mmol\/L, P<.001) at 4-hour-post-GBCA.\nC_LI","rel_num_authors":17,"rel_authors":[{"author_name":"Xuehua Wen","author_inst":"Neurosection, Division of MRI Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimo"},{"author_name":"Yuanqi Sun","author_inst":"Neurosection, Division of MRI Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimo"},{"author_name":"Xinyi Zhou","author_inst":"Neurosection, Division of MRI Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimo"},{"author_name":"Yinghao Li","author_inst":"Neurosection, Division of MRI Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimo"},{"author_name":"Adrian Paez","author_inst":"Neurosection, Division of MRI Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimo"},{"author_name":"Jacob Varghese","author_inst":"Neurosection, Division of MRI Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimo"},{"author_name":"Jay J. Pillai MD","author_inst":"Division of Neuroradiology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, United States"},{"author_name":"Linda Knutsson","author_inst":"F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, United States"},{"author_name":"Peter C.M. Van Zijl","author_inst":"Neurosection, Division of MRI Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimo"},{"author_name":"Richard Leigh","author_inst":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States"},{"author_name":"David O. Kamson","author_inst":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States"},{"author_name":"Christina R. Graley","author_inst":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States"},{"author_name":"Shiv Saidha","author_inst":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States"},{"author_name":"Arnold Bakker","author_inst":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States"},{"author_name":"Bryan K. Ward","author_inst":"Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States"},{"author_name":"Amir H. Kashani","author_inst":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, United States"},{"author_name":"Jun Hua","author_inst":"F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, United States"}],"rel_date":"2026-04-08","rel_site":"medrxiv"},{"rel_title":"Age-dependent acceleration of structural brain aging in medication-free major depressive disorder linked to neuroanatomical phenotype findings from COORDINATE-MDD consortium","rel_doi":"10.64898\/2026.03.31.26349338","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349338","rel_abs":"BackgroundMajor depressive disorder (MDD) is associated with altered brain structure and evidence of accelerated brain aging. However, previous studies have been limited by clinical samples with mixed medication status and multiple mood states, modest sample sizes, small percentage of MDD individuals older than 65 years of age, and\/or reliance on summary-level data.\n\nMethodsHarmonized T1-weighted MRI from MDD (n = 645), all medication-free and in a current depressive episode, and matched healthy controls (n = 645), segmented into 145 regional volumes, from 11 sites in COORDINATE-MDD consortium. Brain age gap (BAG) was estimated using gradient boosting regression with nested cross-validation. Group differences in BAG (and age-corrected BAG [cBAG]) were examined across age strata. Regional contributions were evaluated using Shapley Additive exPlanations.\n\nResultsMDD was associated with significantly elevated cBAG compared with healthy controls (mean difference + 2.01 years). Age-stratified analyses showed no differences before mid-30s, with progressively larger gaps thereafter, reaching +6.85 years in MDD aged 55 and older. cBAG differed across neuroanatomical phenotypes associated with differential antidepressant response, cognitive impairment, increased adverse life events, increased self-harm and suicide attempts, and a pro-atherogenic metabolic profile. Key contributing regions included lateral and medial prefrontal regions, middle temporal gyrus, putamen, supplementary motor cortex, central operculum, and cerebellum.\n\nConclusionsAccelerated structural brain aging in MDD is age-dependent and is most pronounced in a neuroanatomical phenotype associated with worse key clinical outcomes. The findings support neuroprogression models of MDD while demonstrating that cBAG is not a uniform feature of MDD and seem to be more strongly expressed in a specifically clinically vulnerable disease phenotype.","rel_num_authors":52,"rel_authors":[{"author_name":"Bhanu Sharma","author_inst":"McMaster University"},{"author_name":"Pedro L Ballester","author_inst":"Hospital for Sick Children"},{"author_name":"Luciano Minuzzi","author_inst":"McMaster University"},{"author_name":"Wenyi Xiao","author_inst":"University of East London"},{"author_name":"Mathilde Antoniades","author_inst":"University of Pennsylvania"},{"author_name":"Dhivya Srinivasan","author_inst":"University of Pennsylvania"},{"author_name":"Guray Erus","author_inst":"University of Pennsylvania"},{"author_name":"Jose Garcia","author_inst":"University of Pennsylvania"},{"author_name":"Yong Fan","author_inst":"University of Pennsylvania"},{"author_name":"Danilo Arnone","author_inst":"King's College London"},{"author_name":"Stephen Arnott","author_inst":"Rotman Research Institute"},{"author_name":"Taolin Chen","author_inst":"West China Hospital of Sichuan University"},{"author_name":"Ki Seung Choi","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Katharine Dunlop","author_inst":"University of Toronto"},{"author_name":"Cherise Chin Fatt","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Rachel D Woodham","author_inst":"University of East London"},{"author_name":"Beata Godlewska","author_inst":"University of Oxford"},{"author_name":"Stefanie Hassel","author_inst":"University of Calgary"},{"author_name":"Keith Ho","author_inst":"University Health Network"},{"author_name":"Andrew M McIntosh","author_inst":"University of Edinburgh"},{"author_name":"Kun Qin","author_inst":"West China Hospital of Sichuan University"},{"author_name":"Susan Rotzinger","author_inst":"University Health Network"},{"author_name":"Matthew Sacchet","author_inst":"Harvard University"},{"author_name":"Jonathan Savitz","author_inst":"Laureate Institute for Brain Research"},{"author_name":"Haochang Shou","author_inst":"University of Pennsylvania"},{"author_name":"Ashish Singh","author_inst":"University of Pennsylvania"},{"author_name":"Vibe Frokjaer","author_inst":"University Hospital Rigshospitalet"},{"author_name":"Melanie Ganz","author_inst":"University Hospital Rigshospitalet"},{"author_name":"Aleks Stolicyn","author_inst":"University of Edinburgh"},{"author_name":"Irina Strigo","author_inst":"University of California San Francisco"},{"author_name":"Duygu Tosun","author_inst":"University of California - San Francisco"},{"author_name":"Dongtao Wei","author_inst":"Southwest University"},{"author_name":"Ian Anderson","author_inst":"University of Manchester"},{"author_name":"Edward Craighead","author_inst":"Emory Unviersity"},{"author_name":"Bill Deakin","author_inst":"University of Manchester"},{"author_name":"Boadie Dunlop","author_inst":"Emory University School of Medicine"},{"author_name":"Rebecca Elliot","author_inst":"Manchester University"},{"author_name":"Qiyong Gong","author_inst":"West China Hospital of Sichuan University"},{"author_name":"Ian Gotlib","author_inst":"Stanford University"},{"author_name":"Catherine Harmer","author_inst":"University of Oxford"},{"author_name":"Sidney H Kennedy","author_inst":"University of Toronto"},{"author_name":"Gitte  Moos Knudsen","author_inst":"Rigshospitalet"},{"author_name":"Helen Mayberg","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Martin  P. Paulus","author_inst":"Laureate Institute for Brain Research"},{"author_name":"Jiang Qiu","author_inst":"Southwest University"},{"author_name":"Madhukar Trivedi","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Heather C Whalley","author_inst":"University of Edinburgh"},{"author_name":"Chao-Gan Yan","author_inst":"Institute of Psychology"},{"author_name":"Allan Young","author_inst":"King's College London"},{"author_name":"Christos Davatzikos","author_inst":"University of Pennsylvania"},{"author_name":"Cynthia H.Y. Fu","author_inst":"University of East London"},{"author_name":"Benicio N H.Y. Frey","author_inst":"McMaster University"}],"rel_date":"2026-04-08","rel_site":"medrxiv"},{"rel_title":"Uptake and retention in HIV care among pregnant and postpartum women living with HIV under different eras of vertical transmission prevention policies in sub-Saharan Africa: a systematic review and meta-analysis","rel_doi":"10.64898\/2026.04.02.26350030","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.02.26350030","rel_abs":"Objectives: This systematic review and meta-analysis (2010 - 2025) examines changes in uptake and retention rates among pregnant and postpartum women with HIV in sub-Saharan Africa as countries adopted Option B+ for preventing vertical transmission. Design and data sources: We searched PubMed, Embase, Cochrane Library, Scopus, and African Index Medicus from 10\/2021 - 05\/2025 for eligible studies that measured HIV care uptake or retention for pregnant\/postpartum women under prevention policies before or during Option B+. Study designs were limited to cohort, case-control, cross-sectional, or interventional studies. Exclusions were white papers, commentaries, modeling, cost-effectiveness, and qualitative studies. Data extraction and synthesis: Outcomes were (i) HIV care uptake defined as initiation of ART during pregnancy or prior to initial antenatal care (ANC) visit and (ii) proportion of women retained in HIV care as defined by study authors after ART initiation (or entry to antenatal care). These were synthesized in meta-analyses stratified by policy era (pre-Option B+ vs. Option B+) at different times for different countries. Comparisons between policy eras were made using relative risk with a 95% confidence interval. Pooled retention estimates at 6- and 12-months post ART initiation used crude relative risks (RR) with 95% confidence intervals (CI). Results: Among 4,752 articles, 82 from 17 countries were included; 60 reported HIV care uptake, 31 reported retention outcomes. Pooled HIV uptake rose by 8% (RR=1.08; 95% CI:1.06-1.09) and pooled retention in HIV care rose by 46% (RR=1.46; 95% CI:1.41-1.51) after Option B+ implementation. Pooled estimates of retention in care were 36.9% (95% CI: 13.9%, 59.9%) at 6 months post ART initiation before the implementation of Option B+ and 72.7% (95% CI: 66.3%, 79.1%) after implementation. Conclusion: HIV care uptake and retention improved after Option B+ implementation in 15 countries reporting results, but retention remains suboptimal for meeting UNAIDS 95-95-95 targets.","rel_num_authors":11,"rel_authors":[{"author_name":"Nelly N Jinga","author_inst":"Health Economics and Epidemiology Research Office, University of the Witwatersrand, Johannesburg, South Africa."},{"author_name":"Candice Hwang","author_inst":"Department of Medicine, Stanford University School of Medicine, Stanford, California, USA."},{"author_name":"Laura Rossouw","author_inst":"Health Economics and Epidemiology Research Office, University of the Witwatersrand, Johannesburg, South Africa."},{"author_name":"Kate Clouse","author_inst":"University of North Carolina, Greensboro, NC, USA"},{"author_name":"Cornelius Nattey","author_inst":"Health Economics and Epidemiology Research Office, University of the Witwatersrand, Johannesburg, South Africa."},{"author_name":"Bernard Mbwele","author_inst":"Department of Epidemiology, University of Dar es Salaam Mbeya College of Health and Allied Sciences, Mbeya, Tanzania."},{"author_name":"Nkosinathi Blessing Ngcobo","author_inst":"Health Economics and Epidemiology Research Office, University of the Witwatersrand, Johannesburg, South Africa."},{"author_name":"Molly Beestrum","author_inst":"Galter Health Sciences Library, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."},{"author_name":"Mark D Huffman","author_inst":"Division of Cardiology, Department of Medicine, Washington University in St. Louis, USA"},{"author_name":"Matthew  P. Fox","author_inst":"Department of Global Health, Boston University School of Public Health, Boston, Massachusetts, USA."},{"author_name":"Mhairi Maskew","author_inst":"Health Economics and Epidemiology Research Office, University of the Witwatersrand, Johannesburg, South Africa."}],"rel_date":"2026-04-08","rel_site":"medrxiv"},{"rel_title":"Epigenetic Signatures in Monozygotic and Dizygotic Twins Discordant for Orofacial Clefts","rel_doi":"10.64898\/2026.04.07.26350251","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.07.26350251","rel_abs":"IntroductionNonsyndromic cleft lip with or without cleft palate (NSCL\/P) is a common congenital malformation with complex etiology involving both genetic and environmental factors. Epigenetic mechanisms may mediate environmental contributions, but separating genetic from environmental effects remains challenging.\n\nMethodsWe present an epigenome-wide association study with 32 monozygotic and 22 dizygotic twin pairs discordant for NSCL\/P on blood and saliva samples. Differential methylation analysis was conducted using linear models to identify CpG sites showing significant methylation differences between affected and unaffected twins followed by functional annotation and pathway enrichment analysis.\n\nResultsThe top-ranked finding is a differentially methylated region comprising two CpG sites at the CYP26A1 locus, cg12110262 (P = 3.21x10-7) and cg15055355 (P = 1.39x10-3). CYP26A1 is essential for retinoic acid catabolism and craniofacial patterning. The chromatin regulator ANKRD11, which causes KBG syndrome featuring cleft palate was the second best hit. Differentially methylated CpG sites showed significant enrichment in craniofacial enhancers and overlap with multiple GWAS-validated cleft genes including VAX1, PVRL1, SMAD3, and PRDM16.\n\nConclusionsOur findings implicate retinoic acid signaling and chromatin regulation in NSCL\/P etiology and demonstrate the value of discordant twin designs for distinguishing environmental from genetic epigenetic contributions to complex malformations.","rel_num_authors":10,"rel_authors":[{"author_name":"Aline L Petrin","author_inst":"University of Iowa College of Dentistry and Dental Clinics"},{"author_name":"Henry L Keen","author_inst":"University of Iowa Carver College of Medicine"},{"author_name":"Lindsey Dunlay","author_inst":"University of Iowa College of Dentistry and Dental Clinics"},{"author_name":"Xian J Xie","author_inst":"Florida State University College of Medicine"},{"author_name":"Erliang Zeng","author_inst":"University of Iowa College of Dentistry and Dental Clinics"},{"author_name":"Azeez Butali","author_inst":"University of Iowa College of Dentistry and Dental Clinics"},{"author_name":"Allen Wilcox","author_inst":"Epidemiology Branch of the National Institute of Environmental Health Sciences"},{"author_name":"Mary  L. Marazita","author_inst":"University of Pittsburgh"},{"author_name":"Jeffrey C. Murray","author_inst":"University of Iowa Carver College of Medicine"},{"author_name":"Lina Moreno-Uribe","author_inst":"University of Iowa College of Dentistry and Dental Clinics"}],"rel_date":"2026-04-08","rel_site":"medrxiv"},{"rel_title":"Assessing the Impact of Timing and Coverage of United States COVID-19 Vaccination Campaigns: A Multi-Model Approach","rel_doi":"10.64898\/2026.04.07.26349269","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.07.26349269","rel_abs":"Six years after its emergence, SARS-CoV-2 continues to have a substantial burden, however, the impact of vaccination and the optimal timing of its rollout remain uncertain. To explore these uncertainties, the US Scenario Modeling Hub convened its 19th round of ensemble projections for COVID-19 hospitalizations and deaths in the United States. Eight teams provided outcomes for each US state and nationally from April 2025 to April 2026 under five scenarios regarding vaccine recommendations and timing. We assessed recommendations with two eligibility scenarios (high-risk individuals only and all-eligible) and two timing scenarios (classic start: mid-August, earlier start: late June). These were crossed to create four scenarios and were compared against a counterfactual scenario with no vaccination. We found that compared to no vaccination, our ensemble projections estimated 90,000 (95% PI 53,000-126,000) hospitalizations averted in the high-risk and classic timing scenario across the US. Expanding coverage averted an additional 26,000 (95% PI 14,000-39,000) hospitalizations, which when coupled with earlier vaccination timing further reduced national hospitalizations by 15,000 (95% PI -3,000-33,000). These findings estimate significant benefits from a broad all-eligible vaccination recommendation, and suggest an additional benefit is likely to be gained from an earlier vaccination campaign.","rel_num_authors":35,"rel_authors":[{"author_name":"Anjalika Nande","author_inst":"University of Oxford"},{"author_name":"Soren L Larsen","author_inst":"University of Illinois, Urbana Champaign \/ University of California, Berkeley"},{"author_name":"James Turtle","author_inst":"Predictive Science Inc."},{"author_name":"Jessica T Davis","author_inst":"Northeastern University"},{"author_name":"Shraddha Ramdas Bandekar","author_inst":"University of Texas at Austin"},{"author_name":"Bryan Lewis","author_inst":"University of Virginia"},{"author_name":"Shi Chen","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Lucie Contamin","author_inst":"University of Pittsburgh"},{"author_name":"Sung-mok Jung","author_inst":"National Unversity of Singapore"},{"author_name":"Emily Howerton","author_inst":"Princeton University"},{"author_name":"Katriona Shea","author_inst":"The Pennsylvania State University"},{"author_name":"Clara Bay","author_inst":"Northeastern University"},{"author_name":"Michal Ben-Nun","author_inst":"Predictive Science Inc."},{"author_name":"Kaiming Bi","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Anass Bouchnita","author_inst":"University of Texas at El Paso"},{"author_name":"Jiangzhuo Chen","author_inst":"University of Virginia"},{"author_name":"Matteo Chinazzi","author_inst":"Northeastern University"},{"author_name":"Spencer J Fox","author_inst":"Northern Arizona University"},{"author_name":"Alison L Hill","author_inst":"Johns Hopkins University"},{"author_name":"Harry Hochheiser","author_inst":"University of Pittsburgh"},{"author_name":"Joseph C Lemaitre","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Sara L Loo","author_inst":"Johns Hopkins University"},{"author_name":"Madhav Marathe","author_inst":"University of Virginia"},{"author_name":"Lauren Ancel Meyers","author_inst":"University of Texas at Austin"},{"author_name":"Carl A.B Pearson","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Przemyslaw Porebski","author_inst":"University of Virginia"},{"author_name":"Emily Przykucki","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Claire P Smith","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Srinivasan Venkatramanan","author_inst":"University of Virginia"},{"author_name":"Alessandro Vespignani","author_inst":"Northeastern University"},{"author_name":"Timothy C Willard","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Katie Yan","author_inst":"The Pennsylvania State University"},{"author_name":"Cecile Viboud","author_inst":"National Institutes of Health Fogarty International Center"},{"author_name":"Justin Lessler","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Shaun Truelove","author_inst":"Johns Hopkins University"}],"rel_date":"2026-04-08","rel_site":"medrxiv"},{"rel_title":"Assessing the Impact of Timing and Coverage of United States COVID-19 Vaccination Campaigns: A Multi-Model Approach","rel_doi":"10.64898\/2026.04.07.26349269","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.07.26349269","rel_abs":"Six years after its emergence, SARS-CoV-2 continues to have a substantial burden, however, the impact of vaccination and the optimal timing of its rollout remain uncertain. To explore these uncertainties, the US Scenario Modeling Hub convened its 19th round of ensemble projections for COVID-19 hospitalizations and deaths in the United States. Eight teams provided outcomes for each US state and nationally from April 2025 to April 2026 under five scenarios regarding vaccine recommendations and timing. We assessed recommendations with two eligibility scenarios (high-risk individuals only and all-eligible) and two timing scenarios (classic start: mid-August, earlier start: late June). These were crossed to create four scenarios and were compared against a counterfactual scenario with no vaccination. We found that compared to no vaccination, our ensemble projections estimated 90,000 (95% PI 53,000-126,000) hospitalizations averted in the high-risk and classic timing scenario across the US. Expanding coverage averted an additional 26,000 (95% PI 14,000-39,000) hospitalizations, which when coupled with earlier vaccination timing further reduced national hospitalizations by 15,000 (95% PI -3,000-33,000). These findings estimate significant benefits from a broad all-eligible vaccination recommendation, and suggest an additional benefit is likely to be gained from an earlier vaccination campaign.","rel_num_authors":35,"rel_authors":[{"author_name":"Anjalika Nande","author_inst":"University of Oxford"},{"author_name":"Soren L Larsen","author_inst":"University of Illinois, Urbana Champaign \/ University of California, Berkeley"},{"author_name":"James Turtle","author_inst":"Predictive Science Inc."},{"author_name":"Jessica T Davis","author_inst":"Northeastern University"},{"author_name":"Shraddha Ramdas Bandekar","author_inst":"University of Texas at Austin"},{"author_name":"Bryan Lewis","author_inst":"University of Virginia"},{"author_name":"Shi Chen","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Lucie Contamin","author_inst":"University of Pittsburgh"},{"author_name":"Sung-mok Jung","author_inst":"National Unversity of Singapore"},{"author_name":"Emily Howerton","author_inst":"Princeton University"},{"author_name":"Katriona Shea","author_inst":"The Pennsylvania State University"},{"author_name":"Clara Bay","author_inst":"Northeastern University"},{"author_name":"Michal Ben-Nun","author_inst":"Predictive Science Inc."},{"author_name":"Kaiming Bi","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Anass Bouchnita","author_inst":"University of Texas at El Paso"},{"author_name":"Jiangzhuo Chen","author_inst":"University of Virginia"},{"author_name":"Matteo Chinazzi","author_inst":"Northeastern University"},{"author_name":"Spencer J Fox","author_inst":"Northern Arizona University"},{"author_name":"Alison L Hill","author_inst":"Johns Hopkins University"},{"author_name":"Harry Hochheiser","author_inst":"University of Pittsburgh"},{"author_name":"Joseph C Lemaitre","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Sara L Loo","author_inst":"Johns Hopkins University"},{"author_name":"Madhav Marathe","author_inst":"University of Virginia"},{"author_name":"Lauren Ancel Meyers","author_inst":"University of Texas at Austin"},{"author_name":"Carl A.B Pearson","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Przemyslaw Porebski","author_inst":"University of Virginia"},{"author_name":"Emily Przykucki","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Claire P Smith","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Srinivasan Venkatramanan","author_inst":"University of Virginia"},{"author_name":"Alessandro Vespignani","author_inst":"Northeastern University"},{"author_name":"Timothy C Willard","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Katie Yan","author_inst":"The Pennsylvania State University"},{"author_name":"Cecile Viboud","author_inst":"National Institutes of Health Fogarty International Center"},{"author_name":"Justin Lessler","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Shaun Truelove","author_inst":"Johns Hopkins University"}],"rel_date":"2026-04-08","rel_site":"medrxiv"},{"rel_title":"Assessing the Impact of Timing and Coverage of United States COVID-19 Vaccination Campaigns: A Multi-Model Approach","rel_doi":"10.64898\/2026.04.07.26349269","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.07.26349269","rel_abs":"Six years after its emergence, SARS-CoV-2 continues to have a substantial burden, however, the impact of vaccination and the optimal timing of its rollout remain uncertain. To explore these uncertainties, the US Scenario Modeling Hub convened its 19th round of ensemble projections for COVID-19 hospitalizations and deaths in the United States. Eight teams provided outcomes for each US state and nationally from April 2025 to April 2026 under five scenarios regarding vaccine recommendations and timing. We assessed recommendations with two eligibility scenarios (high-risk individuals only and all-eligible) and two timing scenarios (classic start: mid-August, earlier start: late June). These were crossed to create four scenarios and were compared against a counterfactual scenario with no vaccination. We found that compared to no vaccination, our ensemble projections estimated 90,000 (95% PI 53,000-126,000) hospitalizations averted in the high-risk and classic timing scenario across the US. Expanding coverage averted an additional 26,000 (95% PI 14,000-39,000) hospitalizations, which when coupled with earlier vaccination timing further reduced national hospitalizations by 15,000 (95% PI -3,000-33,000). These findings estimate significant benefits from a broad all-eligible vaccination recommendation, and suggest an additional benefit is likely to be gained from an earlier vaccination campaign.","rel_num_authors":35,"rel_authors":[{"author_name":"Anjalika Nande","author_inst":"University of Oxford"},{"author_name":"Soren L Larsen","author_inst":"University of Illinois, Urbana Champaign \/ University of California, Berkeley"},{"author_name":"James Turtle","author_inst":"Predictive Science Inc."},{"author_name":"Jessica T Davis","author_inst":"Northeastern University"},{"author_name":"Shraddha Ramdas Bandekar","author_inst":"University of Texas at Austin"},{"author_name":"Bryan Lewis","author_inst":"University of Virginia"},{"author_name":"Shi Chen","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Lucie Contamin","author_inst":"University of Pittsburgh"},{"author_name":"Sung-mok Jung","author_inst":"National Unversity of Singapore"},{"author_name":"Emily Howerton","author_inst":"Princeton University"},{"author_name":"Katriona Shea","author_inst":"The Pennsylvania State University"},{"author_name":"Clara Bay","author_inst":"Northeastern University"},{"author_name":"Michal Ben-Nun","author_inst":"Predictive Science Inc."},{"author_name":"Kaiming Bi","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Anass Bouchnita","author_inst":"University of Texas at El Paso"},{"author_name":"Jiangzhuo Chen","author_inst":"University of Virginia"},{"author_name":"Matteo Chinazzi","author_inst":"Northeastern University"},{"author_name":"Spencer J Fox","author_inst":"Northern Arizona University"},{"author_name":"Alison L Hill","author_inst":"Johns Hopkins University"},{"author_name":"Harry Hochheiser","author_inst":"University of Pittsburgh"},{"author_name":"Joseph C Lemaitre","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Sara L Loo","author_inst":"Johns Hopkins University"},{"author_name":"Madhav Marathe","author_inst":"University of Virginia"},{"author_name":"Lauren Ancel Meyers","author_inst":"University of Texas at Austin"},{"author_name":"Carl A.B Pearson","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Przemyslaw Porebski","author_inst":"University of Virginia"},{"author_name":"Emily Przykucki","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Claire P Smith","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Srinivasan Venkatramanan","author_inst":"University of Virginia"},{"author_name":"Alessandro Vespignani","author_inst":"Northeastern University"},{"author_name":"Timothy C Willard","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Katie Yan","author_inst":"The Pennsylvania State University"},{"author_name":"Cecile Viboud","author_inst":"National Institutes of Health Fogarty International Center"},{"author_name":"Justin Lessler","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Shaun Truelove","author_inst":"Johns Hopkins University"}],"rel_date":"2026-04-08","rel_site":"medrxiv"},{"rel_title":"Reusing Blood Samples from a Hospital-based Cohort to Apixaban Plasma Concentrations","rel_doi":"10.64898\/2026.04.07.26350322","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.07.26350322","rel_abs":"In the management of atrial fibrillation, the most frequently prescribed oral anticoagulant is apixaban, given at a fixed dose of 5mg BID. Apixaban is predominantly metabolized by cytochrome P4503A4 (CYP3A4) and is also a substrate for the drug efflux transporter P-glycoprotein (P-gp). In nearly 300,000 Medicare patients with AF receiving apixaban, we previously showed that concomitant therapy with drugs that inhibit both CYP3A4 and P-gp, specifically amiodarone or diltiazem, significantly increased serious bleeding that caused hospitalization and\/or death. We hypothesized that this adverse effect was mediated by an increase in apixaban plasma concentrations caused by concomitant therapy that reduced drug elimination. Utilizing left-over samples obtained from clinically indicated blood draws that would typically be discarded, the Vanderbilt University Medical Center biobank BioVU contains >353,000 samples linked to de-identified electronic medical records (EMRs), with both DNA and plasma harvested. Of 35 samples drawn from patients taking apixaban 5mg BID, 5 were identified to be drawn from patients concomitantly taking drugs inhibiting both CYP3A4 and P-gp. Using a chromogenic anti-Xa assay, we found that plasma concentrations of apixaban were significantly higher (347{+\/-}64 ng\/mL; mean{+\/-}SEM) for patients receiving concomitant CYP3A4\/P-gp-inhibiting drugs compared to those not treated with these drugs (166{+\/-}67 ng\/mL; P=0.025, Mann Whitney). There were no differences between the 2 patient groups with respect to age, weight, or serum creatinine. The results of this pilot study provide preliminary data to support our hypothesis, and they demonstrate the practicality of obtaining pharmacokinetic data from a large cohort of plasma samples linked to deidentified EMRs. This approach could be used to define the role of apixaban levels in high-risk clinical scenarios and to better understand the relationship between drug levels and bleeding risk.","rel_num_authors":7,"rel_authors":[{"author_name":"Katherine T. Murray","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Daniel V. Fabbri","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jeffrey S. Annis","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Cynthia R. Clark","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jill M. Pulley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Evan Brittain","author_inst":"Vanderbilt University Medical Center"},{"author_name":"David Gailani","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-04-08","rel_site":"medrxiv"},{"rel_title":"Structural Basis of Polypurine Track Strand Displacement by HIV-1 Reverse Transcriptase","rel_doi":"10.64898\/2026.04.07.717013","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.07.717013","rel_abs":"To complete reverse transcription, HIV-1 reverse transcriptase (RT) must displace the RNase H-resistant polypurine tract (PPT) primers. This enables synthesis of the long terminal repeats and formation of the central cDNA flap. However, the molecular mechanism of this PPT strand displacement (SD) has remained unknown, and no structural data exist on how a retroviral polymerase execute these reactions. We report the first cryo-EM structures of HIV-1 RT bound to nucleic acid substrates containing either a PPTRNA or PPTDNA displacement strand, with incoming dATP positioned at the polymerase catalytic site. These structures reveal key features of the PPT displacement mechanism by RT. Specifically, we observed a binding mode where the template nucleotide (T1) base-paired to the first displacement nucleotide (D1) undergoes a 90{degrees} rotation relative to the preceding template base (T0). This sharp template flip positions D1 [~]30 [A] away from the primers 3-end and is coordinated by RTp66 residues at the SD interface: F61 and R78 contact T1\/T0 to drive template translocation, while W24 engages both T1 and D1 to stabilize the displacement strand. Biochemical and virological mutagenesis experiments confirm that interactions with F61 and R78 are essential for both canonical cDNA polymerization and SD, whereas the W24-nucleotide interactions are required exclusively for SD but are dispensable for standard cDNA synthesis. These results contribute to the structural and functional understanding of PPT strand displacement by HIV-1 RT and reveal a distinct mechanistic vulnerability for the design of next-generation antiretrovirals.","rel_num_authors":7,"rel_authors":[{"author_name":"Xin Wen","author_inst":"Emory University"},{"author_name":"Rachel Lee","author_inst":"Emory University"},{"author_name":"Sri Dhanya Muppalla","author_inst":"Georgia Institute of Technology"},{"author_name":"William M McFadden","author_inst":"Emory University"},{"author_name":"Karen A Kirby","author_inst":"Emory University"},{"author_name":"Robert A Dick","author_inst":"Emory University"},{"author_name":"Stefan G Sarafianos","author_inst":"Emory University"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"A MinD-like ATPase couples flagellation and cell division in spirochetes","rel_doi":"10.64898\/2026.04.08.717139","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.08.717139","rel_abs":"Spirochetes are evolutionarily distinct bacteria defined by their spiral morphology, unique means of motility, and periplasmic flagella (PFs). Because these filaments reside within the periplasm and are mechanically integrated with the cell body, their assembly must be precisely coordinated with cell growth and cytokinesis. However, the mechanism that couples flagellar biogenesis to cell division in spirochetes remains unclear. Using the Lyme disease spirochete Borrelia burgdorferi as a model, we identify FlhG (BB0269), a MinD-like ATPase, as a spatial regulator that links cell division to flagellar patterning. In wild-type cells, 7-11 long helical PFs originate from cell poles and assemble into ribbon-like bundles that wrap around the cell cylinder to drive motility. Deletion of flhG disrupts this ordered architecture, causing marked heterogeneity in flagellar number, defective ribbon assembly, aberrant septation, and severe motility impairment. Mechanistically, FlhG dynamically localizes to the poles and midcell during division, where it directs the positioning of FlhF, a signal recognition particle (SRP) -type GTPase controlling flagellar number and placement, and FliF, the MS-ring protein that nucleates flagellar assembly. Through this spatial regulation, FlhG coordinates flagellar assembly with cytokinetic progression. Together, these findings reveal a spatial regulatory mechanism coupling cell division to flagellation, providing insight into understanding how spirochetes coordinate their distinctive morphogenesis, flagellation and motility.\n\nSignificanceSpirochetes such as Borrelia burgdorferi, the causative agent of Lyme disease, rely on periplasmic flagella for motility and cell shape, yet how these structures are coordinated with cell division has remained unclear. We identify a MinD-like ATPase, FlhG, as a spatial regulator that couples flagellar assembly to cytokinesis. In contrast to its homologs in other bacteria, FlhG does not regulate flagellar protein levels but instead directs subcellular positioning of key assembly factors. By dynamically redistributing between the cell poles and division site, FlhG synchronizes flagellar patterning with septum formation. These findings uncover a previously unrecognized mechanism linking cell morphogenesis to the cell cycle and reveal how conserved ATPases can be repurposed to organize complex bacterial architectures.","rel_num_authors":6,"rel_authors":[{"author_name":"Chunhao Li","author_inst":"Philips Research Institute for Oral Health, School of Dentistry, Virginia Commonwealth University"},{"author_name":"Kai Zhang","author_inst":"Virginia Commonwealth University"},{"author_name":"Wangbiao Guo","author_inst":"Yale University"},{"author_name":"Michael J Lynch","author_inst":"Cornell University College of Arts and Sciences"},{"author_name":"Brian Crane","author_inst":"Cornell University"},{"author_name":"Jun Liu","author_inst":"Yale University"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Intranasal Anti-CD3 Antibody Treatment Attenuates Post-COVID Neuroinflammation and Enhances Hippocampal Neurogenesis and Cognitive Function in Mice","rel_doi":"10.64898\/2026.04.07.716934","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.07.716934","rel_abs":"Cognitive impairment is a disabling feature of Long COVID, with data supporting neuroinflammation and maladaptive glial responses as primary drivers. Nasal administration of an anti-CD3 monoclonal antibody (aCD3 mAb) has shown therapeutic benefits in autoimmune and CNS disease models. Using a respiratory-restricted mild SARS-CoV-2 mouse model of Long COVID, we show that nasal anti-CD3 mAb, administered shortly after infection or during chronic neuroinflammation, increased brain FoxP3+ IL-10+ Tregs, reduced microglial and astrocytic gliosis in the white matter and hippocampus, restored neurogenesis, and improved short-term memory. Nasal aCD3 mAb reprogrammed microglia from an antigen-presenting, NF-{kappa}B-driven inflammatory state toward chemokine signaling, phagosome, and TGF {beta}-related regulatory phenotype. Patients with Long COVID with neurological symptoms had lower circulating Treg populations. These findings identify nasal administration of aCD3 mAb as a noninvasive strategy to control neuroinflammation, restore the neurogenic niche, and offer a novel approach to treating cognitive impairment in Long COVID.","rel_num_authors":12,"rel_authors":[{"author_name":"Peiwen Lu","author_inst":"Department of Immunobiology, Yale University, New Haven CT USA"},{"author_name":"Saef Izzy","author_inst":"Immunology of Brain Injury Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Patrick Da Silva","author_inst":"Immunology of Brain Injury Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Harm Tjebbe Imkamp","author_inst":"Immunology of Brain Injury Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Jonathan R. Christenson","author_inst":"Immunology of Brain Injury Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Taha Yahya","author_inst":"Immunology of Brain Injury Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Maryam Hazim Al Mansi","author_inst":"Immunology of Brain Injury Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Amir Alawi","author_inst":"Immunology of Brain Injury Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Thais G. Moreira","author_inst":"Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Michelle Monje","author_inst":"Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA"},{"author_name":"Howard L. Weiner","author_inst":"Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Akiko Iwasaki","author_inst":"Department of Immunobiology, Yale University, New Haven CT USA"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Decoding concept representations in aphasia after stroke","rel_doi":"10.64898\/2026.04.07.717076","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.07.717076","rel_abs":"Many stroke survivors with aphasia struggle to map their thoughts into words or motor plans. Neuroprostheses that decode concept representations could help these individuals communicate by predicting the words, phrases, or sentences that they are struggling to produce. Here we decoded concept representations measured using functional magnetic resonance imaging (fMRI) from participants with different aphasia profiles. The decoders generated continuous word sequences that could describe the concepts that the participants were hearing about, seeing, or imagining. To forecast how this approach would generalize across the heterogeneity of aphasia profiles, we characterized how stroke affects the anatomical organization and information capacity of conceptual processing. Mapping how concepts are organized across the brain, we found that conceptual tuning during non-linguistic processing was largely consistent between the participants with aphasia and neurologically healthy participants. Comparing information processing between the participants with aphasia and neurologically healthy participants, we found that both groups processed similar amounts of non-linguistic information. Our findings indicate that concept representations can be largely spared in individuals with aphasia and demonstrate how these representations can be decoded to support communication.","rel_num_authors":9,"rel_authors":[{"author_name":"Jerry Tang","author_inst":"The University of Texas at Austin"},{"author_name":"Carly Millanski","author_inst":"The University of Texas at Austin"},{"author_name":"Allison Chen","author_inst":"The University of Texas at Austin"},{"author_name":"Lisa D Wauters","author_inst":"The University of Texas at Austin"},{"author_name":"Jordyn Anders","author_inst":"The University of Texas at Austin"},{"author_name":"Shilpa Shamapant","author_inst":"Austin Speech Labs"},{"author_name":"Stephen M Wilson","author_inst":"The University of Queensland"},{"author_name":"Alexander G Huth","author_inst":"University of California, Berkeley"},{"author_name":"Maya Henry","author_inst":"The University of Texas at Austin"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Intrinsically disordered ligands for the control of receptor uptake by endocytosis","rel_doi":"10.64898\/2026.04.06.716760","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716760","rel_abs":"Endocytosis plays a crucial role in signaling, recycling, and degradation of receptors. Controlling endocytosis of specific receptors is therefore a major goal for both basic science and medicine. While antibody-induced dimerization can drive signaling-induced uptake of some receptors, the steric bulk of antibodies generally inhibits endocytosis, such that control over receptor uptake remains an unmet need. Recent work has demonstrated that attractive interactions between intrinsically disordered proteins drive inward membrane curvature, a key step in endocytosis. To harness this phenomenon for the control of receptor uptake, we designed chimeras that consisted of disordered domains fused to ligands for specific receptors. These chimeras condensed on membrane surfaces, driving receptor clustering and uptake via clathrin-mediated endocytosis. In contrast, chimeras that repelled one another resisted condensation, helping receptors escape endocytosis and remain on the cell surface. Taken together, these results suggest that by modulating the amino acid sequence of intrinsically disordered ligands, we can promote or hinder the internalization of specific receptors by endocytic pathways. More broadly, these findings suggest a generalizable strategy for controlling the plasma membrane lifetime of diverse receptors, opening up new pathways for modulating cellular behavior and delivering therapeutics.\n\nSignificance StatementCells regulate signaling by continuously internalizing receptors from their surfaces using endocytosis. Controlling receptor internalization would provide new tools for addressing diverse diseases. While antibodies can cluster specific receptors on the cell surface, their steric bulk and rigidity inhibit endocytosis. In contrast, here we demonstrate that engineered ligands containing intrinsically disordered domains form flexible complexes that precisely control receptor internalization. Disordered ligands that attract one another condense receptors at sites of endocytosis, driving uptake, while repulsive disordered ligands prevent condensation such that receptors remain on the cell surface. By tuning the amino acid sequence of the disordered domain, a ligand can be switched from promoting to inhibiting receptor internalization, offering the opportunity to control cell signaling and therapeutic delivery.","rel_num_authors":7,"rel_authors":[{"author_name":"Sujeong Park","author_inst":"The University of Texas at Austin"},{"author_name":"Irene Sarro","author_inst":"The University of Texas at Austin"},{"author_name":"Advika Kamatar","author_inst":"The University of Texas at Austin"},{"author_name":"Liping Wang","author_inst":"The University of Texas at Austin"},{"author_name":"Padmini Rangamani","author_inst":"University of California San Diego"},{"author_name":"Eileen M Lafer","author_inst":"University of Texas Health Science Center San Antonio"},{"author_name":"Jeanne Stachowiak","author_inst":"University of Texas at Austin"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"UQ-PhysiCell: An extensible Python framework for uncertainty quantification and model analysis in PhysiCell","rel_doi":"10.64898\/2026.04.06.716692","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716692","rel_abs":"Agent-based models (ABMs) are widely used to study complex multiscale biological systems, particularly in cancer research. However, their high-dimensional parameter spaces, stochasticity, and computational costs pose significant challenges for uncertainty quantification, calibration, and systematic comparison of competing mechanistic hypotheses. PhysiCell has evolved into a growing ecosystem of open-source tools supporting physics-based multicellular modeling, including model construction, visualization, and data integration. However, despite these advances, systematic support for uncertainty-aware model analysis, scalable parameter exploration, and formal calibration workflows remains limited. Here, we introduce UQ-PhysiCell, an open-source Python package that enables uncertainty quantification, calibration, and model selection for PhysiCell models using a modular and scalable workflow. UQ-PhysiCell acts as a manager of PhysiCell simulation inputs and outputs, including parameters, initial conditions, rules, and MultiCellDS-compliant objects, and provides automated orchestration of large ensembles of simulations. The framework supports multiple levels of parallelism to accelerate the analysis, including the parallel execution of independent simulations, stochastic replicates, and downstream analysis tasks. UQ-PhysiCell integrates seamlessly with established Python libraries for sensitivity analysis, optimization, Bayesian inference, and surrogate modeling, allowing users to construct customized pipelines that match their modeling goals and computational resource requirements. By decoupling model execution from statistical analysis and emphasizing extensibility and reproducibility, UQ-PhysiCell lowers the barrier to applying rigorous uncertainty-aware methodologies to agent-based modeling and supports the systematic evaluation of PhysiCell models in biological and biomedical research.\n\nAuthor summaryWe developed UQ-PhysiCell to address a key challenge in agent-based modeling: the systematic quantification of uncertainty in complex stochastic simulations. PhysiCell is widely used to model multicellular biological systems, particularly in cancer research; however, practical tools for uncertainty analysis, calibration, and model comparison are often developed in an ad hoc manner. This makes the results difficult to reproduce and limits the ability to rigorously evaluate competing biological hypotheses. UQ-PhysiCell provides a flexible Python framework that manages the inputs and outputs of PhysiCell simulations and enables large-scale computational analysis. We designed the software to be modular, allowing users to build their own analysis pipelines and combine different methodologies for sensitivity analysis, calibration, and model selection. Rather than enforcing a single workflow, UQ-PhysiCell supports customization to match specific scientific questions and computational requirements. To make uncertainty-aware analyses feasible for computationally intensive agent-based models, UQ-PhysiCell implements multiple parallelism strategies, enabling the concurrent execution of simulations, stochastic replicates, and downstream analyses. By promoting reproducibility, scalability, and methodological flexibility, UQ-PhysiCell helps researchers move beyond single best-fit simulations toward more reliable and interpretable computational modeling.","rel_num_authors":7,"rel_authors":[{"author_name":"Heber L. Rocha","author_inst":"Indiana University"},{"author_name":"Elmar Bucher","author_inst":"Indiana University"},{"author_name":"Shuming Zhang","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Atul Deshpande","author_inst":"Johns Hopkins University"},{"author_name":"Daniel R Bergman","author_inst":"University of Maryland Baltimore"},{"author_name":"Randy Heiland","author_inst":"Indiana University"},{"author_name":"Paul R Macklin","author_inst":"Indiana University"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"PA-SfM: Tracker-free differentiable acoustic radiation for freehand 3D photoacoustic imaging","rel_doi":"10.64898\/2026.04.06.716718","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716718","rel_abs":"Three-dimensional (3D) handheld photoacoustic tomography typically relies on bulky and expensive external positioning trackers to correct motion artifacts, which severely limits its clinical flexibility and accessibility. To address this challenge, we present PA-SfM, a tracker-free framework that leverages exclusively single-modality photoacoustic data for both sensor pose recovery and high-fidelity 3D reconstruction via differentiable acoustic radiation modeling. Unlike traditional Structure-from-Motion (SfM) methods that formulate pose estimation as a geometry-driven optimization over visual features, PA-SfM integrates the acoustic wave equation into a differentiable programming pipeline. By leveraging a high-performance, GPU-accelerated acoustic radiation kernel, the framework simultaneously optimizes the 3D photoacoustic source distribution and the sensor array pose via gradient descent. To ensure robust convergence in freehand scenarios, we introduce a coarse-to-fine optimization strategy that incorporates geometric consistency checks and rigid-body constraints to eliminate motion outliers. We validated the proposed method through both numerical simulations and in-vivo rat experiments. The results demonstrate that PA-SfM achieves sub-millimeter positioning accuracy and restores high-resolution 3D vascular structures comparable to ground-truth benchmarks, offering a low-cost, softwaredefined solution for clinical freehand photoacoustic imaging. The source code is publicly available at https:\/\/github.com\/JaegerCQ\/PA-SfM.","rel_num_authors":13,"rel_authors":[{"author_name":"Shuang Li","author_inst":"Peking University"},{"author_name":"Jian Gao","author_inst":"Nanjing University"},{"author_name":"Chulhong Kim","author_inst":"Pohang University of Science and Technology"},{"author_name":"Seongwook Choi","author_inst":"Pohang University of Science and Technology"},{"author_name":"Qian Chen","author_inst":"Peking University"},{"author_name":"Yibing Wang","author_inst":"Peking University"},{"author_name":"Shuang Wu","author_inst":"Nanjing University"},{"author_name":"Yu Zhang","author_inst":"Peking University"},{"author_name":"Tingting Huang","author_inst":"Peking University"},{"author_name":"Yucheng Zhou","author_inst":"Peking University"},{"author_name":"Boxin Yao","author_inst":"Peking University"},{"author_name":"Yao Yao","author_inst":"Nanjing University"},{"author_name":"Changhui Li","author_inst":"Peking University"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"A basophil-specific GPCR mediates the immune response to helminth infection","rel_doi":"10.64898\/2026.04.06.716327","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716327","rel_abs":"Basophils are rare innate immune cells that contribute to type 2 immunity in allergy and parasitic helminth infection, yet the receptors governing their activation remain poorly defined. Here, we identify the G protein-coupled receptor (GPCR) Mrgpra6 as a basophil-specific gene that mediates the host response to helminth infection. Mrgpra6 expression is restricted to basophils in blood and lung and is uniformly expressed across the population. Knockout of Mrgpra6 impairs early innate immunity to invading helminths, resulting in increased larval burden, elevated mortality, and disrupted parasite progression within the host. Transcriptional profiling of FACS-sorted basophils during helminth infection reveals how Mrgpra6 shapes the basophil transcriptional landscape needed for effective host defense. Together, these findings identify Mrgpra6 as a functional regulator of basophil-mediated anti-helminth immunity.","rel_num_authors":7,"rel_authors":[{"author_name":"Xinzhong Dong","author_inst":"Johns Hopkins University"},{"author_name":"Aleksander K Geske","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Rachel Pan","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Celeste Flores","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Taylor Follansbee","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Nathachit Limjunyawong","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Xintong Dong","author_inst":"University of Texas at Dallas"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Quantifying PD1 saturation by PDL1 in tumor tissue using a novel RNA aptamer-based assay","rel_doi":"10.64898\/2026.04.06.716702","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716702","rel_abs":"BackgroundTherapeutic agents targeting the PD1-PDL1 interaction are of great clinical value, however accurately predicting which patients are most likely to benefit is challenging. Improved predictive biomarkers for anti-PD1 therapy are clearly needed. Quantifying PD1 saturation by PDL1 in tumor tissue has the potential to serve as such a biomarker. Here we report a novel bioassay called the PD1 Ligand Receptor Complex Aptamer (LIRECAP) assay and demonstrate it can be used to quantify the saturation of PD1 by PDL1 in formalin-fixed paraffin-embedded tumor biospecimens.\n\nResultsThe PD1 LIRECAP assay was developed by identifying a pair of RNA aptamers. One aptamer preferentially binds to unoccupied PD1 (P aptamer) and the other to the PD1-PDL1 complex (C aptamer). P and C aptamers were added together to a formalin-fixed sample, and bound aptamer extracted. A 2-color qRT-PCR assay using a single set of primers was used to determine the ratio of the sample-bound C to P aptamers (C:P ratio) which reflected PD1 saturation by PDL1 in the sample. Quantification of PD1 saturation by PDL1 as determined by the PD1 LIRECAP assay correlated closely with PD1-mediated signaling and PD1-PDL1 proximity. Analysis of sarcoma FFPE biospecimens confirmed the assay is technically reproducible on clinical biospecimens. There were significant differences in PD1 saturation by PDL1 between patients as well as considerable intratumoral heterogeneity.\n\nConclusionsThe PD1 LIRECAP assay is novel assay that can be used to quantify PD1 saturation by PDL1 in clinical biospecimens. The assay is technically feasible, reproducible, and has the potential to serve as a superior predictive biomarker for PD1\/PDL1-based therapy. Similar assays based on this platform could be used in other systems and settings to quantify interaction between two molecules.","rel_num_authors":6,"rel_authors":[{"author_name":"Suresh Veeramani","author_inst":"University of Iowa"},{"author_name":"Chaobo Yin","author_inst":"University of Iowa"},{"author_name":"Nanmeng Yu","author_inst":"University of Iowa"},{"author_name":"Kristen L Coleman","author_inst":"University of Iowa"},{"author_name":"Brian J Smith","author_inst":"University of Iowa"},{"author_name":"George J Weiner","author_inst":"University of Iowa"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Hierarchical decoding of targeting tripeptide motif by the cytosolic iron-sulfur cluster assembly targeting complex","rel_doi":"10.64898\/2026.04.06.716496","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716496","rel_abs":"Iron-sulfur (Fe-S) clusters are essential cofactors required for diverse cellular processes, yet how the Fe-S cluster biogenesis machinery selectively recognizes apo-client proteins remain poorly understood. In eukaryotes, many cytosolic and nuclear Fe-S proteins are recruited to the cytosolic iron-sulfur cluster assembly (CIA) system through a short C-terminal targeting complex recognition (TCR) motif having a [ILM]-[DES]-FW] consensus. Currently, the physicochemical properties underlying this molecular recognition event are undefined. By combining quantitative binding measurements, bioinformatic analysis, and structural modeling, we define the molecular basis for TCR peptide recognition by the CIA targeting complex (CTC). This systematic energetic dissection reveals a hierarchy of binding determinants, in which the side chain and C-terminal carboxylate of the aromatic residue provide the dominant energetic contributor, whereas the upstream residues modulate affinity in a sequence context-dependent manner. Computational docking and molecular dynamics simulations identify an interfacial binding site at the Cia1-Cia2 interface that can accommodate these TCR moieties complementary interaction surfaces. Mutational analysis the identified interaction site is consistent with an aromatic pocket and an adjacent hydrophobic groove on Cia2 accommodating the TCRs terminal aromatic and antepenultimate aliphatic residues. Together, these results reveal the physicochemical decoding grammar by which the CTC recognizes targeting peptides with divergent sequences, illustrating how short targeting motifs can achieve both the specificity and adaptability required for Fe-S protein maturation.\n\nSignificance StatementIron-sulfur (Fe-S) clusters are essential metallocofactors requiring dedicated pathways for their assembly and insertion into proteins. How Fe-S cluster biogenesis systems selectively recognize their Fe-S binding client proteins in the crowded cellular environment remains poorly understood, in part because these machineries must engage dozens of clients rather than relying on the one-to-one metallochaperone-client pairings commonly used to assemble other types of metalloproteins. In eukaryotes, many cytosolic and nuclear Fe-S proteins are recruited to the cytosolic iron-sulfur assembly (CIA) machinery through a C-terminal targeting tripeptide motif. Here we combine biochemical measurements and structural modeling to define the molecular rules governing recognition of CIA targeting peptides. We show that a hierarchy of physicochemical peptide features, rather than a strict sequence consensus, guides recruitment of clients to the targeting complex, explaining how a single binding site can decode multiple targeting peptide signals.","rel_num_authors":6,"rel_authors":[{"author_name":"Anastasiya Buzuk","author_inst":"Boston University"},{"author_name":"Omeir Khan","author_inst":"Boston University"},{"author_name":"Soyoon Kang","author_inst":"Boston University"},{"author_name":"Leah Yim","author_inst":"Boston University"},{"author_name":"Sandor Vajda","author_inst":"Boston University"},{"author_name":"Deborah Perlstein","author_inst":"Boston University"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"A High-throughput Fluorescence Polarization Assay for Screening Sirtuin Inhibitors","rel_doi":"10.64898\/2026.04.06.716694","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716694","rel_abs":"Sirtuins (SIRTs), which remove protein lysine acyl modifications, play crucial roles in diverse cellular processes, including metabolism, gene transcription, DNA damage repair, cell survival, and stress response. Several sirtuins are considered non-oncogene addiction of cancer cells and promising targets for anticancer drug development. High-throughput screening (HTS) methods for sirtuins are critical for the development of potent and isoform-selective sirtuin inhibitors, which are needed to validate the therapeutic potential. Herein, we designed and synthesized a fluorescent polarization (FP) tracer, KP-SC-1. Using this high-affinity tracer, we developed a robust, high-throughput FP competition assay for screening SIRT1-3 inhibitors. The assay was validated by testing known SIRT1-3 inhibitors. The assay can detect NAD+-independent SIRT1-3 inhibitors, as well as NAD+-dependent inhibitors, such as Ex-527 and TM. Finally, our assay showed satisfactory stability and outstanding performance in a pilot library screening. Compared to previous assays, the FP assay uses much less SIRT1-3 enzymes, a feature important for high-throughput library screening. We believe that the FP assay developed here will accelerate the discovery and development of SIRT1-3 inhibitors.","rel_num_authors":4,"rel_authors":[{"author_name":"Kewen Peng","author_inst":"The University of Chicago"},{"author_name":"Suryadeep Chakraborty","author_inst":"The University of Chicago"},{"author_name":"Yizhen Jin","author_inst":"The University of Chicago"},{"author_name":"Hening Lin","author_inst":"Howard Hughes Medical Institute, The University of Chicago"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Density-dependent facilitation of livestock by small mammal ecosystem engineers","rel_doi":"10.64898\/2026.04.06.716644","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716644","rel_abs":"Small mammals and large herbivores have co-evolved in grasslands for millions of years, yet how they interplay remains unclear. On the Qinghai-Tibetan Plateau, plateau pikas (Ochotona curzoniae) are often considered pests that compete with livestock at high densities. Using field experiments, we show that pikas facilitate yaks (Bos grunniens) below a moderate density threshold ([~]200 active burrows\/ha). By selectively clipping tall poisonous forbs, especially Stellera chamaejasme, pikas reduced their cover by two-thirds, increased the abundance and protein content of palatable grasses and sedges, improved yak foraging efficiency, and enhanced weight gain by up to 67%. These results provide the first empirical evidence of a density-dependent transition from antagonism to facilitation between small and large herbivores. They highlight how moderate populations of ecosystem-engineering small mammals can sustain both biodiversity and pastoral productivity in rangelands.","rel_num_authors":16,"rel_authors":[{"author_name":"Zhiwei Zhong","author_inst":"Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences"},{"author_name":"Bingbo Ni","author_inst":"Northeast Institute of Geography and Agroecology, Chinese Academy of Science"},{"author_name":"Douglas Lawton","author_inst":"Arizona State University"},{"author_name":"Xiaofei Li","author_inst":"Jilin Agricultural University"},{"author_name":"Xiaona Zheng","author_inst":"Northeast Normal UniversityC"},{"author_name":"Huakun Zhou","author_inst":"Northwest Institute of Plateau Biology"},{"author_name":"Junhu Su","author_inst":"Gansu Agricultural University"},{"author_name":"Wenjin Li","author_inst":"Lanzhou University"},{"author_name":"Fujiang Hou","author_inst":"Lanzhou University"},{"author_name":"Zhenggang Guo","author_inst":"Lanzhou University"},{"author_name":"Quanmin Dong","author_inst":"Qinghai University"},{"author_name":"Shikui Dong","author_inst":"Beijing Forestry University"},{"author_name":"Christopher Dickman","author_inst":"The University of Sydney"},{"author_name":"Jens-Christian Svenning","author_inst":"Aarhus University"},{"author_name":"Ying Gao","author_inst":"Northeast Normal University"},{"author_name":"Zhibin Zhang","author_inst":"Institute of Zoology"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Thermodynamic rigidity of harmonic brain states relates to general mental ability in juvenile myoclonic epilepsy","rel_doi":"10.64898\/2026.04.06.715875","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.715875","rel_abs":"Cognitive difficulties are increasingly recognized in juvenile myoclonic epilepsy (JME), but scalable biomarkers linking resting-state brain dynamics to general mental ability remain limited. Here, we combined topological data analysis, graph signal processing, machine learning, inverse Langevin modeling, and biophysical simulations to test whether EEG-derived network dynamics capture individual differences in general mental ability in JME.\n\nWe studied 54 patients with JME and 45 healthy controls using resting-state high-density EEG and the raw estimated full-scale score derived from the Wechsler Abbreviated Scale of Intelligence (WASI), used here as an index of general mental ability. Subject-specific low-alpha activity was reconstructed with generalized eigendecomposition, and graph-derived features were extracted from the projection of topological and alpha-power signals onto the functional connectome, providing a graph-harmonic description of large-scale brain-state dynamics. In controls, dynamic EEG-derived features significantly predicted general mental ability, whereas the same framework failed in JME. Because prediction in controls was driven mainly by dynamic measures of smoothness (Dirichlet energy), we next examined the temporal organization of alpha-power smoothness using an inverse Langevin framework. Within the patient group, greater thermodynamic rigidity--that is, stronger confinement of fluctuations around preferred network states--was associated with lower general mental ability. Relative to controls, patients also showed lower thermodynamic noise, indicating a reduced tendency to explore alternative network regimes.\n\nBiophysical simulations suggested that reduced dendritic arborization can generate rigidity directly, whereas pharmacological stabilization of hyperexcitable circuits can shift the system toward a more rigid, lower-noise regime. Together, these findings suggest that cognition in JME is linked not only to altered resting-state network dynamics but also to stronger confinement of network-state fluctuations, with both intrinsic circuit abnormalities and treatment-related stabilization representing plausible routes to this rigid phenotype.","rel_num_authors":10,"rel_authors":[{"author_name":"Felipe Branco de Paiva","author_inst":"University of Helsinki"},{"author_name":"Meixian Zhao","author_inst":"Johns Hopkins University"},{"author_name":"Meishu Zhao","author_inst":"Johns Hopkins University"},{"author_name":"Santiago Philibert-Rosas","author_inst":"Washington University in St. Louis"},{"author_name":"Cameron J. Brace","author_inst":"Washington University in St. Louis"},{"author_name":"Erika Moe","author_inst":"University of Wisconsin-Madison"},{"author_name":"Steven E. Haworth","author_inst":"University of Wisconsin-Madison"},{"author_name":"Bruce P. Hermann","author_inst":"University of Wisconsin-Madison"},{"author_name":"Moo K. Chung","author_inst":"University of Wisconsin-Madison"},{"author_name":"Aaron F. Struck","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Thermodynamic rigidity of harmonic brain states relates to general mental ability in juvenile myoclonic epilepsy","rel_doi":"10.64898\/2026.04.06.715875","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.715875","rel_abs":"Cognitive difficulties are increasingly recognized in juvenile myoclonic epilepsy (JME), but scalable biomarkers linking resting-state brain dynamics to general mental ability remain limited. Here, we combined topological data analysis, graph signal processing, machine learning, inverse Langevin modeling, and biophysical simulations to test whether EEG-derived network dynamics capture individual differences in general mental ability in JME.\n\nWe studied 54 patients with JME and 45 healthy controls using resting-state high-density EEG and the raw estimated full-scale score derived from the Wechsler Abbreviated Scale of Intelligence (WASI), used here as an index of general mental ability. Subject-specific low-alpha activity was reconstructed with generalized eigendecomposition, and graph-derived features were extracted from the projection of topological and alpha-power signals onto the functional connectome, providing a graph-harmonic description of large-scale brain-state dynamics. In controls, dynamic EEG-derived features significantly predicted general mental ability, whereas the same framework failed in JME. Because prediction in controls was driven mainly by dynamic measures of smoothness (Dirichlet energy), we next examined the temporal organization of alpha-power smoothness using an inverse Langevin framework. Within the patient group, greater thermodynamic rigidity--that is, stronger confinement of fluctuations around preferred network states--was associated with lower general mental ability. Relative to controls, patients also showed lower thermodynamic noise, indicating a reduced tendency to explore alternative network regimes.\n\nBiophysical simulations suggested that reduced dendritic arborization can generate rigidity directly, whereas pharmacological stabilization of hyperexcitable circuits can shift the system toward a more rigid, lower-noise regime. Together, these findings suggest that cognition in JME is linked not only to altered resting-state network dynamics but also to stronger confinement of network-state fluctuations, with both intrinsic circuit abnormalities and treatment-related stabilization representing plausible routes to this rigid phenotype.","rel_num_authors":10,"rel_authors":[{"author_name":"Felipe Branco de Paiva","author_inst":"University of Helsinki"},{"author_name":"Meixian Zhao","author_inst":"Johns Hopkins University"},{"author_name":"Meishu Zhao","author_inst":"Johns Hopkins University"},{"author_name":"Santiago Philibert-Rosas","author_inst":"Washington University in St. Louis"},{"author_name":"Cameron J. Brace","author_inst":"Washington University in St. Louis"},{"author_name":"Erika Moe","author_inst":"University of Wisconsin-Madison"},{"author_name":"Steven E. Haworth","author_inst":"University of Wisconsin-Madison"},{"author_name":"Bruce P. Hermann","author_inst":"University of Wisconsin-Madison"},{"author_name":"Moo K. Chung","author_inst":"University of Wisconsin-Madison"},{"author_name":"Aaron F. Struck","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Low-Intensity Focused Ultrasound Enhances Meningeal Lymphatic Drainage for Preventing Cognitive Decline in Alzheimer's Disease","rel_doi":"10.64898\/2026.04.06.716653","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716653","rel_abs":"Meningeal lymphatic vessels (mLVs) are vital for brain waste clearance, making them a promising therapeutic target. However, effective modulation strategies for mLVs with translational potential remain underdeveloped. Here, we develop a low-intensity focused ultrasound (LIFU) strategy that precisely targets the vault cranial meninges to non-invasively facilitate mLVs drainage. Using models of Alzheimers disease (AD) and aging, we demonstrate that this approach promotes CSF drainage, prevents cognitive decline, and reduces pathological biomarkers. Mechanistically, RNA sequencing combined with calcium imaging in vitro reveals that LIFU activates the Piezo1 ion channel in lymphatic endothelial cells, whereas pharmacological inhibition of Piezo1 abolishes LIFUs therapeutic effects. Compliant with FDA safety guidelines, this LIFU protocol demonstrates strong clinical translatability. If its efficacy is clinically confirmed, LIFU offers a promising therapy for neurodegenerative diseases triggered by waste accumulation.","rel_num_authors":9,"rel_authors":[{"author_name":"Zhou Feng","author_inst":"Third Military Medical University"},{"author_name":"Jingming Hou","author_inst":"Third Military Medical University"},{"author_name":"Xiaoli Li","author_inst":"Beijing Normal University"},{"author_name":"Xingjun Xu","author_inst":"Third Military Medical University"},{"author_name":"Tao Jiang","author_inst":"Third Military Medical University"},{"author_name":"Caixin Zhu","author_inst":"Third Military Medical University"},{"author_name":"Yu Tang","author_inst":"Third Military Medical University"},{"author_name":"Yue Shu","author_inst":"Third Military Medical University"},{"author_name":"Qining Wang","author_inst":"Peking University"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Negative affective states are not detected in rats following an intravenous self-administration regimen leading to incubation of oxycodone craving","rel_doi":"10.64898\/2026.04.06.716594","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716594","rel_abs":"In rats, cue-induced opioid craving intensifies (incubates) during abstinence from opioid self-administration and then remains high for a prolonged period. The prolonged plateau models persistent vulnerability to cue-induced craving and relapse in humans recovering from opioid use disorder. However, a very significant contributor to relapse vulnerability in these individuals is the presence of negative affective states that can persist for months to years, far beyond physical dependence. The goal of this study was to determine if the incubation of craving model recapitulates this aspect of relapse vulnerability. We began by comparing rats trained to self-administer oxycodone using a regimen leading to persistent elevation of cue-induced craving (6 h\/d x 10 d) and rats trained to self-administer saline. We assessed somatic withdrawal signs in early abstinence and conducted behavioral tests modeling negative affect (open field, social preference, sucrose preference, and elevated plus maze) in late abstinence. Some somatic withdrawal signs were greater in oxycodone rats on abstinence day (AD)1, but cumulative scores did not differ between groups on AD1-3. On AD41-46, no group differences were found in behavioral tests modeling negative affect. To compare early and late abstinenceperiods, a second cohort of rats self-administered saline and oxycodoneand then received two cue-induced seeking tests (AD1 and AD40; oxycodone rats exhibited incubation of craving) and two series of negative affect tests (AD2-7 and AD41-48). While some time-dependent changes in affect were observed within each group, they were suggestive of reduced anxiety-like behavior in oxycodone rats. Finally, because rats are single-housed during our incubation studies, we compared drug-naive rats after 8-9 weeks of single vs pair housing and found no difference in behavioral tests modeling negative affect. We conclude that the persistence of elevated cue-induced craving observed after a standard opioid incubation regimen is not accompanied by negative affective states, probably due to lower drug intake during the intravenous regimen compared to non-contingent escalating dose regimens typically used to study withdrawal signs. This does not negate the utility of the incubation model for studying cue-induced opioid craving and its neurobiological basis.","rel_num_authors":8,"rel_authors":[{"author_name":"Amanda M. Wunsch","author_inst":"National Center for Wellness & Recovery"},{"author_name":"Kimberley A. Mount","author_inst":"Division of Behavioral Health and Recovery, Washington State Health Care Authority"},{"author_name":"Asia Guzman","author_inst":"Oregon Health & Science University"},{"author_name":"Alex B. Kawa","author_inst":"University of New Mexico"},{"author_name":"Jonathan G. Westlake","author_inst":"Oregon Health & Science University"},{"author_name":"Hayley M. Kuhn","author_inst":"Oregon Health & Science University"},{"author_name":"Madelyn M. Beutler","author_inst":"Oregon Health & Science University"},{"author_name":"Marina E. Wolf","author_inst":"Oregon Health & Science University"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Comparison of Extraction Methods for the Quantification of Phytohormones from Tomato Fruits and Leaves by LC-MS\/MS","rel_doi":"10.64898\/2026.04.06.716604","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716604","rel_abs":"Accurate, simultaneous, and efficient quantification of chemically diverse phytohormone species is a critical task towards understanding the complex system of phytohormone signaling pathways. Quantification of phytohormones with the commonly used technique liquid chromatography coupled to tandem mass spectrometry is susceptible to the influence of non-phytohormone components present in the sample, a phenomenon referred to as matrix effect. To reduce matrix effect, some phytohormone quantification methods include additional steps of cleanup of crude extracts. However, to what extent additional purification steps provide increased accuracy compared to simpler, less laborious methods is seldomly evaluated. We evaluated three previously described phytohormone extraction methods, two of which include solid-phase extraction and one that does not, in their ability to minimize matrix effect and generate accurate estimates of phytohormone species spanning six classifications, from fruit and leaf tissue of Solanum lycopersicum cv. Micro-Tom (tomato). Our results show that, while the methods that included solid phase extraction occasionally outperformed each other regarding matrix effect and\/or recovery efficiency for broad range of phytohormones, they rarely outperformed the simpler single-phase extraction method.\n\nShort AbstractAccurate, simultaneous quantification of chemically diverse phytohormones by LC-MS\/MS is frequently confounded by matrix effects, leading to the incorporation of additional purification steps. We systematically compared three published extraction protocols with or without solid-phase extraction in tomato tissues across six hormone classes. Solid-phase methods occasionally improved matrix suppression or recovery, but did not consistently outperform the single-phase approach, questioning the added value of extra cleanup steps, particularly when high-throughput is desired, as in the case of systems biology interrogations.","rel_num_authors":4,"rel_authors":[{"author_name":"Carlos A Juarez Guzman","author_inst":"Colorado State University"},{"author_name":"Linxing Yao","author_inst":"Colorado State University"},{"author_name":"Corey D Broeckling","author_inst":"Colorado State University"},{"author_name":"Cristiana T Argueso","author_inst":"Colorado State University"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Early Epigenetic and Metabolic Responses to the Adipocyte Secretome Reveal Stress-Adaptive States in Triple-Negative Breast Cancer","rel_doi":"10.64898\/2026.04.06.716548","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716548","rel_abs":"Obesity is a well-established risk factor for triple-negative breast cancer (TNBC), yet how adipocyte-derived signals reprogram cancer cell metabolism and chromatin states remains poorly defined. Here, we investigate how adipocyte-driven lipogenesis reshapes metabolic-epigenetic coupling to support stress-adaptive cell states and functional changes in epithelial TNBC cells. Using an integrated multi-omic approach, we combine RNA sequencing (RNA-seq), chromatin accessibility (ATAC-seq), metabolic flux modeling, and functional metabolic assays in lipogenic BT-549 cells. Computational modeling trained on RNA-seq predicts shifts in metabolic pathway usage, including enhanced NAD-linked metabolism. RNA-seq reveals a predominance of gene activation, consistent with ATAC-seq data showing a strong bias toward increased accessibility. Regions of increased accessibility are enriched for stress-adaptive and antioxidant pathways, including superoxide dismutase 2 (SOD2) and metallothioneins (MT1F, MT1E, MT2A). Functionally, lipogenic cells exhibit increased spare respiratory capacity, altered ATP-linked respiration, elevated extracellular acidification, and reduced reactive oxygen species (ROS) accumulation, consistent with a bioenergetically flexible, stress-adaptive metabolic state. Together, these findings reveal that adipocyte-driven metabolic rewiring promotes selective chromatin opening and activation of stress-adaptive gene programs, enabling TNBC cells to buffer oxidative pressure for enhanced proliferation and survival after exposure to the adipocyte secretome.","rel_num_authors":9,"rel_authors":[{"author_name":"Ashley Townsel","author_inst":"Emory University"},{"author_name":"Maya Jaffe","author_inst":"Emory University"},{"author_name":"Shiyu He","author_inst":"Georgia Institute of Technology"},{"author_name":"Yifei Wu","author_inst":"Emory University"},{"author_name":"Asia Ingram","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Madison Tipton","author_inst":"The University of Colorado Anschutz Medical Campus"},{"author_name":"Melissa L. Kemp","author_inst":"Georgia Institute of Technology"},{"author_name":"Curtis J. Henry","author_inst":"The University of Colorado Anschutz Medical Campus"},{"author_name":"Karmella A. Haynes","author_inst":"Emory University"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Geometry-enhanced protein language modeling enables discovery of novel antibiotic resistance genes","rel_doi":"10.64898\/2026.04.05.716581","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.05.716581","rel_abs":"The global antibiotic resistome remains largely unexplored, not because antibiotic resistance genes (ARGs) are rare in the environment, but because many are evolutionarily distant from known ARGs. Current computational approaches primarily rely on sequence homology, and thus miss distant homologues. We develop GeoARG, a geometry-enhanced framework that integrates structural features with protein language models through knowledge distillation, enabling efficient large-scale screening using sequence input alone. Across multiple benchmarks, GeoARG substantially improves the detection of remotely homologous ARGs, particularly under low sequence identity and fragmented conditions. Large-scale metagenomic analysis uncovers 1,485 high-confidence ARG candidates that are highly divergent from known ARGs, expanding the phylogenetic and functional landscape of the resistome. Structural analyses further show that these candidates preserve active-site geometry and maintain stable ligand-binding configurations consistent with known resistance mechanisms. These results demonstrate that geometric constraints enable systematic expansion of the resistome and facilitate the discovery of evolutionarily distant yet functionally conserved genes. A public web server is available at https:\/\/ycclab.cuhk.edu.cn\/GeoARG\/.","rel_num_authors":20,"rel_authors":[{"author_name":"Xingqiao Lin","author_inst":"Xiamen University, Carnegie Mellon University"},{"author_name":"Jiahui Guan","author_inst":"The University of Hong Kong"},{"author_name":"Yue Hong","author_inst":"Xiamen University"},{"author_name":"Yilian Guo","author_inst":"The Chinese University of Hong Kong-Shenzhen"},{"author_name":"Yutao Yang","author_inst":"Xiamen University"},{"author_name":"Peilin Xie","author_inst":"The Chinese University of Hong Kong-Shenzhen"},{"author_name":"Zhihao Zhao","author_inst":"The Chinese University of Hong Kong-Shenzhen"},{"author_name":"Xingchen Liu","author_inst":"The Chinese University of Hong Kong-Shenzhen"},{"author_name":"Yixian Huang","author_inst":"Shenzhen University of Advanced Technology"},{"author_name":"Yujing Ye","author_inst":"Xiamen University"},{"author_name":"Yun Tang","author_inst":"National Yang Ming Chiao Tung University"},{"author_name":"Tzong-Yi Lee","author_inst":"National Yang Ming Chiao Tung University"},{"author_name":"Ying-Chih Chiang","author_inst":"The Chinese University of Hong Kong-Shenzhen"},{"author_name":"Leyi Wei","author_inst":"Macao Polytechnic University"},{"author_name":"Xiangrong Liu","author_inst":"Xiamen University"},{"author_name":"Junwen Wang","author_inst":"The University of Hong Kong"},{"author_name":"Yi Pan","author_inst":"Shenzhen University of Advanced Technology"},{"author_name":"Jijun Tang","author_inst":"Shenzhen University of Advanced Technology"},{"author_name":"Yao Pei","author_inst":"The University of Hong Kong"},{"author_name":"Lantian Yao","author_inst":"Xiamen University, Shenzhen University of Advanced Technology"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"Successful dendritic cell vaccines require lasting in-situ TNF \u03b1 secretion to license antitumor CD8 + T cell cytotoxicity","rel_doi":"10.64898\/2026.04.06.716539","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.06.716539","rel_abs":"Dendritic cells (DCs) are central to activating cytotoxic CD8 T cells, yet DC-based vaccines have achieved limited success against established tumors. To address this gap, we analyzed the transcriptomic and functional changes CD8 T cells undergo following interactions with DC subsets in lymphoid organs and tumor sites. This approach allowed us to map their trajectory from naive to fully cytotoxic effector cells. We found that classical DCs in lymphoid organs provide essential antigen presentation but fail to elicit cytotoxicity. Instead, antigenexperienced CD8 T cells require additional inflammatory signals, primarily through TNF, delivered at tumor sites by infiltrating myeloid DCs. Effective cytotoxic responses therefore depend on the synchronization of these distinct, temporally separated signals. Notably, tumor antigen-pulsed DC vaccines rapidly lose TNF expression after infiltrating tumors, limiting their efficacy. These findings establish a sequential model of T cell activation and suggest strategies to enhance the potency of DC-based immunotherapies.","rel_num_authors":21,"rel_authors":[{"author_name":"Aseel Radi Khateeb","author_inst":"Tel Aviv University"},{"author_name":"Nadine Santana Magal","author_inst":"Tel Aviv University"},{"author_name":"Kfir Inbal","author_inst":"Tel Aviv UNIVERSITY"},{"author_name":"Annette Gleiberman","author_inst":"Tel Aviv University"},{"author_name":"Ayelet Kaminitz","author_inst":"Tel Aviv University"},{"author_name":"Tomer Weiss","author_inst":"Tel Aviv University"},{"author_name":"Gal Verbin","author_inst":"Tel Aviv University"},{"author_name":"Alon Richter","author_inst":"Tel Aviv University"},{"author_name":"Amichai Zarfin","author_inst":"Tel Aviv University"},{"author_name":"Leen Farhat Younis","author_inst":"tel aviv university"},{"author_name":"Amit Gutwillig","author_inst":"tel aviv university"},{"author_name":"Adi Frish","author_inst":"tel aviv university"},{"author_name":"Eric Shifrut","author_inst":"tel aviv university"},{"author_name":"Inbal Reuveni Reuveni","author_inst":"tel aviv university"},{"author_name":"Adi Barzel","author_inst":"tel aviv university"},{"author_name":"Carmit Levi","author_inst":"tel aviv university"},{"author_name":"Peleg Rider","author_inst":"tel aviv university"},{"author_name":"Matthew H. Spitzer","author_inst":"University of California, San Francisco"},{"author_name":"Edgar G. Engleman","author_inst":"Center for Cancer Systems Biology"},{"author_name":"Asaf Madi","author_inst":"tel aviv university"},{"author_name":"Yaron Carmi","author_inst":"Tel-Aviv University"}],"rel_date":"2026-04-08","rel_site":"biorxiv"},{"rel_title":"An Empirical Assessment of Inferential Reproducibility of Linear Regression in Health and Biomedical Research Papers","rel_doi":"10.64898\/2026.04.07.26350296","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.07.26350296","rel_abs":"BackgroundIn health research, variability in modelling decisions can lead to different conclusions even when the same data are analysed, a challenge known as inferential reproducibility. In linear regression analyses, incorrect handling of key assumptions, such as normality of the residuals and linearity, can undermine reproducibility. This study examines how violations of these assumptions influence inferential conclusions when the same data are reanalysed.\n\nMethodsWe randomly sampled 95 health-related PLOS ONE papers from 2019 that reported linear regression in their methods. Data were available for 43 papers, and 20 were assessed for computational reproducibility, with three models per paper evaluated. The 14 papers that included a model at least partially computationally reproduced were then examined for inferential reproducibility. To assess the impact of assumption violations, differences in coefficients, 95% confidence intervals, and model fit were compared.\n\nResultsOf the fourteen papers assessed, only three were inferentially reproducible. The most frequently violated assumptions were normality and independence, each occurring in eight papers. Violations of independence were particularly consequential and were commonly associated with inferential failure. Although reproduced analyses often retained the same binary statistical significance classification as the original studies, confidence intervals were frequently wider, indicating greater uncertainty and reduced precision. Such uncertainty may affect the interpretation of results and, in turn, influence treatment decisions and clinical practice.\n\nConclusionOur findings demonstrate that substantial violations of key modelling assumptions often went undetected by authors and peer reviewers and, in many cases, were associated with inferential reproducibility failure. This highlights the need for stronger statistical education and greater transparency in modelling decisions. Rather than applying rigid or misinformed rules, such as incorrectly testing the normality of the outcome variable, researchers should adopt modelling frameworks guided by the research question and the study design. When assumptions are violated, appropriate alternatives, such as robust methods, bootstrapping, generalized linear models, or mixed-effects models, should be considered. Given that assumption violations were common even in relatively simple regression models, early and sustained collaboration with statisticians is critical for supporting robust, defensible, and clinically meaningful conclusions.","rel_num_authors":4,"rel_authors":[{"author_name":"Lee Jones","author_inst":"QUT: Queensland University of Technology"},{"author_name":"Adrian Barnett","author_inst":"QUT: Queensland University of Technology"},{"author_name":"Gunter Hartel","author_inst":"QIMR Berghofer"},{"author_name":"Dimitrios Vagenas","author_inst":"QUT: Queensland University of Technology"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"Care Models for the Genetic Evaluation of Dilated Cardiomyopathy at Sites of the DCM Consortium.","rel_doi":"10.64898\/2026.04.06.26350275","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.06.26350275","rel_abs":"BackgroundClinical genetic evaluation for patients with dilated cardiomyopathy (DCM) is minimally implemented and models of care are not defined. To understand current genetics care for DCM, a systematic needs assessment was conducted.\n\nMethodsPrincipal Investigators (PIs) of the DCM Consortium convened at the Summer Scientific Symposium in July 2025. An electronic needs assessment was collected from the 24 PIs in advance to define current care models by evaluating which Heart Failure Society of America-recommended genetic evaluation components are conducted, by whom, and time required. Descriptive statistics were generated to characterize model features. Focus group discussions explored barriers and facilitators to implementing genetic services.\n\nResultsFour care models emerged from the PI responses: 1 - Traditional-Synchronous (25%, n=6, requiring the most time per patient), 2 - Traditional-Asynchronous (33%, n=8), 3 - Externally Sourced (17%, n=4), and 4 - Physician\/Advanced Practice Provider Conducted (25%, n=6, requiring the least time per patient). All models used genetic testing, whereas other components were implemented variably or not at all. Models 1 (15.7{+\/-}4.1) and 2 (15.4{+\/-}3.0) were rated more acceptable than Model 4 (9.8{+\/-}2.9; 1 vs 4: p=0.027; 2 vs 4, p=0.023). Notably, 88% of PIs used genetic information for treatment decisions, including ICD placement (83%; n=20) or cardiac transplant (63%; n=15). Major facilitator themes from focus group discussions included having a genetic counselor on the HF team and developing authoritative standards directing provision of DCM genetic services. Barrier themes included operational challenges, limited personnel, clinician under-recognition, need for new service delivery models, and billing\/reimbursement.\n\nConclusionsDCM genetic care models and components were highly variable across the 24 sites of the DCM Consortium, even though all sites discussed similar factors that enable or hinder implementing genetic services for DCM. Understanding the basis of practice model variability may provide insight to yield more scalable care approaches.\n\nClinical PerspectiveWhat is new?\n\nO_LIFour care models to deliver genetic evaluation services for the assessment of dilated cardiomyopathy (DCM) were identified across the 24 sites of the DCM Consortium.\nC_LIO_LIDespite universal use of genetic testing and shared barriers and facilitators across sites, substantial variability exists across and within identified model types, and clinical genetic evaluation is not routinely implemented for all patients with DCM.\nC_LI\n\nWhat are the clinical implications?\n\nO_LIFor Heart Failure (HF) centers seeking to implement genetics services for DCM patients and families, the DCM Consortium describes the scaffolding of current care models implemented at HF centers across the US to inform local program development.\nC_LIO_LIThe incompletely and variably implemented care models highlight the need for a standardized, scalable framework to enhance consistent and equitable integration of clinical genetic evaluation into routine DCM care.\nC_LI","rel_num_authors":51,"rel_authors":[{"author_name":"Elizabeth Jordan","author_inst":"The Ohio State University Wexner Medical Center Department of Internal Medicine"},{"author_name":"Tia Moscarello","author_inst":"Stanford University"},{"author_name":"Hibatallah Khafagy","author_inst":"The Ohio State University Wexner Medical Center Department of Internal Medicine"},{"author_name":"Patricia K Parker","author_inst":"The Ohio State University Wexner Medical Center Department of Internal Medicine"},{"author_name":"Phoenix Grover","author_inst":"Duke University Medical Center"},{"author_name":"Simone Weinman","author_inst":"NYU Langone Health"},{"author_name":"Joseph Liu","author_inst":"Cleveland Clinic"},{"author_name":"Alberta Nomo","author_inst":"The Ohio State University Wexner Medical Center Department of Internal Medicine"},{"author_name":"Naomi Barker","author_inst":"Medical University of South Carolina"},{"author_name":"Emily Brown","author_inst":"Johns Hopkins University"},{"author_name":"Akos Berthold","author_inst":"Inova Schar Heart and Vascular"},{"author_name":"Jessica Chowns","author_inst":"Perelman School of Medicine at the University of Pennsylvania"},{"author_name":"Susan Christian","author_inst":"University of Alberta"},{"author_name":"Amy Ekwurtzel","author_inst":"Emory University"},{"author_name":"Judy Fan","author_inst":"University of California Los Angeles"},{"author_name":"Monisha Kisling","author_inst":"Genome Medical"},{"author_name":"Daria Ma","author_inst":"Cedars-Sinai Medical Center Smidt Heart Institute"},{"author_name":"Erin M Miller","author_inst":"Cincinnati Children's Hospital Medical Center"},{"author_name":"Jessica Sweeney","author_inst":"Medstar Heart and Vascular Institute\/Georgetown University"},{"author_name":"Brian Reyes","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Nancy Robles","author_inst":"Stanford"},{"author_name":"Lisa von Wald","author_inst":"University of Minnesota Medical School"},{"author_name":"Wendy Flowers","author_inst":"DCM Consortium"},{"author_name":"Gregory Hershberger","author_inst":"DCM Consortium"},{"author_name":"Krishna G Aragam","author_inst":"Massachusetts General Hospital"},{"author_name":"Michael A. Burke","author_inst":"Emory University Division of Cardiology"},{"author_name":"Jamie Diamond","author_inst":"Emory University Medical Center"},{"author_name":"Mark H. Drazner","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Gregory A Ewald","author_inst":"Washington University in St Louis"},{"author_name":"Stephen Gottlieb","author_inst":"University of Maryland Baltimore"},{"author_name":"Garrie Joseph Haas","author_inst":"Ohio State University College of Medicine"},{"author_name":"Mark R. Hofmeyer","author_inst":"MedStar Heart and Vascular Institute"},{"author_name":"Gordon S Huggins","author_inst":"Tufts Medical Center"},{"author_name":"Javier Jimenez","author_inst":"Miami Cardiac & Vascular Institute"},{"author_name":"Daniel Judge","author_inst":"Medical University of South Carolina"},{"author_name":"Stuart D. Katz","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Masataka Kawana","author_inst":"Stanford University"},{"author_name":"Evan Kransdorf","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Cindy M. Martin","author_inst":"Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital"},{"author_name":"Elena Minami","author_inst":"University of Washington"},{"author_name":"Anjali T. Owens","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Palak Shah","author_inst":"Inova Schar Heart and Vascular"},{"author_name":"Chetan Shenoy","author_inst":"University of Minnesota Medical School"},{"author_name":"Supriya Shore","author_inst":"University of Michigan Medical School"},{"author_name":"Frank Smart","author_inst":"LSU Health Sciences Center"},{"author_name":"Douglas Stoller","author_inst":"University of Nebraska Medical Center"},{"author_name":"Jose A Tallaj","author_inst":"The University of Alabama at Birmingham"},{"author_name":"W. H. Wilson Tang","author_inst":"Cleveland Clinic"},{"author_name":"Jessica Wang","author_inst":"UCLA Health Internal Medicine"},{"author_name":"Jane Wilcox","author_inst":"Northwestern University"},{"author_name":"Ray E Hershberger","author_inst":"Ohio State University College of Medicine"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"Care Models for the Genetic Evaluation of Dilated Cardiomyopathy at Sites of the DCM Consortium.","rel_doi":"10.64898\/2026.04.06.26350275","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.06.26350275","rel_abs":"BackgroundClinical genetic evaluation for patients with dilated cardiomyopathy (DCM) is minimally implemented and models of care are not defined. To understand current genetics care for DCM, a systematic needs assessment was conducted.\n\nMethodsPrincipal Investigators (PIs) of the DCM Consortium convened at the Summer Scientific Symposium in July 2025. An electronic needs assessment was collected from the 24 PIs in advance to define current care models by evaluating which Heart Failure Society of America-recommended genetic evaluation components are conducted, by whom, and time required. Descriptive statistics were generated to characterize model features. Focus group discussions explored barriers and facilitators to implementing genetic services.\n\nResultsFour care models emerged from the PI responses: 1 - Traditional-Synchronous (25%, n=6, requiring the most time per patient), 2 - Traditional-Asynchronous (33%, n=8), 3 - Externally Sourced (17%, n=4), and 4 - Physician\/Advanced Practice Provider Conducted (25%, n=6, requiring the least time per patient). All models used genetic testing, whereas other components were implemented variably or not at all. Models 1 (15.7{+\/-}4.1) and 2 (15.4{+\/-}3.0) were rated more acceptable than Model 4 (9.8{+\/-}2.9; 1 vs 4: p=0.027; 2 vs 4, p=0.023). Notably, 88% of PIs used genetic information for treatment decisions, including ICD placement (83%; n=20) or cardiac transplant (63%; n=15). Major facilitator themes from focus group discussions included having a genetic counselor on the HF team and developing authoritative standards directing provision of DCM genetic services. Barrier themes included operational challenges, limited personnel, clinician under-recognition, need for new service delivery models, and billing\/reimbursement.\n\nConclusionsDCM genetic care models and components were highly variable across the 24 sites of the DCM Consortium, even though all sites discussed similar factors that enable or hinder implementing genetic services for DCM. Understanding the basis of practice model variability may provide insight to yield more scalable care approaches.\n\nClinical PerspectiveWhat is new?\n\nO_LIFour care models to deliver genetic evaluation services for the assessment of dilated cardiomyopathy (DCM) were identified across the 24 sites of the DCM Consortium.\nC_LIO_LIDespite universal use of genetic testing and shared barriers and facilitators across sites, substantial variability exists across and within identified model types, and clinical genetic evaluation is not routinely implemented for all patients with DCM.\nC_LI\n\nWhat are the clinical implications?\n\nO_LIFor Heart Failure (HF) centers seeking to implement genetics services for DCM patients and families, the DCM Consortium describes the scaffolding of current care models implemented at HF centers across the US to inform local program development.\nC_LIO_LIThe incompletely and variably implemented care models highlight the need for a standardized, scalable framework to enhance consistent and equitable integration of clinical genetic evaluation into routine DCM care.\nC_LI","rel_num_authors":51,"rel_authors":[{"author_name":"Elizabeth Jordan","author_inst":"The Ohio State University Wexner Medical Center Department of Internal Medicine"},{"author_name":"Tia Moscarello","author_inst":"Stanford University"},{"author_name":"Hibatallah Khafagy","author_inst":"The Ohio State University Wexner Medical Center Department of Internal Medicine"},{"author_name":"Patricia K Parker","author_inst":"The Ohio State University Wexner Medical Center Department of Internal Medicine"},{"author_name":"Phoenix Grover","author_inst":"Duke University Medical Center"},{"author_name":"Simone Weinman","author_inst":"NYU Langone Health"},{"author_name":"Joseph Liu","author_inst":"Cleveland Clinic"},{"author_name":"Alberta Nomo","author_inst":"The Ohio State University Wexner Medical Center Department of Internal Medicine"},{"author_name":"Naomi Barker","author_inst":"Medical University of South Carolina"},{"author_name":"Emily Brown","author_inst":"Johns Hopkins University"},{"author_name":"Akos Berthold","author_inst":"Inova Schar Heart and Vascular"},{"author_name":"Jessica Chowns","author_inst":"Perelman School of Medicine at the University of Pennsylvania"},{"author_name":"Susan Christian","author_inst":"University of Alberta"},{"author_name":"Amy Ekwurtzel","author_inst":"Emory University"},{"author_name":"Judy Fan","author_inst":"University of California Los Angeles"},{"author_name":"Monisha Kisling","author_inst":"Genome Medical"},{"author_name":"Daria Ma","author_inst":"Cedars-Sinai Medical Center Smidt Heart Institute"},{"author_name":"Erin M Miller","author_inst":"Cincinnati Children's Hospital Medical Center"},{"author_name":"Jessica Sweeney","author_inst":"Medstar Heart and Vascular Institute\/Georgetown University"},{"author_name":"Brian Reyes","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Nancy Robles","author_inst":"Stanford"},{"author_name":"Lisa von Wald","author_inst":"University of Minnesota Medical School"},{"author_name":"Wendy Flowers","author_inst":"DCM Consortium"},{"author_name":"Gregory Hershberger","author_inst":"DCM Consortium"},{"author_name":"Krishna G Aragam","author_inst":"Massachusetts General Hospital"},{"author_name":"Michael A. Burke","author_inst":"Emory University Division of Cardiology"},{"author_name":"Jamie Diamond","author_inst":"Emory University Medical Center"},{"author_name":"Mark H. Drazner","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Gregory A Ewald","author_inst":"Washington University in St Louis"},{"author_name":"Stephen Gottlieb","author_inst":"University of Maryland Baltimore"},{"author_name":"Garrie Joseph Haas","author_inst":"Ohio State University College of Medicine"},{"author_name":"Mark R. Hofmeyer","author_inst":"MedStar Heart and Vascular Institute"},{"author_name":"Gordon S Huggins","author_inst":"Tufts Medical Center"},{"author_name":"Javier Jimenez","author_inst":"Miami Cardiac & Vascular Institute"},{"author_name":"Daniel Judge","author_inst":"Medical University of South Carolina"},{"author_name":"Stuart D. Katz","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Masataka Kawana","author_inst":"Stanford University"},{"author_name":"Evan Kransdorf","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Cindy M. Martin","author_inst":"Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital"},{"author_name":"Elena Minami","author_inst":"University of Washington"},{"author_name":"Anjali T. Owens","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Palak Shah","author_inst":"Inova Schar Heart and Vascular"},{"author_name":"Chetan Shenoy","author_inst":"University of Minnesota Medical School"},{"author_name":"Supriya Shore","author_inst":"University of Michigan Medical School"},{"author_name":"Frank Smart","author_inst":"LSU Health Sciences Center"},{"author_name":"Douglas Stoller","author_inst":"University of Nebraska Medical Center"},{"author_name":"Jose A Tallaj","author_inst":"The University of Alabama at Birmingham"},{"author_name":"W. H. Wilson Tang","author_inst":"Cleveland Clinic"},{"author_name":"Jessica Wang","author_inst":"UCLA Health Internal Medicine"},{"author_name":"Jane Wilcox","author_inst":"Northwestern University"},{"author_name":"Ray E Hershberger","author_inst":"Ohio State University College of Medicine"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"The effects on global health outcomes of switching from regular salt to potassium-enriched salt: a modelling study","rel_doi":"10.64898\/2026.04.06.26350270","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.06.26350270","rel_abs":"ObjectiveTo estimate the benefit and risk of replacing regular salt with potassium-enriched salt.\n\nDesignComparative risk assessment modelling.\n\nSettingWorldwide\n\nParticipantsAdult populations aged 25 and above.\n\nIntervention(1) worldwide replacement of all salt (discretionary salt used for seasoning or cooking in the home, and non-discretionary salt used in processed and restaurant foods); (2) worldwide replacement of just discretionary salt; (3) worldwide replacement of just non-discretionary salt; (4) replacement of discretionary salt just for people with diagnosed hypertension; and (5) replacement of discretionary salt just for people with treated hypertension.\n\nMain outcome measuresFor scenarios 1-3, we estimated benefits including deaths, new cases and disability-adjusted-life-years (DALYs) from cardiovascular disease and chronic kidney disease (CKD), from blood pressure-lowering as well as harms (CVD deaths) caused by hyperkalaemia among people with CKD stages G3-G5.\n\nResultsReplacement of all salt worldwide could prevent 2.96 (95% uncertainty interval 2.81-3.12) million deaths, 10.17 (9.59-10.70) million new cases of disease and 69.43 (65.61-72.92) million disability-adjusted life years (DALYs) each year. These figures represent 14.6%, 13.1% and 16.5% of the annual global disease burden attributable to CVD and CKD. Replacement of all discretionary salt (1.85, 1.74-1.97 million deaths) would have a greater impact on mortality than replacement of all non-discretionary salt (1.56, 1.46-1.67 million deaths). In people with CKD Stage G3-G5, there would be a net benefit - replacement of all salt would prevent 0.75 (0.71-0.80) million deaths but might cause 0.10 (0.09-0.11) million deaths from hyperkalaemia. Discretionary salt replacement only among diagnosed or treated hypertensives would prevent 0.59 (0.55-0.63) million and 0.48 (0.45-0.52) million deaths, respectively.\n\nConclusionSwitching regular salt to potassium-enriched salt appears to offer large potential for health gains under diverse scenarios, including for people with CKD.\n\nFundingThis work did not receive specific funding.\n\nWhat is already known on this topic- Excess dietary sodium and low dietary potassium intake both cause high blood pressure, which causes a significant burden of cardiovascular disease (CVD) and chronic kidney disease (CKD).\n- Efforts to cut dietary sodium intake as a strategy to control blood pressure have mostly been unsuccessful, with no country expected to meet the World Health Organisation (WHO) 2025 goal of reducing sodium intake by 30%.\n- Switching regular salt to potassium-enriched salt has shown clear protection against CVD and causes minimal change in taste and has low cost to scale up, but concerns remain about the potential of causing deaths due to hyperkalaemia among people with advanced chronic kidney disease.\n\n\nWhat this study adds- The study modelled five different possible approaches to the implementation of potassium-enriched salt that will suit a range of different circumstances, including countries with different levels of discretionary versus non-discretionary salt intake.\n- The study indicates switching to potassium-enriched salt can prevent very large numbers of CVD and CKD events worldwide, while the potential for causing harm in people with CKD is small in comparison.\n- There was also net benefit in analyses restricted to just people with CKD, where benefits of blood pressure lowering outweigh potential harms from hyperkalaemia.","rel_num_authors":11,"rel_authors":[{"author_name":"Liping Huang","author_inst":"The George Institute for Global Health"},{"author_name":"Xiaoyue Xu","author_inst":"School of Population Health, University of New South Wales, Sydney, NSW, Australia"},{"author_name":"Kunihiro Matsushita","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA"},{"author_name":"Tammy M Brady","author_inst":"Department of Paediatrics, Division of Nephrology, Johns Hopkins University School of Medicine and Dentistry, Baltimore, MD, USA"},{"author_name":"Lawrence J Appel","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA"},{"author_name":"Ewout J Hoorn","author_inst":"Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherl"},{"author_name":"Maoyi Tian","author_inst":"School of Public Health, Harbin Medical University, Harbin, Heilongjiang, China"},{"author_name":"Leopold N Aminde","author_inst":"Public Health & Economics Modelling Group, School of Medicine, Griffith University, Gold Coast, QLD, Australia"},{"author_name":"Kathy Trieu","author_inst":"The George Institute for Global Health, UNSW, Sydney, NSW, Australia"},{"author_name":"Bruce Neal","author_inst":"The George Institute for Global Health, UNSW, Sydney, NSW, Australia"},{"author_name":"Matti Marklund","author_inst":"Department of Paediatrics, Division of Nephrology, Johns Hopkins University School of Medicine and Dentistry, Baltimore, MD, USA"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"The effects on global health outcomes of switching from regular salt to potassium-enriched salt: a modelling study","rel_doi":"10.64898\/2026.04.06.26350270","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.06.26350270","rel_abs":"ObjectiveTo estimate the benefit and risk of replacing regular salt with potassium-enriched salt.\n\nDesignComparative risk assessment modelling.\n\nSettingWorldwide\n\nParticipantsAdult populations aged 25 and above.\n\nIntervention(1) worldwide replacement of all salt (discretionary salt used for seasoning or cooking in the home, and non-discretionary salt used in processed and restaurant foods); (2) worldwide replacement of just discretionary salt; (3) worldwide replacement of just non-discretionary salt; (4) replacement of discretionary salt just for people with diagnosed hypertension; and (5) replacement of discretionary salt just for people with treated hypertension.\n\nMain outcome measuresFor scenarios 1-3, we estimated benefits including deaths, new cases and disability-adjusted-life-years (DALYs) from cardiovascular disease and chronic kidney disease (CKD), from blood pressure-lowering as well as harms (CVD deaths) caused by hyperkalaemia among people with CKD stages G3-G5.\n\nResultsReplacement of all salt worldwide could prevent 2.96 (95% uncertainty interval 2.81-3.12) million deaths, 10.17 (9.59-10.70) million new cases of disease and 69.43 (65.61-72.92) million disability-adjusted life years (DALYs) each year. These figures represent 14.6%, 13.1% and 16.5% of the annual global disease burden attributable to CVD and CKD. Replacement of all discretionary salt (1.85, 1.74-1.97 million deaths) would have a greater impact on mortality than replacement of all non-discretionary salt (1.56, 1.46-1.67 million deaths). In people with CKD Stage G3-G5, there would be a net benefit - replacement of all salt would prevent 0.75 (0.71-0.80) million deaths but might cause 0.10 (0.09-0.11) million deaths from hyperkalaemia. Discretionary salt replacement only among diagnosed or treated hypertensives would prevent 0.59 (0.55-0.63) million and 0.48 (0.45-0.52) million deaths, respectively.\n\nConclusionSwitching regular salt to potassium-enriched salt appears to offer large potential for health gains under diverse scenarios, including for people with CKD.\n\nFundingThis work did not receive specific funding.\n\nWhat is already known on this topic- Excess dietary sodium and low dietary potassium intake both cause high blood pressure, which causes a significant burden of cardiovascular disease (CVD) and chronic kidney disease (CKD).\n- Efforts to cut dietary sodium intake as a strategy to control blood pressure have mostly been unsuccessful, with no country expected to meet the World Health Organisation (WHO) 2025 goal of reducing sodium intake by 30%.\n- Switching regular salt to potassium-enriched salt has shown clear protection against CVD and causes minimal change in taste and has low cost to scale up, but concerns remain about the potential of causing deaths due to hyperkalaemia among people with advanced chronic kidney disease.\n\n\nWhat this study adds- The study modelled five different possible approaches to the implementation of potassium-enriched salt that will suit a range of different circumstances, including countries with different levels of discretionary versus non-discretionary salt intake.\n- The study indicates switching to potassium-enriched salt can prevent very large numbers of CVD and CKD events worldwide, while the potential for causing harm in people with CKD is small in comparison.\n- There was also net benefit in analyses restricted to just people with CKD, where benefits of blood pressure lowering outweigh potential harms from hyperkalaemia.","rel_num_authors":11,"rel_authors":[{"author_name":"Liping Huang","author_inst":"The George Institute for Global Health"},{"author_name":"Xiaoyue Xu","author_inst":"School of Population Health, University of New South Wales, Sydney, NSW, Australia"},{"author_name":"Kunihiro Matsushita","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA"},{"author_name":"Tammy M Brady","author_inst":"Department of Paediatrics, Division of Nephrology, Johns Hopkins University School of Medicine and Dentistry, Baltimore, MD, USA"},{"author_name":"Lawrence J Appel","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA"},{"author_name":"Ewout J Hoorn","author_inst":"Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherl"},{"author_name":"Maoyi Tian","author_inst":"School of Public Health, Harbin Medical University, Harbin, Heilongjiang, China"},{"author_name":"Leopold N Aminde","author_inst":"Public Health & Economics Modelling Group, School of Medicine, Griffith University, Gold Coast, QLD, Australia"},{"author_name":"Kathy Trieu","author_inst":"The George Institute for Global Health, UNSW, Sydney, NSW, Australia"},{"author_name":"Bruce Neal","author_inst":"The George Institute for Global Health, UNSW, Sydney, NSW, Australia"},{"author_name":"Matti Marklund","author_inst":"Department of Paediatrics, Division of Nephrology, Johns Hopkins University School of Medicine and Dentistry, Baltimore, MD, USA"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"Challenges in the Computational Reproducibility of Linear Regression Analyses: An Empirical Study","rel_doi":"10.64898\/2026.04.07.26350286","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.07.26350286","rel_abs":"BackgroundReproducibility concerns in health research have grown, as many published results fail to be independently reproduced. Achieving computational reproducibility, where others can replicate the same results using the same methods, requires transparent reporting of statistical tests, models, and software use. While data-sharing initiatives have improved accessibility, the actual usability of shared data for reproducing research findings remains underexplored. Addressing this gap is crucial for advancing open science and ensuring that shared data meaningfully support reproducibility and enable collaboration, thereby strengthening evidence-based policy and practice.\n\nMethodsA random sample of 95 PLOS ONE health research papers from 2019 reporting linear regression was assessed for data-sharing practices and computational reproducibility. Data were accessible for 43 papers. From the randomly selected sample, the first 20 papers with available data were assessed for computational reproducibility. Three regression models per paper were reanalysed.\n\nResultsOf the 95 papers, 68 reported having data available, but 25 of these lacked the data required to reproduce the linear regression models. Only eight of 20 papers we analysed were computationally reproducible. A major barrier to reproducing the analyses was the great difficulty in matching the variables described in the paper to those in the data. Papers sometimes failed to be reproduced because the methods were not adequately described, including variable adjustments and data exclusions.\n\nConclusionMore than half (60%) of analysed studies were not computationally reproducible, raising concerns about the credibility of the reported results and highlighting the need for greater transparency and rigour in research reporting. When data are made available, authors should provide a corresponding data dictionary with variable labels that match those used in the paper. Analysis code, model specifications, and any supporting materials detailing the steps required to reproduce the results should be deposited in a publicly accessible repository or included as supplementary files. To increase the reproducibility of statistical results, we propose a Model Location and Specification Table (MLast), which tracks where and what analyses were performed. In conjunction with a data dictionary, MLast enables the mapping of analyses, greatly aiding computational reproducibility.","rel_num_authors":4,"rel_authors":[{"author_name":"Lee Vanessa Jones","author_inst":"QUT: Queensland University of Technology"},{"author_name":"Adrian Barnett","author_inst":"QUT: Queensland University of Technology"},{"author_name":"Gunter Hartel","author_inst":"QIMR Berghofer"},{"author_name":"Dimitrios Vagenas","author_inst":"QUT: Queensland University of Technology"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"Religious beliefs and practices, political orientation, and distrust in healthcare predict attitudes toward mRNA vaccines in the United States","rel_doi":"10.64898\/2026.04.06.26350267","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.06.26350267","rel_abs":"Religion has contributed to societal divides regarding COVID-19 mRNA vaccines. In this study, we conducted a secondary analysis of a survey of U.S. adults (N=4939) focused on how religious affiliations, beliefs, and practices impact attitudes toward genetic and genomic activities, one of which was mRNA vaccines. The dataset included large samples of participants from six religious groups in the U.S. (Black Protestant, Catholic, Evangelical Protestant, Jewish, Mainline Protestant, and Muslim), as well as individuals who were atheist, agnostic, or spiritual. ANCOVA results indicated that Evangelical Protestant participants showed significantly less support for mRNA vaccines than other groups, while atheist participants were the most supportive. Muslim participants had the highest concerns, whereas atheist participants had the lowest. Regression analyses indicated the strongest predictors of support for mRNA vaccines were more spiritual community support for community health, followed by higher acceptance of evolution, more liberal political orientation, less distrust toward the healthcare system, higher frequency of attending religious activities, higher income, lower fundamentalist religious beliefs, and more spiritual community support for liberal reproductive and end of life views. The strongest predictors of concerns about mRNA vaccines were more distrust toward the healthcare system and more conservative political orientation, followed by less spiritual community support for community health, stronger beliefs about God in the body, more fundamentalist religious beliefs, and lower knowledge of genetics. The large sample size, and examination of a broad array of religious variables alongside distrust and political orientation offer new insights. These findings add to the literature on the culture wars surrounding mRNA vaccines, and can perhaps aid in future efforts to build trust and relationships between public health and religious communities.","rel_num_authors":5,"rel_authors":[{"author_name":"Erin  D. Solomon","author_inst":"Washington University in St Louis School of Medicine"},{"author_name":"Eu Gene Chin","author_inst":"Biola University Rosemead School of Psychology"},{"author_name":"Kari Baldwin","author_inst":"Washington University in St Louis School of Medicine"},{"author_name":"Lauren  L Baker","author_inst":"Washington University in St Louis School of Medicine"},{"author_name":"James  M. DuBois","author_inst":"Washington University in Saint Louis School of Medicine"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"Multiplex Portuguese Families as a Lens into rare mutations and the Shared Genetic Architecture of Schizophrenia, Mood Disorders, and Autism Spectrum Disorders","rel_doi":"10.64898\/2026.04.06.26350177","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.06.26350177","rel_abs":"In an analysis of 173 multiplex families from the Portuguese Island Collection (PIC) this study characterizes the shared genetic architecture of serious mental illnesses (SMI) including schizophrenia (SZ), bipolar disorder (BP), major depression (MDD), and autism (ASD). Within this cohort, co-segregation of psychotic and mood disorders occurred in 28% of families, while 7% demonstrated co-segregation of intellectual disability or ASD with SZ and mood disorder phenotypes. Whole-genome sequencing (WGS) was performed on a three-generation PIC family to identify rare, large-effect variants. This led to the identification of an extremely rare predicted loss of function (LoF) mutation in the Chromodomain Helicase DNA Binding Protein 2 (CHD2) gene. These results demonstrate that high-density multiplex families in founder populations are a powerful resource for mapping rare, large-effect variants that cross clinical diagnostic boundaries, as the identified CHD2 mutation suggests that the disruption of a single neurodevelopmental gene may lead to diverse SMI phenotypes. By combining population and family-based methodologies, this approach leverages shared genetic backgrounds and environments to provide a unique opportunity for cellular studies to explore the biological mechanisms underlying SMI, offering significant potential to inform future functional research and identify novel therapeutic targets.","rel_num_authors":19,"rel_authors":[{"author_name":"Carlos N Pato","author_inst":"Rutgers University"},{"author_name":"Michele T Pato","author_inst":"Rutgers University"},{"author_name":"Jennifer Mulle","author_inst":"Rutgers University"},{"author_name":"Ronald P Hart","author_inst":"Rutgers University"},{"author_name":"Zhiping Pang","author_inst":"Rutgers University"},{"author_name":"James A Knowles","author_inst":"Rutgers University"},{"author_name":"Tarjinder Singh","author_inst":"Columbia University, NY Genome Center"},{"author_name":"Priya Maddhesiya","author_inst":"New York Genome Center"},{"author_name":"Celia Carvalho","author_inst":"Faculty of Social and Human Sciences, University of Azores"},{"author_name":"Alison Merikangas","author_inst":"Rutgers University"},{"author_name":"Helena Medeiros","author_inst":"Rutgers University"},{"author_name":"Tim B Bigdeli","author_inst":"SUNY Downstate"},{"author_name":"Hamed Kazemi","author_inst":"Department of Psychiatry, University of Arizona College of Medicine-Phoenix"},{"author_name":"John Drake","author_inst":"Department of Psychiatry, University of Arizona College of Medicine-Phoenix"},{"author_name":"Vladmir Vladimrov","author_inst":"Department of Psychiatry, University of Arizona College of Medicine-Phoenix"},{"author_name":"Brion Maher","author_inst":"Department of Mental Health, Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Silviu-Alin Bacanu","author_inst":"Department of Psychiatry, Virginia Commonwealth University"},{"author_name":"Benjamin Neale","author_inst":"Broad Institute"},{"author_name":"Ayman Fanous","author_inst":"Department of Psychiatry, University of Arizona College of Medicine-Phoenix"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"Multiplex Portuguese Families as a Lens into rare mutations and the Shared Genetic Architecture of Schizophrenia, Mood Disorders, and Autism Spectrum Disorders","rel_doi":"10.64898\/2026.04.06.26350177","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.06.26350177","rel_abs":"In an analysis of 173 multiplex families from the Portuguese Island Collection (PIC) this study characterizes the shared genetic architecture of serious mental illnesses (SMI) including schizophrenia (SZ), bipolar disorder (BP), major depression (MDD), and autism (ASD). Within this cohort, co-segregation of psychotic and mood disorders occurred in 28% of families, while 7% demonstrated co-segregation of intellectual disability or ASD with SZ and mood disorder phenotypes. Whole-genome sequencing (WGS) was performed on a three-generation PIC family to identify rare, large-effect variants. This led to the identification of an extremely rare predicted loss of function (LoF) mutation in the Chromodomain Helicase DNA Binding Protein 2 (CHD2) gene. These results demonstrate that high-density multiplex families in founder populations are a powerful resource for mapping rare, large-effect variants that cross clinical diagnostic boundaries, as the identified CHD2 mutation suggests that the disruption of a single neurodevelopmental gene may lead to diverse SMI phenotypes. By combining population and family-based methodologies, this approach leverages shared genetic backgrounds and environments to provide a unique opportunity for cellular studies to explore the biological mechanisms underlying SMI, offering significant potential to inform future functional research and identify novel therapeutic targets.","rel_num_authors":19,"rel_authors":[{"author_name":"Carlos N Pato","author_inst":"Rutgers University"},{"author_name":"Michele T Pato","author_inst":"Rutgers University"},{"author_name":"Jennifer Mulle","author_inst":"Rutgers University"},{"author_name":"Ronald P Hart","author_inst":"Rutgers University"},{"author_name":"Zhiping Pang","author_inst":"Rutgers University"},{"author_name":"James A Knowles","author_inst":"Rutgers University"},{"author_name":"Tarjinder Singh","author_inst":"Columbia University, NY Genome Center"},{"author_name":"Priya Maddhesiya","author_inst":"New York Genome Center"},{"author_name":"Celia Carvalho","author_inst":"Faculty of Social and Human Sciences, University of Azores"},{"author_name":"Alison Merikangas","author_inst":"Rutgers University"},{"author_name":"Helena Medeiros","author_inst":"Rutgers University"},{"author_name":"Tim B Bigdeli","author_inst":"SUNY Downstate"},{"author_name":"Hamed Kazemi","author_inst":"Department of Psychiatry, University of Arizona College of Medicine-Phoenix"},{"author_name":"John Drake","author_inst":"Department of Psychiatry, University of Arizona College of Medicine-Phoenix"},{"author_name":"Vladmir Vladimrov","author_inst":"Department of Psychiatry, University of Arizona College of Medicine-Phoenix"},{"author_name":"Brion Maher","author_inst":"Department of Mental Health, Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Silviu-Alin Bacanu","author_inst":"Department of Psychiatry, Virginia Commonwealth University"},{"author_name":"Benjamin Neale","author_inst":"Broad Institute"},{"author_name":"Ayman Fanous","author_inst":"Department of Psychiatry, University of Arizona College of Medicine-Phoenix"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"Connectomics-guided meta-learning for decoding and anticipatory prediction of sleep spindles from basal ganglia local field potentials in Parkinson's disease","rel_doi":"10.64898\/2026.04.01.26349783","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349783","rel_abs":"Sleep disturbances are pervasive, debilitating non-motor symptoms of Parkinsons disease (PD), where sleep spindle deficits directly drive cognitive decline and disease progression. Current adaptive deep brain stimulation (aDBS) for PD is largely limited to motor symptom management, with no established technical foundation for sleep spindle-targeted closed-loop modulation. The functional role of the basal ganglia in human sleep spindle regulation remains incompletely characterized, and no robust cross-subject pipeline exists to decode these transient events from clinically implanted DBS electrodes. Here, we developed a connectomics-guided meta-learning framework for cross-subject sleep spindle decoding and anticipatory prediction, using whole-night synchronized basal ganglia local field potential and polysomnography data from 17 PD patients with bilateral DBS implants. Our framework achieved 92.63% accuracy for concurrent spindle decoding and 83.44% accuracy for 2-second-ahead prediction, with optimal signals localized to the limbic subthalamic nucleus and <50 ms total latency meeting real-time closed-loop requirements. This work defines the neuroanatomical substrate of basal ganglia spindle signaling in PD, establishes the cross-subject spindle decoding pipeline for clinical DBS systems, and provides a critical translational foundation for sleep-targeted closed-loop aDBS to mitigate PD non-motor burden.","rel_num_authors":8,"rel_authors":[{"author_name":"Chenfei Ye","author_inst":"Harbin Institute of Technology (Shenzhen)"},{"author_name":"Jiahui Liao","author_inst":"Harbin Institute of Technology (Shenzhen)"},{"author_name":"Zixiao Yin","author_inst":"Beijing Tiantan Hospital, Capital Medical University"},{"author_name":"Yue Li","author_inst":"Harbin Institute of Technology (Shenzhen)"},{"author_name":"Yichen Xu","author_inst":"Beijing Tiantan Hospital, Capital Medical University"},{"author_name":"Houyou Fan","author_inst":"Beijing Tiantan Hospital, Capital Medical University"},{"author_name":"Ting Ma","author_inst":"Harbin Institute of Technology (Shenzhen)"},{"author_name":"Jianguo Zhang","author_inst":"Beijing Tiantan Hospital, Capital Medical University"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"Disrupted Coupling of Heart Rate Dependent Brain Network Switching and Attentional Task Performance in Schizophrenia Spectrum Disorders","rel_doi":"10.64898\/2026.04.06.26350241","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.06.26350241","rel_abs":"Cognitive deficits are a core feature of schizophrenia, yet their neural mechanisms remain poorly understood. Network switching--a measure of how frequently brain networks change their interactions over time--has been linked to cognitive performance in healthy individuals and has been reported to be altered in schizophrenia. Recent evidence further suggests that the relationship between network switching and cognition depends on arousal, which is itself disrupted in schizophrenia. However, whether arousal-related alterations in network switching contribute to cognitive impairment in schizophrenia remains unclear. Here, we used concurrent resting-state functional MRI (fMRI) and pulse oximetry data from 39 healthy controls (HC), 27 psychiatric controls (PC), and 39 individuals with schizophrenia spectrum disorders (SSD) to examine whether network switching relates to indices of autonomic arousal. Additionally, in HC and SSD participants, we tested whether arousal moderated the association between network switching and performance on an attention task. We observed no group differences in autonomic arousal. However, PC exhibited higher dorsal default mode and anterior salience network switching rates compared to SSD participants. Additionally, autonomic arousal significantly moderated the relationship between network switching and cognitive performance in HC, an effect that was absent in SSD. Notably, these findings implicate network switching as a potential neural biomarker that differentiates PC from SSD. They also suggest that disrupted coupling between arousal state and network switching, rather than switching alone, may underlie cognitive dysfunction in SSD.","rel_num_authors":10,"rel_authors":[{"author_name":"Kimberly Kundert-Obando","author_inst":"Vanderbilt"},{"author_name":"Andrew Kittleson","author_inst":"Vanderbilt University"},{"author_name":"Shiyu Wang","author_inst":"Vanderbilt University"},{"author_name":"Haatef Pourmotabbed","author_inst":"Vanderbilt University"},{"author_name":"Ella Provancher","author_inst":"Vanderbilt University"},{"author_name":"Anna Machado","author_inst":"Vanderbilt University"},{"author_name":"Sohee Park","author_inst":"Vanderbilt University"},{"author_name":"Julia M Sheffield","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Heather Burrell Ward","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Catie Chang","author_inst":"Vanderbilt University"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"Association Between Hospital Tiers and Cardiogenic Shock Mortality: Mitigating the Transfer Penalty Through a Regionalized Hub-and-Spoke Model","rel_doi":"10.64898\/2026.04.05.26350211","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.05.26350211","rel_abs":"BackgroundCardiogenic shock (CS) remains associated with high short-term mortality despite contemporary advances in care. The association between institutional cardiac capability and outcomes--particularly among transferred patients and after accounting for clinical instability--remains incompletely defined.\n\nObjectivesTo evaluate the association between hierarchical hospital cardiac capability and in-hospital mortality using a latent measure of acute physiologic severity.\n\nMethodsUsing the National Inpatient Sample (2016-2022), hospitals were classified into five hierarchical tiers ranging from non-PCI (Tier 1) to heart transplant\/durable LVAD centers (Tier 5). Generalized structural equation modeling (GSEM) assessed the relationship between hospital tier and mortality. A latent \"Acute Severity\" construct--comprising cardiac arrest, acute kidney and liver injury, and mechanical ventilation--was incorporated to model the effects of clinical instability\n\nResultsAmong an estimated 1,177,180 CS hospitalizations, most occurred at cardiac surgical and transplant\/LVAD centers. Crude mortality declined stepwise from non-PCI hospitals (64.5%) to transplant\/LVAD centers (36.5%). After adjustment, higher hospital tier was independently associated with lower mortality (Tier 2 OR 0.43 [95% CI 0.38-0.48]; Tier 3 OR 0.37 [0.32- 0.43]; Tier 4 OR 0.33 [0.30-0.38]; Tier 5 OR 0.35 [0.31-0.40]). Although transfer-in status was associated with increased mortality (OR 1.39 [1.33-1.46]), this association was attenuated at cardiac surgical and transplant\/LVAD centers, consistent with a mitigation of transfer associated risk.\n\nConclusionsHigher hospital cardiac capability is independently associated with lower mortality in CS. Advanced centers are associated with mitigation transfer-associated risk, supporting regionalized hub-and-spoke systems with early referral to high-capability centers.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC=\"FIGDIR\/small\/26350211v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (51K):\norg.highwire.dtl.DTLVardef@1b909d6org.highwire.dtl.DTLVardef@134de35org.highwire.dtl.DTLVardef@1e87ba1org.highwire.dtl.DTLVardef@cba45_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":8,"rel_authors":[{"author_name":"Ankur Sethi","author_inst":"Robert Wood Johnson University Hospital"},{"author_name":"Emily Hiltner","author_inst":"Robert Wood Johnson University Hospital"},{"author_name":"ashish awasthi","author_inst":"Robert Wood Johnson University Hospital"},{"author_name":"Casey Panebianco","author_inst":"Robert Wood Johnson University Hospital"},{"author_name":"Tana LaPlaca","author_inst":"Robert Wood Johnson Medical School"},{"author_name":"Nancy Rizzuto","author_inst":"Robert Wood Johnson University Hospital"},{"author_name":"Leonard Lee","author_inst":"Rutgers Robert Wood University Hospital"},{"author_name":"Mark Russo","author_inst":"Rutgers Health"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"Causal Machine Learning for Comparative Effectiveness of GLP-1 RA versus SGLT2i in Heart Failure Using Real-World EHR Data","rel_doi":"10.64898\/2026.04.06.26350259","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.06.26350259","rel_abs":"Clinicians lack precision medicine tools to estimate individualized treatment effects for patients with heart failure (HF). Causal machine learning leveraging electronic health records can estimate both average and individualized treatment effects, enabling estimation of treatment heterogeneity. Using Stony Brook University Hospital data, we compared the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RA) versus sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with HF. Under a doubly robust framework, we found a stable population-average effect: GLP-1 RA was associated with a lower risk than SGLT2i for a 1-year composite outcome of all-cause mortality or HF-related hospitalization. Heterogeneity analyses provided limited evidence for individualized treatment selection, although subgroup tests identified loop diuretic use, body mass index, and estimated glomerular filtration rate as potential effect modifiers. While these models hold promise for translating observational data into actionable precision care, careful assessment of causal assumptions and rigorous validation are essential before clinical implementation.","rel_num_authors":5,"rel_authors":[{"author_name":"Grace Y Han","author_inst":"Renaissance School of Medicine at Stony Brook University"},{"author_name":"Andreas P Kalogeropoulos","author_inst":"Renaissance School of Medicine at Stony Brook University"},{"author_name":"Zach Butzin-Dozier","author_inst":"University of California, Berkeley"},{"author_name":"Rachel Wong","author_inst":"Renaissance School of Medicine at Stony Brook University"},{"author_name":"Fusheng Wang","author_inst":"Stony Brook University"}],"rel_date":"2026-04-07","rel_site":"medrxiv"},{"rel_title":"Biologically informed geometry and force distribution improve task performance in agonist\/antagonist tendon-driven prosthetic hands","rel_doi":"10.64898\/2026.04.06.26350199","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.06.26350199","rel_abs":"Prosthetic devices balance functionality and usability to support activities of daily living (ADLs). However, many designs rely on rigid end effectors that, while anthropomorphic in form, lack biomimetic design principles. This mismatch increases cognitive and physical burden, reducing adoption rates. We developed the Human-inspired Actuator Modeling and Reconstruction (HAMR) process, a user-centered framework informed by individual morphology and functional needs, to generate customized agonist\/antagonist tendon-actuated end effectors. Using HAMR, we created the Tendon Actuated Prosthetic Hand (TAPH), which integrates human-derived geometry with adaptive force distribution to promote natural object interaction. In a study with 12 participants without limb difference, TAPH was compared to a structurally similar tendon-actuated hand with generalized anthropomorphic geometry across three ADL tasks of varying complexity. TAPH significantly improved task performance and reduced physical effort, mental workload, and frustration, particularly during gross motor tasks. For fine motor tasks, performance improved under stable conditions but not during tasks requiring dynamic precision and continuous coordination. These findings highlight the functional benefits of biologically informed prosthesis design and support biomimetic principles in enhancing performance and user experience.","rel_num_authors":2,"rel_authors":[{"author_name":"Lorena Isabel Velasquez","author_inst":"Johns Hopkins University"},{"author_name":"Jeremy Delaine Brown","author_inst":"Johns Hopkins University"}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"MyGeneRisk Colon: A Web-Based Tool for Personalized Colorectal Cancer Risk Prediction Based on Genetics and Lifestyle","rel_doi":"10.64898\/2026.04.03.26349669","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26349669","rel_abs":"Colorectal cancer (CRC) is a leading cause of cancer-related death, with incidence rising substantially among individuals under 50 years of age. Polygenic risk scores (PRS) hold promise for identifying high-risk individuals; when combined with lifestyle factors, they substantially improve prediction accuracy compared with models based on lifestyle factors alone. However, few clinical tools currently exist that facilitate this integrated, PRS-enhanced risk assessment. To bridge this gap, we developed MyGeneRisk Colon, a publicly accessible web portal that delivers individualized CRC risk prediction by incorporating genetic, demographic, family history, and lifestyle factors. This paper details the development of the underlying risk prediction model, the portals architecture and data security, our reporting framework, and engagement with a community advisory panel. Designed as a user-friendly platform, MyGeneRisk Colon aims to effectively communicate personalized CRC risk profiles and educate users and healthcare providers about prevention strategies.","rel_num_authors":44,"rel_authors":[{"author_name":"Jiayin Zheng","author_inst":"Department of Biostatistics, Epidemiology, and Informatics at the University of Pennsylvania Perelman School of Medicine"},{"author_name":"Robert S Steinfelder","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Hang Yin","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Conghui Qu","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Minta Thomas","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Sushma S Thomas","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Cynthia Andrews","author_inst":"North Sound Accountable Communities of Health, Bellingham Washington, USA"},{"author_name":"Bianca Augusto","author_inst":"Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida, USA."},{"author_name":"Douglas C Corley","author_inst":"Division of Research, Kaiser Permanente Northern California, Oakland, California, USA."},{"author_name":"Jeffrey K Lee","author_inst":"Department of Gastroenterology, Kaiser Permanente San Francisco Medical Center, San Francisco, California, USA."},{"author_name":"Sonja I Berndt","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."},{"author_name":"Andrew T Chan","author_inst":"Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA."},{"author_name":"Stephen J Chanock","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."},{"author_name":"Chris Gignoux","author_inst":"Colorado Center for Personalized Medicine, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, USA."},{"author_name":"Shauna R Goldberg","author_inst":"Kaiser Permanente Colorado Institute for Health Research, Aurora, Colorado, USA."},{"author_name":"Christopher A Haiman","author_inst":"Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, C"},{"author_name":"Jeroen R Huyghe","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Motoki Iwasaki","author_inst":"Division of Epidemiology, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan."},{"author_name":"Loic Le Marchand","author_inst":"Population Sciences in the Pacific Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA."},{"author_name":"Soo Chin Lee","author_inst":"National University Cancer Institute, Singapore, Singapore"},{"author_name":"Johana Melendez","author_inst":"Hillsborough College, Plant City, Fl. USA"},{"author_name":"Ivan Mesa","author_inst":"Hillsborough College, Tampa, FL, USA"},{"author_name":"Shuji Ogino","author_inst":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA."},{"author_name":"Viviam Sifontes","author_inst":"Moffitt Cancer Center, Tampa, FL, USA"},{"author_name":"Caroline Y Um","author_inst":"Department of Population Science, American Cancer Society, Atlanta, Georgia."},{"author_name":"Kala Visvanathan","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA and Department of Oncology, Johns Hopkins Kimmel Cancer Ce"},{"author_name":"Larissa L White","author_inst":"Institute for Health Research, Kaiser Permanente Colorado, Aurora, Colorado, USA."},{"author_name":"Andrea Williams","author_inst":"Southside Coalition of Community Health Centers"},{"author_name":"Waverly Willis","author_inst":"Independent researcher"},{"author_name":"Alicja Wolk","author_inst":"Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden."},{"author_name":"Taiki Yamaji","author_inst":"Division of Epidemiology, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan."},{"author_name":"Susan T Vadaparampil","author_inst":"Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida, USA."},{"author_name":"Gail P Jarvik","author_inst":"Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, Washington, USA."},{"author_name":"Andrea N Burnett-Hartman","author_inst":"Institute for Health Research, Kaiser Permanente Colorado, Denver, Colorado, USA."},{"author_name":"Roger L Milne","author_inst":"Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia."},{"author_name":"Elizabeth A Platz","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA."},{"author_name":"Jane C Figueiredo","author_inst":"Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA."},{"author_name":"Wei Zheng","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nas"},{"author_name":"Robert J MacInnis","author_inst":"Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia."},{"author_name":"Julie R Palmer","author_inst":"Slone Epidemiology Center at Boston University, Boston Massachusetts"},{"author_name":"Stephanie L Schmit","author_inst":"Genomic Sciences and Systems Biology, Cleveland Clinic, Cleveland, Ohio, USA."},{"author_name":"Iris Landorp-Vogelaar","author_inst":"Department of Public Health, Erasmus MC, University Medical Center, Rotterdam, The Netherlands."},{"author_name":"Ulrike Peters","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Li Hsu","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"MyGeneRisk Colon: A Web-Based Tool for Personalized Colorectal Cancer Risk Prediction Based on Genetics and Lifestyle","rel_doi":"10.64898\/2026.04.03.26349669","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26349669","rel_abs":"Colorectal cancer (CRC) is a leading cause of cancer-related death, with incidence rising substantially among individuals under 50 years of age. Polygenic risk scores (PRS) hold promise for identifying high-risk individuals; when combined with lifestyle factors, they substantially improve prediction accuracy compared with models based on lifestyle factors alone. However, few clinical tools currently exist that facilitate this integrated, PRS-enhanced risk assessment. To bridge this gap, we developed MyGeneRisk Colon, a publicly accessible web portal that delivers individualized CRC risk prediction by incorporating genetic, demographic, family history, and lifestyle factors. This paper details the development of the underlying risk prediction model, the portals architecture and data security, our reporting framework, and engagement with a community advisory panel. Designed as a user-friendly platform, MyGeneRisk Colon aims to effectively communicate personalized CRC risk profiles and educate users and healthcare providers about prevention strategies.","rel_num_authors":44,"rel_authors":[{"author_name":"Jiayin Zheng","author_inst":"Department of Biostatistics, Epidemiology, and Informatics at the University of Pennsylvania Perelman School of Medicine"},{"author_name":"Robert S Steinfelder","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Hang Yin","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Conghui Qu","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Minta Thomas","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Sushma S Thomas","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Cynthia Andrews","author_inst":"North Sound Accountable Communities of Health, Bellingham Washington, USA"},{"author_name":"Bianca Augusto","author_inst":"Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida, USA."},{"author_name":"Douglas C Corley","author_inst":"Division of Research, Kaiser Permanente Northern California, Oakland, California, USA."},{"author_name":"Jeffrey K Lee","author_inst":"Department of Gastroenterology, Kaiser Permanente San Francisco Medical Center, San Francisco, California, USA."},{"author_name":"Sonja I Berndt","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."},{"author_name":"Andrew T Chan","author_inst":"Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA."},{"author_name":"Stephen J Chanock","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."},{"author_name":"Chris Gignoux","author_inst":"Colorado Center for Personalized Medicine, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, USA."},{"author_name":"Shauna R Goldberg","author_inst":"Kaiser Permanente Colorado Institute for Health Research, Aurora, Colorado, USA."},{"author_name":"Christopher A Haiman","author_inst":"Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, C"},{"author_name":"Jeroen R Huyghe","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Motoki Iwasaki","author_inst":"Division of Epidemiology, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan."},{"author_name":"Loic Le Marchand","author_inst":"Population Sciences in the Pacific Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA."},{"author_name":"Soo Chin Lee","author_inst":"National University Cancer Institute, Singapore, Singapore"},{"author_name":"Johana Melendez","author_inst":"Hillsborough College, Plant City, Fl. USA"},{"author_name":"Ivan Mesa","author_inst":"Hillsborough College, Tampa, FL, USA"},{"author_name":"Shuji Ogino","author_inst":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA."},{"author_name":"Viviam Sifontes","author_inst":"Moffitt Cancer Center, Tampa, FL, USA"},{"author_name":"Caroline Y Um","author_inst":"Department of Population Science, American Cancer Society, Atlanta, Georgia."},{"author_name":"Kala Visvanathan","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA and Department of Oncology, Johns Hopkins Kimmel Cancer Ce"},{"author_name":"Larissa L White","author_inst":"Institute for Health Research, Kaiser Permanente Colorado, Aurora, Colorado, USA."},{"author_name":"Andrea Williams","author_inst":"Southside Coalition of Community Health Centers"},{"author_name":"Waverly Willis","author_inst":"Independent researcher"},{"author_name":"Alicja Wolk","author_inst":"Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden."},{"author_name":"Taiki Yamaji","author_inst":"Division of Epidemiology, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan."},{"author_name":"Susan T Vadaparampil","author_inst":"Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida, USA."},{"author_name":"Gail P Jarvik","author_inst":"Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, Washington, USA."},{"author_name":"Andrea N Burnett-Hartman","author_inst":"Institute for Health Research, Kaiser Permanente Colorado, Denver, Colorado, USA."},{"author_name":"Roger L Milne","author_inst":"Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia."},{"author_name":"Elizabeth A Platz","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA."},{"author_name":"Jane C Figueiredo","author_inst":"Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA."},{"author_name":"Wei Zheng","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nas"},{"author_name":"Robert J MacInnis","author_inst":"Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia."},{"author_name":"Julie R Palmer","author_inst":"Slone Epidemiology Center at Boston University, Boston Massachusetts"},{"author_name":"Stephanie L Schmit","author_inst":"Genomic Sciences and Systems Biology, Cleveland Clinic, Cleveland, Ohio, USA."},{"author_name":"Iris Landorp-Vogelaar","author_inst":"Department of Public Health, Erasmus MC, University Medical Center, Rotterdam, The Netherlands."},{"author_name":"Ulrike Peters","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Li Hsu","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"MyGeneRisk Colon: A Web-Based Tool for Personalized Colorectal Cancer Risk Prediction Based on Genetics and Lifestyle","rel_doi":"10.64898\/2026.04.03.26349669","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26349669","rel_abs":"Colorectal cancer (CRC) is a leading cause of cancer-related death, with incidence rising substantially among individuals under 50 years of age. Polygenic risk scores (PRS) hold promise for identifying high-risk individuals; when combined with lifestyle factors, they substantially improve prediction accuracy compared with models based on lifestyle factors alone. However, few clinical tools currently exist that facilitate this integrated, PRS-enhanced risk assessment. To bridge this gap, we developed MyGeneRisk Colon, a publicly accessible web portal that delivers individualized CRC risk prediction by incorporating genetic, demographic, family history, and lifestyle factors. This paper details the development of the underlying risk prediction model, the portals architecture and data security, our reporting framework, and engagement with a community advisory panel. Designed as a user-friendly platform, MyGeneRisk Colon aims to effectively communicate personalized CRC risk profiles and educate users and healthcare providers about prevention strategies.","rel_num_authors":44,"rel_authors":[{"author_name":"Jiayin Zheng","author_inst":"Department of Biostatistics, Epidemiology, and Informatics at the University of Pennsylvania Perelman School of Medicine"},{"author_name":"Robert S Steinfelder","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Hang Yin","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Conghui Qu","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Minta Thomas","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Sushma S Thomas","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Cynthia Andrews","author_inst":"North Sound Accountable Communities of Health, Bellingham Washington, USA"},{"author_name":"Bianca Augusto","author_inst":"Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida, USA."},{"author_name":"Douglas C Corley","author_inst":"Division of Research, Kaiser Permanente Northern California, Oakland, California, USA."},{"author_name":"Jeffrey K Lee","author_inst":"Department of Gastroenterology, Kaiser Permanente San Francisco Medical Center, San Francisco, California, USA."},{"author_name":"Sonja I Berndt","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."},{"author_name":"Andrew T Chan","author_inst":"Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA."},{"author_name":"Stephen J Chanock","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."},{"author_name":"Chris Gignoux","author_inst":"Colorado Center for Personalized Medicine, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, USA."},{"author_name":"Shauna R Goldberg","author_inst":"Kaiser Permanente Colorado Institute for Health Research, Aurora, Colorado, USA."},{"author_name":"Christopher A Haiman","author_inst":"Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, C"},{"author_name":"Jeroen R Huyghe","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Motoki Iwasaki","author_inst":"Division of Epidemiology, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan."},{"author_name":"Loic Le Marchand","author_inst":"Population Sciences in the Pacific Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA."},{"author_name":"Soo Chin Lee","author_inst":"National University Cancer Institute, Singapore, Singapore"},{"author_name":"Johana Melendez","author_inst":"Hillsborough College, Plant City, Fl. USA"},{"author_name":"Ivan Mesa","author_inst":"Hillsborough College, Tampa, FL, USA"},{"author_name":"Shuji Ogino","author_inst":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA."},{"author_name":"Viviam Sifontes","author_inst":"Moffitt Cancer Center, Tampa, FL, USA"},{"author_name":"Caroline Y Um","author_inst":"Department of Population Science, American Cancer Society, Atlanta, Georgia."},{"author_name":"Kala Visvanathan","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA and Department of Oncology, Johns Hopkins Kimmel Cancer Ce"},{"author_name":"Larissa L White","author_inst":"Institute for Health Research, Kaiser Permanente Colorado, Aurora, Colorado, USA."},{"author_name":"Andrea Williams","author_inst":"Southside Coalition of Community Health Centers"},{"author_name":"Waverly Willis","author_inst":"Independent researcher"},{"author_name":"Alicja Wolk","author_inst":"Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden."},{"author_name":"Taiki Yamaji","author_inst":"Division of Epidemiology, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan."},{"author_name":"Susan T Vadaparampil","author_inst":"Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida, USA."},{"author_name":"Gail P Jarvik","author_inst":"Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, Washington, USA."},{"author_name":"Andrea N Burnett-Hartman","author_inst":"Institute for Health Research, Kaiser Permanente Colorado, Denver, Colorado, USA."},{"author_name":"Roger L Milne","author_inst":"Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia."},{"author_name":"Elizabeth A Platz","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA."},{"author_name":"Jane C Figueiredo","author_inst":"Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA."},{"author_name":"Wei Zheng","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nas"},{"author_name":"Robert J MacInnis","author_inst":"Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia."},{"author_name":"Julie R Palmer","author_inst":"Slone Epidemiology Center at Boston University, Boston Massachusetts"},{"author_name":"Stephanie L Schmit","author_inst":"Genomic Sciences and Systems Biology, Cleveland Clinic, Cleveland, Ohio, USA."},{"author_name":"Iris Landorp-Vogelaar","author_inst":"Department of Public Health, Erasmus MC, University Medical Center, Rotterdam, The Netherlands."},{"author_name":"Ulrike Peters","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"author_name":"Li Hsu","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"Sound of Aging: Large-Scale Evidence for a Voice-Based Biological Clock","rel_doi":"10.64898\/2026.04.05.26350190","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.05.26350190","rel_abs":"Using 30-second voice recordings from 7,081 adults aged 40-70, we trained gender-specific models to estimate voice-predicted age (Voice Age). Voice Age correlated with chronological age comparably to established omic and physiological aging clocks, while capturing an independent dimension of biological aging. Accelerated vocal aging showed association with higher adiposity, impaired sleep physiology, and cardiometabolic risk markers, supporting voice as a scalable, non-invasive functional aging biomarker.","rel_num_authors":6,"rel_authors":[{"author_name":"David Krongauz","author_inst":"Weizmann Institute of Science"},{"author_name":"Yanir Marmor","author_inst":"Weizmann Institute of Science"},{"author_name":"Arad Zulti","author_inst":"Weizmann Institute of Science"},{"author_name":"Anastasia Godneva","author_inst":"Weizmann Institute of Science"},{"author_name":"Adina Weinberger","author_inst":"Weizmann Institute of Science"},{"author_name":"Eran Segal","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"Self-reported sleep problems are associated with impaired daily-life gait quality and increased fall risk in older people","rel_doi":"10.64898\/2026.03.30.26349800","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349800","rel_abs":"BackgroundSleep problems are common in older people and have been associated with increased fall risk, but the mechanisms underlying this relationship remain unclear. Gait quality reflects balance control and neurological function and may provide insight into pathways linking sleep health and falls.\n\nMethodsData from 758 community-dwelling older people ([&ge;]65 years; mean age 75.8 years, 69.3% women) were analysed. Sleep problems were assessed at baseline using a self-reported item (Patient Health Questionnaire-9, question 3). Daily-life gait quality and habitual walking speed were derived from one week of wearable sensor monitoring. Falls and injurious falls were prospectively recorded over 12 months. Associations between sleep problems, gait quality, and fall incidence were examined using regression models adjusted for demographic, pain and cognitive factors, and use of sleeping medication.\n\nResultsSleep problems were reported by 43.9% of participants. Sleep problems were not associated with habitual walking speed, but were associated with lower gait quality in daily life (adjusted {beta} = -0.15, 95% CI -0.27 to -0.03). Participants reporting sleep problems had higher incidence rates of total falls (adjusted IRR = 1.42, 95% CI 1.07 to 1.90) and injurious falls (adjusted IRR = 1.50, 95% CI 1.07 to 2.10).\n\nConclusionsSelf-reported sleep problems were associated with impaired real-world gait quality and substantially higher rates of falls and injurious falls in older people. These findings suggest that sleep problems may increase fall risk by altering balance control rather than by reducing walking speed. Sleep should be considered when managing fall risk, and fall risk should be considered in older people with sleep complaints.\n\nKEY POINTS BOXO_ST_ABSKey pointsC_ST_ABSO_LISleep problems in older people were not associated with habitual walking speed, but were associated with lower gait quality in daily life.\nC_LIO_LIPeople reporting sleep problems had 42% higher rates of falls, and 50% higher rates of injurious falls.\nC_LI\n\nWhy does this paper matter?This paper highlights that sleep problems are an important and under-recognised marker of fall risk among older people. It advocates for the need to consider sleep in fall risk management and fall risk in those presenting with sleep complaints.","rel_num_authors":6,"rel_authors":[{"author_name":"Kimberley S van Schooten","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Andrew Vakulin","author_inst":"Flinders Health and Medical Research Institute (FHMRI), Sleep Health, Flinders University, Adelaide, South Australia, Australia"},{"author_name":"Rajani Khanal","author_inst":"Flinders Health and Medical Research Institute (FHMRI), Sleep Health, Flinders University, Adelaide, South Australia, Australia"},{"author_name":"Kelly Sansom","author_inst":"Flinders Health and Medical Research Institute (FHMRI), Sleep Health, Flinders University, Adelaide, South Australia, Australia"},{"author_name":"James Bletsas","author_inst":"School of Biomedical Science, University of New South Wales, Kensington, New South Wales, Australia"},{"author_name":"Kim Delbaere","author_inst":"School of Health Sciences, University of New South Wales, Kensington, New South Wales, Australia"}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"Shared Genetic Architecture Between Kidney Function and Alzheimer Disease Across Ancestries","rel_doi":"10.64898\/2026.04.04.26350158","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.04.26350158","rel_abs":"Epidemiological studies have consistently shown that chronic kidney disease is associated with increased Alzheimer disease risk. However, the underlying genetic architecture connecting these two conditions remains largely unexplored beyond genome-wide correlation analyses. Here, we conducted the first comprehensive, multi-ancestry, large-scale genetic investigation to identify shared genetic components between kidney function and Alzheimer disease.\n\nWe leveraged large-scale genome-wide association study summary statistics for estimated glomerular filtration rate (N{approx}1.5 million European, N{approx}145,000 African ancestry) and late-onset Alzheimer disease (N=63,926 and N=398,058 in two European cohorts; N=9,168 in African ancestry) corrected for competing risk bias. We deployed a novel analytical framework integrating linkage disequilibrium score regression and polygenic risk score analysis, local analysis of [co]variant association, conjunctional false discovery rate analysis with Bayesian colocalization and fine-mapping, and bidirectional cis-Mendelian randomization to identify vertical pleiotropy.\n\nDespite the absence of genome-wide genetic correlation (rg {approx} 0, p > 0.1), local genetic analysis uncovered striking regional heterogeneity. Sixteen pleiotropic loci were identified in individuals of European ancestry (conjunctional false discovery rate < 0.05), including APOE, PICALM, SPI1, and EFTUD1, alongside 15 loci with significant local genetic correlations. Fine-mapping revealed that most pleiotropic loci harbored distinct causal variants for kidney function and Alzheimer disease, indicating horizontal pleiotropy. An APOE {varepsilon}4-defining allele (rs429358) was the sole variant with shared causality across both traits. We identified vertical pleiotropy using cis-Mendelian randomization at the PICALM and EFTUD1 loci, providing evidence that kidney function-related genetic variants can causally affect Alzheimer disease risk at specific genomic loci. In contrast, loci such as CD2AP, MAT1A, and SYMPK demonstrated horizontal pleiotropy, reflecting shared upstream biological pathways rather than direct causal mediation. Notably, APOE was the only pleiotropic locus shared between European and African ancestry groups, underscoring marked ancestry-specific genetic architectures with critical implications for risk prediction and therapeutic translation.\n\nAlzheimer disease and kidney function share genetic components at specific loci rather than genome-wide, with mixed directional effects and horizontal pleiotropy explaining the absent global correlation despite strong local signals. At a subset of loci, we identified directional effects linking kidney genetic determinants to Alzheimer disease risk using cis-Mendelian randomization, supporting a complex kidney-brain genetic axis. Most overlap reflects horizontal pleiotropy, with limited loci showing vertical pleiotropy. APOE was the only shared locus across ancestries, underscoring ancestry-specific architectures with implications for risk prediction. The multi-scale approach used here also provides a methodological framework for dissecting complex disease relationships missed by traditional genome-wide analyses.","rel_num_authors":14,"rel_authors":[{"author_name":"Diya Yang","author_inst":"Case Western Reserve University"},{"author_name":"Yihe Yang","author_inst":"Case Western Reserve University"},{"author_name":"Nicholas R. Ray","author_inst":"Columbia University"},{"author_name":"Mengxuan Li","author_inst":"Case Western Reserve University"},{"author_name":"Penelope Benchek","author_inst":"Case Western Reserve University"},{"author_name":"Dana C. Crawford","author_inst":"Case Western Reserve University"},{"author_name":"John F. O'Toole","author_inst":"Cleveland Clinic \/ Case Western Reserve University"},{"author_name":"John R. Sedor","author_inst":"Cleveland Clinic \/ Case Western Reserve University"},{"author_name":"Christiane Reitz","author_inst":"Columbia University"},{"author_name":"Audrey Lynn","author_inst":"Case Western Reserve University"},{"author_name":"Xiaofeng Zhu","author_inst":"Case Western Reserve University"},{"author_name":"Jonathan L. Haines","author_inst":"Case Western Reserve University"},{"author_name":"- Alzheimer's Disease Genetics Consortium (ADGC)","author_inst":""},{"author_name":"William S. Bush","author_inst":"Case Western Reserve University"}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"Shared Genetic Architecture Between Kidney Function and Alzheimer Disease Across Ancestries","rel_doi":"10.64898\/2026.04.04.26350158","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.04.26350158","rel_abs":"Epidemiological studies have consistently shown that chronic kidney disease is associated with increased Alzheimer disease risk. However, the underlying genetic architecture connecting these two conditions remains largely unexplored beyond genome-wide correlation analyses. Here, we conducted the first comprehensive, multi-ancestry, large-scale genetic investigation to identify shared genetic components between kidney function and Alzheimer disease.\n\nWe leveraged large-scale genome-wide association study summary statistics for estimated glomerular filtration rate (N{approx}1.5 million European, N{approx}145,000 African ancestry) and late-onset Alzheimer disease (N=63,926 and N=398,058 in two European cohorts; N=9,168 in African ancestry) corrected for competing risk bias. We deployed a novel analytical framework integrating linkage disequilibrium score regression and polygenic risk score analysis, local analysis of [co]variant association, conjunctional false discovery rate analysis with Bayesian colocalization and fine-mapping, and bidirectional cis-Mendelian randomization to identify vertical pleiotropy.\n\nDespite the absence of genome-wide genetic correlation (rg {approx} 0, p > 0.1), local genetic analysis uncovered striking regional heterogeneity. Sixteen pleiotropic loci were identified in individuals of European ancestry (conjunctional false discovery rate < 0.05), including APOE, PICALM, SPI1, and EFTUD1, alongside 15 loci with significant local genetic correlations. Fine-mapping revealed that most pleiotropic loci harbored distinct causal variants for kidney function and Alzheimer disease, indicating horizontal pleiotropy. An APOE {varepsilon}4-defining allele (rs429358) was the sole variant with shared causality across both traits. We identified vertical pleiotropy using cis-Mendelian randomization at the PICALM and EFTUD1 loci, providing evidence that kidney function-related genetic variants can causally affect Alzheimer disease risk at specific genomic loci. In contrast, loci such as CD2AP, MAT1A, and SYMPK demonstrated horizontal pleiotropy, reflecting shared upstream biological pathways rather than direct causal mediation. Notably, APOE was the only pleiotropic locus shared between European and African ancestry groups, underscoring marked ancestry-specific genetic architectures with critical implications for risk prediction and therapeutic translation.\n\nAlzheimer disease and kidney function share genetic components at specific loci rather than genome-wide, with mixed directional effects and horizontal pleiotropy explaining the absent global correlation despite strong local signals. At a subset of loci, we identified directional effects linking kidney genetic determinants to Alzheimer disease risk using cis-Mendelian randomization, supporting a complex kidney-brain genetic axis. Most overlap reflects horizontal pleiotropy, with limited loci showing vertical pleiotropy. APOE was the only shared locus across ancestries, underscoring ancestry-specific architectures with implications for risk prediction. The multi-scale approach used here also provides a methodological framework for dissecting complex disease relationships missed by traditional genome-wide analyses.","rel_num_authors":14,"rel_authors":[{"author_name":"Diya Yang","author_inst":"Case Western Reserve University"},{"author_name":"Yihe Yang","author_inst":"Case Western Reserve University"},{"author_name":"Nicholas R. Ray","author_inst":"Columbia University"},{"author_name":"Mengxuan Li","author_inst":"Case Western Reserve University"},{"author_name":"Penelope Benchek","author_inst":"Case Western Reserve University"},{"author_name":"Dana C. Crawford","author_inst":"Case Western Reserve University"},{"author_name":"John F. O'Toole","author_inst":"Cleveland Clinic \/ Case Western Reserve University"},{"author_name":"John R. Sedor","author_inst":"Cleveland Clinic \/ Case Western Reserve University"},{"author_name":"Christiane Reitz","author_inst":"Columbia University"},{"author_name":"Audrey Lynn","author_inst":"Case Western Reserve University"},{"author_name":"Xiaofeng Zhu","author_inst":"Case Western Reserve University"},{"author_name":"Jonathan L. Haines","author_inst":"Case Western Reserve University"},{"author_name":"- Alzheimer's Disease Genetics Consortium (ADGC)","author_inst":""},{"author_name":"William S. Bush","author_inst":"Case Western Reserve University"}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"Clinical and pathological characteristics of thin cutaneous melanomas with rapid recurrence.","rel_doi":"10.64898\/2026.04.04.26350182","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.04.26350182","rel_abs":"BackgroundAlthough thin, T1 melanomas have an excellent cure rate with surgery alone, >25% of melanoma deaths originate from thin melanomas (TMs). There is, therefore, an urgent need to improve the identification and management of patients with TMs at high risk of recurrence.\n\nMethodsPatients with T1 melanoma and recurrence [&le;] 2 years of diagnosis (T1 rapid group) were compared to patients with T1 melanoma and recurrence [&ge;]10 years after diagnosis (T1 late group).\n\nResults442 patients from 14 sites were included: 310 and 132 patients in the T1 rapid and late groups, respectively. Median age at primary melanoma diagnosis was 51 years [15-85], 272 (62%) male, 254 (58%) superficial spreading and 101 (23%) head\/neck primary. The majority (73%) of recurrences in the T1 rapid group were locoregional. Using univariable logistic regression analysis, age >65 years (p<0.0001), lentigo maligna (LM) melanoma subtype (p=0.025), head\/neck primary site (p=0.0065), mitoses [&ge;]1\/mm2 (p=0.0181) and ulceration (p=0.0087) were significantly associated with T1 rapid recurrence compared to T1 late recurrence. Using multivariable analysis, age >65 years (p=0.0010), mitoses [&ge;]1\/mm2 (p=0.049) and ulceration (p=0.037) remained significant.\n\nConclusionsRapid recurrence of TM is associated with age >65 years, LM subtype, head\/neck primary site, mitoses [&ge;]1\/mm2 and ulceration.","rel_num_authors":19,"rel_authors":[{"author_name":"Prachi Bhave","author_inst":"Sir Peter MacCallum Cancer Centre Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia Department of Bioinformatics, Walter and E"},{"author_name":"Terence Wong","author_inst":"Melanoma Institute Australia, The University of Sydney, New South Wales, Australia"},{"author_name":"Kim Margolin","author_inst":"St Johns Cancer Institute, California, USA"},{"author_name":"Lotte Hoeijmakers","author_inst":"Department of Medical Oncology, Netherlands Cancer Institute, Netherlands"},{"author_name":"Johanna Mangana","author_inst":"Department of Dermatology, University Hospital Zurich, Zurich, Switzerland Faculty of Medicine, University of Zurich, Zurich, Switzerland"},{"author_name":"Maria Grazia Vitale","author_inst":"Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione G.Pascale, Napoli, Italy"},{"author_name":"Paolo A Ascierto","author_inst":"Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione G.Pascale, Napoli, Italy Universita di Napoli Federico I"},{"author_name":"Andrea Maurichi","author_inst":"Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy"},{"author_name":"Mario Santinami","author_inst":"Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy"},{"author_name":"Georgina Heddle","author_inst":"Department of Dermatology, Queen Elizabeth Hospital, Adelaide, South Australia, Australia"},{"author_name":"Clara Allayous","author_inst":"AP-HP Department of Dermatology, Hopital Saint-Louis, Paris, France"},{"author_name":"Celeste Lebbe","author_inst":"Universite Paris Cite, AP-HP Dermato-oncology and CIC, Cancer institute APHP, nord Paris cite, Saint Louis Hospital, Paris, France"},{"author_name":"Adnan Kattak","author_inst":"Department of Medical Oncology, Fiona Stanley Hospital & Edith Cowan University, Perth, Western Australia, Australia"},{"author_name":"Stephan Forchhammer","author_inst":"Department of Dermatology, Eberhard Karls University, Tuebingen, Germany"},{"author_name":"Jolien I Kessels","author_inst":"Department of Dermatology, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, University Hospital Brussels, Brussels, Belgium"},{"author_name":"Peter Lau","author_inst":"Sir Charles Gairdener Hospital, University of Western Australia, Perth, Western Australia, Australia"},{"author_name":"Serigne N Lo","author_inst":"Melanoma Institute Australia, The University of Sydney, New South Wales, Australia Faculty of Medicine and Health, The University of Sydney, Sydney, New South W"},{"author_name":"Anthony A Papenfuss","author_inst":"Department of Bioinformatics, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia"},{"author_name":"Grant A McArthur","author_inst":"Sir Peter MacCallum Cancer Centre Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia"}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"Cell-free chromatin epigenomic profiling enables non-invasive pancreatic cancer cell-state identification","rel_doi":"10.64898\/2026.04.02.26349987","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.02.26349987","rel_abs":"Classical and basal-like transcriptional subtypes of pancreatic ductal adenocarcinoma (PDAC) are prognostic and may predict response to different chemotherapy regimens and RAS inhibitors. Current subtyping methods rely on tissue biopsies and remain challenging to integrate into clinical workflows. Herein, we present a novel approach for non-invasive subtyping of PDAC based on epigenomic profiling of circulating tumor DNA (ctDNA). In a multi-omics cohort of patient-derived xenografts, we identify highly recurrent regulatory elements associated with classical and basal-like PDAC. We then demonstrate that these epigenomic signatures can identify PDAC subtype from plasma epigenomic profiling in a multi-institutional cohort of patients with metastatic PDAC and integrate information from circulating histone modifications and DNA methylation to develop the Pancreatic Integrated Epigenomic Score (PIES). PIES is concordant with tissue-based labels and captures transcriptional subtype heterogeneity observed within biopsies. Furthermore, it improves prognostication over tissue-based subtyping suggestive of the recovery of ground truth tumor biology from plasma ctDNA. Our work provides a proof-of-concept for a circulating biomarker that enables transcriptional subtyping and informs therapeutic decisions in pancreatic cancer.\n\nSignificanceTranscriptional subtyping of pancreatic cancer can improve prognostication and inform treatment selection. Current subtyping approaches rely on tissue biopsy, are challenging to implement in clinical practice, and are limited by tumor heterogeneity and sampling error. Herein, we introduce a cell-free DNA-based epigenomic assay capable of inferring pancreatic cancer subtypes noninvasively.","rel_num_authors":43,"rel_authors":[{"author_name":"Karl Semaan","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Marc Eid","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Damien Vasseur","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Gunsagar S. Gulati","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Cibelle Lima","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Elio Ibrahim","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ji-Heui Seo","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"John J. Canniff","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Hunter Savignano","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Alexander Jordan","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Leigh Culane","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Noa Philips","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Rashad Nawfal","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Aislyn Schalck","author_inst":"MD Anderson Cancer Center"},{"author_name":"Andressa Dias Costa","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Elizabeth A. Andrews","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Emma C. Coleman","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Talal El Zarif","author_inst":"Yale School of Medicine"},{"author_name":"Garyoung Gary Lee","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Razane El Hajj Chehade","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ze Zhang","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Gaelle Nafeh","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Wassim Daoud Khatoun","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"James Brady","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Zhenjie Jin","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Paulo Da Silva Cordeiro","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Brad Fortunato","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"David Peng","author_inst":"MD Anderson Cancer Center"},{"author_name":"Christopher Vellano","author_inst":"MD Anderson Cancer Center"},{"author_name":"Tim Heffernan","author_inst":"MD Anderson Cancer Center"},{"author_name":"Antoine Hollebecque","author_inst":"Department of Medical Oncology, Gustave Roussy, Villejuif, France"},{"author_name":"Antoine Italiano","author_inst":"Department of Medical Oncology, Gustave Roussy, Villejuif, France"},{"author_name":"Brandon M. Huffman","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"James M. Cleary","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Jacob E. Berchuck","author_inst":"Winship Cancer Institute of Emory University"},{"author_name":"Toni K. Choueiri","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Kimberly Perez","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Jonathan Nowak","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Andrew J. Aguirre","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Brian M. Wolpin","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Sylvan C Baca","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Matthew L. Freedman","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Harshabad Singh","author_inst":"Dana-Farber Cancer Institute"}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"Backfill Bayesian Ordered Lattice Design for Phase I Clinical Trials","rel_doi":"10.64898\/2026.04.02.26350086","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.02.26350086","rel_abs":"The Bayesian Ordered Lattice Design (BOLD) method for Phase I clinical trials is extended to address an important challenge. It is widely understood that conventional Phase I trial designs are not consistently effective in determining safe and active dose levels. The US FDA launched the Project Optimus, aimed at reforming the paradigms of dose optimization and selection. We propose a backfill BOLD design (BF-BOLD) that centers on BOLD for dose-finding but also adds an activity evaluation for each patient. Our method for determining the optimal biological dose (OBD) first involves identifying the maximum tolerated dose (MTD) and then assessing activity rates among dose levels below the identified MTD. This approach is straight-forward and does not require complex statistical modeling. The results of the simulation indicate that performing dose-finding trials with backfilling can both enhance safety and activity assessment, thereby improving treatment sustainability while also preserving the potential for efficacy of the Recommended Phase II Dose (RP2D). We also demonstrate the applicability of the backfill design for reducing overdose rates, and as a more attractive alternative to small-scale dose expansion trials that follow dose escalation. Backfill designs are an important design approach for early phase trials.","rel_num_authors":2,"rel_authors":[{"author_name":"GI-MING WANG","author_inst":"Case Comprehensive Cancer Center"},{"author_name":"Curtis Tatsuoka","author_inst":"University of Maryland Baltimore"}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"Racial and Ethnic Differences in Cesarean Delivery Across Insurance Types, United States, 2014-2024","rel_doi":"10.64898\/2026.04.04.26350151","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.04.26350151","rel_abs":"IntroductionCesarean delivery accounts for nearly one-third of U.S. births and is associated with substantial maternal morbidity and health care costs. Persistent racial disparities have been documented, yet the structural factors contributing to these differences remain incompletely understood. The extent to which insurance coverage shapes racial disparities in cesarean delivery remains unclear.\n\nObjectiveTo evaluate the independent and interactive associations of race\/ethnicity and insurance coverage with cesarean delivery in the United States.\n\nMethodsPopulation-based retrospective cohort study using singleton live births recorded in the United States Vital Statistics Natality files from 2014 to 2024. Multivariable logistic regression was used to estimate the independent effects of race\/ethnicity and insurance status on cesarean delivery, including interaction terms to test effect modification, using national birth certificate data. Models were adjusted for maternal demographics, clinical factors, and temporal covariates. Adjusted odds ratios, predicted probabilities, and absolute risk differences were derived from post-estimation marginal effects. The main outcome measure was cesarean delivery (yes vs no).\n\nResultsAmong 41,543,568 deliveries from 2014 to 2024, 13,312,221 (32.0%) were cesarean deliveries. After adjustment, both race and ethnicity and insurance status were independently associated with cesarean delivery. Compared with non-Hispanic White women, non-Hispanic Black women had higher odds of cesarean delivery (odds ratio [OR], 1.22; 95% CI, 1.22-1.23). Relative to uninsured women, those with private insurance had 59% higher odds of cesarean delivery (OR, 1.59; 95% CI, 1.58-1.60). Significant interaction effects were observed, indicating that insurance coverage modified racial and ethnic differences in cesarean delivery. Non-Hispanic Black women had the highest predicted probabilities across all insurance categories, with the largest absolute disparities observed among uninsured women.\n\nConclusionRacial and ethnic differences in cesarean delivery persist in the United States and are modified by insurance coverage, suggesting that coverage-related differences may contribute to inequities in obstetric care.","rel_num_authors":11,"rel_authors":[{"author_name":"Oluwasegun Akinyemi","author_inst":"Howard University College of Medicine"},{"author_name":"Mojisola Fasokun","author_inst":"University of Alabama at Birmingham"},{"author_name":"Delia Singleton","author_inst":"Howard University College of Medicine"},{"author_name":"Fadeke Ogunyankin","author_inst":"Cook Children's Health Care System: Cook Children's Medical Center"},{"author_name":"Samar Khalil","author_inst":"Howard University College of Medicine"},{"author_name":"Kaelyn Gordon","author_inst":"Howard University College of Medicine"},{"author_name":"Miriam Michael","author_inst":"Howard University College of Medicine"},{"author_name":"Kakra Hughes","author_inst":"Howard University College of Medicine"},{"author_name":"Guoyang Luo","author_inst":"Inova Health System: Inova"},{"author_name":"Shari Lawson","author_inst":"Howard University College of Medicine"},{"author_name":"Eke Ahizechukwu","author_inst":"Johns Hopkins School of Medicine: The Johns Hopkins University School of Medicine"}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"Obstructive Sleep Apnea is Associated with Peri-Lead Edema Following Deep Brain Stimulation for Parkinson's Disease","rel_doi":"10.64898\/2026.04.05.26350193","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.05.26350193","rel_abs":"BackgroundPeri-lead edema (PLE) occurs in up to 15% of Deep Brain Stimulation (DBS) cases, can cause morbidity, and its etiology remains unknown. We hypothesized that PLE represents a secondary brain injury modulated by hypoxemia, and that patients with obstructive sleep apnea (OSA) are at elevated risk.\n\nMethodsWe conducted a retrospective case-control study of 121 Parkinsons disease (PD) patients undergoing DBS at a single center (2019-2024). PLE severity was quantified by CT volumetric segmentation and Hounsfield unit (HU) measures. Perioperative SpO2 and PaO2 were recorded. Polysomnography (PSG) was available in 26 patients; and the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) was administered retrospectively.\n\nResultsSymptomatic PLE occurred in 12 patients (9.9%), with onset at 3.5 (2-9) days postoperatively. PLE patients had higher body mass index (p = 0.022) and higher OSA prevalence (75% vs. 30%; p = 0.002). Perioperative SpO2 was lower in the PLE group in both the operating room and post-anesthesia care unit (PACU; p < 0.05); PaO2 was lower in the PACU (p = 0.037). In the PSG subgroup, REM Sleep Behavior Disorder (RBD) incidence was lower in PLE patients (20% vs. 60%; unadjusted p = 0.048), and PLE severity correlated significantly with sleep-related hypoxemia and respiratory indices. RBDSQ scores were positively associated with edema density (normalized HU: rho = 0.86, p = 0.024).\n\nConclusionsOSA and perioperative hypoxemia are associated with symptomatic PLE following DBS, while RBD appears protective. Preoperative sleep evaluation and optimized perioperative airway management warrant prospective investigation as PLE prevention strategies.","rel_num_authors":12,"rel_authors":[{"author_name":"Evgeniya Kornilov","author_inst":"Weizmann Institute of Science"},{"author_name":"Uri Alkan","author_inst":"Department of Otorhinolaryngology, Head and Neck Surgery, Rabin Medical Center, Petach-Tikva, Israel"},{"author_name":"Ella Harari","author_inst":"Department of Neurosurgery, Rabin Medical center, Petach Tikva, Israel"},{"author_name":"Karam Azem","author_inst":"Department of Anesthesiology, Beilinson Hospital, Rabin Medical Centre"},{"author_name":"Shlomo Fireman","author_inst":"Department of Anesthesiology, Beilinson Hospital, Rabin Medical Centre"},{"author_name":"Eilat Kahana","author_inst":"Department of Anesthesiology, Beilinson Hospital, Rabin Medical Centre"},{"author_name":"Johnathan Reiner","author_inst":"Department of Neurology, Rabin Medical Center, Petach-Tikva, Israel."},{"author_name":"Eilat Sapirstein","author_inst":"Department of Neurosurgery, Rabin Medical center, Petach Tikva, Israel."},{"author_name":"Gal Sela","author_inst":"Department of Neurology, Rabin Medical Center, Petach-Tikva, Israel."},{"author_name":"Amir Glik","author_inst":"Department of Neurology, Rabin Medical Center, Petach-Tikva, Israel."},{"author_name":"Shai Fein","author_inst":"Department of Anesthesiology, Beilinson Hospital, Rabin Medical Centre"},{"author_name":"Idit Tamir","author_inst":"Department of Neurosurgery, Rabin Medical center, Petach Tikva, Israel."}],"rel_date":"2026-04-06","rel_site":"medrxiv"},{"rel_title":"Hierarchical Barycentric Multimodal Representation Learning for Medical Image Analysis","rel_doi":"10.64898\/2026.04.05.26350202","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.05.26350202","rel_abs":"Multimodal medical image analysis exploits complementary information from multiple data sources (e.g., multi-contrast Magnetic Resonance Imaging (MRI), Diffusion Tensor Imaging (DTI), and Positron Emission Tomography (PET)) to enhance diagnostic accuracy and support clinical decision-making. Central to this process is the learning of robust representations that capture both modality-invariant and modality-specific features, which can then be leveraged for downstream tasks such as MRI segmentation and normative modeling of population-level variation and individual deviations. However, learning robust and generalizable representations becomes particularly challenging in the presence of missing modalities and heterogeneous data distributions. Most existing methods address this challenge primarily from a statistical perspective, yet they lack a theoretical understanding of the underlying geometric behavior--such as how probability mass is allocated across modalities. In this paper, we introduce a generalized geometric perspective for multimodal representation learning grounded in the concept of barycenters, which unifies a broad class of existing methods under a common theoretical perspective. Building on this barycentric formulation, we propose a novel approach that leverages generalized Wasserstein barycenters with hierarchical modality-specific priors to better preserve the geometry of unimodal distributions and enhance representation quality. We evaluated our framework on two key multimodal tasks--brain tumor MRI segmentation and normative modeling--demonstrating consistent improvements over a variety of multimodal approaches. Our results highlight the potential of scalable, theoretically grounded approaches to advance robust and generalizable representation learning in medical imaging applications.","rel_num_authors":6,"rel_authors":[{"author_name":"Peijie Qiu","author_inst":"Mallinckrodt Institute of Radiology,  Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Zhaoqi An","author_inst":"Division of Computational and Data Sciences, Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Sungmin Ha","author_inst":"Mallinckrodt Institute of Radiology,  Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Sayantan Kumar","author_inst":"National Library or Medicine, National Institutes on Health"},{"author_name":"Xiaobing Yu","author_inst":"Mallinckrodt Institute of Radiology,  Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Aristeidis Sotiras","author_inst":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"rel_date":"2026-04-06","rel_site":"medrxiv"}]}