{"gname":"Washington University in St. Louis","grp_id":"11","rels":[{"rel_title":"Preserved Medial Temporal Lobe Flexibility Predicts Memory Generalization Only in the Context of Good Sleep Quality among Older African Americans","rel_doi":"10.64898\/2026.06.15.26355704","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355704","rel_abs":"Objectives: Poor sleep quality is a risk factor for Alzheimer's disease (AD). Older African Americans experience disproportionately high rates of sleep disturbance and AD. Medial temporal lobe (MTL) flexibility reflects dynamic neural reorganization and may be a marker of generalization performance. This study examined whether sleep quality moderates the association between MTL flexibility and memory generalization. Methods: Fifty older African Americans (MeanAge=69.7{+\/-}6.21 years; 80% women) underwent rs-fMRI to quantify MTL flexibility, Rutgers Acquired Equivalence Task for memory generalization, and Pittsburgh Sleep Quality Index for sleep quality. Results: Greater MTL flexibility was associated with better generalization (r=0.367, p=.017). Good sleepers showed higher MTL flexibility (F(1,44)=8.11, p2=.156, p=.007) and superior generalization (F(1,46)= 12.33, p2=.211, p=.001). Sleep quality significantly moderated the MTL flexibility and generalization relationship ({beta}=-1.519, p=.012). Conclusions: Preserved MTL flexibility may confer generalization only in good sleepers, suggesting that sleep disturbance may disrupt the MTL neural resilience among older African Americans.","rel_num_authors":5,"rel_authors":[{"author_name":"Payton G White","author_inst":"Rutgers University- Newark"},{"author_name":"Miray Budak","author_inst":"Rutgers University- Newark"},{"author_name":"Soodeh Moallemian","author_inst":"Rutgers University-Newark"},{"author_name":"Bernadette Fausto","author_inst":"Thomas Jefferson University"},{"author_name":"Mark Gluck","author_inst":"Rutgers University-Newark"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Reverse engineering of motor unit discharge in multiple sclerosis reveals heterogeneity of voluntary motor commands","rel_doi":"10.64898\/2026.06.15.26355613","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355613","rel_abs":"Central nervous system injury causes motor deficits through derangement of excitatory, inhibitory, and\/or neuromodulatory inputs to motoneurons, the three fundamental components of motor commands. Typically, study of pathologic neural control in humans is restricted to only one of the three. Chardon et al. (2024) presented a fundamentally new approach to comprehensively study all components by reverse engineering motor unit firing patterns. We apply their framework to motor unit firing patterns from 89 people with multiple sclerosis (MS) and 34 controls to study excitatory, inhibitory, and neuromodulatory contributions to pathologic motor output. Disruptions to all components are plausible in MS, a disease hallmarked by heterogeneity in nearly all aspects. Accordingly, we found abnormalities in MS for all three components. Notably, neuromodulation included both high and low extremes. Our results suggest that pathophysiology of motor commands in MS varies among patients, a finding fundamentally different from other studied populations showing relative consistency.","rel_num_authors":8,"rel_authors":[{"author_name":"Laura M. McPherson","author_inst":"Washington University School of Medicine"},{"author_name":"Keith Lohse","author_inst":"Washington University School of Medicine"},{"author_name":"Skyler M. Simon","author_inst":"Washington University School of Medicine"},{"author_name":"Daniel B. Free","author_inst":"Washington University School of Medicine"},{"author_name":"James Andrew Beauchamp","author_inst":"Carnegie Mellon University"},{"author_name":"Francesco Negro","author_inst":"University of Brescia"},{"author_name":"Robert T. Naismith","author_inst":"Washington University School of Medicine"},{"author_name":"Anne H. Cross","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Reverse engineering of motor unit discharge in multiple sclerosis reveals heterogeneity of voluntary motor commands","rel_doi":"10.64898\/2026.06.15.26355613","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355613","rel_abs":"Central nervous system injury causes motor deficits through derangement of excitatory, inhibitory, and\/or neuromodulatory inputs to motoneurons, the three fundamental components of motor commands. Typically, study of pathologic neural control in humans is restricted to only one of the three. Chardon et al. (2024) presented a fundamentally new approach to comprehensively study all components by reverse engineering motor unit firing patterns. We apply their framework to motor unit firing patterns from 89 people with multiple sclerosis (MS) and 34 controls to study excitatory, inhibitory, and neuromodulatory contributions to pathologic motor output. Disruptions to all components are plausible in MS, a disease hallmarked by heterogeneity in nearly all aspects. Accordingly, we found abnormalities in MS for all three components. Notably, neuromodulation included both high and low extremes. Our results suggest that pathophysiology of motor commands in MS varies among patients, a finding fundamentally different from other studied populations showing relative consistency.","rel_num_authors":8,"rel_authors":[{"author_name":"Laura M. McPherson","author_inst":"Washington University School of Medicine"},{"author_name":"Keith Lohse","author_inst":"Washington University School of Medicine"},{"author_name":"Skyler M. Simon","author_inst":"Washington University School of Medicine"},{"author_name":"Daniel B. Free","author_inst":"Washington University School of Medicine"},{"author_name":"James Andrew Beauchamp","author_inst":"Carnegie Mellon University"},{"author_name":"Francesco Negro","author_inst":"University of Brescia"},{"author_name":"Robert T. Naismith","author_inst":"Washington University School of Medicine"},{"author_name":"Anne H. Cross","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"A multistate model of frailty progression after severe infections in adults >=65 years in England: a matched-cohort study","rel_doi":"10.64898\/2026.06.16.26355787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355787","rel_abs":"Background Evidence on frailty progression following severe infections is limited. We compared rates of transition to greater frailty or death between adults with and without severe infection in England. Methods We conducted a matched-cohort study among adults aged [&ge;]65 years (1,452,117: median age 76 years, 45% male) in Clinical Practice Research Datalink Aurum (2006-2019). Adults with severe infection (hospitalised primarily due to infection) were matched on calendar time to individuals without severe infection on age, sex, and primary care practice. The admission date was used as index date and same was assigned to matched unexposed adults. We measured frailty using Electronic Frailty Index, a proportion of 36 health deficits in validated categories (Fit 0-0.12, Mild >0.12-0.24, Moderate >0.24-0.36, Severe >0.36). In a time-varying Markov multistate model, we focused on forward transitions from baseline or intermediate frailty states to higher states or death. For each transition, we used Cox regression to estimate cause-specific transition hazard ratios (HR) with 95% confidence intervals (CIs), comparing adults with and without severe infection. We adjusted for baseline frailty score, age, sex, deprivation, harmful alcohol use, smoking, and primary care infection history 5 years before index date. We estimated state occupancy probabilities, and expected length of stay (ELOS) in each state at year five among adults with and without severe infection. We explored effect modification by infection type. Results Across all transitions, severe infection was associated with higher adjusted hazards of transitioning to worsening frailty or death, HR, 95% CI: (fit to: mild[1.56, 1.54-1.58], moderate[2.51, 1.79-3.51], death[4.57, 4.50-4.65]; mild to: moderate[1.52, 1.50-1.53], severe[1.90, 1.43-2.52], death[2.67, 2.64-2.70]; moderate to: severe[1.40, 1.38-1.42], death[1.87, 1.85-1.90]; severe to death[1.48, 1.46-1.50]). Transition hazard ratios were strongest for lower respiratory tract infections, followed by sepsis, urinary tract infections, meningitis\/encephalitis, gastroenteritis, and skin and soft tissue infections. At five years, adults with severe infection had higher probabilities of transitioning to greater frailty or death across all transitions and lower ELOS in each frailty state than those without severe infection. Interpretation Severe infections may accelerate frailty deterioration in older age. Prevention through vaccination, early detection, and prompt management may help mitigate this decline.","rel_num_authors":10,"rel_authors":[{"author_name":"Kwabena Asare","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine"},{"author_name":"Kate E. Mansfield","author_inst":"School of Health and Care Sciences, University of Lincoln, Lincoln, United Kingdom."},{"author_name":"Georgia R. Gore-Langton","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom."},{"author_name":"Eleanor Barry","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom."},{"author_name":"Ruth Keogh","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom."},{"author_name":"Vincent Lo Re III","author_inst":"Center for Pharmacoepidemiology and Treatment Science, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, NJ, Unite"},{"author_name":"Maria C. Rodriguez-Barradas","author_inst":"Michael E. DeBakey VA Medical Center, Houston, TX, United States."},{"author_name":"Amy c. Justice","author_inst":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States."},{"author_name":"Christopher T. Rentsch","author_inst":"US Department of Veterans Affairs, London School of Hygiene and Tropical Medicine"},{"author_name":"Charlotte Warren-Gash","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom."}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Identifying anaphylaxis using weakly-supervised prediction models and natural language processing","rel_doi":"10.64898\/2026.06.09.26355005","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355005","rel_abs":"Objectives Scalable computable phenotyping algorithms are critical for conducting high-throughput disease-outcome research in large, distributed-data electronic health record (EHR) and claims data settings. We developed and evaluated a claims- and EHR-based computable phenotyping algorithm for anaphylaxis, a rare acute condition that is challenging to accurately identify using claims data alone. Materials and Methods Potential anaphylaxis events came from two healthcare systems (Kaiser Permanente Washington [KPWA] and Vanderbilt University Medical Center [VUMC]). We engineered features from clinical text using automated natural language processing (NLP) methods. We then developed a phenotyping algorithm using four NLP- and diagnosis code-based silver labels (proxies for the gold-standard labels). Gold-standard abstracted outcomes were used to evaluate algorithm performance. Results The largest area under the receiver operating characteristic curve (AUC) was 0.931 for an NLP-based silver-label model at KPWA. Depending on the model and healthcare system site, positive predictive value (PPV) and sensitivity at the threshold of predicted probability that maximized F1 score ranged from 0.52 to 0.77 (PPV) and 0.78 to 1 (sensitivity). Discussion NLP-based silver-label models had large AUC at KPWA but not at VUMC. This may be because clinical text at KPWA is only available for outpatient encounters and secure messaging. High sensitivity for identifying anaphylaxis can be obtained using our best-performing models. Conclusion The best-performing models had better PPV and sensitivity tradeoffs than prior bespoke anaphylaxis models with costly, manually curated features. The simplicity of the approach compared to traditional phenotyping methods allows it to be deployed easily at multiple health care systems.","rel_num_authors":19,"rel_authors":[{"author_name":"Brian D Williamson","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"David J Cronkite","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Onchee Yu","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Arvind Ramaprasan","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Sharon Fuller","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Jennifer Covey","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Erika Kiniry","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Daniel Park","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Robert Winter","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jill Whitaker","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Michael F McLemore","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Saranrat Wittayanukorn","author_inst":"US Food and Drug Administration"},{"author_name":"Danijela Stojanovic","author_inst":"US Food and Drug Administration"},{"author_name":"Yueqin Zhao","author_inst":"US Food and Drug Administration"},{"author_name":"Sarah Dutcher","author_inst":"US Food and Drug Administration"},{"author_name":"David S Carrell","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Lisa A Jackson","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Jennifer C Nelson","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Joshua C Smith","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Diagnostic Concordance of Immediate Versus 1-Hour Technetium-99m Hydroxydiphosphonate Scintigraphy in Suspected Transthyretin Amyloid Cardiomyopathy","rel_doi":"10.64898\/2026.06.16.26355752","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355752","rel_abs":"Background Bone-avid tracer myocardial scintigraphy for the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) has traditionally employed imaging at one or 3-hour intervals. Technetium-99m hydroxydiphosphonate (99mTc-HDP) has unique characteristics that may enable earlier imaging. We investigated the diagnostic concordance of immediate versus 1-hour acquisitions. Methods Consecutive patients with suspected ATTR-CM underwent planar imaging and SPECT\/CT immediately and at 1-hour following the administration of 99mTc-HDP. Perugini grades and heart to contralateral lung (H\/CL) ratios were assessed. Target-to-background ratios (TBRs) were calculated on the SPECT\/CT acquisitions using the left ventricular (LV) septum and three background regions: aorta, LV blood-pool, and vertebrae. We assessed diagnostic concordance using Cohen's Kappa ({kappa}), temporal stability using paired t-tests, and correlation between timepoints using Pearson's coefficient (r). The 1-hour SPECT\/CT interpretation served as the protocol reference standard. Results Forty-eight patients (83% male; median age, 80 [73-85] years) were evaluated. One-hour SPECT\/CT identified 19 positive and 29 negative cases. Immediate SPECT\/CT demonstrated 100% diagnostic concordance with the 1-hour reference standard ({kappa} = 1.000; 95% CI: 1.00 to 1.00; p < 0.001). The LV septum\/LV Blood-Pool TBR showed the highest correlation (r = 0.956; 95% CI: 0.922 to 0.975; p < 0.001). The LV Septum\/Aorta TBR demonstrated high correlation (r = 0.918; 95% CI: 0.857 to 0.953; p < 0.001) and remained stable in the ATTR-negative cohort (-0.02; 95% CI: -0.08 to 0.04; p = 0.54). Significant decrease in the LV Septum\/Vertebrae TBR in the ATTR-negative (-0.55; 95% CI: -0.64 to -0.47; p < 0.001) and ATTR-positive cohorts (-1.14; 95% CI: -1.39 to -0.89; p < 0.001) was observed. Conclusions Immediate 99mTc-HDP SPECT\/CT is diagnostically concordant with standard 1-hour protocols. By leveraging SPECT\/CT and the favorable kinetics of 99mTc-HDP, immediate-phase imaging can accurately reproduce 1-hour acquisitions in cases of suspected ATTR-CM. This expedited approach may improve nuclear laboratory throughput and patient satisfaction.","rel_num_authors":12,"rel_authors":[{"author_name":"Andrew Costa","author_inst":"Oregon Health and Science University"},{"author_name":"Austen Suits","author_inst":"Oregon Health and Science University"},{"author_name":"Jack Miller","author_inst":"Oregon Health and Science University"},{"author_name":"Maros Ferencik","author_inst":"Oregon Health and Science University"},{"author_name":"David M. German","author_inst":"Oregon Health and Science University"},{"author_name":"Evan F. Shalen","author_inst":"Oregon Health and Science University"},{"author_name":"Gagandeep Choudhary","author_inst":"Oregon Health and Science University"},{"author_name":"Laszlo Szidonya","author_inst":"Oregon Health and Science University"},{"author_name":"Mike Nguyen","author_inst":"Oregon Health and Science University"},{"author_name":"Nadine Mallak","author_inst":"Oregon Health and Science University"},{"author_name":"Sebastan Obrzut","author_inst":"Oregon Health and Science University"},{"author_name":"Ahmad Masri","author_inst":"Oregon Health and Science University"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Proteomics Uncovers Cryptic JPH2 Loss in Paediatric Dilated Cardiomyopathy","rel_doi":"10.64898\/2026.06.16.26355718","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355718","rel_abs":"Despite recent advances in next-generation sequencing, genetic diagnostic rates for dilated cardiomyopathy (DCM) remain low. Among paediatric DCM, causes are often heritable, with a greater frequency of de novo, recessive and syndromic causes of disease. Novel diagnostic methods are therefore required to solve monogenic cases. To assess the value of proteomics as a diagnostic tool for paediatric DCM, we obtained left ventricle myocardial samples from paediatric patients undergoing heart transplantation at the Royal Children's Hospital, Melbourne. We performed genome sequencing and proteomics and leveraged this multi-omics dataset to uncover the molecular cause of disease in a gene elusive proband. The proband carried a heterozygous JPH2 frameshift variant identified on clinical exome sequencing. However, proteomic analysis showed a pronounced downregulation of JPH2, suggestive of biallelic loss-of-function. Closer inspection of the genomic data revealed a large inversion (~8.34 Mb) with a breakpoint falling within intron 5 of JPH2 that displaces the 3'UTR from the coding transcript. The two variants were confirmed to be in trans using long read DNA sequencing, consistent with a diagnosis of JPH2 autosomal recessive DCM. Finally, we applied RNA sequencing with total RNA library preparation to show that transcripts containing a 3'UTR were reduced to ~10% relative to controls. As a proof-of-principle, we present the first reported use of proteomics from explanted cardiac tissue to provide a genetic diagnosis. Our methodology has broad relevance to patients with genetically unsolved Mendelian diseases, who might undergo organ transplantation as part of clinical management.","rel_num_authors":29,"rel_authors":[{"author_name":"Carlos C Smith-Diaz","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Valerii Iaprintsev","author_inst":"The Royal Children's Hospital Melbourne; University of Melbourne; Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine"},{"author_name":"Hannah Huckstep","author_inst":"Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine"},{"author_name":"Ivan Macciocca","author_inst":"Victorian Clinical Genetics Services; University of Melbourne; Murdoch Children's Research Institute"},{"author_name":"Adam T Piers","author_inst":"Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine; Centre for Population Genomics"},{"author_name":"Natasha Henden","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Samantha Bryen","author_inst":"Centre for Population Genomics"},{"author_name":"Natalie Stewart","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Alexandra Butters","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Amy Baker","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Laura Catto","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Leah Kemp","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Ingrid King","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Lina H H Le","author_inst":"Murdoch Children's Research Institute"},{"author_name":"David A Elliott","author_inst":"University of Melbourne; Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine; Melbourne Centre for Cardiovascular Genom"},{"author_name":"Kevin I Watt","author_inst":"Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine; The University of Melbourne"},{"author_name":"Jacob Mathew","author_inst":"Murdoch Children's Research Institute; The Royal Children's Hospital Melbourne"},{"author_name":"Robert Justo","author_inst":"Queensland Childrens Hospital"},{"author_name":"Ebony Richardson","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Cas Simons","author_inst":"Centre for Population Genomics"},{"author_name":"Andrew P Landstrom","author_inst":"The Children's Hospital of Philadelphia; University of Pennsylvania"},{"author_name":"Christina V Theodoris","author_inst":"Gladstone Institute of Cardiovascular Disease; Gladstone Institute of Data Science and Biotechnology; University of California, San Francisco"},{"author_name":"Ira W Deveson","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Daniel G MacArthur","author_inst":"Centre for Population Genomics"},{"author_name":"Igor Konstantinov","author_inst":"The Royal Children's Hospital, Melbourne; University of Melbourne; Murdoch Children's Research Institute; Melbourne Centre for Cardiovascular Genomics and Regen"},{"author_name":"Robert Weintraub","author_inst":"Murdoch Children's Research Institute; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine; The Royal Children's Hospital, Melbourne"},{"author_name":"Enzo R Porrello","author_inst":"University of Melbourne; Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine; Melbourne Centre for Cardiovascular Genom"},{"author_name":"Sean J Humphrey","author_inst":"Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine"},{"author_name":"Jodie Ingles","author_inst":"Garvan Institute of Medical Research"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Characterizing the genetic basis of Cardio-Renal-Metabolic multimorbidity using multivariate genomic modelling","rel_doi":"10.64898\/2026.06.16.26355643","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355643","rel_abs":"Cardio-renal-metabolic multimorbidity (CRMM) encompasses interrelated conditions affecting the heart, kidneys, and metabolic systems. Although the genetics of individual components are well studied, their shared architecture remains unclear. Here, we performed the largest multi-ancestry multivariate GWAS of CRMM across seven biobanks, including individuals of European (EUR; neff = 353,130), African (AFR; neff = 75,436), and East Asian (EAS; neff = 164,373) ancestry. We identified 287 lead loci in EUR, 30 in AFR, and 202 in EAS. Cross-ancestry analyses revealed ancestry-specific signals and 24 shared loci mapping to FTO and TCF7L2. Drug-repurposing highlighted candidates used for type 2 diabetes and hypertension. Mendelian randomization supported causal links with diverse diseases, while polygenic risk scores showed improved prediction across ancestries. Collectively, these findings advance understanding of CRMM genetics and inform precision medicine.","rel_num_authors":4,"rel_authors":[{"author_name":"Abhiram D. B.","author_inst":"Institute for Biomedicine and Glycomics, Griffith University, Brisbane, Australia"},{"author_name":"Vignesh Arunachalam","author_inst":"Department of Dermatology, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Rodney A Lea","author_inst":"Centre for Genomics and Personalised Health, School of Biomedical Science, Queensland"},{"author_name":"Shivashankar H. Nagaraj","author_inst":"Institute for Biomedicine and Glycomics, Griffith University, Brisbane, Australia"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Azacytidine restores T cell function in AML by modulating DNA methylation","rel_doi":"10.64898\/2026.06.14.732148","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732148","rel_abs":"AML is an aggressive blood cancer associated with poor clinical outcomes. Chemotherapy remains the standard of treatment, but unfortunately relapse is very common, highlighting the need for alternative therapies. T cell dysfunction and exhaustion are prominent in AML and may represent a barrier to effective immunotherapy yet remains poorly studied in AML. DNA methylation is a major driver of T cell exhaustion and inhibition of de novo methylation can block exhaustion and restore T cell function in chronic viral infections and other cancers but is understudied in AML. Here, we investigated the impact of azacytidine (Aza), an FDA-approved hypomethylating agent, on T cell exhaustion in AML. Using a spontaneous AML mouse model and samples from patients with AML, we found that Aza treatment modulates T cell function. In vivo Aza-treatment of AML-bearing mice decreased tumor burden and reshaped CD8+ T cell states, with increases in frequencies of memory subsets and decreases in regulatory T cells (Tregs). Functionally, Aza treatment overcame the impaired proliferation displayed by both CD4 and CD8+ T cells in our model. DNA methylation sequencing of T cells after Aza treatment revealed hypomethylation and increased expression of stem-like precursor gene TCF7 and E2F2, a regulator of cell cycle progression and proliferation. Similar changes in phenotypes were observed in cultures of AML patient samples treated with Aza. Collectively, we show that Aza remodels epigenetic and functional states in AML and has the potential to reverse T cell exhaustion, with enhanced memory and proliferation capacity. Our work generates a mechanistic framework that provides rationale of combining hypomethylating agents with T cell-based immunotherapies in this lethal disease.","rel_num_authors":7,"rel_authors":[{"author_name":"Ravina Pandita","author_inst":"Oregon Health & Science University"},{"author_name":"Yoko Kosaka","author_inst":"Oregon Health & Science University"},{"author_name":"Jessica S Mulkey","author_inst":"Oregon Health & Science University"},{"author_name":"Cora E Layman","author_inst":"Oregon Health & Science University"},{"author_name":"Brett E Davis","author_inst":"Oregon Health & Science University"},{"author_name":"Lucia Carbone","author_inst":"Oregon health & science university"},{"author_name":"Evan F Lind","author_inst":"Oregon Health & Science University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"FALCON: Closed-Loop Multi-Objective Optimization of Lipid Nanoparticles for Cell-Selective mRNA Delivery","rel_doi":"10.64898\/2026.06.13.731774","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.731774","rel_abs":"Efficient, cell type-selective delivery of genetic payloads remains a central challenge in the development of gene and cell therapies. Lipid nanoparticles (LNPs) offer a versatile delivery platform, but their optimization is hindered by reliance on brute-force screening methods that are laborious, resource-intensive, and focus on single targets. Here, we present FALCON (Framework for Active Learning-driven Compositional Optimization of Nanoparticles), a closed-loop pipeline that leverages iterative screening, surrogate modeling, and multi-objective optimization to accelerate LNP compositional design. In B cell-targeted validation experiments, FALCON-optimized LNPs achieved a 1.8-fold increase in splenic B cell transfection in vivo compared with reference compositions. When optimized for selectivity, FALCON LNPs displayed an 84-fold improvement in selective transfection of splenic B cells over off-target liver populations and enabled spleen-tropic behavior across factorial panels of varying ionizable and helper lipid chemistries. In vaccine studies, these LNPs induced higher IgG2c antibody titers and a more Th1-biased immune profile. FALCON was also deployed to optimize LNPs for myeloid cell-selective delivery, achieving enhanced in vivo selectivity following systemic administration both across and within spleen and liver compartments. Our results establish FALCON as a useful tool for data-driven design of LNP compositions for precision gene delivery.","rel_num_authors":28,"rel_authors":[{"author_name":"Wu Han Toh","author_inst":"Johns Hopkins University"},{"author_name":"Leonardo Cheng","author_inst":"Johns Hopkins University"},{"author_name":"Brandon Chang","author_inst":"Johns Hopkins University"},{"author_name":"Di Yu","author_inst":"Johns Hopkins University"},{"author_name":"Jingyao Ma","author_inst":"Johns Hopkins University"},{"author_name":"Xiuchun Huang","author_inst":"Johns Hopkins University"},{"author_name":"Gene Weng","author_inst":"Johns Hopkins University"},{"author_name":"Yining Zhu","author_inst":"Johns Hopkins University"},{"author_name":"Xiaoya Lu","author_inst":"Johns Hopkins University"},{"author_name":"Jinghan Lin","author_inst":"Johns Hopkins University"},{"author_name":"Jin Liu","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Joseph Choy","author_inst":"Johns Hopkins University"},{"author_name":"Autumn Greco","author_inst":"Johns Hopkins University"},{"author_name":"Manav Jain","author_inst":"Johns Hopkins University"},{"author_name":"Joanna Yang","author_inst":"Johns Hopkins University"},{"author_name":"Milan Patel","author_inst":"Johns Hopkins University"},{"author_name":"Grace Shoemaker","author_inst":"Johns Hopkins University"},{"author_name":"Isabella Cozzone","author_inst":"Johns Hopkins University"},{"author_name":"Daniel Antov","author_inst":"Johns Hopkins University"},{"author_name":"Kevin Zhang","author_inst":"Johns Hopkins University"},{"author_name":"Sarp Kayabas","author_inst":"Johns Hopkins University"},{"author_name":"Charles Shin","author_inst":"Johns Hopkins University"},{"author_name":"Ataes Aggarwal","author_inst":"Johns Hopkins University"},{"author_name":"Jordan Green","author_inst":"Johns Hopkins University"},{"author_name":"Stephany Tzeng","author_inst":"Johns Hopkins University"},{"author_name":"Ramya Kumar","author_inst":"Colorado School of Mines"},{"author_name":"Maximilian F Konig","author_inst":"Johns Hopkins University"},{"author_name":"Hai-Quan Mao","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Colorful connections: pigment-based plumage and breeding condition are associated with gut microbiome variation in the Common Yellowthroat","rel_doi":"10.64898\/2026.06.16.732689","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732689","rel_abs":"Carotenoid- and melanin-based plumage coloration traits are key signals in avian communication and sexual selection as they are often thought to provide \"honest\" information about individual condition and fitness. These traits arise through distinct but interconnected physiological and genetic pathways. Recent work suggests that there may be a link between host-associated gut microbiota and the functional pathways leading to pigment-based plumage coloration, but this remains largely unexplored in wild populations. To address this gap, we tested whether variation in plumage coloration, as well as breeding condition, is associated with gut microbiome variation in wild populations of male Common Yellowthroats (Parulidae: Geothlypis trichas). We quantified multiple plumage coloration traits and characterized gut microbiome bacterial diversity using 16S rRNA metabarcoding. Through a comprehensive modeling framework, we found that individuals with brighter, more orange-tinted breast feathers and smaller cloacal protuberances (a proxy for breeding condition) exhibited higher gut microbiome diversity. At the taxonomic level, Methylobacterium-Methylorubrum, a carotenoid-producing bacteria, showed strong associations with multiple plumage traits, including mask area, breast feather hue, and saturation. Our results demonstrate that gut microbiome diversity is associated with variation in carotenoid-based coloration traits and breeding condition in Common Yellowthroats. More broadly, these results highlight the potential for host-microbiome interactions to shape phenotypic variation through physiological pathways in wild animal populations.","rel_num_authors":7,"rel_authors":[{"author_name":"Alix E Matthews","author_inst":"University at Buffalo"},{"author_name":"Maxima Gomez-Palmer","author_inst":"Department of Biology, Carleton College, Northfield, MN 55057, USA"},{"author_name":"Sebastian Gallego","author_inst":"Department of Biological Sciences, University at Buffalo (SUNY), Buffalo, NY 14260, USA"},{"author_name":"Mads Moore","author_inst":"Department of Ecology, Evolutionary Biology, and Environmental Sciences, Columbia University, New York, NY 10027, USA"},{"author_name":"Lan-Nhi Phung","author_inst":"Center for Innovation in Health Sciences, VinUniversity, Hanoi, Vietnam 10000"},{"author_name":"Daniel T Baldassarre","author_inst":"SUNY Oswego"},{"author_name":"Marcella D Baiz","author_inst":"Department of Biological Sciences, University at Buffalo (SUNY), Buffalo, NY 14260, USA"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Stability and Compressibility of Tear Film Lipid Layer: Impact of Benzalkonium Chloride Presence","rel_doi":"10.64898\/2026.06.13.731656","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.731656","rel_abs":"PURPOSE.: Benzalkonium chloride (BAK), a common preservative in eye drops, has a major side effect of dry eye. The mechanisms are typically attributed to BAK cytotoxicity. However, due to its surfactant properties, BAK can disrupt the tear film lipid layer (TFLL), leading to dry eye. This study examined the stability and compressibility of the TFLL and the impact of the presence of BAK. METHODS.: Meibomian gland secretion (meibum, source of the TFLL) was collected from sacrificed cows ' eyelids. Lipids were extracted by dissolving meibum in chloroform to a final concentration of 1 mg\/mL, with one solution additionally containing 0.1 mg\/mL BAK. Each solution was overlaid on a water subphase in a Langmuir Trough-Blodgett trough. The changes of surface pressure ({pi}) with area (A) for the lipid film upon compression were monitored, and the corresponding compression modulus (Cs-1) at each data point was determined. RESULTS.: The {pi}-A isotherms for meibum lipid monolayers exhibited near-reversible behavior with a smooth profile with a maximum {pi} of approximately 32 mN\/m. The Cs-1-{pi} isotherms of the meibum lipid monolayer show that the films are gel-like with a constant compressive modulus of 24-32 mN\/m within the surface pressure range of 8-30 mN\/m. In contrast, adding BAK dramatically decreased the maximum surface pressure to only 10 mN\/m and the compressive modulus to only 2-10 mN\/m. CONCLUSIONS.: This study demonstrated that BAK disrupts the meibum lipid layer by forming a monolayer with decreased stability and reduced compressive resistance, a mechanism that may underlie its dry-eye side effect yet has largely been neglected.","rel_num_authors":4,"rel_authors":[{"author_name":"Jianzhong Chen","author_inst":"Medical College of Georgia, Augusta University"},{"author_name":"Yiming Zhang","author_inst":"School of Materials Science and Engineering, Georgia Institute of Technology"},{"author_name":"Thai Minh Han Nguyen","author_inst":"Medical College of Georgia, Augusta University"},{"author_name":"Vladimir V Tsukruk","author_inst":"School of Materials Science and Engineering, Georgia Institute of Technology"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Correcting spatial transcriptomics data affected by a prevalent transcript leakage problem across platforms, species, and tissues","rel_doi":"10.64898\/2026.06.13.732076","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.732076","rel_abs":"Spatial transcriptomics has been widely applied to study the spatial distribution of cell types, cell states, and specific gene expression in tissue samples. However, we show that there is a prevalent transcript leakage problem in spatial transcriptomics data, where transcripts expressed by a cell diffuse to its neighborhood and are recurrently detected in the nearby cells. By analyzing published data sets, we show that this problem is general across data produced from different tissues and different species using different imaging-based and sequencing-based spatial transcriptomics platforms. It affects both upstream tasks such as expression quantification as well as downstream tasks such as cell-type annotation and detection of spatially-dependent gene expression. To tackle the transcript leakage problem, we propose a reference-free Bayesian model-based method, DeLeakage, which cleans up the data much more effectively than existing denoising methods. DeLeakage also improves cell-type annotation and avoids false detection of spatially dependent expression.","rel_num_authors":14,"rel_authors":[{"author_name":"Christina Huan Shi","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Yibo Zhai","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Savio Ho-Chit Chow","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Liangbang Li","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Chase M Carver","author_inst":"Mayo Clinic"},{"author_name":"Marcos Garcia Teneche","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Jesus Flores","author_inst":"University of California San Diego"},{"author_name":"Colin Kern","author_inst":"University of California San Diego"},{"author_name":"Peter D Adams","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Bing Ren","author_inst":"New York Genome Center"},{"author_name":"Marissa J Schafer","author_inst":"Mayo Clinic"},{"author_name":"Quan Zhu","author_inst":"University of California San Diego"},{"author_name":"Yingying Wei","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Kevin Y. Yip","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Correcting spatial transcriptomics data affected by a prevalent transcript leakage problem across platforms, species, and tissues","rel_doi":"10.64898\/2026.06.13.732076","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.732076","rel_abs":"Spatial transcriptomics has been widely applied to study the spatial distribution of cell types, cell states, and specific gene expression in tissue samples. However, we show that there is a prevalent transcript leakage problem in spatial transcriptomics data, where transcripts expressed by a cell diffuse to its neighborhood and are recurrently detected in the nearby cells. By analyzing published data sets, we show that this problem is general across data produced from different tissues and different species using different imaging-based and sequencing-based spatial transcriptomics platforms. It affects both upstream tasks such as expression quantification as well as downstream tasks such as cell-type annotation and detection of spatially-dependent gene expression. To tackle the transcript leakage problem, we propose a reference-free Bayesian model-based method, DeLeakage, which cleans up the data much more effectively than existing denoising methods. DeLeakage also improves cell-type annotation and avoids false detection of spatially dependent expression.","rel_num_authors":14,"rel_authors":[{"author_name":"Christina Huan Shi","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Yibo Zhai","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Savio Ho-Chit Chow","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Liangbang Li","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Chase M Carver","author_inst":"Mayo Clinic"},{"author_name":"Marcos Garcia Teneche","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Jesus Flores","author_inst":"University of California San Diego"},{"author_name":"Colin Kern","author_inst":"University of California San Diego"},{"author_name":"Peter D Adams","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Bing Ren","author_inst":"New York Genome Center"},{"author_name":"Marissa J Schafer","author_inst":"Mayo Clinic"},{"author_name":"Quan Zhu","author_inst":"University of California San Diego"},{"author_name":"Yingying Wei","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Kevin Y. Yip","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Simultaneous regeneration of skin and bone in full-thickness cranial composite defects","rel_doi":"10.64898\/2026.06.16.732662","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732662","rel_abs":"Traumatic cranial defects often involve concurrent loss of soft and hard tissues and can progress to chronic defects due to delayed healing associated with infection or other co-morbidities. Despite autologous reconstruction remaining the clinical standard, it requires staged procedures using heterogeneous tissues, increasing operative time, costs, and surgical risks. Moreover, current tissue engineering approaches focus on single tissues or acute tissue defect models, limiting their clinical applications. Herein, we describe an acellular, material-driven 3D-printed composite scaffold designed to regenerate both bone and skin within composite cranial defects. The scaffold integrates controlled copper ion release from both organic and inorganic components with 3D-printed citrate polymer and citrate polymer-ceramic composites. Integrated thermoresponsive citrate-based hydrogels further enable spatially defined dermoconductive and osteoconductive properties, supporting a one-step surgical approach. At 12 weeks post-implantation, our scaffold enhanced keratinocyte organization, collagen deposition, and defect coverage with mature bone, achieving histological outcomes comparable to autografts. Furthermore, the system suppressed bacterial burden. Thus, this acellular platform represents a clinically promising synchronized strategy to address the complex demands of traumatic craniofacial composite defects.","rel_num_authors":9,"rel_authors":[{"author_name":"Mirae Kim","author_inst":"Northwestern University"},{"author_name":"Yi Zhu","author_inst":"The University of Chicago"},{"author_name":"Shivakalyani Adepu","author_inst":"Northwestern University"},{"author_name":"Caralyn Paige Collins","author_inst":"Northwestern University"},{"author_name":"Maria Mendez-Santos","author_inst":"Northwestern University"},{"author_name":"Cheng Sun","author_inst":"Northwestern University"},{"author_name":"Tong-Chuan He","author_inst":"The University of Chicago"},{"author_name":"Russell Reid","author_inst":"The University of Chicago"},{"author_name":"Guillermo Antonio Ameer","author_inst":"Northwestern University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Label-Free All-Electrical Tracking of Individual and Collective Cell Migration on a Megapixel CMOS Capacitance Sensor","rel_doi":"10.64898\/2026.06.16.731623","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.731623","rel_abs":"Label-free tracking of adherent cell migration could enable important insights into biological processes such as tissue repair, inflammatory response, or cancer progression. Nevertheless, visualizing unlabeled animal cells using optical microscopy remains challenging due to low contrast as well as frequent changes in cell shape and number. A promising alternative uses electrical capacitance measurements, which are sensitive to cell adhesion to electrode surfaces. However, prior examples often utilized electrodes with areas larger than single cells, resulting in averaged readouts over multiple cells. Here, we demonstrate label-free, live-cell tracking using a capacitance sensor array with more than 1 million pixels on a 10 micron pitch across an area larger than 1 square centimeter. We show that single cell morphology can be clearly segmented, and then used to reconstruct migration and proliferation dynamics using optical flow. We further track the spreading of multicellular spheroids, revealing fast-moving peripheral regions led by a collective leader cell ``front.'' Finally, we demonstrate label-free imaging of millimeter-scale honeycomb-shaped tissues without the multi-image stitching often required for conventional microscopy. We utilize mutual capacitance measurements with electrically-programmable electrode spacing to reconstruct topographical features of these engineered tissues. Overall, CMOS capacitance imaging arrays enables label-free imaging spanning from single cells to large tissues, in a portable and scalable format for settings where optical microscopy may be difficult to access.","rel_num_authors":7,"rel_authors":[{"author_name":"Hyuntae Jeong","author_inst":"Brown University"},{"author_name":"Pushkaraj S Joshi","author_inst":"Brown University"},{"author_name":"Yinshi Hu","author_inst":"Brown University"},{"author_name":"Jiwon Kim","author_inst":"Brown University"},{"author_name":"Anh Hoang Vu","author_inst":"Brown University"},{"author_name":"Jacob K Rosenstein","author_inst":"Brown University"},{"author_name":"Ian Y Wong","author_inst":"Brown University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"HyenaSET: Hyena Sound Event Transcripts and benchmark animal2vec performance for parsing animal communication","rel_doi":"10.64898\/2026.06.14.732108","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732108","rel_abs":"Here, we present HyenaSET, a large (~1640 hours) bioacoustic dataset derived from collar-mounted audio recorders deployed on 19 spotted hyenas in the Maasai Mara National Reserve, Kenya. Within this dataset, 243 hours have been strongly labeled by identifying the onset and offset of all vocalizations as well as their types, and the labels have been validated by experts on hyena vocalizations and behavior. Within the strongly labeled data, the total amount of time hyenas were vocalizing was 9.5 hours (3.9%). Furthermore, each vocalization has been manually identified as \"focal\" (emitted by the hyena wearing the collar) or \"non-focal\" (emitted by a nearby conspecific), making use of information from collar-mounted accelerometers that picked up vibrations of the animal's throat when it produced vocalizations. In addition to the labeled data, we also provide a large corpus of unlabeled data from the same recordings, which can be used for un- or self-supervised machine learning tasks. To ensure reproducibility of this dataset as a benchmark in machine learning studies, we present it alongside five stratified cross-validation train\/test splits to enable accurate comparisons, and we also provide a train\/test split in which specific individuals are left out of the training set to assess generalizability across individuals. Finally, as a performance benchmark, we present baseline results for this dataset using animal2vec, a recently developed transformer-based model optimized for bioacoustic data.","rel_num_authors":11,"rel_authors":[{"author_name":"Jana Maria Woerner","author_inst":"Michigan State University"},{"author_name":"C\u00e9line Angonin","author_inst":"Tilburg University"},{"author_name":"Andrew S. Gersick","author_inst":"Princeton University"},{"author_name":"Kay E. Holekamp","author_inst":"Michigan State University"},{"author_name":"Frants Havmand Jensen","author_inst":"Aarhus University"},{"author_name":"Mark P. Johnson","author_inst":"Aarhus University"},{"author_name":"Marsden H. M. Onsare","author_inst":"Mara Hyena Project"},{"author_name":"Malit O. Pioon","author_inst":"Mara Hyena Project"},{"author_name":"Julian Sch\u00e4fer-Zimmermann","author_inst":"Max Planck Institute of Animal Behavior"},{"author_name":"Ariana Strandburg-Peshkin","author_inst":"Max Planck Institute of Animal Behavior"},{"author_name":"Eli D. Strauss","author_inst":"Michigan State University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Emergent feasibility in random ecological systems with higher-order interactions","rel_doi":"10.64898\/2026.06.11.728491","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.728491","rel_abs":"A recurring lesson from random ecological models is that coexistence is hard to come by: in the Generalized Lotka-Volterra (GLV) model with pairwise interactions, the probability that randomly sampled parameters admit a positive (feasible) equilibrium -- a necessary condition for coexistence - is exactly 1\/2^n in n species, vanishing rapidly with diversity. This rarity is often read as evidence that coexistence demands specific ecological mechanisms. Real interactions, however, are rarely strictly pairwise: any nonlinear dependence of one species' growth rate on another's abundance, Taylor-expanded, generates higher-order interactions (HOIs) of increasing degree. Treating the interaction order d as a knob that indexes this nonlinearity, we map the random GLV with HOIs onto the Kostlan-Shub-Smale class of random polynomial systems and approximate the probability of feasibility (P_f) analytically. We find a phase transition at d=4: below this threshold, P_f decays with diversity as in the pairwise case; above it, the exponential proliferation of equilibria outpaces the probability that any given equilibrium is feasible, and the probability of feasibility increases with n, approaching one. The transition appears to be universal across symmetric coefficient distributions, but vanishes when sign symmetry of the parameter distribution is broken. This work uncovers a route by which feasibility emerges from nonlinearity alone, with no fine-tuning of parameters and no appeal to specific ecological mechanisms.","rel_num_authors":4,"rel_authors":[{"author_name":"Pablo Lechon-Alonso","author_inst":"University of Chicago"},{"author_name":"Alexander Strang","author_inst":"University of California Berkeley"},{"author_name":"Paul Breiding","author_inst":"OsnabrukUniversity"},{"author_name":"Stefano Allesina","author_inst":"University of Chicago"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Emergent feasibility in random ecological systems with higher-order interactions","rel_doi":"10.64898\/2026.06.11.728491","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.728491","rel_abs":"A recurring lesson from random ecological models is that coexistence is hard to come by: in the Generalized Lotka-Volterra (GLV) model with pairwise interactions, the probability that randomly sampled parameters admit a positive (feasible) equilibrium -- a necessary condition for coexistence - is exactly 1\/2^n in n species, vanishing rapidly with diversity. This rarity is often read as evidence that coexistence demands specific ecological mechanisms. Real interactions, however, are rarely strictly pairwise: any nonlinear dependence of one species' growth rate on another's abundance, Taylor-expanded, generates higher-order interactions (HOIs) of increasing degree. Treating the interaction order d as a knob that indexes this nonlinearity, we map the random GLV with HOIs onto the Kostlan-Shub-Smale class of random polynomial systems and approximate the probability of feasibility (P_f) analytically. We find a phase transition at d=4: below this threshold, P_f decays with diversity as in the pairwise case; above it, the exponential proliferation of equilibria outpaces the probability that any given equilibrium is feasible, and the probability of feasibility increases with n, approaching one. The transition appears to be universal across symmetric coefficient distributions, but vanishes when sign symmetry of the parameter distribution is broken. This work uncovers a route by which feasibility emerges from nonlinearity alone, with no fine-tuning of parameters and no appeal to specific ecological mechanisms.","rel_num_authors":4,"rel_authors":[{"author_name":"Pablo Lechon-Alonso","author_inst":"University of Chicago"},{"author_name":"Alexander Strang","author_inst":"University of California Berkeley"},{"author_name":"Paul Breiding","author_inst":"OsnabrukUniversity"},{"author_name":"Stefano Allesina","author_inst":"University of Chicago"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Experimental landscape connectivity decreases temporal variability in communities over 24 years of assembly","rel_doi":"10.64898\/2026.06.16.732628","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732628","rel_abs":"Landscape connectivity is a key regulator of dispersal, which is an important process in community assembly. Theory predicts that connectivity may influence spatial and temporal patterns of community assembly; however, empirically evaluating the role of connectivity is nearly impossible due to the need to isolate its influence over long time frames and large spatial extents. We overcome these challenges through a large-scale, long-term connectivity experiment to test how connectivity affects plant community turnover and directionality of change over 24 years of assembly. Plant communities within connected patches had lower temporal variability in composition compared to plant communities within unconnected patches. Differences in composition between patches and the directionality of compositional changes were driven more by the amount of edge habitat in a patch and the time since the start of assembly. All community responses to connectivity were stronger for species with wind or unassisted dispersal compared to those with seeds dispersed by animals. Connectivity's role in regulating local community dynamics is critical for understanding community assembly and increasingly relevant in an era of anthropogenic land-use change.","rel_num_authors":6,"rel_authors":[{"author_name":"Katherine A Hulting","author_inst":"Michigan State University"},{"author_name":"Lars A Brudvig","author_inst":"Michigan State University"},{"author_name":"Melissa A Burt","author_inst":"Tusculum University"},{"author_name":"Christopher R Warneke","author_inst":"University of Wisconsin-Madison"},{"author_name":"Ellen I Damschen","author_inst":"University of Wisconsin-Madison"},{"author_name":"Nick M Haddad","author_inst":"Michigan State University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"NKG2C+CD27- Defines Human CD8+ Regulatory T Cells","rel_doi":"10.64898\/2026.06.15.732401","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732401","rel_abs":"Here we identify NKG2C+CD27- as a novel surface marker unifying multiple previously reported CD8+ regulatory T cell (Treg) populations. This population displays high clonality and divides into CD226- (Treg1) and CD226+ (Treg2) subsets, with Treg2 exhibiting stronger suppressive activities. Up to 35% of CD8+ TEMRA cells are Tregs, whereas approximately 85% of CD8+ Tregs are TEMRA cells, which increase with aging. These findings establish a unified and novel cell surface marker for CD8+ Tregs and their subsets, which resolves prior heterogeneity in the field, and show that CD8+ TEMRA cells are a heterogeneous population that includes T cells with regulatory function. Our findings provide a critical framework for the isolation and in-depth functional characterization of CD8+ Tregs in health, aging, and disease.","rel_num_authors":7,"rel_authors":[{"author_name":"Xuyang Li","author_inst":"Johns Hopkins University"},{"author_name":"Somen K. Mistri","author_inst":"Mass General Brigham, Boston"},{"author_name":"Tian Cao","author_inst":"Mass General Brigham"},{"author_name":"Rajesh K. Krishnan","author_inst":"Mass General Brigham"},{"author_name":"Martin Hemberg","author_inst":"Mass General Brigham"},{"author_name":"Howard L. Weiner","author_inst":"Mass General Brigham"},{"author_name":"Dan Hu","author_inst":"Mass General Brigham"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Characterizing the Effects of Chronic Cannabis Vapour Exposure and Withdrawal on Cannabinoid Triad, Somatic Signs and Behavioural Network Reorganization Adult Male Rats","rel_doi":"10.64898\/2026.06.12.731896","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731896","rel_abs":"Rationale: Cannabis withdrawal contributes to relapse in individuals with cannabis use disorder, yet preclinical studies have largely focused on withdrawal induced by injected cannabinoids rather than inhaled cannabis, which remains the most common route in humans. The behavioural effects of chronic exposure to vapourized cannabis flower and resulting withdrawal after cessation of exposure remain poorly characterized. Objectives: To determine the behavioural effects of chronic vapourized high-THC cannabis flower exposure on cannabinoid tetrad, somatic withdrawal and behavioural transition networks in rats following both chronic vapour exposure and administration of the cannabinoid receptor 1 (CB1) receptor antagonist SR141716A (rimonabant). Methods: Two studies were conducted using adult male Sprague Dawley rats. The first study (N = 16) exposed rats to either air or vapourized high-THC cannabis flower three times a day for seven days using a Volcano vapourizer, followed by intraperitoneal administration of the CB1 antagonist SR141716A (3 mg\/kg). The second study (N = 24) included two air controls and two cannabis groups, with one of each receiving either saline or SR141716A. Behavioural assessments included triad measurements to confirm the cannabis effect, along with withdrawal assessment via a sucrose preference test and somatic signs 30 minutes following rimonabant administration. Results: Repeated cannabis vapour exposure produced reduced locomotor activity, hypothermia, and increased tail-flick latency. Rimonabant administration precipitated withdrawal characterized by increased total withdrawal scores and somatic signs, including blinking, body shakes\/tremors, and grooming-related behaviours. Behavioural network analyses revealed substantial reorganization of behavioural transition structure during both chronic cannabis exposure and withdrawal. Chronic cannabis exposure was associated with reduced network modularity, a condensed behavioural repertoire, and altered behavioural centrality measures. At the same time, precipitated withdrawal further increased the influence of exploratory behaviours, particularly sniffing, and reduced the network prominence of locomotor-associated behaviours, such as walking, beyond that detected using conventional behavioural measures alone. Conclusion: Chronic exposure to vapourized cannabis flower followed by CB1 receptor antagonism produces reliable withdrawal symptoms in rats. Behavioural network analyses further reveal that cannabis exposure and withdrawal are both associated with widespread reorganization of behavioural dynamics, suggesting that withdrawal alters not only individual behaviours but also the structure of behavioural transitions. These findings establish a translational model of cannabis withdrawal using inhaled cannabis flower vapour and identify behavioural network analysis as a sensitive approach for characterizing withdrawal-related behavioural states.","rel_num_authors":11,"rel_authors":[{"author_name":"Abdalla M Albeely","author_inst":"Western University"},{"author_name":"Hakan Kayir","author_inst":"Western University"},{"author_name":"Richard Quansah Amissah","author_inst":"Western University"},{"author_name":"Bahar Zali","author_inst":"Western University"},{"author_name":"Selim Karahan","author_inst":"Western University"},{"author_name":"Jaiden Smith","author_inst":"University of Guelph"},{"author_name":"Asim A Ibrahim","author_inst":"Western University"},{"author_name":"Ahmad Hassan","author_inst":"University of Guelph"},{"author_name":"Sara Hussein","author_inst":"University of Guelph"},{"author_name":"Jude A Frie","author_inst":"Western University"},{"author_name":"Jibran Khokhar","author_inst":"Western University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Incorporation of single-neuron projectome-based connectivity motifs enhances the cortex-specific performance of artificial neural networks","rel_doi":"10.64898\/2026.06.12.732007","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.732007","rel_abs":"The organizational principles of natural neural networks could inspire the new architecture design of artificial neural networks (ANNs). Analysis of single-neuron connectomes of mouse brains revealed distinct profiles of three-node connectivity motifs in various cortical areas and hippocampal formation. A connectome-informed neural network algorithm (\"CINA\") was developed to incorporate natural connectivity motifs into ANN algorithms represented by recurrent neural network (RNN) and transformer-based large language model (LLM). We found that incorporation of the average profile of cortical motifs improved the RNN's performance in noise-resistant categorization and motor learning benchmark tasks, as compared with RNNs with random connectivity. Notably, incorporating cortex-specific motifs further elevated the RNN's performance in tasks related to the cortical function, and this effect was enhanced by artificially increasing the bias in the motif profile. Similar experimental results were verified on an LLM using Motif-Transformer for natural language question answering and brain-signal decoding tasks. Graph-theoretic analyses showed that incorporating natural motifs drove the emergence of modular and small-world properties in ANNs. Together, we demonstrated not only connectome-inspired optimization of ANN architecture but also functional significance of specific motif profiles in various cortices.","rel_num_authors":16,"rel_authors":[{"author_name":"Yue Sun","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Wangzi Yao","author_inst":"Institute of Automation, Chinese Academy of Sciences"},{"author_name":"Jian Zhang","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Wei Song","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Xuanle Zhao","author_inst":"Institute of Automation, Chinese Academy of Sciences"},{"author_name":"Chonghe Hao","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Xinyu Chen","author_inst":"School of Artificial Intelligence, China University of Mining and Technology-Beijing"},{"author_name":"Shuxin Zeng","author_inst":"School of Artificial Intelligence, University of Chinese Academy of Sciences"},{"author_name":"Shuncheng Jia","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Yun Yang","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Xu Chen","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Xiong Xiao","author_inst":"Center for Excellence in Brain Science and Intelligence Technology"},{"author_name":"Mu-ming Poo","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Yangang Sun","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Bo Xu","author_inst":"Institute of Automation, Chinese Academy of Sciences"},{"author_name":"Tielin Zhang","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Experiment-free learning of exoskeleton assistance is not an unsolved problem","rel_doi":"10.64898\/2026.06.16.731058","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.731058","rel_abs":"We present three quantitative methods: 1) estimation of exoskeleton mechanical power and energy ratio from published data, 2) a systematic review of the exoskeleton literature on reported energy ratios, and 3) timing correction analysis of the replication experiment, to address concerns raised by Collins et al. (2026) about Luo et al. (2024). Together, these analyses support the reported metabolic reductions and the validity of exoskeleton control via learning in simulation. The critique rests on an unsupported premise: that exoskeleton energy ratios above 4 are physiologically implausible. This premise of Collins et al. (2026) is not supported by the cited evidence, and the error originates in their own cited source. Sawicki and Ferris (2009), the paper they invoke as authority for the limit of 4, state explicitly that \"reported values of the muscular efficiency range from 0.10 to 0.34, with many sources assuming an average of ~0.25.\" The value of 4 corresponds to this average, it is not a physiological ceiling. Treating an average as a physiological upper limit is a fundamental error. The published exoskeleton literature further contradicts the claim, including work by the authors of the critique themselves (Collins et al., 2015: 4.3; Young et al., 2017: 5.0) and independent work (Malcolm et al., 2013: 4.8; Seo et al., 2017: 6.7). In contrast, our walking energy ratio is 2.4, calculated directly from Fig. 4 of our paper. Our device delivers higher peak torque (14.1 Nm vs. 10.9 Nm, Lim et al., 2019) and achieves a slightly larger metabolic reduction (24.3% vs. 21%). Independent groups have since demonstrated meaningful metabolic reductions using learning-in-simulation frameworks, including Barati et al. (2026, 15.2% mean and 22.5% maximum) and Zhou et al. (2025, ~20% during running). The claim of Collins et al. (2026) that this problem \"remains unsolved\" is directly contradicted by these independent results.","rel_num_authors":10,"rel_authors":[{"author_name":"Shuzhen Luo","author_inst":"Mechanical Engineering, Embry-Riddle Aeronautical University"},{"author_name":"Menghan Jiang","author_inst":"Mechanical & Aerospace Engineering, North Carolina State University"},{"author_name":"Sainan Zhang","author_inst":"Mechanical Engineering, Kennesaw State University"},{"author_name":"Junxi Zhu","author_inst":"Siemens"},{"author_name":"Shuangyue Yu","author_inst":"Beijing University of Technology"},{"author_name":"Israel Dominguez Silva","author_inst":"Amazon Robotics"},{"author_name":"Bolei Zhou","author_inst":"Computer Science, University of California, Los Angeles"},{"author_name":"Hyunwoo Yuk","author_inst":"Mechanical Engineering, Korea Advanced Institute of Science and Technology"},{"author_name":"Xianlian Zhou","author_inst":"Biomedical Engineering, New Jersey Institute of Technology"},{"author_name":"Hao Su","author_inst":"Biomedical Engineering, Computer Science, New York University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Towards Passive Dietary Monitoring: Dilated CNN-Based Meal Detection Using Ambulatory High-Resolution Electrogastrography","rel_doi":"10.64898\/2026.06.13.731982","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.731982","rel_abs":"Background: Objective tools for longitudinal dietary monitoring, despite its importance in the health triad of diet, sleep, and exercise, remain limited. Widely available ambulatory options include continuous glucose monitoring, which is a delayed response, and manual logging, which is rife with human error. Clinical tools such as gastric emptying scintigraphy are impractical for everyday use. High-resolution electrogastrography (HR-EGG) offers an alternative by treating gastric myoelectric activity as a biomarker of digestive state. However, its utility for ambulatory meal detection remains unclear. We hypothesize that HR-EGG and accelerometry together encode distinct postprandial gastric signatures to enable automated meal detection, and that postural context represents a relevant source of variation in signal detectability. Methods: HR-EGG and accelerometry data were collected from seven healthy adults across sixteen 150-minute meal sessions under IRB-approved protocol. Each session included a 30-minute fasted baseline, consumption of a standardized meal, and 90-minute postprandial period of sitting, walking, and lying in a randomized order. Features of the gastric slow wave, including raw and normalized bandpower, phase gradient directionality (PGD), wave direction, and wave speed, were extracted alongside triaxial accelerometer magnitude. A dilated one-dimensional convolutional network (1D CNN) was trained to classify meal consumption at five-minute resolution using leave-one-subject-out cross-validation. Postural effects on gastric myoelectric metrics were assessed using the Friedman test. Results: The model achieved a mean AUROC of 0.925 (95% CI: [0.857, 0.993]) and mean AUPRC of 0.824 (95% CI: [0.668, 0.980]; null model: 0.20). Feature ablation showed PGD as the most informative input ({Delta}AUPRC = -0.188), with wave propagation speed the least informative ({Delta}AUPRC = - 0.105). Walking produced the highest signal-to-noise ratio (9.94 dB), lying had the most stable gastric rhythm (89.1% normogastric), and sitting demonstrated the greatest frequency instability (dominant frequency standard deviation = 0.825 cpm). Conclusion: A dilated 1D CNN applied to spatiotemporal HR-EGG features enables temporally aware passive meal detection across ambulatory contexts. This study framework addresses a gap between clinical need for objective dietary monitoring and the limitations of current detection methods.","rel_num_authors":2,"rel_authors":[{"author_name":"Belinda Chen","author_inst":"University of California, San Francisco"},{"author_name":"Sandya Subramanian","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Towards Passive Dietary Monitoring: Dilated CNN-Based Meal Detection Using Ambulatory High-Resolution Electrogastrography","rel_doi":"10.64898\/2026.06.13.731982","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.731982","rel_abs":"Background: Objective tools for longitudinal dietary monitoring, despite its importance in the health triad of diet, sleep, and exercise, remain limited. Widely available ambulatory options include continuous glucose monitoring, which is a delayed response, and manual logging, which is rife with human error. Clinical tools such as gastric emptying scintigraphy are impractical for everyday use. High-resolution electrogastrography (HR-EGG) offers an alternative by treating gastric myoelectric activity as a biomarker of digestive state. However, its utility for ambulatory meal detection remains unclear. We hypothesize that HR-EGG and accelerometry together encode distinct postprandial gastric signatures to enable automated meal detection, and that postural context represents a relevant source of variation in signal detectability. Methods: HR-EGG and accelerometry data were collected from seven healthy adults across sixteen 150-minute meal sessions under IRB-approved protocol. Each session included a 30-minute fasted baseline, consumption of a standardized meal, and 90-minute postprandial period of sitting, walking, and lying in a randomized order. Features of the gastric slow wave, including raw and normalized bandpower, phase gradient directionality (PGD), wave direction, and wave speed, were extracted alongside triaxial accelerometer magnitude. A dilated one-dimensional convolutional network (1D CNN) was trained to classify meal consumption at five-minute resolution using leave-one-subject-out cross-validation. Postural effects on gastric myoelectric metrics were assessed using the Friedman test. Results: The model achieved a mean AUROC of 0.925 (95% CI: [0.857, 0.993]) and mean AUPRC of 0.824 (95% CI: [0.668, 0.980]; null model: 0.20). Feature ablation showed PGD as the most informative input ({Delta}AUPRC = -0.188), with wave propagation speed the least informative ({Delta}AUPRC = - 0.105). Walking produced the highest signal-to-noise ratio (9.94 dB), lying had the most stable gastric rhythm (89.1% normogastric), and sitting demonstrated the greatest frequency instability (dominant frequency standard deviation = 0.825 cpm). Conclusion: A dilated 1D CNN applied to spatiotemporal HR-EGG features enables temporally aware passive meal detection across ambulatory contexts. This study framework addresses a gap between clinical need for objective dietary monitoring and the limitations of current detection methods.","rel_num_authors":2,"rel_authors":[{"author_name":"Belinda Chen","author_inst":"University of California, San Francisco"},{"author_name":"Sandya Subramanian","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Evolutionary Coupling of Flagellar Motility and Type VI Secretion Systems Across Bacteria","rel_doi":"10.64898\/2026.06.16.732483","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732483","rel_abs":"Bacteria use both motility and antagonism to compete in spatially structured environments, but whether these traits evolve together across broad bacterial diversity remains unclear. We developed a spatial kin-competition model predicting that motility should couple robustly with contact-dependent weapons by increasing encounter rates with competitors, whereas coupling with diffusible weapons should be weaker and context-dependent. To test these predictions, we performed a comprehensive analysis of 11,365 bacterial genomes across the Tree of Life (ToL). By utilising large-scale homology-based searches, we annotated flagellar, T6SS, and bacteriocin components and then applied phylogenetic comparative models to examine evolutionary associations. T6SS presence was strongly associated with flagellar motility: T6SS-positive lineages were predominantly flagellated, and BayesTraits supported a dependent model of FliC and T6SS evolution. In contrast, bacteriocins showed no detectable evolutionary coupling with flagellar motility. Transition-rate analyses further indicated that T6SS gain was strongly biased towards motile lineages, even though T6SS loss was common overall. These results support an asymmetric macroevolutionary relationship between bacterial motility and antagonism, in which flagellar motility is robustly coupled to contact-dependent competition but not to diffusible antagonistic systems.","rel_num_authors":3,"rel_authors":[{"author_name":"Jamiema Sara Philip","author_inst":"University of New South Wales"},{"author_name":"Luke McNally","author_inst":"University of Edinburgh"},{"author_name":"Matthew AB Baker","author_inst":"University of New South Wales"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"RNA virus-mediated metabolic reprogramming in a bloom-forming, marine diatom","rel_doi":"10.64898\/2026.06.16.732687","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732687","rel_abs":"Diatoms are a widespread group of phytoplankton that disproportionately influence the global carbon cycle through substantial contributions to primary production and carbon export in the ocean. Marine viruses are major drivers of host metabolic reprogramming and mortality and it is increasingly clear that RNA viruses, which primarily infect eukaryotes, are abundant and distributed throughout the global ocean. Using an integrated, multi-omics approach, we characterized the molecular and metabolic response of the model, bloom-forming, centric diatom Chaetoceros tenuissimus to RNA virus infection. Time-resolved transcriptomics revealed coordinated, differential regulation of more than a third of host genes prior to host lysis, eliciting a cascade of metabolic responses that included early shifts in sulfur and lipid metabolism, induction of nitrogen assimilation pathways, and late-stage activation of stress, signaling and death-related genes. Lipidomics revealed substantial cellular enrichment of phosphatidylethanolamine, ceramide and triacylglycerol during RNA virus infection, as well as an infection-specific shift in fatty acid composition. Collectively, these findings provide insight into the intracellular requirements for RNA virus replication and illustrate a fundamental shift in resource partitioning in infected diatoms, advancing our understanding of how RNA virus infection transforms diatom host metabolic function and downstream ecosystem dynamics.","rel_num_authors":9,"rel_authors":[{"author_name":"Chana F. Kranzler","author_inst":"Bar-Ilan University"},{"author_name":"Daniel P. Lowenstein","author_inst":"Woods Hole Oceanographic Institution, Massachusetts Institute of Technology"},{"author_name":"Linoy Bamshid","author_inst":"Bar-Ilan University"},{"author_name":"Hiba Waldman Ben-Asher","author_inst":"Bar-Ilan University"},{"author_name":"Helen Fredricks","author_inst":"Woods Hole Oceanographic Institution"},{"author_name":"Ehud Zelzion","author_inst":"Rutgers University"},{"author_name":"Jolie M. Tosten","author_inst":"Rutgers University"},{"author_name":"Benjamin A.S. Van Mooy","author_inst":"Woods Hole Oceanographic Institution"},{"author_name":"Kimberlee Thamatrakoln","author_inst":"Rutgers University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Mitochondrial Complex I Modulator Restores Network Resilience in Advanced Alzheimer's Disease Through Metabolic Reprogramming","rel_doi":"10.64898\/2026.06.14.732179","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732179","rel_abs":"Mitochondrial dysfunction and lipid dysregulation are among the earliest abnormalities in Alzheimer's disease (AD), yet their mechanistic interplay and therapeutic potential remain poorly understood. Here, we investigated whether restoration of mitochondrial function can reverse metabolic dysfunction and promote resilience in advanced-stage AD. Female APP\/PS1 mice were treated with the brain-penetrant mitochondrial complex I (mtCI) modulator CP2 beginning at 19 months of age, when pathology and cognitive deficits were well established. To define the metabolic mechanisms underlying therapeutic response, we developed iMiceBrain, the first brain-specific genome-scale metabolic model of the mouse brain, and integrated transcriptomics, targeted metabolomics, lipidomics, and metabolic network analyses. CP2 treatment broadly reprogrammed AD-associated molecular signatures and restored pathways involved in mitochondrial function, glucose utilization, lipid metabolism, synaptic activity, and cellular stress responses. Metabolic modeling identified enhanced mitochondrial substrate flexibility, activation of fatty acid utilization, restoration of pyruvate dehydrogenase flux, and normalization of cholesterol metabolism as key features of the therapeutic response. Lipidomic analyses further demonstrated correction of disease-associated alterations in cholesteryl esters, phospholipids, and sphingolipids. Together, these findings demonstrate that mild mtCI modulation restores metabolic resilience by coordinating mitochondrial and lipid metabolism, establishing it as a disease-modifying therapeutic strategy for AD.","rel_num_authors":8,"rel_authors":[{"author_name":"Esraa Gabal","author_inst":"School of Health Sciences and Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA"},{"author_name":"Thi Kim Oanh Nguyen","author_inst":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"author_name":"Tetiana Kovalenko","author_inst":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"author_name":"Huanyao Gao","author_inst":"Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA"},{"author_name":"Noa Rappaport","author_inst":"Institute for Systems Biology, Seattle, WA 98109, USA"},{"author_name":"Cory C. Funk","author_inst":"Institute for Systems Biology, Seattle, WA 98109, USA"},{"author_name":"Priyanka Baloni","author_inst":"School of Health Sciences and Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA"},{"author_name":"Eugenia Trushina","author_inst":"Department of Neurology and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Disrupted Mitochondrial Copper Homeostasis Promotes Ferroptotic Stress, Senescence and MASLD Progression","rel_doi":"10.64898\/2026.06.15.731916","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.731916","rel_abs":"Background & Aims: Systemic metabolic dysfunction promotes degenerative diseases in many organs, including liver and kidney. The liver is a master regulator of systemic metal ion homeostasis. Hepatic copper deficiency is increasingly observed in metabolic dysfunction associated steatotic liver disease (MASLD) and is associated with greater disease severity and poor outcomes. However, mechanisms linking copper dysregulation to MASLD and its co-morbidities remain poorly defined. We investigated whether impaired mitochondrial copper homeostasis contributes to MASLD-related pathobiology and represents a modifiable therapeutic axis. Methods & Results: Using dietary mouse models of MASLD and in vitro systems, we found that dietary copper deficiency induces lipotoxicity and suppresses mitochondrial metabolic programs. MASLD livers exhibited marked depletion of copper, impaired cytochrome c oxidase integrity, and bioenergetic failure. Targeted restoration of mitochondrial copper with the copper ionophore elesclomol normalized copper-handling programs, improved mitochondrial function, and suppressed ferroptotic stress, hepatocyte senescence, and fibroinflammatory remodeling. Mechanistically, reduced expression of the mitochondrial copper transporter SLC25A3 and MT-CO1 disrupted the SLC25A3\/SCO1\/MT-CO1\/CTR1 axis, limited copper uptake and destabilized copper-iron balance, promoting maladaptive cell fate changes. Across multiple human cohorts and mouse models, copper-iron imbalance tracks with MASLD progression, clinical outcomes, and multiple extrahepatic comorbidities; restoring copper homeostasis in mice with MASLD attenuates both liver and kidney inflammation and fibrosis. Conclusions: Mitochondrial copper deficiency is a mechanistically actionable driver of MASLD that promotes bioenergetic failure, ferroptosis, senescence and fibroinflammatory damage in the liver and other organs. Targeting copper-centered mitochondrial regulation represents a novel biomarker and therapeutic strategy for MASLD and its systemic complications.","rel_num_authors":10,"rel_authors":[{"author_name":"Niansheng Ren","author_inst":"Duke University"},{"author_name":"Liuyang Wang","author_inst":"Duke University"},{"author_name":"Rajesh Dutta","author_inst":"Duke University"},{"author_name":"David Umbaugh","author_inst":"Duke University"},{"author_name":"Qiaojuan Zhang","author_inst":"University of Kansas Medical Center"},{"author_name":"Seh Hoon Oh","author_inst":"Duke University"},{"author_name":"Dennis C Ko","author_inst":"Duke University"},{"author_name":"Ming Song","author_inst":"University of Louisville"},{"author_name":"Anna Mae Diehl","author_inst":"Duke University"},{"author_name":"KUO DU","author_inst":"Duke University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"MacaSurfer: unified surface-volume mapping of the macaque brain across the lifespan","rel_doi":"10.64898\/2026.06.14.732101","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732101","rel_abs":"Macaque brain MRI is central to translational and comparative neuroscience, yet multi-site, longitudinal, and cross-species analyses are hindered by a lack of unified, automated structural processing tools. Existing pipelines, mostly adapted from human neuroimaging or restricted to fragmented steps, fail to provide robust surface-volume representations across heterogeneous acquisitions and developmental stages. Here we introduce MacaSurfer, a fully automated, containerized framework for unified surface-volume mapping of the macaque brain across the lifespan. MacaSurfer features components tailored for macaque anatomy: a tissue segmentation model, a tissue-guided bias-field correction method optimizing structural mapping from T1-weighted images alone, topology-aware surface reconstruction, and surface-aware volumetric registration. Validated on 1,346 imaging sessions from 965 macaques across 39 international sites (spanning 2 weeks to 23 years of age), MacaSurfer demonstrated exceptional anatomical consistency, test-retest precision, and robustness against image degradation. Leveraging MacaSurfer-derived morphometry, we established normative trajectories from 835 macaques, providing a standardized reference for downstream individualized deviation analysis. MacaSurfer is openly available with source code, containers, and pretrained models, offering a reproducible ecosystem to accelerate developmental, translational, and comparative neuroimaging.","rel_num_authors":13,"rel_authors":[{"author_name":"Yahui Wei","author_inst":"Beijing Key Laboratory of Brainnetome and Brain-Computer Interface; Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, Ch"},{"author_name":"Haiyan Wang","author_inst":"Beijing Key Laboratory of Brainnetome and Brain-Computer Interface; Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, Ch"},{"author_name":"Yufan Wang","author_inst":"Beijing Key Laboratory of Brainnetome and Brain-Computer Interface; Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, Ch"},{"author_name":"Lixin Chen","author_inst":"Key Laboratory of Cyberspace Security Defense, Institute of Information Engineering, University of Chinese Academy of Sciences, Beijing 100085, China"},{"author_name":"Luqi Cheng","author_inst":"School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin 541004, China"},{"author_name":"Jinquan Gao","author_inst":"New Cornerstone Science Laboratory, Chinese Institute for Brain Research, Beijing, Beijing 102206, China"},{"author_name":"Qi Zhu","author_inst":"Cognitive Neuroimaging Unit, INSERM, CEA, Universite Paris-Saclay, NeuroSpin Center, Gif-sur-Yvette, France"},{"author_name":"Congying Chu","author_inst":"Beijing Key Laboratory of Brainnetome and Brain-Computer Interface; Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, Ch"},{"author_name":"Ting Xu","author_inst":"Center for the Integrative Developmental Neuroscience, Child Mind Institute, New York, NY 10022, USA; Kunming Institute of Zoology, Chinese Academy of Sciences,"},{"author_name":"Chaohong Gao","author_inst":"Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, Guangdong 519031, China"},{"author_name":"Tianzi Jiang","author_inst":"Beijing Key Laboratory of Brainnetome and Brain-Computer Interface; Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, Ch"},{"author_name":"Wim Vanduffel","author_inst":"Department of Neurosciences, Laboratory of Neuro- and Psychophysiology, KU Leuven Medical School, Leuven, Belgium; Leuven Brain Institute, KU Leuven, Leuven, Be"},{"author_name":"Lingzhong Fan","author_inst":"Beijing Key Laboratory of Brainnetome and Brain-Computer Interface; Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, Ch"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Enteral docosahexaenoic and arachidonic acid supplementation and retinopathy of prematurity: a re-analysis of randomized controlled trials in preterm infants","rel_doi":"10.64898\/2026.06.12.26355524","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355524","rel_abs":"Background. A recent meta-analysis by Dang et al. [1] concluded that enteral supplementation with docosahexaenoic acid (DHA), with or without arachidonic acid (ARA) did not significantly affect retinopathy of prematurity (ROP) outcomes in preterm infants. Of four eligible trials that supplemented both DHA and ARA, only two contributed to each ROP outcome analyzed, and severe ROP was not assessed. Methods. We replicated the eligibility criteria and search strategy of Dang et al., restricted to trials that supplemented both DHA and ARA, and reanalyzed three ROP endpoints (any ROP, ROP requiring treatment, and severe ROP [stage 3 and\/or treated]) using complete outcome records from all eligible trials. Crude risk ratios (RR) were pooled by Mantel-Haenszel fixed-effect meta-analysis. Gestational age-adjusted odds ratios (adjOR) were pooled on the log scale by inverse-variance random-effects meta-analysis with restricted maximum likelihood (REML) estimation of between-study variance and Hartung-Knapp confidence intervals. Results. Five trials were included; one trial was identified in our replicated search but was excluded by Dang et al. without a stated rationale. The pooled estimate for any ROP was consistent with Dang et al. (RR 0.87 [95% CI 0.71-1.08]; adjOR 0.70 [0.46-1.08]). For ROP requiring treatment, the crude RR suggested a lower risk but did not reach statistical significance (RR 0.60 [0.35-1.04]), whereas the gestational age-adjusted estimate indicated lower odds (adjOR 0.47 [0.23-0.94]). For severe ROP, DHA+ARA supplementation produced a significant protective effect in both unadjusted and adjusted models (RR 0.56 [0.36-0.86]; adjOR 0.42 [0.19-0.96]). Conclusions. When all eligible trials contribute to each endpoint and severe ROP is included as an outcome, enteral DHA+ARA supplementation reduces severe ROP and is associated with lower odds of ROP requiring treatment after adjustment for gestational age. These findings differ from the conclusions of Dang et al. and support reconsideration of DHA+ARA supplementation as a strategy to reduce sight-threatening ROP in preterm infants.","rel_num_authors":9,"rel_authors":[{"author_name":"Ulrika Sjoebom","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"author_name":"Aldina Pivodic","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"author_name":"Pia Lundgren","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"author_name":"Sissel J Moltu","author_inst":"Department of Neonatal Intensive Care, Oslo University Hospital, Norway."},{"author_name":"Brandy Frost","author_inst":"Department of Pediatrics, Division of Neonatology, Endeavor Health, Evanston, IL; Pritzker School of Medicine, University of Chicago, Chicago, IL, USA."},{"author_name":"Daniel T Robinson","author_inst":"Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Christine Henriksen","author_inst":"Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Norway."},{"author_name":"Ann Hellstroem","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"author_name":"Anders K Nilsson","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Adverse Childhood Experiences and Growth Outcomes in Childhood: A Longitudinal EHR-Based Study","rel_doi":"10.64898\/2026.06.15.26355527","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355527","rel_abs":"Question Are adverse childhood experiences (ACEs) associated with altered growth trajectories in childhood? Findings In this cohort study of 412,549 children and adolescents, ACEs were associated with lower height throughout childhood, earlier pubertal timing, and shorter final stature. Height differences emerged approximately 2 years before ACE documentation and were greatest among those with earlier documentation. Meaning These findings suggest that early adversity affects physical growth in children and may serve as a measurable indicator of the biological consequences of early-life stress, especially in those with documentation of ACEs prior to the onset of typical pubertal growth. Importance Adverse childhood experiences (ACEs) are among the strongest risk factors for long-term mental and physical health complications, yet their impact on physical growth in childhood remains incompletely understood. Objective To determine the association of ACEs on childhood growth trajectories and growth dynamics. Design, Setting and Participants Retrospective cohort study using longitudinal electronic health record data. Data was collected from participants between February 1999 and August 2025. A large academic medical center biobank linked to deidentified electronic health records in the southeastern United States. A total of 412,549 individuals with at least 2 recorded height measurements between the ages of 2 and 20 were included in the primary analysis. Growth curve analyses were performed in a subset of 199,844 individuals with at least 3 height measurements spanning at least 2 years. Genetic analyses were performed in a subset of 10,114 individuals of primarily European ancestry. Exposure(s) Documented exposure to adverse childhood experiences before age 18 years identified through a natural language processing algorithm. Main Outcome(s) and Measure(s) Height-for-age z-scores across childhood, final attained height, and growth curve parameters estimated using SuperImposition by Translation and Rotation (SITAR) modeling. Results Among 412,549 participants, 18,502 (4.5%) had clinically documented ACEs during childhood. ACE documentation was associated with lower height-for-age z-scores throughout childhood and adolescence. Final attained height was significantly lower among ACE-documented individuals, with mean differences of -3.0 cm among males (174.0 cm vs 177.0 cm, p < 0.001) and -1.3 cm among females (161.8 cm vs 163.1 cm, p < 0.001). Height differences emerged approximately 2 years before clinical ACE documentation. Earlier age at first ACE documentation was associated with progressively shorter final attained height, with each year decrease in age at ACE documentation associated with a decrease in final height of -0.20 cm in females and -0.35 cm in males. Those with first ACE documented prior to pubertal age also showed the most pronounced growth dynamic differences, with males demonstrating a mean reduction in size of 5.25 cm (95% CI, -6.79 cm to -3.70 cm) and 1.26-year earlier pubertal timing (95% CI, -1.50 to -1.03 years), and females demonstrating a reduction in growth curve size of 3.62 cm (95% CI, -4.83 to -2.41 cm) and 1.14-year earlier pubertal timing (95% CI, -1.29 to -0.99 years). Conclusions and Relevance In this large clinical cohort, clinically documented ACEs were associated with time-dependent reductions in stature, earlier pubertal timing, and short final attained height. These findings suggest that early childhood adversity may have lasting effects on physical development and highlight growth trajectories as a potential marker of the biological consequences of early-life stress.","rel_num_authors":9,"rel_authors":[{"author_name":"Samuel Palmer","author_inst":"Vanderbilt University"},{"author_name":"Cathy Shyr","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Theodore J Morley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"John Shelley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Lide Han","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jill H Simmons","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Cosmin Bejan","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Colin Walsh","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Douglas M Ruderfer","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Validating an Early Pregnancy HbA1c as the Screening Test for Gestational Diabetes Mellitus: Findings from PRISMA Pakistan Cohort","rel_doi":"10.64898\/2026.06.08.26355138","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355138","rel_abs":"Background: Early identification of gestational diabetes mellitus (GDM) is critical to improving maternal and neonatal outcomes, particularly in resource-constrained settings where universal oral glucose tolerance testing (OGTT) is burdensome. We assessed whether early-pregnancy HbA1c alone or combined with common risk factors can predict GDM and reduce the burden of OGTT requirements in a peri-urban cohort in Karachi, Pakistan. Methods: We conducted a secondary analysis of the Pregnancy Risk Infant Surveillance and Measurement Alliance (PRISMA) Pakistan cohort. Women enrolled before 20 weeks' gestation with available early-pregnancy HbA1c and a 2-hour 75g OGTT at 24 to 28 weeks were included. We externally validated GDM prediction models originally developed in the STRiDE-India cohort. Model performance was evaluated using receiver operating characteristic (ROC) curves and area under the curve (AUC). We assessed four models: HbA1c alone (Model 1a); age, BMI, and family history of diabetes mellitus (FH DM) (Model 1b); HbA1c combined with age, BMI, and FH DM (Model 2); and an extended model, i.e., Model 2 combined with socioeconomic status, gestational age, parity, systolic and diastolic blood pressure (Model 3). A dual-threshold approach was applied to assess rule-in and rule-out performance. Results: Among 2,489 women, GDM incidence was 7.5% (n=186). Models with a broader set of predictors demonstrated higher AUC values, with Model 2 achieving an AUC of 0.61 (95% CI: 0.57, 0.66). Including additional factors (Model 3) did not further improve predictive ability (AUC: 0.62; 95% CI: 0.58, 0.66). In addition, at predefined thresholds, Model 2 achieved sensitivity of 73.7% (rule-out) and specificity of 83.5% (rule-in), with the potential to reduce OGTT requirements (58.5%). Conclusions: Early-pregnancy risk stratification using HbA1c combined with simple clinical predictors offers a pragmatic approach to streamline GDM screening among high-risk pregnant women. A dual-threshold strategy using Model 2 could reduce reliance on universal OGTT while prioritizing high-risk women for confirmatory testing.","rel_num_authors":9,"rel_authors":[{"author_name":"Sabahat Naz","author_inst":"Aga Khan University"},{"author_name":"Nida Yazdani","author_inst":"Aga Khan University"},{"author_name":"Zahra Hoodbhoy","author_inst":"The Aga Khan University"},{"author_name":"Yonas Ghebremihael-Weldeselassie","author_inst":"University of Warwick"},{"author_name":"Azqa Mazhar","author_inst":"The Aga Khan University"},{"author_name":"Aneeta Hotwani","author_inst":"Aga Khan University"},{"author_name":"Fyezah Jehan","author_inst":"Aga Khan University"},{"author_name":"Muhammad Imran Nisar","author_inst":"Aga Khan University"},{"author_name":"Romaina Iqbal","author_inst":"Aga Khan University"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Development of an automated, imaging-based preoperative screening model for early identification of malnutrition in an abdominal surgery cohort","rel_doi":"10.64898\/2026.06.08.26355187","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355187","rel_abs":"Background: Clinical malnutrition affects one in five abdominal surgery patients and increases postoperative complications and mortality. Current screening occurs after admission, closing the window for preoperative nutritional intervention. No objective, scalable preoperative screening tool exists. Objective: To determine whether automated volumetric CT-based body composition analysis improves preoperative identification of surgical patients at risk for clinical malnutrition compared to clinical variables or single slice imaging alone. Methods: Retrospective cohort study of adults undergoing elective abdominal surgery at a quaternary academic medical center (2018 to 2021) with a preoperative CT scan within 90 days and complete nutrition assessment. Clinical malnutrition was diagnosed by a registered dietitian using ASPEN\/AND criteria. Three sex stratified Elastic Net models were compared: (1) base clinical variables; (2) base plus L3 single slice skeletal muscle index and attenuation; and (3) base plus comprehensive 3D volumetric quantification of five muscle groups and two fat depots. Discrimination (AUROC), calibration (Brier score), and clinical utility (decision curve analysis) were assessed via 10-fold cross-validation. Results: Among 1,143 patients (52.4% female; mean age 60.5 years), 231 (20.2%) were diagnosed with malnutrition. Malnourished patients had significantly higher complication rates (36.4% vs. 15.4%, p<0.001) and prolonged length of stay (45.9% vs. 16.4%, p<0.001). Critically, 27.2% of malnourished patients were not flagged as at-risk by the standard Malnutrition Screening Tool. The volumetric model (Model 3) achieved the highest discrimination (males: AUROC 0.808; females: 0.794) and best calibration (males: Brier 0.129; females: 0.124), significantly outperforming both the base model (males: p=0.004; females: p<0.001) and L3 model (males: p=0.019; females: p<0.001). L3 features modestly improved discrimination but paradoxically worsened calibration; an effect corrected by volumetric features. Sex-specific risk profiles differed markedly, with ASA classification dominating female models and demographic factors dominating male models. Conclusions: Automated volumetric CT body composition analysis significantly improves preoperative malnutrition risk identification, with sex-stratified models revealing distinct risk profiles. Leveraging imaging already obtained for surgical planning, this approach opens a preoperative window for nutritional intervention that current practice fails to utilize.","rel_num_authors":14,"rel_authors":[{"author_name":"Victoria M Gershuni","author_inst":"University of Pennsylvania"},{"author_name":"Raheema A Damani","author_inst":"University of Pennsylvania"},{"author_name":"Shubha Vasisht","author_inst":"University of Pennsylvania"},{"author_name":"Rakesh Sharma","author_inst":"University of Pennsylvania"},{"author_name":"James Rowe","author_inst":"University of Pennsylvania"},{"author_name":"Charlene Compher","author_inst":"University of Pennsylvania"},{"author_name":"Jeffrey Duda","author_inst":"University of Pennsylvania"},{"author_name":"Hersh Sagreiya","author_inst":"University of Pennsylvania"},{"author_name":"Rachel Kelz","author_inst":"University of Pennsylvania"},{"author_name":"Hongzhe Lee","author_inst":"University of Pennsylvania"},{"author_name":"Gregory Tasian","author_inst":"University of Pennsylvania"},{"author_name":"Scott M. Damrauer","author_inst":"University of Pennsylvania"},{"author_name":"Gary D. Wu","author_inst":"University of Pennsylvania"},{"author_name":"Walter R Witschey","author_inst":"University of Pennsylvania"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"MRMU: A New Paradigm for Mendelian Randomization by Accounting for Measured Covariates and Unmeasured Confounders","rel_doi":"10.64898\/2026.06.15.26355649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355649","rel_abs":"Mendelian randomization (MR) is a powerful approach for causal inference, however, its reliability is frequently compromised by unadjusted covariates and unmeasured confounders, such as unmeasured pleiotropy and sample structure. To address these challenges, we introduce MRMU, a novel paradigm for the MR framework. Unlike traditional single-variable or multivariable MR methods, MRMU selects instrumental variables only from the exposure of interest and estimates one exposure effect at a time, while jointly accounting for measured covariates and unmeasured confounders. This design improves the reliability of MR analyses. In simulations and real data, MRMU achieved better type I error control, higher statistical power, and more accurate effect estimation than existing MR methods. Applying to coronary artery disease (CAD), MRMU identified robust cardiometabolic risk factors, including LDL-C, APOB, systolic blood pressure, body mass index, and smoking initiation, with consistent evidence across multiple CAD datasets. In contrast, traits such as HDL-C, height, and educational attainment, which were found to be significant by existing MR methods, were no longer supported by MRMU. MRMU further supported blood pressure-related traits, rather than lipid traits, as the more relevant pathway linking urate to CAD. Finally, by integrating large-scale plasma proteomics data, MRMU identified candidate CAD drug targets beyond established HMGCR- and PCSK9-related pathways, highlighting its utility for therapeutic target prioritization.","rel_num_authors":6,"rel_authors":[{"author_name":"Xianghong Hu","author_inst":"Shenzhen University"},{"author_name":"Jiashun Xiao","author_inst":"Sun Yat-sen University"},{"author_name":"Xinrui Huang","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Zhiwei Wang","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Hongyu Zhao","author_inst":"Yale School of Public Health"},{"author_name":"Can Yang","author_inst":"The Hong Kong University of Science and Technology"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Investigating naming error patterns after non-invasive brain stimulation and language treatment in persons with aphasia","rel_doi":"10.64898\/2026.06.08.26354856","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26354856","rel_abs":"Abstract Background: Transcranial direct current stimulation (tDCS) paired with behavioral language therapy can improve naming in persons with aphasia (PWA), yet naming errors persist. Little is known about how naming error patterns change after non-invasive brain stimulation is combined with language treatment. Aims: To examine whether right cerebellar tDCS plus computerized aphasia therapy changes the types of naming errors in people with chronic aphasia across timepoints, and to determine whether effects differ by cerebellar tDCS polarity (anode vs. cathode). Methods and Procedures: In a randomized, double-blind, sham-controlled, within-subject crossover study, we retrospectively analyzed behavioral data from 24 individuals with post-stroke aphasia. Each participant completed two 15-session intervention periods (3-5 sessions\/week) with active cerebellar tDCS + computerized aphasia therapy and sham + computerized aphasia therapy, separated by a two-month washout. General linear models (GLMs) assessed longitudinal changes in six error types (semantic, phonological real word, phonological nonword, no response, mixed, unrelated) on an untrained picture naming task (Philadelphia Naming Test; PNT) and a trained task (Naming 80; N80). Additional GLMs evaluated polarity effects with 2 (Group: anode vs. cathode) x 2 (Treatment) interactions, and treatment-order effects with 2 (Group: tDCS-first vs. sham-first) x 2 (Treatment) interactions. Outcomes and Results: Active cerebellar tDCS did not significantly change error types for trained items (N80). For untrained items (PNT), active tDCS reduced several error types relative to sham, with the clearest and most durable reduction in phonological nonword errors; more moderate reductions occurred for phonological real word and unrelated errors. Mixed errors showed a marginally opposite pattern, tending to increase after tDCS and decrease after sham. Polarity analyses indicated broadly similar effects across anodal and cathodal stimulation overall, but only the anode group showed a reliable treatment effect for phonological nonword errors on the PNT. Treatment-order analyses revealed no significant order effects. Conclusions: Our results indicate a shift in naming error types, particularly after tDCS treatment for the untrained naming task (PNT). These findings may help guide the course of treatment approaches of those with aphasia and what error naming pattern types may show changes post stroke when combining non-invasive brain stimulation and computerized aphasia therapy. Clinical Trial Registration: Cerebellar Transcranial Direct Current Stimulation and Aphasia Treatment [NCT02901574] Keywords: aphasia, naming errors, non-invasive brain stimulation, cerebellar tDCS, computerized aphasia treatment","rel_num_authors":6,"rel_authors":[{"author_name":"Myra J. Sydnor","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Micah Alan Johnson","author_inst":"Johns Hopkins University Department of Biostatistics, Bloomberg School of Public Health"},{"author_name":"Becky Lammers","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Jamie L. Murter","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Martin Lindquist","author_inst":"Johns Hopkins University Department of Biostatistics, Bloomberg School of Public Health"},{"author_name":"Rajani Sebastian","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Adherence to Red Reflex and Vision Screening Recommendations: A Deep Dive into Primary Care Implementation Gaps","rel_doi":"10.64898\/2026.06.08.26355190","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355190","rel_abs":"Introduction: Early childhood vision screening is critical for detecting amblyopia and other vision-threatening conditions. Despite screening recommendations during well-child visits, rates remain low. Red reflex assessment is recommended to identify serious ocular pathology, yet its use in primary care is not well described. We examined rates and drivers of vision screening in pediatric primary care. Methods: We conducted a retrospective review of electronic health records for children 3 to 5 years attending well-child visits in 2022 in one of three representative primary care clinics within a university health system. Outcomes were documented red reflex and functional vision tests. We evaluated associations with patient demographics and clinic site using multivariable logistic regression Results: Among 1,003 visits, 21.1% (n=212) had a documented red reflex assessment, and 60.8% (n=610) a functional vision test. Younger children (ages 3 and 4 vs. 5 years) had higher odds of red reflex assessment [adjusted odds ratio (aOR) 9.00 and 8.64], and lower odds of a functional vision (aOR 0.47 and 0.59) test. Females had higher odds of red reflex assessment (aOR 1.53). Other\/Multiracial children had lower odds of red reflex assessment than Non-Hispanic White children (aOR 0.48). Screening rates varied significantly by clinic site Conclusions: Visual function and red reflex assessment are inconsistently performed in pediatric primary care, with particularly low rates of red reflex documentation. Screening rates varied between clinics and were affected by age. These findings highlight missed opportunities for early detection of vision-threatening conditions and identify targets for improving adherence to pediatric vision screening recommendations","rel_num_authors":13,"rel_authors":[{"author_name":"Afua O Asare","author_inst":"University of Utah Health John A Moran Eye Center"},{"author_name":"Giovani Robles","author_inst":"The University of Utah Spencer Fox Eccles School of Medicine"},{"author_name":"E Eugenie Hartmann","author_inst":"Akron Childrens Hospital"},{"author_name":"Carole Stipelman","author_inst":"Department of Pediatrics, University of Utah Health"},{"author_name":"Dallen Calder","author_inst":"The University of Utah Spencer Fox Eccles School of Medicine"},{"author_name":"Olaoluwa Omotowa","author_inst":"The University of Utah Spencer Fox Eccles School of Medicine"},{"author_name":"Jessie Montgomery","author_inst":"The University of Utah Spencer Fox Eccles School of Medicine"},{"author_name":"Bryce T Baugh","author_inst":"John A. Moran Eye Center, University of Utah Health"},{"author_name":"Brian Stagg","author_inst":"University of Utah Health John A Moran Eye Center"},{"author_name":"Guilherme Del Fiol","author_inst":"Department of Biomedical Informatics, University of Utah"},{"author_name":"Melissa  H. Watt","author_inst":"Department of Population Health Sciences, The University of Utah"},{"author_name":"Michelle R Hribar","author_inst":"University of Illinois Chicago"},{"author_name":"JD Smith","author_inst":"Department of Population Health Sciences, University of Utah"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Prevalence and Correlates of Ideal Cardiovascular Health among Ugandan Adolescents: A Cross-Sectional Study","rel_doi":"10.64898\/2026.06.13.26355572","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355572","rel_abs":"Introduction: Cardiovascular disease (CVD) risk factors often emerge during adolescence and track into adulthood, yet data on cardiovascular health (CVH) in sub-Saharan Africa remain limited. We assessed the prevalence and correlates of ideal CVH among Ugandan adolescents. Methods: We analysed baseline data of adolescents enrolled in a cluster-randomised controlled trial being conducted in urban (Kampala) and rural (Jinja) districts of Uganda. In this study, Ideal CVH was defined as meeting \"ideal\" status of 5-7 of the American Heart Association's Life's Simple 7 metrics. Random-effects logistic regression was used to identify factors associated with ideal CVH, accounting for village-level clustering. Results: We recruited 1316 participants with a mean age of 13.2 years, of whom 58.1% were female. Overall, the prevalence of ideal CVH was 66.8% (95% CI: 64.2% - 69.3%). The prevalence was higher in Jinja (74.4%, 95%CI: 70.9% - 77.7%) than Kampala (59.6%, 95%CI: 55.8%-63.2%) and the difference was evident (p<0.001). Male adolescents had higher odds of ideal CVH than  females in both rural (aOR=1.55, 95%CI: 1.05-2.29) and urban (aOR=1.90, 95%CI: 1.38-2.63) settings. Increasing age and higher education level were  associated with lower odds of ideal CVH in both settings, likely reflecting age-related behavioural changes. Conclusion: More than half of Ugandan adolescents have ideal CVH, with disparities by sex, age, and urbanisation. These findings suggest that cardiovascular health declines during adolescence and highlight the need for early, targeted interventions, particularly among female and urban adolescents.","rel_num_authors":24,"rel_authors":[{"author_name":"Levicatus Mugenyi","author_inst":"MRC\/UVRI Uganda Research Unit On AIDS: MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Simple Ouma","author_inst":"TASO: AIDS Support Organisation"},{"author_name":"Ivan Namakoola","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Arthur Namara","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Isaac  Samuel Kintu","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Francis  Xavier Namugera","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Sumayiya Nalubega","author_inst":"TASO: AIDS Support Organisation"},{"author_name":"Sanula Nanozi","author_inst":"TASO: AIDS Support Organisation"},{"author_name":"Faith Tumuhairwe","author_inst":"TASO: AIDS Support Organisation"},{"author_name":"Dorothy Mirembe","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Charles Ssekyanzi","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Costella Tindyebwa","author_inst":"Roundoff Synergy"},{"author_name":"Martin Muddu","author_inst":"Infectious Diseases Research Collaboration"},{"author_name":"Flavia Zalwango","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Mathias Akugizibwe","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Moreen  Chaka Namulundu","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Perez  Nicholas Ochanda","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Eleanor Namusoke","author_inst":"Republic of Uganda Ministry of Health"},{"author_name":"Mina Nakawuka","author_inst":"Republic of Uganda Ministry of Health"},{"author_name":"Gerald Mutungi","author_inst":"Republic of Uganda Ministry of Health"},{"author_name":"Rachel King","author_inst":"University of California San Francisco"},{"author_name":"Moffat Nyirenda","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"David Moore","author_inst":"The University of British Columbia"},{"author_name":"Josephine Birungi","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Orion: Towards Lab Automation with Computer-Using Agents","rel_doi":"10.64898\/2026.06.13.732095","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.732095","rel_abs":"Laboratory discovery increasingly depends on computational workflows that connect experimental data to analysis, interpretation and follow-up hypotheses. Yet these workflows remain constrained by labor-intensive use of specialized software, visual inspection through graphical user interfaces, and integration of knowledge across multiple sources. Here, we present Orion, a computer-using AI agent for biomedical image analysis and interpretation that moves towards lab automation by automating this computational layer of laboratory work. Orion combines large language models with terminal execution, GUI control and adaptive multi-step reasoning in a shared computing environment. It can inspect visual data, operate standard scientific software, mine web resources and conduct end-to-end analysis and interpretation workflows without requiring bespoke software integrations. Across benchmarks, Orion achieved over 90% accuracy on biomedical database and literature retrieval tasks, learned to use the popular tools CellProfiler and QuPath for quantitative analysis of cellular and tissue images, respectively, and facilitated autonomous discovery in experimental imaging data. In 100 hours of autonomous exploration of a large-scale perturbation imaging dataset, Orion generated 52 research reports, of which human scientist review prioritized 22 plausible mechanistic hypotheses. These results show that computer-using AI agents can substantially expand the reach of laboratory automation, providing a scalable and auditable route from experimental imaging data to quantitative analysis, reports and biologically grounded hypotheses.","rel_num_authors":5,"rel_authors":[{"author_name":"Chang Ma","author_inst":"The University of Hong Kong"},{"author_name":"Linh Trinh","author_inst":"Genentech"},{"author_name":"Matt Bucci","author_inst":"Genentech"},{"author_name":"Aviv Regev","author_inst":"Genentech"},{"author_name":"Hanchen Wang","author_inst":"Genentech"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Environmental microbial extracts for longitudinal studies of gut microbiome assembly and maintenance","rel_doi":"10.64898\/2026.06.12.732002","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.732002","rel_abs":"Animals harbor diverse gut microorganisms that influence host health and fitness. Synthetic microbial communities have been instrumental in enabling reductionist studies of host-microbiome interactions, but some questions require microbial communities with more natural-like complexity while preserving experimental tractability, in vivo monitoring, and quantitative analysis. Here, we describe a method optimized for longitudinal studies of host-microbiome-environment interactions in the nematode Caenorhabditis elegans. In this approach, complex microbial extracts (CMEs) are generated from environmental samples and applied to worm culture plates, providing a diverse yet experimentally convenient microbial environment. We show that CME composition remains stable during cold storage, enabling reproducible longitudinal experiments while minimizing confounding environmental drift over time. As a proof of principle, we apply this method to examine age-dependent changes in the worm gut microbiome, providing support for previous reports of age-dependent increase in the abundance of gut Enterobacteriaceae. CMEs provide a practical and reproducible framework that complements experiments using monocultures or synthetic communities, enabling longitudinal studies of host-microbiome interactions under conditions that better approximate natural microbial complexity.","rel_num_authors":3,"rel_authors":[{"author_name":"Rahul Bodkhe","author_inst":"University of California, Berkeley"},{"author_name":"Rebecca Choi","author_inst":"University of California Berkeley"},{"author_name":"Michael Shapira","author_inst":"University of California Berkeley"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Whole-proteome structure\/function prediction in Uropathogenic E. coli reveals previously missed host-microbe and microbe-phage interaction pathways","rel_doi":"10.64898\/2026.06.16.732597","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732597","rel_abs":"The rapid advancement of high-throughput sequencing technologies has vastly increased the number of known protein sequences, but the experimental characterization of their structures and functions lags behind. This gap in knowledge impedes our understanding of biological mechanisms of these proteins, hinders the interpretation of high-throughput experiments, and exposes a significant challenge in modern biology: deducing the structural and functional information of proteins based on their sequences. Most computational approaches rely on homology with well-annotated proteins, yet many proteins lack identifiable homologues, reducing the power of this approach. Here, we integrated cutting-edge protein structure and function prediction methods to develop a complete sequence-structure-function pipeline that predicts structures and functions based on primary sequences. We applied this pipeline to predict the structure and function of all proteins in Escherichia coli UTI89, a model strain of uropathogenic E. coli. Based on the predicted functions, we performed enrichment analysis on the whole genome and revealed the possible roles and related biological mechanisms of poorly annotated proteins in this organism. Moreover, the performance of our pipeline was further validated through detailed case studies of the UTI89_C0931 and ybtS genes. Finally, we compiled the UTI89 structure and function database (https:\/\/seq2fun.dcmb.med.umich.edu\/UTI89), offering it as a community resource to aid researchers in elucidating the roles of unannotated proteins in uropathogenic E. coli. This database aims to bridge critical knowledge gaps in microbial pathogenicity and resistance, enhancing our capacity to tackle emerging health threats.","rel_num_authors":6,"rel_authors":[{"author_name":"Chunxiang Peng","author_inst":"University of Michigan"},{"author_name":"Henry Schreiber","author_inst":"Washington University"},{"author_name":"Chengxin Zhang","author_inst":"University of Michigan"},{"author_name":"Quancheng Liu","author_inst":"University of Michigan"},{"author_name":"Scott  J Hultgren","author_inst":"Washington University in Saint Louis"},{"author_name":"Lydia Freddolino","author_inst":"University of Michigan"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Structural and Functional Principles of Hcp-Mediated Antibacterial Toxin Delivery by the Type VI Secretion System","rel_doi":"10.64898\/2026.06.15.732508","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732508","rel_abs":"The type VI secretion system (T6SS) is a bacterial contractile nanomachine that translocates toxic effectors into neighboring cells, helping bacteria to survive and compete in polymicrobial environments. The core T6SS structural protein Hcp forms the inner tube and mediates the loading and delivery of diverse effectors. Yet, how Hcp selectively recruits structurally and functionally distinct effectors in the absence of recognizable secretion signals remains poorly understood. Here, using Pseudomonas aeruginosa H1-T6SS as a model, we combined competition-coupled deep mutational scanning with cryo-EM based structural analysis to determine how Hcp accommodates distinct effectors. The resulting mutational landscape distinguishes structurally constrained residues required for Hcp tube assembly from lumen-facing residues specialized for cargo engagement. Near-atomic-resolution structures of Hcp bound to Tse2 and Tse4, together with a high-confidence Hcp-Tse1 model, revealed that while effector-specific contacts exist, Hcp engages different cargos through largely shared, dispersed interfaces characterized by polar-biased and variation-tolerant interactions. Comparative structural analyses further showed that effector-interacting residues are not governed by conserved primary-sequence motifs, but by conserved lumen-facing geometry and permissive physicochemical properties across distantly related bacteria. Together, our findings support a model in which Hcp acts as a selective yet adaptable scaffold that accommodates diverse antibacterial effectors through conserved structural features and flexible interaction surfaces, providing a mechanistic framework for understanding cargo selection by the T6SS and explaining how a conserved secretion nanomachine can evolve to deliver diverse toxic payloads.","rel_num_authors":6,"rel_authors":[{"author_name":"Po-Yin Chen","author_inst":"Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan."},{"author_name":"Yung-Chih Chen","author_inst":"Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan."},{"author_name":"Chun-Hsiung Wang","author_inst":"Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan."},{"author_name":"Jia-Ying Su","author_inst":"Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan."},{"author_name":"Chien-Ling Lin","author_inst":"Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan."},{"author_name":"See-Yeun Ting","author_inst":"Academia Sinica"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"A dish-to-biobank framework links \u03b2-cell nutrient-stress programs to genetic and dietary risk for Type 2 Diabetes","rel_doi":"10.64898\/2026.06.12.731989","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731989","rel_abs":"Type 2 diabetes (T2D) arises from genetic susceptibility and chronic metabolic stress, but whether these converge on shared molecular programs in human populations remains unclear. Here, we develop a dish-to-biobank framework linking controlled beta cell perturbation to population-scale disease genetics through the circulating plasma proteome, and apply it to T2D. scRNA-seq of human stem cell-derived islets under factorial glucose and palmitate exposure identifies their combination (glucolipotoxicity) as the condition eliciting the strongest SC-beta cell transcriptional response, with glucolipotoxicity-upregulated genes uniquely enriched for T2D heritability, monogenic diabetes genes, and rare-variant burden signals. CRISPR knockout of beta cell identity regulators PAX6 and PDX1 aligns with this program, establishing convergence of environmental and genetic perturbations on a shared disease-relevant state. We then used the plasma proteome as an accessible population-scale readout of these experimentally defined beta cell stress programs, scoring 45,956 UK Biobank White British participants. We define heritable stress signatures that associate with refined carbohydrate and saturated fat intake, and undergo trans-tissue genetic regulation, with a subset of variants showing diet-dependent effects. Together, these findings establish glucolipotoxicity as a genetically anchored model of beta cell dysfunction and provide a generalizable framework for linking controlled cellular perturbations to human disease genetics at population scale.","rel_num_authors":15,"rel_authors":[{"author_name":"Xianming Wang","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Hanbyul Lee","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Ann Le","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Berk Turhan","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Nan Hu","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Pretty S Garcia","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Xuewei Cao","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Dingyu Liu","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Thahmina A Ali","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Nan Zhang","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Breanna Williams","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Caleb A Lareau","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Gao Wang","author_inst":"Columbia University Medical Center"},{"author_name":"Danwei Huangfu","author_inst":"Memorial Sloan-Kettering Cancer Center"},{"author_name":"Kushal K Dey","author_inst":"Memorial Sloan Kettering Cancer Center"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Summarizing Evolutionary Trajectories from Phylogenetic Character Maps of Discrete Traits","rel_doi":"10.64898\/2026.06.14.732171","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732171","rel_abs":"When reconstructing phylogenetic character histories, biologists aim to identify distinct evolutionary trajectories, or paths of character state evolution. However, biologists typically wish to summarize the information representing large numbers of potential character histories for a single phylogeny. For discrete characters, few approaches exist for summarizing the number of unique evolutionary trajectories beyond the frequency of specific events (i.e., state transition types) or the time lineages spend in each state. Here, we introduce a framework for summarizing the evolutionary trajectories of discrete character histories by compressing them into trajectory trees, where branches represent unique character-evolution pathways rather than lineages. This framework includes a novel compressed tree representation, called a scenario tree, that retains temporal information, ensuring that each root-to-tip path represents a unique, temporally explicit evolutionary trajectory. We describe and apply several approaches to summarize phylogenetic trees into transition trees. We include visual summaries, such as consensus trajectory trees, trajectory tree tanglegrams, and 'trajectory-through-time plots', to compare how unique evolutionary trajectories accumulate across lineages and state transitions. We also include quantitative summaries, such as the time spent in unique evolutionary trajectories and the number of transitions that follow unique character-state transitions. We use our new trajectory-wise summaries to evaluate the adequacy of commonly used continuous-time Markov models of character evolution, which are memoryless and consider only the rates between pairs of states. We conducted multiple simulation-based experiments demonstrating the utility of our novel trajectory-wise approaches. We also apply our new trajectory-wise approaches to Greater Antillean Anolis lizard biogeography and ecomorph evolution, and find that Anoles evolved along considerably more unique evolutionary trajectories than expected under simulations of our best-fitting character evolution model. The number of unique evolutionary paths accumulated in an early burst pattern relative to simulated trajectories, with this burst being more intense than expected across all character state transition events.","rel_num_authors":2,"rel_authors":[{"author_name":"Sean W McHugh","author_inst":"Washington University in St. Louis"},{"author_name":"Michael J Landis","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Structural Basis of Nidovirus Replication Organelle Evolution Revealed by the Arterivirus DMV Pore Complex","rel_doi":"10.64898\/2026.06.15.732489","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732489","rel_abs":"Positive-strand RNA viruses of the order Nidovirales - which include coronaviruses and arteriviruses - remodel host membranes into double-membrane vesicles (DMVs) as replication organelle to shield viral RNA synthesis from immune sensors. In coronaviruses, newly synthesized RNA is exported to the cytoplasm through a massive DMV pore complex formed by viral non-structural proteins (nsps). However, it remains unknown whether this elaborate architecture is unique to large-genome coronaviruses or a universal hallmark of the order. Here, we integrate in situ cryo-electron tomography and single-particle cryo-electron microscopy to resolve the atomic structure of DMV pore complex within its native membrane environment, from Equine Arteritis Virus (EAV), a prototype arterivirus with small genome. Despite lacking obvious sequence homology, the minimal EAV pore shares conserved architectural principles with its elaborate coronavirus counterpart. EAV pore complex is formed by a 12:12 stoichiometry of nsp2 and nsp3 protomers organized into four stacked concentric rings on double-membrane, yet generating pronounced structure symmetry mismatch. Functionally, the complex displays a distinct pore profile while preserving a positively charged central channel, essential for viral replication and transport. These findings demonstrate that, despite diversity in genome size and virion morphology, nidovirus replication organelles exhibit striking evolutionary conservation at the atomic structural level. Collectively, we propose that the order Nidovirales can be unified at the ultrastructural level by this conserved signature pore complex on the DMV-based replication organelle.","rel_num_authors":13,"rel_authors":[{"author_name":"Wenxin Zhang","author_inst":"The University of Hong Kong"},{"author_name":"Tingting Yang","author_inst":"The University of Hong Kong"},{"author_name":"Wanglong Hu","author_inst":"The University of Hong Kong"},{"author_name":"Le Zheng","author_inst":"The University of Hong Kong"},{"author_name":"Yixin Huang","author_inst":"The University of Hong Kong"},{"author_name":"Lijie Zhong","author_inst":"The University of Hong Kong"},{"author_name":"Qiannan Li","author_inst":"The Hong Kong Polytechnic University"},{"author_name":"Yuxin Gao","author_inst":"The University of Hong Kong"},{"author_name":"Qian Yang","author_inst":"The University of Hong Kong"},{"author_name":"Yanfei Wang","author_inst":"The University of Hong Kong"},{"author_name":"Haibo Jiang","author_inst":"The University of Hong Kong"},{"author_name":"Xiulian Yu","author_inst":"The Hong Kong Polytechnic University"},{"author_name":"Tao Ni","author_inst":"The University of Hong Kong"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Biodiversity data portals as methodological filters for iNaturalist: how platform choice can shape biodiversity assessments","rel_doi":"10.64898\/2026.06.12.731923","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731923","rel_abs":"iNaturalist has rapidly grown to become one of the largest contributors of global biodiversity data, being widely used in academic research, to support and inform applied conservation, and to help develop policy indicators for decision makers. However, the availability of iNaturalist data varies based on the digital platform it is accessed from. Here, we assess whether the pathway used to access iNaturalist data from three commonly available biodiversity data sources: iNaturalist, the Global Biodiversity Information Facility (GBIF) and ESRI's ArcGIS Online, alters occurrence record availability and downstream analyses for ecological inference. First, we investigate iNaturalist data availability on ArcGIS Online and find that the reduced field metadata for record location and obscuration information can lead to biased assumptions in the spatial ranges of sensitive species. Second, when assessing iNaturalist records available through GBIF, we find that restrictive Creative Commons observation licenses prevent an average of 26.1% of iNaturalist Research Grade records from being exported to GBIF, and this can lead to differences in environmental niche analysis when compared to datasets including all available research grade records. Understanding differences in platform licensing when integrating across biodiversity data repositories is another consideration for researchers and practitioners when conducting biodiversity assessments. Our results show that the pathway through which iNaturalist data are accessed can function as a methodological filter, potentially altering spatial coverage, the climatic conditions represented by occurrence datasets, and downstream ecological analysis.","rel_num_authors":4,"rel_authors":[{"author_name":"Elizabeth Edson","author_inst":"California Academy of Sciences"},{"author_name":"Diego Ellis-Soto","author_inst":"University of California, Berkeley"},{"author_name":"Avery P. Hill","author_inst":"California Academy of Sciences"},{"author_name":"Rebecca F. Johnson","author_inst":"California Academy of Sciences"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Transcriptional regulation of the rainbow trout spleen corticotropin-releasing factor system in response to inflammatory challenges: roles of NF-kB and cortisol","rel_doi":"10.64898\/2026.06.12.731886","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731886","rel_abs":"The corticotropin-releasing factor (CRF) system bidirectionally interacts with cytokines and other immune-related components in mammals. However, the nature of these interactions remains poorly characterized in other vertebrates, including teleost fishes. To gain insight into the relationship between immune responses and the CRF system in teleosts, we explored how CRF system components were transcriptionally regulated in immune organs of rainbow trout (Oncorhynchus mykiss). We first characterized the CRF system in the spleen and head kidney, two primary immune organs in teleosts, and found that many CRF system components were present in both tissues, but splenic expression was consistently greater. Changes in the abundance of splenic CRF system components following vaccination (which transiently stimulated inflammatory responses and cytokine production) indicated contrasting and time-dependent regulation of CRF receptor 1 (CRFR1; suppression) and CRFR2 (stimulation) activities in response to an inflammatory challenge. Using spleen explant cultures, we then evaluated whether these effects were mediated by either of nuclear factor kappa B (NF-kB; a pro-inflammatory transcription factor) or cortisol (an anti-inflammatory hormone). At baseline, cultured spleens increased cytokine production and exhibited transcriptional changes in CRF system components comparable to those observed following vaccination. Cortisol treatment and NF-kB inhibition both attenuated the rise in cytokine transcription; however, cortisol treatment generally affected transcripts influencing CRFR1 activity, while NF-kB inhibition reduced CRFR2 activity. Overall, our data provide novel insight into CRF system regulation in the spleen and suggest that cortisol and inflammatory cytokines differentially regulate CRFR1 and CRFR2 activity within this organ.","rel_num_authors":5,"rel_authors":[{"author_name":"Brett M Culbert","author_inst":"University of Cincinnati"},{"author_name":"Leah Grosman","author_inst":"University of Guelph"},{"author_name":"Tania Rodr\u00edguez-Ramos","author_inst":"University of Waterloo"},{"author_name":"Brian Dixon","author_inst":"University of Waterloo"},{"author_name":"Nicholas J Bernier","author_inst":"University of Guelph"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Distinct thermal responses of a host plant and an invertebrate herbivore affect ecosystem productivity and disease dynamics in a coastal marine ecosystem","rel_doi":"10.64898\/2026.06.12.731926","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731926","rel_abs":"Biological rates, like growth, tend to have unimodal (hump-shaped) responses to temperature, and these relationships can vary among species and biological processes. In most systems, full thermal performance relationships are rarely characterized for interacting species (e.g., consumer-resource or host-pathogen pairs), making it challenging to predict how their interactions, and subsequently, how communities, will shift with climate change. We investigated how the thermal responses of eelgrass (Zostera marina, an important marine foundation species in the N. hemisphere) and an isopod grazer (Pentidotea resecata), which putatively acts as an indirect vector of eelgrass wasting disease, interact to affect eelgrass productivity and wasting disease dynamics. In a laboratory experiment crossing five temperatures, two grazing, and two disease exposure treatments, across various metrics, eelgrass growth responded unimodally to temperature in the absence of grazers. Grazers depressed plant growth and flattened its thermal performance curves. Thermal performance curves for isopods indicated that increases in grazing and survival at intermediate temperatures negated concurrent gains in plant growth at these temperatures, while decreased isopod survival at high temperatures reduced their top-down effect on eelgrass. Isopods had negligible effects on plant disease responses, but warming reduced the time to disease onset and increased final disease severity. Overall, whole-plant disease severity remained low and did not substantially affect eelgrass leaf elongation, net growth, or rhizome dry mass. However, disease-treatment plants grew more new leaves at intermediate temperatures, possibly to combat losses in photosynthetic capacity in diseased leaf tissue. These results indicate that climate change-associated warming will likely increase eelgrass vulnerability to wasting disease. However, in sublethal outbreaks, disease could have less of an impact on eelgrass productivity than warming-induced increases in grazing. Thus, ignoring grazer responses to temperature could result in unreliable predictions of eelgrass productivity under climate change.","rel_num_authors":5,"rel_authors":[{"author_name":"Amy A Briggs","author_inst":"University of California Davis"},{"author_name":"Grace Callahan","author_inst":"Northeastern University"},{"author_name":"Nicholas Yoong","author_inst":"University of California Davis"},{"author_name":"John J Stachowicz","author_inst":"University of California Davis"},{"author_name":"Anya L Brown","author_inst":"University of California Davis"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Biologic therapy is associated with selective changes in airway eosinophil subpopulations in severe asthma","rel_doi":"10.64898\/2026.06.12.731433","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731433","rel_abs":"Rationale: Eosinophilic airway inflammation is common in severe asthma and strongly associated with symptoms, exacerbations, and impaired lung function. Although type 2 (T2)-targeted biologics improve outcomes and reduce eosinophils, many patients experience residual symptoms and exacerbations. Emerging evidence suggests that these biologics may differentially affect specific airway eosinophil subpopulations, representing a potential mechanism of suboptimal treatment response. Objective: Determine the effect of biologic treatment on eosinophil subpopulations in adults with severe asthma using in-depth immune profiling with mass cytometry (CyTOF). Methods: Fifty adults with severe asthma (28 biologic-naive, 22 on stable-dose biologic therapy for [&ge;]6 months) underwent clinical phenotyping, spirometry, blood sampling, and sputum induction. Twenty-nine sputum samples passed quality control thresholds and were profiled by CyTOF. Manually gated sputum eosinophils were clustered using FlowSOM to identify eosinophil subpopulations, and cluster abundances and marker expression were compared across treatment groups. Measurements and Main Results: CyTOF revealed treatment-associated shifts in circulating immune cells (lower CD4+ T cells and B cells, higher monocytes) and lower sputum CD8+ T cells. Unsupervised clustering of sputum eosinophils identified eight distinct subpopulations, and selective depletion of Cluster 6 was noted in biologic-treated participants (biologic-naive vs anti-TSLP logFC -4.98, p=0.003; biologic-naive vs anti-IL5 logFC -6.89, p=0.01). Higher Cluster 6 proportion correlated with worse ACT scores (rho = -0.44, p = 0.02) and lung function (FEV1 % predicted: rho = -0.47, p < 0.01; FEV1\/FVC: rho = -0.40, p = 0.03). Functionally, Cluster 6 displayed enriched trafficking\/activation markers (CCR3\/Eotaxin-1, CD69, CD80, CRTH2) and non-T2 inflammatory mediators (TNF, IL-8, TLR7). Conclusion: Biologic therapy in severe asthma was associated with selective depletion of a highly activated sputum eosinophil subpopulation with capability to drive both T2 and non-T2 inflammatory pathways. This cluster correlated with worse asthma control and lung function, indicating it may be a biologically important driver of persistent disease and potential biomarker to more accurately predict treatment response.","rel_num_authors":11,"rel_authors":[{"author_name":"Gabriella Wilson","author_inst":"Yale School of Medicine"},{"author_name":"Sandra Zaeh","author_inst":"Yale School of Medicine"},{"author_name":"Samir Gautam","author_inst":"Yale School of Medicine"},{"author_name":"Xiting Yan","author_inst":"Yale School of Medicine"},{"author_name":"Qing Liu","author_inst":"Yale School of Medicine"},{"author_name":"Olivia Hay","author_inst":"Yale School of Medicine"},{"author_name":"Nicole Grant","author_inst":"Yale School of Medicine"},{"author_name":"Jean Estrom","author_inst":"Yale School of Medicine"},{"author_name":"William Busse","author_inst":"University of Wisconsin School of Medicine and Public Health"},{"author_name":"Ruth R Montgomery","author_inst":"Yale University"},{"author_name":"Geoffrey  Lowell Chupp","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Dissecting and directing pathology foundation models","rel_doi":"10.64898\/2026.06.12.731496","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731496","rel_abs":"Foundation models (FMs) are central to digital pathology, encoding histology images into dense embeddings for facilitating diagnostic classification, molecular alteration prediction, and clinical outcome modeling. However, the opacity of these embeddings renders FM-based systems \"black boxes,\" limiting their trustworthiness for clinical translation and utility for scientific discovery. Here, we introduce PICASSO (Pathology Image Concept Atlas built via SparSe dictiOnary learning), a framework that makes pathology FMs interpretable and controllable. PICASSO decomposes FM embeddings into human-interpretable visual concepts using a sparse autoencoder. It is trained on more than 120 million tissue patches across 32 cancer types, producing the first pan-cancer atlas of histomorphological concepts. We demonstrate that PICASSO enables diverse downstream applications of FM embeddings by exposing interpretable structure within learned representations and supporting concept-level intervention. It enables auditing of clinical model behavior by revealing the morphological features driving predictions. Beyond transparency and validation, PICASSO enables the discovery of new biological insights; for example, it identified hobnailing epithelial morphology as a previously unrecognized biomarker of EGFR mutations in lung adenocarcinoma. By linking PICASSO-derived concepts with spatial transcriptomics, we uncover associations between morphological patterns and gene expression programs. Furthermore, PICASSO allows suppression of concepts associated with technical artifacts, thereby reducing model reliance on spurious signals. Finally, PICASSO enables controlled manipulation of learned concepts to generate counterfactual embeddings for exploratory therapeutic analysis, such as modulating tumour-infiltrating lymphocyte density to assess impacts on predict survival outcomes. Together, PICASSO provides a principled framework for transforming pathology FMs into platforms for mechanistic insight and discovery.","rel_num_authors":6,"rel_authors":[{"author_name":"Chanwoo Kim","author_inst":"University of Washington"},{"author_name":"Jakub Kaczmarzyk","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Deepika Savant","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Zhen Zhao","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Peter Koo","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Su-In Lee","author_inst":"University of Washington"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Buprenorphine Restricts the Conformational Landscape of the \u03bc-Opioid Receptor","rel_doi":"10.64898\/2026.06.12.731880","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731880","rel_abs":"Biased signaling and partial agonism in GPCRs are considered promising strategies to develop safer and more effective drugs. Various mechanisms have been proposed to explain these phenomena, including the ability of biased and partial ligands to promote specific receptor conformations able to engage distinct intracellular partners. Recent cryo-electron microscopy structures of the -opioid receptor (MOR) bound to both G-proteins and {beta}-arrestins have shown clear structural differences shedding light into the putative signaling states. However, the accessibility of such conformations in the absence of the intracellular partner and the mechanisms by which ligands modulate their populations remain poorly understood. In the present manuscript, we employ extensive enhanced-sampling simulations to explore the free-energy landscapes of MOR bound to a biased partial agonist (buprenorphine) and a full unbiased agonist (endomorphin-1) showing that the ligands indeed stabilize distinct ensembles of active-like states. In particular, we observe that endomorphin-1, the natural ligand, explores two different ensembles of active-like conformations, including states compatible with either G-protein or {beta}-arrestin1 recruitment, whereas buprenorphine restricts access to these conformations and favors a narrower subset of active states more prone to G-protein binding. Moreover, we analyze the allosteric pathways connecting the ligands to the different active-like states. Together, our findings provide a thermodynamic framework for understanding biased signaling at MOR and confirm that in MOR ligand efficacy and signaling preference emerge from the selective redistribution of receptor conformational populations even in the absence of the effector proteins. This perspective may guide the rational design of opioid therapeutics with improved signaling profiles and reduced adverse effects.","rel_num_authors":5,"rel_authors":[{"author_name":"Simone Aureli","author_inst":"University of Geneve"},{"author_name":"Maria Bzowka","author_inst":"University of Geneva"},{"author_name":"Nicola Piasentin","author_inst":"University of Geneva"},{"author_name":"Massimo Fuss","author_inst":"University of Geneva"},{"author_name":"Francesco Luigi Gervasio","author_inst":"University of Geneva"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"OmicOS: A Comprehensive Omics Ecosystem Infrastructure and Agent System for the AI Era","rel_doi":"10.64898\/2026.06.11.731775","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731775","rel_abs":"Biology has accumulated a vast ecosystem of omics methods, but much of this ecosystem remains built for expert humans rather than scientific agents. Methods are scattered across Python packages, R\/Bioconductor and CRAN workflows, command-line tools, incompatible data containers and implicit object states, making even routine analyses difficult for an AI system to choose, execute and verify reliably. Here we introduce OmicOS, a comprehensive omics ecosystem infrastructure and agent system that turns OmicVerse V2, an open-source omics community, into an executable foundation for agentic biology. OmicVerse V2 provides the community substrate: scalable AnnDataOOM-compatible rust backends, agent-friendly Python algorithms for single-cell, spatial, bulk and multi-omics analysis, interfaces to single-cell foundation models, and Python-native reconstructions of historically R-centred Bioconductor\/CRAN-style workflows. OmicOS makes this substrate actionable by registering analytical functions as state-aware capability contracts, allowing agents to inspect live data objects, select valid methods, execute controlled workflows and record provenance. The result is not a fixed pipeline, but a programmable omics environment in which agents compose real analyses from verified community methods rather than inventing tools. Across external and purpose-built benchmarks, OmicOS ranked first among the evaluated systems, reaching 81.2% on BiomniBench. Adding OmicVerse to a minimal agent improved task completion by up to 34.2 percentage points with qwen-3.6-35b, and controlled ablations showed that the gains came from registry-grounded execution rather than from larger models, documentation retrieval or unrestricted tool exposure. The same infrastructure scaled to atlas-sized data, reproduced R-centred workflows in Python and converted external pathology software into agent-usable skills. In a discovery task starting from a whole-body spatial map and the term Alzheimer disease, OmicOS composed a non-canonical workflow that integrated spatial expression, genetic association, eQTL and colocalization evidence to nominate a colon epithelial risk axis centred on PICALM, CD2AP and CR1. Together, OmicVerse and OmicOS define an open foundation for AI-era omics, showing how a community of biological methods can be transformed into a reliable, extensible and agent-operable system for discovery.","rel_num_authors":25,"rel_authors":[{"author_name":"Zehua Zeng","author_inst":"Stanford University"},{"author_name":"Xu Meng","author_inst":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University"},{"author_name":"Lei Hu","author_inst":"School of Life Sciences, WestLake University"},{"author_name":"Chen Li","author_inst":"Tsinghua University"},{"author_name":"Peng Liu","author_inst":"Tsinghua University"},{"author_name":"Yu Shi","author_inst":"Tsinghua University"},{"author_name":"Xuejiao Ma","author_inst":"Department of Surgery of Traditional Chinese Medicine, China-Japan Friendship Hospital"},{"author_name":"Lianchong Gao","author_inst":"Nurturing Center of Jiangsu Province for the State Laboratory of AI Imaging and Interventional Radiology, Zhongda Hospital, School of Medicine, Southeast Univer"},{"author_name":"Xuehai Wang","author_inst":"Department of Physiology and Pharmacology, Karolinska Institutet"},{"author_name":"Zhi Luo","author_inst":"Daxing Research Institute,University of Science and Technology Beijing"},{"author_name":"Yawen Zheng","author_inst":"Daxing Research Institute,University of Science and Technology Beijing"},{"author_name":"Jieshen Xian","author_inst":"School of Public Health, Guangzhou Medical University,"},{"author_name":"Ziheng Lin","author_inst":"School of Basic Medical Sciences, Capital Medical University"},{"author_name":"Haoliang Zhu","author_inst":"The First Clinical Medical College, Wenzhou Medical University"},{"author_name":"Zhaorui Jiang","author_inst":"School of Environment and Energy, Peking University"},{"author_name":"Sheng Mao","author_inst":"Westlake University"},{"author_name":"Yifan Lu","author_inst":"Stanford University"},{"author_name":"Wenzhuo Tang","author_inst":"Michigan State University"},{"author_name":"Qiangwei Peng","author_inst":"School of Mathematical Sciences,Peking University"},{"author_name":"Yuqing Ma","author_inst":"Tsinghua University"},{"author_name":"Liping Zhou","author_inst":"School of Chemistry and Biological Engineering,University of Science and Technology Beijing"},{"author_name":"Cencan Xing","author_inst":"School of Chemistry and Biological Engineering,University of Science and Technology Beijing"},{"author_name":"Xuegong Zhang","author_inst":"Tsinghua University"},{"author_name":"Yuanyan Xiong","author_inst":"Department of Biochemistry, Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University"},{"author_name":"Hongwu Du","author_inst":"Daxing Research Institute,University of Science and Technology Beijing"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"OmicOS: A Comprehensive Omics Ecosystem Infrastructure and Agent System for the AI Era","rel_doi":"10.64898\/2026.06.11.731775","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731775","rel_abs":"Biology has accumulated a vast ecosystem of omics methods, but much of this ecosystem remains built for expert humans rather than scientific agents. Methods are scattered across Python packages, R\/Bioconductor and CRAN workflows, command-line tools, incompatible data containers and implicit object states, making even routine analyses difficult for an AI system to choose, execute and verify reliably. Here we introduce OmicOS, a comprehensive omics ecosystem infrastructure and agent system that turns OmicVerse V2, an open-source omics community, into an executable foundation for agentic biology. OmicVerse V2 provides the community substrate: scalable AnnDataOOM-compatible rust backends, agent-friendly Python algorithms for single-cell, spatial, bulk and multi-omics analysis, interfaces to single-cell foundation models, and Python-native reconstructions of historically R-centred Bioconductor\/CRAN-style workflows. OmicOS makes this substrate actionable by registering analytical functions as state-aware capability contracts, allowing agents to inspect live data objects, select valid methods, execute controlled workflows and record provenance. The result is not a fixed pipeline, but a programmable omics environment in which agents compose real analyses from verified community methods rather than inventing tools. Across external and purpose-built benchmarks, OmicOS ranked first among the evaluated systems, reaching 81.2% on BiomniBench. Adding OmicVerse to a minimal agent improved task completion by up to 34.2 percentage points with qwen-3.6-35b, and controlled ablations showed that the gains came from registry-grounded execution rather than from larger models, documentation retrieval or unrestricted tool exposure. The same infrastructure scaled to atlas-sized data, reproduced R-centred workflows in Python and converted external pathology software into agent-usable skills. In a discovery task starting from a whole-body spatial map and the term Alzheimer disease, OmicOS composed a non-canonical workflow that integrated spatial expression, genetic association, eQTL and colocalization evidence to nominate a colon epithelial risk axis centred on PICALM, CD2AP and CR1. Together, OmicVerse and OmicOS define an open foundation for AI-era omics, showing how a community of biological methods can be transformed into a reliable, extensible and agent-operable system for discovery.","rel_num_authors":25,"rel_authors":[{"author_name":"Zehua Zeng","author_inst":"Stanford University"},{"author_name":"Xu Meng","author_inst":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University"},{"author_name":"Lei Hu","author_inst":"School of Life Sciences, WestLake University"},{"author_name":"Chen Li","author_inst":"Tsinghua University"},{"author_name":"Peng Liu","author_inst":"Tsinghua University"},{"author_name":"Yu Shi","author_inst":"Tsinghua University"},{"author_name":"Xuejiao Ma","author_inst":"Department of Surgery of Traditional Chinese Medicine, China-Japan Friendship Hospital"},{"author_name":"Lianchong Gao","author_inst":"Nurturing Center of Jiangsu Province for the State Laboratory of AI Imaging and Interventional Radiology, Zhongda Hospital, School of Medicine, Southeast Univer"},{"author_name":"Xuehai Wang","author_inst":"Department of Physiology and Pharmacology, Karolinska Institutet"},{"author_name":"Zhi Luo","author_inst":"Daxing Research Institute,University of Science and Technology Beijing"},{"author_name":"Yawen Zheng","author_inst":"Daxing Research Institute,University of Science and Technology Beijing"},{"author_name":"Jieshen Xian","author_inst":"School of Public Health, Guangzhou Medical University,"},{"author_name":"Ziheng Lin","author_inst":"School of Basic Medical Sciences, Capital Medical University"},{"author_name":"Haoliang Zhu","author_inst":"The First Clinical Medical College, Wenzhou Medical University"},{"author_name":"Zhaorui Jiang","author_inst":"School of Environment and Energy, Peking University"},{"author_name":"Sheng Mao","author_inst":"Westlake University"},{"author_name":"Yifan Lu","author_inst":"Stanford University"},{"author_name":"Wenzhuo Tang","author_inst":"Michigan State University"},{"author_name":"Qiangwei Peng","author_inst":"School of Mathematical Sciences,Peking University"},{"author_name":"Yuqing Ma","author_inst":"Tsinghua University"},{"author_name":"Liping Zhou","author_inst":"School of Chemistry and Biological Engineering,University of Science and Technology Beijing"},{"author_name":"Cencan Xing","author_inst":"School of Chemistry and Biological Engineering,University of Science and Technology Beijing"},{"author_name":"Xuegong Zhang","author_inst":"Tsinghua University"},{"author_name":"Yuanyan Xiong","author_inst":"Department of Biochemistry, Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University"},{"author_name":"Hongwu Du","author_inst":"Daxing Research Institute,University of Science and Technology Beijing"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"OmicOS: A Comprehensive Omics Ecosystem Infrastructure and Agent System for the AI Era","rel_doi":"10.64898\/2026.06.11.731775","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731775","rel_abs":"Biology has accumulated a vast ecosystem of omics methods, but much of this ecosystem remains built for expert humans rather than scientific agents. Methods are scattered across Python packages, R\/Bioconductor and CRAN workflows, command-line tools, incompatible data containers and implicit object states, making even routine analyses difficult for an AI system to choose, execute and verify reliably. Here we introduce OmicOS, a comprehensive omics ecosystem infrastructure and agent system that turns OmicVerse V2, an open-source omics community, into an executable foundation for agentic biology. OmicVerse V2 provides the community substrate: scalable AnnDataOOM-compatible rust backends, agent-friendly Python algorithms for single-cell, spatial, bulk and multi-omics analysis, interfaces to single-cell foundation models, and Python-native reconstructions of historically R-centred Bioconductor\/CRAN-style workflows. OmicOS makes this substrate actionable by registering analytical functions as state-aware capability contracts, allowing agents to inspect live data objects, select valid methods, execute controlled workflows and record provenance. The result is not a fixed pipeline, but a programmable omics environment in which agents compose real analyses from verified community methods rather than inventing tools. Across external and purpose-built benchmarks, OmicOS ranked first among the evaluated systems, reaching 81.2% on BiomniBench. Adding OmicVerse to a minimal agent improved task completion by up to 34.2 percentage points with qwen-3.6-35b, and controlled ablations showed that the gains came from registry-grounded execution rather than from larger models, documentation retrieval or unrestricted tool exposure. The same infrastructure scaled to atlas-sized data, reproduced R-centred workflows in Python and converted external pathology software into agent-usable skills. In a discovery task starting from a whole-body spatial map and the term Alzheimer disease, OmicOS composed a non-canonical workflow that integrated spatial expression, genetic association, eQTL and colocalization evidence to nominate a colon epithelial risk axis centred on PICALM, CD2AP and CR1. Together, OmicVerse and OmicOS define an open foundation for AI-era omics, showing how a community of biological methods can be transformed into a reliable, extensible and agent-operable system for discovery.","rel_num_authors":25,"rel_authors":[{"author_name":"Zehua Zeng","author_inst":"Stanford University"},{"author_name":"Xu Meng","author_inst":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University"},{"author_name":"Lei Hu","author_inst":"School of Life Sciences, WestLake University"},{"author_name":"Chen Li","author_inst":"Tsinghua University"},{"author_name":"Peng Liu","author_inst":"Tsinghua University"},{"author_name":"Yu Shi","author_inst":"Tsinghua University"},{"author_name":"Xuejiao Ma","author_inst":"Department of Surgery of Traditional Chinese Medicine, China-Japan Friendship Hospital"},{"author_name":"Lianchong Gao","author_inst":"Nurturing Center of Jiangsu Province for the State Laboratory of AI Imaging and Interventional Radiology, Zhongda Hospital, School of Medicine, Southeast Univer"},{"author_name":"Xuehai Wang","author_inst":"Department of Physiology and Pharmacology, Karolinska Institutet"},{"author_name":"Zhi Luo","author_inst":"Daxing Research Institute,University of Science and Technology Beijing"},{"author_name":"Yawen Zheng","author_inst":"Daxing Research Institute,University of Science and Technology Beijing"},{"author_name":"Jieshen Xian","author_inst":"School of Public Health, Guangzhou Medical University,"},{"author_name":"Ziheng Lin","author_inst":"School of Basic Medical Sciences, Capital Medical University"},{"author_name":"Haoliang Zhu","author_inst":"The First Clinical Medical College, Wenzhou Medical University"},{"author_name":"Zhaorui Jiang","author_inst":"School of Environment and Energy, Peking University"},{"author_name":"Sheng Mao","author_inst":"Westlake University"},{"author_name":"Yifan Lu","author_inst":"Stanford University"},{"author_name":"Wenzhuo Tang","author_inst":"Michigan State University"},{"author_name":"Qiangwei Peng","author_inst":"School of Mathematical Sciences,Peking University"},{"author_name":"Yuqing Ma","author_inst":"Tsinghua University"},{"author_name":"Liping Zhou","author_inst":"School of Chemistry and Biological Engineering,University of Science and Technology Beijing"},{"author_name":"Cencan Xing","author_inst":"School of Chemistry and Biological Engineering,University of Science and Technology Beijing"},{"author_name":"Xuegong Zhang","author_inst":"Tsinghua University"},{"author_name":"Yuanyan Xiong","author_inst":"Department of Biochemistry, Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University"},{"author_name":"Hongwu Du","author_inst":"Daxing Research Institute,University of Science and Technology Beijing"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Super-Resolved Single Small Extracellular Vesicle Assay enabled by a Plasmonic Nanohole Array","rel_doi":"10.64898\/2026.06.12.731868","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731868","rel_abs":"The accurate quantification of biological nanoparticles, such as small extracellular vesicles (sEVs), is fundamentally hindered by a resolution-coincidence trade-off in digital assays. While physical confinement can isolate single particles, conventional optical readouts remain diffraction-limited, causing multi-particle occupancy to be miscounted as single events and thereby restricting the analytical dynamic range. Here, we report a nanoplasmonic platform that overcomes this limit by introducing a geometry-defined interface that uniquely unifies nanoscale compartmentalisation and near-field-assisted super-resolution imaging. Utilising a gold plasmonic nanohole array, the strict geometric periodicity of the lattice simultaneously serves as a template for single-vesicle confinement and a deterministic grid that generates an array of localised surface plasmon resonance near-field hotspots. This position-deterministic illumination pattern imposes known geometric priors on the excitation field, shifting high-spatial-frequency information into the detectable bandwidth to achieve sub-100 nm lateral resolution. This dual-purpose geometric determinism enables high-fidelity digital readout of individual vesicles with significantly fewer sub-images than stochastic, speckle-based metasurface structured illumination microscopy approaches. The assay achieves an analytical limit of detection of 143 sEVs\/L, matching the performance of state-of-the-art single-EV counting technologies. It successfully differentiates distinct sEV subpopulations based on surface biomarker expression, establishing a clear pathway for future clinical liquid biopsy applications. By replacing stochastic loading and illumination with geometric design, this work establishes a robust framework for precise vesicle interrogation with broad implications for emerging translational applications and fundamental biology.","rel_num_authors":10,"rel_authors":[{"author_name":"Anthony James El-Helou","author_inst":"University of Technology Sydney"},{"author_name":"Yiting Liu","author_inst":"University of Technology Sydney, NSW 2007, Australia"},{"author_name":"Fatemeh Khosravi","author_inst":"University of Technology Sydney"},{"author_name":"Chaohao Chen","author_inst":"University of Technology Sydney, NSW 2007, Australia"},{"author_name":"Carol H.W Yan","author_inst":"Electron Microscope Unit, UNSW Sydney, NSW 2052, Australia"},{"author_name":"Mark Lockrey","author_inst":"Electron Microscope Unit, UNSW Sydney, NSW 2052, Australia"},{"author_name":"Juanfang Ruan","author_inst":"Electron Microscope Unit, UNSW Sydney, NSW 2052, Australia"},{"author_name":"Zhaowei Liu","author_inst":"University of California, San Diego, California 92093, USA"},{"author_name":"Peter J Reece","author_inst":"School of Physics, UNSW Sydney, NSW 2052, Australia"},{"author_name":"Ying Zhu","author_inst":"University of Technology Sydney, NSW 2007, Australia"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Super-Resolved Single Small Extracellular Vesicle Assay enabled by a Plasmonic Nanohole Array","rel_doi":"10.64898\/2026.06.12.731868","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731868","rel_abs":"The accurate quantification of biological nanoparticles, such as small extracellular vesicles (sEVs), is fundamentally hindered by a resolution-coincidence trade-off in digital assays. While physical confinement can isolate single particles, conventional optical readouts remain diffraction-limited, causing multi-particle occupancy to be miscounted as single events and thereby restricting the analytical dynamic range. Here, we report a nanoplasmonic platform that overcomes this limit by introducing a geometry-defined interface that uniquely unifies nanoscale compartmentalisation and near-field-assisted super-resolution imaging. Utilising a gold plasmonic nanohole array, the strict geometric periodicity of the lattice simultaneously serves as a template for single-vesicle confinement and a deterministic grid that generates an array of localised surface plasmon resonance near-field hotspots. This position-deterministic illumination pattern imposes known geometric priors on the excitation field, shifting high-spatial-frequency information into the detectable bandwidth to achieve sub-100 nm lateral resolution. This dual-purpose geometric determinism enables high-fidelity digital readout of individual vesicles with significantly fewer sub-images than stochastic, speckle-based metasurface structured illumination microscopy approaches. The assay achieves an analytical limit of detection of 143 sEVs\/L, matching the performance of state-of-the-art single-EV counting technologies. It successfully differentiates distinct sEV subpopulations based on surface biomarker expression, establishing a clear pathway for future clinical liquid biopsy applications. By replacing stochastic loading and illumination with geometric design, this work establishes a robust framework for precise vesicle interrogation with broad implications for emerging translational applications and fundamental biology.","rel_num_authors":10,"rel_authors":[{"author_name":"Anthony James El-Helou","author_inst":"University of Technology Sydney"},{"author_name":"Yiting Liu","author_inst":"University of Technology Sydney, NSW 2007, Australia"},{"author_name":"Fatemeh Khosravi","author_inst":"University of Technology Sydney"},{"author_name":"Chaohao Chen","author_inst":"University of Technology Sydney, NSW 2007, Australia"},{"author_name":"Carol H.W Yan","author_inst":"Electron Microscope Unit, UNSW Sydney, NSW 2052, Australia"},{"author_name":"Mark Lockrey","author_inst":"Electron Microscope Unit, UNSW Sydney, NSW 2052, Australia"},{"author_name":"Juanfang Ruan","author_inst":"Electron Microscope Unit, UNSW Sydney, NSW 2052, Australia"},{"author_name":"Zhaowei Liu","author_inst":"University of California, San Diego, California 92093, USA"},{"author_name":"Peter J Reece","author_inst":"School of Physics, UNSW Sydney, NSW 2052, Australia"},{"author_name":"Ying Zhu","author_inst":"University of Technology Sydney, NSW 2007, Australia"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"MicroRNA-181 influences Alzheimer's risk by regulating neprilysin and microtubule-associated tau pathways, offering a novel target","rel_doi":"10.64898\/2026.06.11.731747","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731747","rel_abs":"Alzheimer's disease (AD) is characterized by amyloid-{beta} (A{beta}) peptide plaques and neurofibrillary tangles from hyperphosphorylated tau, though factors linking amyloid and tau pathology remain unclear. We investigated whether microRNA-181d-5p (miR-181d) associates with AD-related brain changes and regulates neprilysin and tau. Modeling miR-181d across individuals with no cognitive impairment, mild cognitive impairment, and AD revealed region- and sex-specific associations. Higher miR-181d levels associated with greater AD probability in the temporal lobe and cerebellum, and lower probability in the posterior cingulate cortex of males; miR-181c attenuated these probabilities. SNPs near MIR181 associated with altered entorhinal cortical thickness. In cellular models, miR-181 reduced neprilysin 3'-UTR activity, mRNA, protein, and enzymatic activity, while increasing tau mRNA and protein. Neprilysin diminution impairs A{beta} clearance and elevates tau, contributing to AD. RNA sequencing identified miR-181d-responsive neurodegenerative pathways. These findings identify miR-181 as a regulator of AD-relevant amyloid and tau pathways, providing novel targets.","rel_num_authors":6,"rel_authors":[{"author_name":"Ruizhi Wang","author_inst":"Indiana University School of Medicine"},{"author_name":"Bryan John Maloney","author_inst":"Indiana University School of Medicine"},{"author_name":"Kwangsik Nho","author_inst":"Indiana University School of Medicine"},{"author_name":"John S Beck","author_inst":"Michigan State University"},{"author_name":"Scott E Counts","author_inst":"Michigan State University"},{"author_name":"Debomoy K. Lahiri","author_inst":"Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Neuraminidase1 Activity Contributes to Vasopressin Receptor-mediated Augmentation of Water and Electrolyte Retention by the Kidney in Eln Haploinsufficient Mice","rel_doi":"10.64898\/2026.06.11.731713","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731713","rel_abs":"Elastin haploinsufficiency is a primary determinant of arteriopathy and hypertension that hallmark Williams syndrome (WS), a rare genetic disorder resulting from microdeletion of genes on human chromosome 7, including the elastin gene (ELN). Accumulating evidence suggests renal dysfunction, including enhanced sodium and water retention as an underlying cause of blood pressure elevation resulting from heterozygous deletion of Eln (Eln+\/-) in mice that recapitulates the cardiovascular phenotype of WS. However, the underlying pathophysiological mechanisms are poorly understood. Here, we determined whether the activity of neuraminidase-1 (NEU1) of the elastin receptor complex (ERC) contributes to abnormal handling of water and electrolytes by the kidney in Eln haploinsufficiency. Adult male and female Eln+\/+ and Eln+\/- mice were subjected to acute extracellular fluid volume expansion with normal saline, combined with pharmacological intervention targeting vasopressin V2 receptor (V2R), NEU1, ENaC, and NKCC2. In male Eln+\/+ mice, V2R blockade induced a dose-dependent increase in urine flow rate without affecting sodium excretion. Conversely, V2R stimulation with desmopressin markedly increased urinary sodium excretion in male Eln+\/+ but not Eln+\/- mice, while both sexes of Eln+\/- mice exhibited marked suppression of urine flow rate. Abrogation of ERC signaling through NEU1 inhibition produced a modest increase in urinary sodium excretion in male mice of both genotypes but augmented urine flow rate only in male Eln+\/+ mice. NEU1 blockade strikingly enhanced the natriuretic effect of furosemide and amiloride in male Eln+\/+ and modestly in Eln+\/- mice. Taken together, we conclude that Eln haploinsufficiency disrupts vasopressin-dependent modulation of sodium and water reabsorption by sex-dependently altering ERC-mediated modulation of NKCC2 and ENaC. These findings reveal a novel mechanism by which abnormal ERC activity due to Eln haploinsufficiency potentially contributes to renal dysfunction and hypertension.","rel_num_authors":5,"rel_authors":[{"author_name":"Gagandeep Kaur","author_inst":"Case Western Reserve University School of Medicine"},{"author_name":"Akua Serwaa-Bonsu","author_inst":"Case Western Reserve University School of Medicine"},{"author_name":"Kisho Miyasako","author_inst":"Oregon Health & Science University"},{"author_name":"James A McCormick","author_inst":"Oregon Health & Science University"},{"author_name":"Patrick Osei-Owusu","author_inst":"Case Western Reserve University School of Medicine"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Neuraminidase1 Activity Contributes to Vasopressin Receptor-mediated Augmentation of Water and Electrolyte Retention by the Kidney in Eln Haploinsufficient Mice","rel_doi":"10.64898\/2026.06.11.731713","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731713","rel_abs":"Elastin haploinsufficiency is a primary determinant of arteriopathy and hypertension that hallmark Williams syndrome (WS), a rare genetic disorder resulting from microdeletion of genes on human chromosome 7, including the elastin gene (ELN). Accumulating evidence suggests renal dysfunction, including enhanced sodium and water retention as an underlying cause of blood pressure elevation resulting from heterozygous deletion of Eln (Eln+\/-) in mice that recapitulates the cardiovascular phenotype of WS. However, the underlying pathophysiological mechanisms are poorly understood. Here, we determined whether the activity of neuraminidase-1 (NEU1) of the elastin receptor complex (ERC) contributes to abnormal handling of water and electrolytes by the kidney in Eln haploinsufficiency. Adult male and female Eln+\/+ and Eln+\/- mice were subjected to acute extracellular fluid volume expansion with normal saline, combined with pharmacological intervention targeting vasopressin V2 receptor (V2R), NEU1, ENaC, and NKCC2. In male Eln+\/+ mice, V2R blockade induced a dose-dependent increase in urine flow rate without affecting sodium excretion. Conversely, V2R stimulation with desmopressin markedly increased urinary sodium excretion in male Eln+\/+ but not Eln+\/- mice, while both sexes of Eln+\/- mice exhibited marked suppression of urine flow rate. Abrogation of ERC signaling through NEU1 inhibition produced a modest increase in urinary sodium excretion in male mice of both genotypes but augmented urine flow rate only in male Eln+\/+ mice. NEU1 blockade strikingly enhanced the natriuretic effect of furosemide and amiloride in male Eln+\/+ and modestly in Eln+\/- mice. Taken together, we conclude that Eln haploinsufficiency disrupts vasopressin-dependent modulation of sodium and water reabsorption by sex-dependently altering ERC-mediated modulation of NKCC2 and ENaC. These findings reveal a novel mechanism by which abnormal ERC activity due to Eln haploinsufficiency potentially contributes to renal dysfunction and hypertension.","rel_num_authors":5,"rel_authors":[{"author_name":"Gagandeep Kaur","author_inst":"Case Western Reserve University School of Medicine"},{"author_name":"Akua Serwaa-Bonsu","author_inst":"Case Western Reserve University School of Medicine"},{"author_name":"Kisho Miyasako","author_inst":"Oregon Health & Science University"},{"author_name":"James A McCormick","author_inst":"Oregon Health & Science University"},{"author_name":"Patrick Osei-Owusu","author_inst":"Case Western Reserve University School of Medicine"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"PhenoBIC: operator-free single-cell spatial phenotyping in multiplex imaging data using deep learning of cell staining patterns","rel_doi":"10.64898\/2026.06.11.731702","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731702","rel_abs":"Multiplex imaging is a valuable tool for spatially examining tissue microenvironments at the single-cell level to uncover biological and clinical insights. However, most multiplex image analysis workflows currently require manual intervention for cell phenotyping, which slows progress, demands human effort, and yields operator-dependent outputs. Here, we developed PhenoBIC, a pre-trained deep learning model for image classification of the multiplexed biomarker signals in a cell (Biomarker Imprint of a Cell) to classify cell phenotypes. We show that PhenoBIC (F1-score ~0.88) outperforms manual gating (widely used) and other machine learning-based computational approaches for cell marker expression classification. We validated this across multiple biomarkers, tissue sampling strategies (whole biopsies and tissue microarrays), multiplex panels, imaging platforms, and tissue types. We have released our in-house training and validation datasets of ~1.4 million manually curated cell expression ground truth labels. We have also open-sourced PhenoBIC and enabled its community-wide deployment via the QuPath interface.","rel_num_authors":11,"rel_authors":[{"author_name":"Abishek Sankaranarayanan","author_inst":"University of Washington"},{"author_name":"Chenkai Zhao","author_inst":"University of Washington"},{"author_name":"Madeline Gabriela Hernandez","author_inst":"University of Washington"},{"author_name":"Elizabeth A. Clemens","author_inst":"University of Washington"},{"author_name":"Kimberly S. Smythe","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Anum S. Kazerouni","author_inst":"University of Washington"},{"author_name":"Lisa L. Carr","author_inst":"Univeristy of Washington Seattle"},{"author_name":"Christopher I. Li","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Savannah C. Partridge","author_inst":"University of Washington"},{"author_name":"Shaveta Vinayak","author_inst":"University of Washington"},{"author_name":"Shachi Mittal","author_inst":"University of Washington"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Elastogenesis by adventitial progenitors acquiring a smooth muscle cell phenotype following aortic dissection","rel_doi":"10.64898\/2026.06.11.731783","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731783","rel_abs":"Following aortic dissection (AD), there is a sustained risk of vascular complications, progressive false lumen aneurysm formation, and rupture. However, no effective therapy exists to prevent these complications, highlighting the need to elucidate the pathophysiology following AD. Elastic fibers are crucial for maintaining aortic wall integrity but are thought to have limited regenerative capacity once disrupted during AD. This study defined that elastic fibers were newly generated in the false lumen wall following AD in humans and mice. In human ADs, new elastic fibers were observed in the false lumen wall 6 months after onset. In mice with descending AD induced by {beta}-aminopropionitrile (BAPN), elastin mRNA was markedly upregulated in the chronic phase following AD, accompanied by elastic fiber formation. These fibers coincided with smooth muscle cell (SMC) markers within the false lumen wall. Of note, lineage tracing studies demonstrated that these cells were not derived from resident SMCs but adventitial progenitor cells. In vitro experiments further demonstrated that adventitial progenitor cells produced elastic fibers while expressing SMC markers. Collectively, these findings suggest that adventitial progenitor cells differentiate into elastogenic SMC-like cells, contributing to false lumen remodeling through de novo elastic fiber formation following AD.","rel_num_authors":9,"rel_authors":[{"author_name":"Sohei Ito","author_inst":"University of Kentucky"},{"author_name":"Preet Patel","author_inst":"University of Kentucky"},{"author_name":"Taishi Inoue","author_inst":"Kobe University"},{"author_name":"Ruizhi Wang","author_inst":"Yale University"},{"author_name":"Yuriko Katsumata","author_inst":"University of Kentucky"},{"author_name":"Hong S. Lu","author_inst":"University of Kentucky"},{"author_name":"Kenji Okada","author_inst":"Kobe University"},{"author_name":"Alan Daugherty","author_inst":"University of Kentucky"},{"author_name":"Hisashi Sawada","author_inst":"University of Kentucky"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Rapid Intracellular Delivery of Human Heat Shock Protein 72 Prevents Memory Loss and Inhibits Neurodegeneration up to 9 Days After a Blast Injury","rel_doi":"10.64898\/2026.06.11.726712","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.726712","rel_abs":"Traumatic brain injuries (TBIs) are increasingly prevalent among military service members and are associated with long-term neurological impairment and neurodegeneration. Heat shock protein 72 (HSP72) has demonstrated cytoprotective properties and has been shown to cross the blood brain barrier in rat models of blast injury, remaining in brain tissue for up to 12 hours. In this study, we evaluate engineered Fv-HSP72 variants for their ability to reduce neurodegeneration and preserve short-term memory following blast-induced TBI. Male Sprague-Dawley rats were assigned to 9 groups of n = 8 rats. Animals were either not exposed to blast (Sham), exposed to blast (Blast Only), blast exposed and given buffer (Vehicle), or blast exposed and treated with one of three Fv-HSP72 variants, dosed at 10 or 30mg\/kg at 15m post-blast. Blast exposure was generated using an Advanced Blast Simulator (ABS) producing positive static pressure to model moderate to severe blast injury. Animals were euthanized 48 hours post injury for neurodegeneration and immunologic biomarker analysis. After selecting an effective Fv-HSP72 variant using the biomarker data, additional rats were divided into Sham, Vehicle, and Fv-HSP72 treatment groups to evaluate short-term memory function through the Novel Object Recognition (NOR) test on days 2 and 8 post-blast. Analysis of cortical and spinal cord tissues demonstrated a statistically significant reduction in expression of neurodegenerative markers of Tau phosphorylation and glial injury (GFAP) for rats receiving a single dose of our clinical candidate, RBB012-CTB. In fact, the drug drove astrogliosis toward a neuroprotective state in blast exposed rats. In the NOR assay, Fv-HSP72 treated rats showed improved recognition performance, indicating preservation of short-term memory function. With similar biomarker results obtained for a controlled cortical impact injury model published elsewhere (Chan et al. manuscript submitted; see bioRxiv preprint 10.64898\/2026.05.03.722564), the analyses suggest Fv-HSP72 is neuroprotective following a blast injury as well.","rel_num_authors":20,"rel_authors":[{"author_name":"Allen Chan","author_inst":"Rubicon Biotechnology, Irvine, California"},{"author_name":"Peethambaran Arun","author_inst":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Springs, Maryland"},{"author_name":"Krutik Patel","author_inst":"Rubicon Biotechnology, Irvine, California"},{"author_name":"Sarah Eintracht","author_inst":"Rubicon Biotechnology, Irvine, California"},{"author_name":"Manoj Govindarajulu","author_inst":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Springs, Maryland"},{"author_name":"Chetan Pundkar","author_inst":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Springs, Maryland"},{"author_name":"Rex Jeya Rajkumar Samdavid Thanapaul","author_inst":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Springs, Maryland"},{"author_name":"Gaurav Phuyal","author_inst":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Springs, Maryland"},{"author_name":"Sonia Su","author_inst":"Rubicon Biotechnology, Irvine, California"},{"author_name":"Lori Demirjian","author_inst":"Rubicon Biotechnology, Irvine, California"},{"author_name":"Peyton Politewicz","author_inst":"Center for Statistical Consulting, Dept. of Statistics, University of California, Irvine"},{"author_name":"Joni Ricks-Oddie","author_inst":"Center for Statistical Consulting, Dept. of Statistics, University of California, Irvine; Biostatistics, Epidemiology, and Research Design Unit, Institute for C"},{"author_name":"Dallas Hack","author_inst":"University of Pittsburgh, Pennsylvania"},{"author_name":"Robert Nishimura","author_inst":"Dept. of Neurology, School of Medicine, University of California, Los Angeles"},{"author_name":"Stephen T Hobson","author_inst":"Rubicon Biotechnology, Irvine, California; Dept. of Biology & Chemistry, Liberty University, Lynchburg, Virginia"},{"author_name":"Richard A Richieri","author_inst":"Rubicon Biotechnology, Irvine, California"},{"author_name":"Courtney L Robertson","author_inst":"Dept. of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland"},{"author_name":"Karolina Krasinska","author_inst":"Stanford University, Palo Alto, California"},{"author_name":"Joseph B Long","author_inst":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Springs, Maryland"},{"author_name":"Missag H Parseghian","author_inst":"Rubicon Biotechnology, Irvine, California"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Super Learner Ensemble Modeling of CPTAC Proteomic Data for Survival Prediction in Head and Neck Squamous Cell Carcinoma","rel_doi":"10.64898\/2026.06.11.731237","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731237","rel_abs":"Survival analysis in head and neck squamous cell carcinoma (HNSCC) is traditionally performed using Cox proportional hazards models, alongside some exploration into black-box machine learning methods. The Super Learner (SL) algorithm addresses this model selection dilemma by combining diverse candidate algorithms into a weighted ensemble to perform comparably to the best candidate method. This study evaluates the performance of SL in HNSCC. Proteomic features as well as clinical covariates from 96 CPTAC HNSCC samples were modeled with three candidate algorithms (Cox LASSO, Cox Ridge, and Random Survival Forest) as well as the ensemble SL method. Models were optimized via Uno's time-dependent Concordance Index (C-index) and tested at 1- and 3-year time horizons using 2000 bootstrap resamples. The Cox Ridge regression model achieved the highest predictive accuracy among the four total methods. However, the SL demonstrated stable performance over both time horizons (1-year C-index: 0.985; 3-year C-index: 0.960). Variable importance analysis of the Cox Ridge model successfully identified malignant proteins (ATR, MAML1, MIEN1) alongside novel potential prognostic indicators (ZNF800, KERA). This analysis emphasizes the statistical necessity for larger cohorts for ensemble learning, while providing a benchmark of proteomic indicators in HNSCC.","rel_num_authors":5,"rel_authors":[{"author_name":"Ethan Park","author_inst":"Rutgers University"},{"author_name":"Hannah Lee","author_inst":"Stanford University"},{"author_name":"Eun Jeong Oh","author_inst":"Northwell"},{"author_name":"Tristan Tham","author_inst":"Stanford University"},{"author_name":"Seungjun Ahn","author_inst":"Icahn School of Medicine at Mount Sinai"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"The Warburg effect as a metabolic niche construction strategy in the tumor microenvironment","rel_doi":"10.64898\/2026.06.12.731860","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731860","rel_abs":"The advantage conferred by the Warburg effect to cancer cells remains unresolved. While extensive research has examined aerobic glycolysis at the intracellular level, emphasizing its possible biosynthetic or ATP-production rate benefits, the fate of the energy-rich lactate exported into the tumor microenvironment (TME) has received comparatively little attention. Yet lactate is far from metabolically inert: it actively shapes the TME, functioning as a toxin to adaptive immune cells and simultaneously promoting growth of several non-cancerous cells in the tumor microenvironment which in turn promote tumor growth. Here, we develop a minimal consumer- resource model incorporating tumor, anti-tumor immune, and pro-tumor stromal populations interacting through shared nutrients, lactate, and metabolic byproducts. We find that lactate secretion imposes a growth-exclusion tradeoff: higher glycolytic allocation suppresses anti-tumor immune cells but simultaneously reduces tumor abundance due to less efficient metabolism. This tradeoff is resolved in the presence of pro-tumor stromal populations capable of metabolic cross- feeding, namely stromal cells that convert lactate into metabolites which feed back to support tumor growth, thereby offsetting the glycolytic cost. The cross-feeding benefit is second-order in population size, requiring a critical tumor mass to operate. Taken together, these results suggest that there may be an ecological advantage of the Warburg effect, contingent on microenvironmental context. Specifically, lactate secretion is beneficial primarily when appropriate stromal partners are present, functioning as a niche-construction strategy that reorganizes the tumor ecosystem in favor of tumor expansion.","rel_num_authors":2,"rel_authors":[{"author_name":"Vaibhav Anand","author_inst":"Northeastern University"},{"author_name":"Herbert Levine","author_inst":"Northeastern Univ."}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Physics-Driven Zero-Shot Reconstruction of Isotropic 3D Fluorescence Microscopy under Undersampled Acquisition","rel_doi":"10.64898\/2026.06.13.732100","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.732100","rel_abs":"Three-dimensional (3D) imaging represents the development of next generation of fluorescence microscopy. However, routine axial down-sampling makes isotropic resolution unrealistic. Here, we propose DeepUI, a physical zero-shot framework designed to achieve isotropic 3D fluorescence images from a low axial sampling rate. DeepUI fully leverages the intrinsic characteristics of 3D images through physics-guided degradation, which incorporates spatial-frequency joint learning to generate a scaled optical transfer function, combined with noise degradation and an up-sampling branch. Typically requiring just 5 minutes for training and 0.5 minutes for high-throughput and fast prediction, we demonstrate the superior performance of DeepUI to get isotropic results, and the exclusivity to axial down-sampling conditions, even in more challenging conditions, including defocused background, noise, and resolution blur.","rel_num_authors":20,"rel_authors":[{"author_name":"Ruijie Cao","author_inst":"Peking University"},{"author_name":"Tong Jin","author_inst":"Peking University"},{"author_name":"Fengyuan Xin","author_inst":"Tsinghua University"},{"author_name":"Yiwei Hou","author_inst":"Peking University"},{"author_name":"Yunzhe Fu","author_inst":"Peking University"},{"author_name":"Boya Jin","author_inst":"Peking University"},{"author_name":"Lijun Li","author_inst":"Hebei University"},{"author_name":"Shu Gao","author_inst":"Peking University"},{"author_name":"Han Wang","author_inst":"Peking University"},{"author_name":"Yaning Li","author_inst":"Peking University"},{"author_name":"Dilzatay Saimi","author_inst":"Peking University"},{"author_name":"Wei Ren","author_inst":"Peking University"},{"author_name":"Wenyi Wang","author_inst":"Peking University"},{"author_name":"Guangwei Xin","author_inst":"Peking University"},{"author_name":"Kexin Yuan","author_inst":"TsinghuaUniversity"},{"author_name":"Zhixing Chen","author_inst":"Peking University"},{"author_name":"Xuantao Su","author_inst":"Shandong University"},{"author_name":"Dongyun Kim","author_inst":"Yonsei University"},{"author_name":"Meiqi Li","author_inst":"Peking University"},{"author_name":"Peng Xi","author_inst":"Peking University"}],"rel_date":"2026-06-16","rel_site":"biorxiv"},{"rel_title":"Nocturnal Respiratory Rate and Variability Predict Long-term Mortality in Stable Outpatients with Cardiovascular Disease","rel_doi":"10.64898\/2026.06.12.26355214","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355214","rel_abs":"BackgroundRespiratory rate (RR) predicts short-term mortality in acute care settings, yet its prognostic significance in clinically stable outpatients remains poorly defined.\n\nObjectivesTo determine whether the median and variability of nocturnal respiratory rate (NRR) are independently associated with long-term cardiovascular and all-cause mortality in outpatients with cardiovascular disease.\n\nMethodsWe analyzed overnight chest belt waveforms from elective polysomnography in 5,679 older adults with cardiovascular disease enrolled in the Sleep Heart Health Study (SHHS). NRR was quantified at 30-second resolution, and per-subject median NRR and within-night variability (standard deviation) were derived. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate associations with cardiovascular and all-cause mortality over 3-year and 15-year follow-up periods, adjusting for demographic characteristics, cardiopulmonary comorbidities, and sleep apnea severity.\n\nResultsHigher median NRR and greater NRR variability were each associated with increased cardiovascular and all-cause mortality. Combining these metrics identified a high-risk group characterized by high median and high variability of NRR, with nearly five-fold higher 3-year all-cause mortality compared with a low-risk group (unadjusted HR: 2.61; 95% CI: 1.65, 4.14; p<0.001; adjusted HR: 2.15; 95% CI: 1.30, 3.55; p=0.003).\n\nConclusionsBoth the baseline level and variability of NRR independently predict morttality in clinically stable outpatients with cardiovascular disease. Densely profiled NRR represents a promising, underutilized biomarker for long-term risk stratification.\n\nCondensed AbstractNocturnal respiratory rate (NRR) is an underutilized biomarker whose prognostic significance in stable cardiovascular outpatients is unknown. In 5,679 participants from the Sleep Heart Health Study, median NRR and within-night variability derived from overnight polysomnography independently predicted cardiovascular and all-cause mortality. Stratification based on these metrics identified a high-risk group with nearly five-fold higher 3-year mortality compared with a low-risk group (adjusted HR: 2.15; 95% CI: 1.30-3.55; p=0.003).","rel_num_authors":8,"rel_authors":[{"author_name":"Raimon Pedros-Valls","author_inst":"University of California San Diego"},{"author_name":"Keshav S Gupta","author_inst":"University of California San Diego"},{"author_name":"Nicholas Harrington","author_inst":"Nightingale Labs"},{"author_name":"Justin D Yu","author_inst":"University of California San Diego"},{"author_name":"Jeremy Orr","author_inst":"University of California San Diego"},{"author_name":"Robert L Owens","author_inst":"University of California San Diego"},{"author_name":"David Torres Barba","author_inst":"University of California San Diego"},{"author_name":"Kevin R King","author_inst":"University of California San Diego"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"RationaleFibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.\n\nObjectivesTo identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.\n\nMethodsWe performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.\n\nResultsTwo molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.\n\nConclusionMulti-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"RationaleFibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.\n\nObjectivesTo identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.\n\nMethodsWe performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.\n\nResultsTwo molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.\n\nConclusionMulti-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"RationaleFibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.\n\nObjectivesTo identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.\n\nMethodsWe performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.\n\nResultsTwo molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.\n\nConclusionMulti-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"RationaleFibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.\n\nObjectivesTo identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.\n\nMethodsWe performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.\n\nResultsTwo molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.\n\nConclusionMulti-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Non-invasive intracranial pressure waveform reconstruction with deep learning","rel_doi":"10.64898\/2026.06.07.26354958","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354958","rel_abs":"Continuous intracranial pressure (ICP) monitoring requires invasive instrumentation and reaches only a subset of the critically ill patients who might need it. We tested whether deep learning models trained on routinely acquired extracranial signals can reconstruct continuous ICP waveforms at clinically relevant accuracy. Using data from adults admitted to the intensive care unit at a single quaternary health system, five deep learning architectures were trained on high-frequency arterial blood pressure, photoplethysmography, and electrocardiography waveforms, using invasive intraparenchymal ICP as ground truth; two fusion strategies and three training objectives were evaluated, and models were externally validated on a held-out independent dataset (the MIMIC-III Waveform Database). Performance was assessed by mean absolute error (MAE) and waveform similarity by Pearson correlation (r). Across 158 critically ill adults ([~]5,322 hours) from two institutions (Johns Hopkins Hospital, Baltimore; Beth Israel Deaconess Medical Center, Boston), external-validation MAE ranged from 4.276 to 4.946 mmHg and Pearson r from 0.599 to 0.722, with the multiscale encoder-decoder model showing the most favorable MAE-correlation tradeoff. These findings provide the first demonstration that continuous ICP waveform reconstruction from bedside signals generalizes across institutions at clinically relevant accuracy, establishing a foundation for non-invasive ICP monitoring and motivating validation across broader populations and ICP ranges.","rel_num_authors":4,"rel_authors":[{"author_name":"Ansh Goyal","author_inst":"Johns Hopkins University"},{"author_name":"Veet Zaveri","author_inst":"Johns Hopkins University"},{"author_name":"Carl W Harris","author_inst":"Johns Hopkins University"},{"author_name":"Robert David Stevens","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Multi-domain AD risk burden and plasma biomarkers in cognitively unimpaired adults","rel_doi":"10.64898\/2026.06.11.26355499","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355499","rel_abs":"IntroductionAlzheimers disease (AD) pathology accumulates decades before symptom onset, yet how the cumulative effect of genetic, familial, and modifiable lifestyle risk burden jointly affects plasma biomarker levels and trajectories in cognitively unimpaired older adults remains unknown.\n\nMethodsWe analyzed data from 261 participants in the PREVENT-AD cohort. A composite risk score integrating APOE {varepsilon}4 status, polygenic score, family history, and modifiable\/lifestyle risk was examined against six plasma biomarkers using linear regression and linear mixed-effects models.\n\nResultsAPOE {varepsilon}4 was the strongest predictor of plasma biomarker levels. Higher composite risk burden was associated with elevated ptau181, ptau217, ptau217\/A{beta}42, and GFAP levels, and lower A{beta}42\/40 levels. A higher risk burden was predictive of accelerated ptau181 accumulation.\n\nDiscussionCumulative AD risk burden is broadly associated with plasma biomarker levels and specifically predicts accelerated ptau181 accumulation in cognitively unimpaired older adults, supporting structured composite risk profiling as a framework for AD risk stratification.","rel_num_authors":5,"rel_authors":[{"author_name":"Michelle Y Li","author_inst":"University of California, San Francisco"},{"author_name":"Paulina Tolosa-Tort","author_inst":"University of California, San Francisco"},{"author_name":"Margo B Heston","author_inst":"University of California, San Francisco"},{"author_name":"Philip Insel","author_inst":"University of California, San Francisco"},{"author_name":"Shea J Andrews","author_inst":"University of California San Francisco"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Fanconi Anemia as a Window into Premalignant Field Cancerization of the Oral Mucosa","rel_doi":"10.64898\/2026.06.13.26354719","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26354719","rel_abs":"Head and neck squamous cell carcinoma (HNSCC) evolves through stepwise clonal expansion within genetically altered mucosa fields, yet actionable biomarkers remain undefined. Leveraging Fanconi anemia (FA), a cancer predisposition syndrome with extreme HNSCC risk due to defective DNA interstrand crosslink repair, we profiled premalignant changes in the oral cavity using noninvasive brush biopsies. Consistent with our prior demonstration of genomic instability in FA-associated SCCs, we detected pathogenic TP53 variants in 26% and copy number alterations in 60.5% in clinically normal-appearing oral mucosa of individuals with FA. These subclinical clonal expansions define candidate biomarkers of early clonal evolution amenable to serial sampling for risk stratification and prevention studies. Since FA-associated SCCs share genomic features with sporadic HNSCC, these findings may extend to the broader population. We also identify somatic reversion of a pathogenic FANCB variant, providing evidence of genomic self-correction and suggesting a potential avenue for gene-based cancer prevention in FA.\n\nStatement of significanceOral mucosa of individuals with Fanconi anemia contains frequent abnormal clones creating a premalignant field that increases cancer risk. The noninvasive brush sampling approach allows repeated measurements, ongoing surveillance, and assessment of prophylactic strategies that may be useful in the prevention of cancers in people with FA and in the general population. Somatic reversion of a pathogenic FANC variant may protect the oral mucosa from DNA repair deficiency and premalignant clonal evolution.","rel_num_authors":24,"rel_authors":[{"author_name":"Tamar Berger","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Frank X. Donovan","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Yu-Chien Lin","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Shivatheja Soma","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Francis May","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Kinjal Bhadresha","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Christine Krieg","author_inst":"Fanconi-Anamie Hilfe e.V, Eschau, Germany"},{"author_name":"Neelam Giri","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Lisa J McReynolds","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Armando Filie","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Zohreh Khavandgar","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Denise M Laronde","author_inst":"University of British Columbia, Vancouver, BC, Canada"},{"author_name":"Martial Guillaud","author_inst":"British Columbia Cancer Research Centre, Vancouver, BC, Canada"},{"author_name":"Sharon A Savage","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"David I. Kutler","author_inst":"Weill Cornell Medical College, New York, NY, USA"},{"author_name":"Wayne Crismani","author_inst":"The University of Melbourne, Parkville, Victoria, Australia"},{"author_name":"Eunike Velleuer","author_inst":"University of Dusseldorf, Germany"},{"author_name":"Rachel Uppgaard","author_inst":"University of Minnesota, Minneapolis, USA"},{"author_name":"Ursula L. Harper","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"K. Olivia Alston","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"James W. Thomas","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Arleen D. Auerbach","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Settara C. Chandrasekharappa","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Agata Smogorzewska","author_inst":"The Rockefeller University, New York, NY, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Using wastewater surveillance to explore community-level dietary intake in sewered and non-sewered sanitation systems in Malawi, Africa","rel_doi":"10.64898\/2026.06.07.26354900","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354900","rel_abs":"Wastewater can be used to measure biomarkers that reflect population-level dietary intake and diversity; however, how this approach may apply in a low-income country remains a knowledge gap. This study aims to evaluate whether select dietary-related metabolites can be detected in wastewater and environmental surveillance (WES) samples from both sewered and non-sewered sanitation systems in Malawi, Africa. Fourteen WES samples were collected and analyzed from two university campuses in Mzuzu and Thyolo, Malawi. Four targets were analyzed: N-methyl-2-pyridone-5-carboxamide (2PY; a biomarker of vitamin B3), 4-pyridoxic acid (4-PA; a biomarker of vitamin B6), as well as enterodiol and enterolactone (biomarkers of dietary fiber and polyphenol consumption). An 18-question survey, paired spatiotemporally with the WES measurements, assessed self-reported daily dietary intake, food insecurity, and nutrient deficiency symptoms among 500 respondents. Among the 14 WES samples, 2PY, 4-PA, and enterolactone were detected, while enterodiol was not detected above the method limit (<0.3 mg\/kg). Most respondents (79%; 397\/500) reported consuming foods associated with the 2PY biomarker. Many respondents (62%; 311\/500) also reported consuming foods linked to the 4-PA biomarker. Fewer respondents (36%; 181\/500) reported consuming foods associated with enterodiol or enterolactone, such as whole grains (e.g., millet) and other fiber-rich plant foods (e.g., beans, chickpeas, or pigeon peas). This study demonstrates the potential feasibility of monitoring dietary-related metabolites in both sewered and non-sewered sanitation systems in a low-income country to augment community-level nutrition data. 2PY, 4-PA, and enterolactone were detectable in WES samples, supporting the advancement of this emerging field in nutrition and food security research.","rel_num_authors":10,"rel_authors":[{"author_name":"Rochelle H Holm","author_inst":"University of Louisville"},{"author_name":"Petros Chigwechokha","author_inst":"Malawi University of Science and Technology"},{"author_name":"Chisomo Kaponda","author_inst":"Malawi University of Science and Technology"},{"author_name":"Makayla Stephens","author_inst":"University of Louisville"},{"author_name":"Hannah Limbong","author_inst":"University of Louisville"},{"author_name":"Ayse Ercumen","author_inst":"North Carolina State University"},{"author_name":"Joy Hart","author_inst":"University of Louisville"},{"author_name":"Cassandra  L Workman","author_inst":"University of North Carolina at Greensboro"},{"author_name":"Francis  L. de los Reyes","author_inst":"North Carolina State University"},{"author_name":"Brighton  Austin Chunga","author_inst":"Mzuzu University"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Instrumental Activities of Daily Living in Older Adults with Epilepsy: A Cross-Sectional and Longitudinal Multicenter Study","rel_doi":"10.64898\/2026.06.13.26355582","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355582","rel_abs":"ObjectiveInstrumental activities of daily living (IADLs) represent a critical but understudied measure of day-to-day function in persons with epilepsy(PWE). In the multicenter Brain Aging and Cognition in Epilepsy (BrACE) study of PWE aged [&ge;]55 years, we examined the proportion, clinical correlates, epilepsy-related predictors, and longitudinal trajectory of IADL impairment.\n\nMethodsIADLs were assessed using the Functional Activities Questionnaire(FAQ; range=0-30; higher=more impaired); FAQ[&ge;]2 defines MCI-level impairment and FAQ[&ge;]5 dementia-level functional impairment. Multivariable logistic regression identified predictors of baseline function. Global cognition (Montreal Cognitive Assessment [MoCA]), individual cognitive measures, and quality of life (QOL) were compared between the impaired and unimpaired groups. Linear regression evaluated predictors of longitudinal functional decline.\n\nResultsOf 57 participants(mean age=66.6{+\/-}7.2 years; female=52.6%), 38.6%(n=22) had MCI-level functional impairment and 17.5%(n=10) had dementia-level functional impairment. In univariate analyses, worse FAQ scores were associated with lower education, higher area deprivation index, early-onset epilepsy (EOE < 60 years), antiseizure medication polytherapy, and epilepsy localization (all p < 0.05). In multivariable analysis, temporal lobe epilepsy (OR=4.46, 95%-CI=1.09-21.83,p=0.047), EOE(OR=7.14,95%-CI=1.16-59.97,p=0.046), and lower education(OR=0.70,95%-CI=0.49-0.93,p=0.025) remained independently associated with baseline MCI-level functional-impairment. Lower education (OR=0.55,95%-CI=0.29-0.84, p=0.021) was the only factor associated with dementia-level IADL-impairment. IADL-impaired participants demonstrated lower verbal memory scores(adjusted-p=0.041) and MoCA(adjusted-p<0.001), particularly in visuospatial\/executive function, attention, and memory subscores, and worse QOL(adjusted-p=0.041). IADL-impairment was greatest in financially-mediated and memory-dependent tasks.\n\nLongitudinally, EOE({beta}=7.51,95%-CI=1.92-13.10,p=0.017) and older age({beta}=0.38,95%-CI=0.12-0.65,p=0.012) predicted greater functional decline. Nearly one-third progressed to significantly worse function over a two-year period, with 15.4% progressing from MCI-level to dementia-level impairment and 15.4% from normal function to MCI-level IADL-impairment.\n\nConclusionsFunctional impairment affects [~]40% of older PWE, with [~]1-in-6 experiencing functional impairment comparable to overt dementias. Temporal lobe localization, EOE, lower education, and poorer cognition are important determinants of baseline functional status. EOE and older age predict accelerated functional decline, suggesting that cumulative disease burden and aging-related processes may drive functional deterioration. These findings provide one of the first epilepsy-specific longitudinal characterizations of IADL impairment and support routine functional assessment in PWE.\n\nKey Points- Functional impairment is common in older PWE, affecting[~] 40%, with 1 in 6 showing dementia-level functional impairment.\n- Temporal lobe epilepsy localization, early-onset epilepsy, and lower education are independently associated with baseline MCI-level functional impairment.\n- Lower education was the only independent predictor of dementia-level IADL impairment.\n- IADL impairment was associated with worse verbal memory, global cognition, and quality of life.\n- Over two years, early-onset epilepsy and older age predicted greater functional decline, with nearly one-third progressing to worse functional status.","rel_num_authors":17,"rel_authors":[{"author_name":"Ifrah Zawar","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Anny Reyes","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Kayela Arrotta","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Bruce P. Hermann","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Robyn M. Busch","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Mark Quigg","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Jaideep Kapur","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Aaron F. Struck","author_inst":"Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"},{"author_name":"Vineet Punia","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Alena Stasenko","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"McKenna E. Williams","author_inst":"Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Katherine J. Bangen","author_inst":"Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Irene Wang","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jerry J. Shih","author_inst":"Department of Neurology, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Lisa Ferguson","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jana E. Jones","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Carrie R. McDonald","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA | Department of Psychiatry, University of Californ"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Instrumental Activities of Daily Living in Older Adults with Epilepsy: A Cross-Sectional and Longitudinal Multicenter Study","rel_doi":"10.64898\/2026.06.13.26355582","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355582","rel_abs":"ObjectiveInstrumental activities of daily living (IADLs) represent a critical but understudied measure of day-to-day function in persons with epilepsy(PWE). In the multicenter Brain Aging and Cognition in Epilepsy (BrACE) study of PWE aged [&ge;]55 years, we examined the proportion, clinical correlates, epilepsy-related predictors, and longitudinal trajectory of IADL impairment.\n\nMethodsIADLs were assessed using the Functional Activities Questionnaire(FAQ; range=0-30; higher=more impaired); FAQ[&ge;]2 defines MCI-level impairment and FAQ[&ge;]5 dementia-level functional impairment. Multivariable logistic regression identified predictors of baseline function. Global cognition (Montreal Cognitive Assessment [MoCA]), individual cognitive measures, and quality of life (QOL) were compared between the impaired and unimpaired groups. Linear regression evaluated predictors of longitudinal functional decline.\n\nResultsOf 57 participants(mean age=66.6{+\/-}7.2 years; female=52.6%), 38.6%(n=22) had MCI-level functional impairment and 17.5%(n=10) had dementia-level functional impairment. In univariate analyses, worse FAQ scores were associated with lower education, higher area deprivation index, early-onset epilepsy (EOE < 60 years), antiseizure medication polytherapy, and epilepsy localization (all p < 0.05). In multivariable analysis, temporal lobe epilepsy (OR=4.46, 95%-CI=1.09-21.83,p=0.047), EOE(OR=7.14,95%-CI=1.16-59.97,p=0.046), and lower education(OR=0.70,95%-CI=0.49-0.93,p=0.025) remained independently associated with baseline MCI-level functional-impairment. Lower education (OR=0.55,95%-CI=0.29-0.84, p=0.021) was the only factor associated with dementia-level IADL-impairment. IADL-impaired participants demonstrated lower verbal memory scores(adjusted-p=0.041) and MoCA(adjusted-p<0.001), particularly in visuospatial\/executive function, attention, and memory subscores, and worse QOL(adjusted-p=0.041). IADL-impairment was greatest in financially-mediated and memory-dependent tasks.\n\nLongitudinally, EOE({beta}=7.51,95%-CI=1.92-13.10,p=0.017) and older age({beta}=0.38,95%-CI=0.12-0.65,p=0.012) predicted greater functional decline. Nearly one-third progressed to significantly worse function over a two-year period, with 15.4% progressing from MCI-level to dementia-level impairment and 15.4% from normal function to MCI-level IADL-impairment.\n\nConclusionsFunctional impairment affects [~]40% of older PWE, with [~]1-in-6 experiencing functional impairment comparable to overt dementias. Temporal lobe localization, EOE, lower education, and poorer cognition are important determinants of baseline functional status. EOE and older age predict accelerated functional decline, suggesting that cumulative disease burden and aging-related processes may drive functional deterioration. These findings provide one of the first epilepsy-specific longitudinal characterizations of IADL impairment and support routine functional assessment in PWE.\n\nKey Points- Functional impairment is common in older PWE, affecting[~] 40%, with 1 in 6 showing dementia-level functional impairment.\n- Temporal lobe epilepsy localization, early-onset epilepsy, and lower education are independently associated with baseline MCI-level functional impairment.\n- Lower education was the only independent predictor of dementia-level IADL impairment.\n- IADL impairment was associated with worse verbal memory, global cognition, and quality of life.\n- Over two years, early-onset epilepsy and older age predicted greater functional decline, with nearly one-third progressing to worse functional status.","rel_num_authors":17,"rel_authors":[{"author_name":"Ifrah Zawar","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Anny Reyes","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Kayela Arrotta","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Bruce P. Hermann","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Robyn M. Busch","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Mark Quigg","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Jaideep Kapur","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Aaron F. Struck","author_inst":"Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"},{"author_name":"Vineet Punia","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Alena Stasenko","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"McKenna E. Williams","author_inst":"Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Katherine J. Bangen","author_inst":"Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Irene Wang","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jerry J. Shih","author_inst":"Department of Neurology, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Lisa Ferguson","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jana E. Jones","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Carrie R. McDonald","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA | Department of Psychiatry, University of Californ"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Pulmonary extracellular vesicles drive alveolar macrophage dysfunction via microRNA transfer in Acute Respiratory Distress Syndrome","rel_doi":"10.64898\/2026.06.13.26355564","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355564","rel_abs":"BackgroundAlveolar macrophage (AM) dysfunction contributes to Acute Respiratory Distress Syndrome (ARDS) pathogenesis. We investigated the role of extracellular vesicles (EVs) in mediating this dysfunction.\n\nMethodsPulmonary EVs were isolated from broncho-alveolar lavage and non-directed bronchial lavage samples of ventilated sepsis patients with and without ARDS, and post-operative control patients via ultracentrifugation. AMs were isolated from lung tissue resections of lobectomy patients. AMs were treated with pooled EVs for 24 hours prior to functional, metabolic and autophagy profiling. EV cargo was profiled via small RNA transcriptomics and proteomics. Mechanistic role of EV microRNAs was assessed via mimic \/ antagomir transfection.\n\nResultsPulmonary EVs from sepsis patients with ARDS impaired AM efferocytosis, and control EVs had no effect. ARDS EV treatment enhanced AM mitochondrial-linked respiration, but not glycolysis. ARDS EV treatment impaired LC3B-II and LAMP1 expression, indicating dysregulated AM autophagy-lysosomal machinery. Proteomics revealed downregulation of innate immune pathways in ARDS EVs. Transcriptomics revealed enrichment of 24 microRNAs in ARDS EVs; miR-652-3p was the most enriched, validated by RT-qPCR. EV miR-652-3p was associated with 90-day mortality (9.20 vs 0.59 RQ, p=0.0295) and inversely correlated with oxygenation (PaO2\/FiO2). AM transfection with miR-652-3p mimic induced similar dysregulation of function and autophagy as ARDS EVs. Transfection of ARDS EVs with antagomirs to miR-652-3p prior to AM treatment partially rescued efferocytosis and autophagy.\n\nConclusionsTargeting EV miR-652-3p may restore alveolar macrophage function and reduce excessive inflammation, thus offering a novel therapeutic strategy for patients with ARDS.","rel_num_authors":16,"rel_authors":[{"author_name":"Katie L. Spencer","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Charlie Mafham","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Joshua Price","author_inst":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, U"},{"author_name":"Ellen Jenkins","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Celine H. Chen","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Samuel Quarton","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Louise E. Crowley","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Xiaohong Jiang","author_inst":"Department of Geriatric Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China"},{"author_name":"Jose R. Hombrebueno","author_inst":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, U"},{"author_name":"Michael A. Matthay","author_inst":"Cardiovascular Research Institute, Department of Medicine, and Department of Anaesthesia, University of California San Francisco, San Francisco, California, U.S"},{"author_name":"Mark Lindsay","author_inst":"Department of Life Sciences, University of Bath, Bath, UK"},{"author_name":"Babu Naidu","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"David R Thickett","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Dhruv Parekh","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Aaron Scott","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Rahul Y Mahida","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Based Detection of Airway Mucus Plugs on CT and Associations With Clinical Outcomes in COPDGene","rel_doi":"10.64898\/2026.06.10.26355393","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355393","rel_abs":"RATIONALEAirway mucus plugging is a clinically relevant manifestation of airway pathology in chronic obstructive pulmonary disease (COPD) and is associated with increased mortality even in early disease; however, visual computed tomography (CT) assessment is subjective and labor intensive.\n\nOBJECTIVESTo develop an AI-based quantitative CT method for automated detection of airway mucus plugging and evaluate associations with physiologic impairment and clinical outcomes.\n\nMETHODSInspiratory CT scans from 8,971 COPDGene Phase 1 (GOLD 0-4 and PRISm) participants were analyzed. An AI-based framework combining 3D airway segmentation discontinuities and convolutional neural network classification identified mucus plug obstructions, yielding mucus plug burden (total plug count). Associations with outcomes were evaluated using covariate-adjusted models.\n\nMEASUREMENTS AND MAIN RESULTSHigher mucus plug burden was associated with lower post-bronchodilator FEV % predicted ({rho} = -0.41; P < 0.001), greater air trapping (LAA < -856 HU; {rho} = 0.33; P < 0.001), worse health status (SGRQ; {rho} = 0.31; P < 0.001), and shorter 6-minute walk distance ({rho} = -0.26; P < 0.001). Among GOLD 1-4 participants, mucus plug presence was independently associated with increased all-cause mortality (adjusted hazard ratio, 1.28; P < 0.005) and exacerbation frequency (adjusted incidence rate ratio, 1.32; P < 0.005). Plug presence was also associated with increased respiratory mortality across GOLD categories and cardiovascular mortality in GOLD 1-2.\n\nCONCLUSIONSAI-based quantitative CT assessment of airway mucus plugging provides a scalable, reproducible measure associated with physiologic impairment and adverse outcomes in COPD, supporting its role in risk stratification and future therapeutic studies.","rel_num_authors":11,"rel_authors":[{"author_name":"John Oyer","author_inst":"University of Michigan"},{"author_name":"Ali Namvar","author_inst":"University of Michigan"},{"author_name":"Benjamin A Hoff","author_inst":"University of Michigan"},{"author_name":"Christopher Bosma","author_inst":"University of Michigan"},{"author_name":"Wassim L Labaki","author_inst":"University of Michigan"},{"author_name":"Ella A Kazerooni","author_inst":"University of Michigan"},{"author_name":"Fernando J Martinez","author_inst":"University of Massachusetts, Worcester"},{"author_name":"Charles R Hatt","author_inst":"4D Medical Inc."},{"author_name":"Meilan K Han","author_inst":"University of Michigan"},{"author_name":"Craig J Galban","author_inst":"University of Michigan"},{"author_name":"Sundaresh Ram","author_inst":"Emory University & Georgia Institute of Technology"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Based Detection of Airway Mucus Plugs on CT and Associations With Clinical Outcomes in COPDGene","rel_doi":"10.64898\/2026.06.10.26355393","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355393","rel_abs":"RATIONALEAirway mucus plugging is a clinically relevant manifestation of airway pathology in chronic obstructive pulmonary disease (COPD) and is associated with increased mortality even in early disease; however, visual computed tomography (CT) assessment is subjective and labor intensive.\n\nOBJECTIVESTo develop an AI-based quantitative CT method for automated detection of airway mucus plugging and evaluate associations with physiologic impairment and clinical outcomes.\n\nMETHODSInspiratory CT scans from 8,971 COPDGene Phase 1 (GOLD 0-4 and PRISm) participants were analyzed. An AI-based framework combining 3D airway segmentation discontinuities and convolutional neural network classification identified mucus plug obstructions, yielding mucus plug burden (total plug count). Associations with outcomes were evaluated using covariate-adjusted models.\n\nMEASUREMENTS AND MAIN RESULTSHigher mucus plug burden was associated with lower post-bronchodilator FEV % predicted ({rho} = -0.41; P < 0.001), greater air trapping (LAA < -856 HU; {rho} = 0.33; P < 0.001), worse health status (SGRQ; {rho} = 0.31; P < 0.001), and shorter 6-minute walk distance ({rho} = -0.26; P < 0.001). Among GOLD 1-4 participants, mucus plug presence was independently associated with increased all-cause mortality (adjusted hazard ratio, 1.28; P < 0.005) and exacerbation frequency (adjusted incidence rate ratio, 1.32; P < 0.005). Plug presence was also associated with increased respiratory mortality across GOLD categories and cardiovascular mortality in GOLD 1-2.\n\nCONCLUSIONSAI-based quantitative CT assessment of airway mucus plugging provides a scalable, reproducible measure associated with physiologic impairment and adverse outcomes in COPD, supporting its role in risk stratification and future therapeutic studies.","rel_num_authors":11,"rel_authors":[{"author_name":"John Oyer","author_inst":"University of Michigan"},{"author_name":"Ali Namvar","author_inst":"University of Michigan"},{"author_name":"Benjamin A Hoff","author_inst":"University of Michigan"},{"author_name":"Christopher Bosma","author_inst":"University of Michigan"},{"author_name":"Wassim L Labaki","author_inst":"University of Michigan"},{"author_name":"Ella A Kazerooni","author_inst":"University of Michigan"},{"author_name":"Fernando J Martinez","author_inst":"University of Massachusetts, Worcester"},{"author_name":"Charles R Hatt","author_inst":"4D Medical Inc."},{"author_name":"Meilan K Han","author_inst":"University of Michigan"},{"author_name":"Craig J Galban","author_inst":"University of Michigan"},{"author_name":"Sundaresh Ram","author_inst":"Emory University & Georgia Institute of Technology"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Challenges and opportunities of gap score methods for studying psychopathology resilience and vulnerability","rel_doi":"10.64898\/2026.06.13.26355592","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355592","rel_abs":"BackgroundThe widespread prevalence of psychopathology, which affects approximately 50% of the global population, often manifests during adolescence. Understanding why some individuals remain resilient while others experience mental health challenges despite similar environmental risks is essential for developing early interventions. However, past efforts have faced challenges with the retrospective definition of resilience. Here, we aim to address these challenges by quantifying resilience to psychopathology at the individual level.\n\nMethodsIn the Adolescent Brain and Cognitive Development (ABCD) Study(R) (N = 11,868), we utilized gradient-boosted tree regression to predict 2-year follow-up psychopathology from 208 Social Determinants of Health features. We used the \"gap score\" method--the difference between model-predicted and reported psychopathology--to quantify individual differences in psychopathology resilience and susceptibility, defined as the Resilience-Susceptibility Gap (RS-Gap). We validated the RS-Gap against independent 3-year follow-up clinical and quality-of-life outcomes.\n\nResultsCollinearity between gap scores and reported symptoms was high (r=-0.84), requiring further correction. Four bias-correction techniques were implemented and compared. After appropriate bias-correction, greater RS-Gap scores were associated with a higher likelihood of poor academic and social outcomes one year later, suggesting that early adaptation to adversity may carry a latent long-term cost.\n\nConclusions\n\nDependency between RS-Gap and psychopathology scores is a statistical challenge for gap score resilience methods. Our comparisons demonstrate that correction is mandatory to separate resilience signal from shared variance with psychopathology scores. Findings converged across different bias correction methods, providing a validated framework for using gap scores to identify high-risk developmental trajectories in youth.","rel_num_authors":7,"rel_authors":[{"author_name":"Hailey Modi","author_inst":"Washington University in St. Louis"},{"author_name":"David AA Baranger","author_inst":"Medical College of Wisconsin"},{"author_name":"Jared V Balbona","author_inst":"Virginia Commonwealth University"},{"author_name":"Samuel Naranjo Rinc\u00f3n","author_inst":"Washington University in St. Louis"},{"author_name":"Aaron John Gorelik","author_inst":"Washington University in St. Louis"},{"author_name":"Ryan Bogdan","author_inst":"Washington University in St. Louis"},{"author_name":"Janine D Bijsterbosch","author_inst":"Washington University in St Louis"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Latent tuberculosis infection workflows in four primary healthcare systems in the United States","rel_doi":"10.64898\/2026.06.12.26355200","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355200","rel_abs":"BackgroundLatent tuberculosis - infection (LTBI) reactivation accounts for most tuberculosis (TB) cases in the United States (U.S.). Expanding primary care LTBI services can improve detection and treatment, but real-world implementation is not well described.\n\nObjectiveDescribe how LTBI screening and treatment workflows are operationalized into practice in diverse U.S. primary care health systems.\n\nDesignDescriptive, multi-site study.\n\nSettingFour U.S. primary care health systems participating in the U.S. Centers for Disease Control and Prevention (CDC) Tuberculosis Epidemiologic Studies Consortium III (TBESC-III, 2020-2022).\n\nPatientsPatients visiting any study site (N = 3,522,077).\n\nMeasurementsElectronic medical record (EMR) data on patient demographics, TB test type, and results. Using narrative reporting and study documentation, LTBI care workflows were summarized by site into six domains: patient registration, TB testing evaluation, TB testing, TB disease assessment, LTBI diagnosis, and LTBI treatment.\n\nResultsSites implemented recommended practices for testing and treatment: interferon-gamma release assays were the predominant test, and short-course rifamycin-based regimens were the primary treatment. Follow-up care practices and documentation of treatment outcomes varied. Country of birth was not consistently recorded at all sites, limiting TB screening capability based on nativity. Physician training, EMR decision-support tools, and patient education resources differed in scope and availability.\n\nLimitationsDescriptive design using self-reported workflows; may not generalize to all primary care settings or reflect physician-level variations.\n\nConclusionWe provide a descriptive snapshot showing how LTBI care workflows varied in approach and consistency at four primary care systems with integrated LTBI services. These real-world examples may serve as templates for U.S. primary care systems seeking to expand TB testing and treatment.\n\nPrimary Funding SourceU.S. Centers for Disease Control and Prevention (TBESC-III).","rel_num_authors":10,"rel_authors":[{"author_name":"Julie Espey","author_inst":"Centers for Disease Control and Prevention, Atlanta"},{"author_name":"Julie Venci","author_inst":"Denver Health and Hospital Authority"},{"author_name":"Paul Y Wada","author_inst":"Kaiser Permanente Northern California, Oakland"},{"author_name":"Yoseph Sorri","author_inst":"Public Health-Seattle and King County, Seattle"},{"author_name":"Amy Tang","author_inst":"North East Medical Services, San Francisco"},{"author_name":"Beatrice Francis","author_inst":"Public Health Institute at Denver Health, Denver"},{"author_name":"Jacek Skarbinski","author_inst":"Kaiser Permanente Northern California, Oakland"},{"author_name":"Masahiro Narita","author_inst":"Public Health-Seattle and King County, Seattle"},{"author_name":"Priya B Shete","author_inst":"University of California San Franciso Medical Center Neurosurgery Clinic"},{"author_name":"Winglee Kathryn","author_inst":"Centers for Disease Control and Prevention, Atlanta"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Bidirectional associations between cannabis use, oddball performance, and P3 event-related potential","rel_doi":"10.64898\/2026.06.09.26355188","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355188","rel_abs":"ImportanceCannabis use remains prevalent in youth despite concerns regarding its potential impact on cognitive function. Unraveling whether the association between cannabis use and cognition is partially due to preexisting differences or primarily related to use is vital to understanding underlying mechanisms.\n\nObjectiveTo estimate the longitudinal association between cannabis initiation and cognitive trajectories, indexed by task performance and P3 event-related potential (ERP), and to estimate whether baseline cognition is associated with cannabis initiation.\n\nDesignData were analyzed from the ongoing longitudinal Collaborative Study on the Genetics of Alcoholism (COGA) cohort, which was followed up approximately every 2-5 years from 2004 to 2025.\n\nSetting6 sites across the United States.\n\nParticipantsAdolescent and young adult offspring of past COGA participants and control families who reported on their cannabis use and who had Visual Oddball (VOP) performance and P3 ERP data (N=4814; 52.4% female, 68.4% white) were grouped based on the timing of cognitive data collection relative to cannabis initiation into Pre-onset (n=2,449; [&ge;]1 assessment) and Post-onset (n=998; [&ge;]3 assessments) subsamples.\n\nMain Outcomes and MeasuresVOP measures include performance accuracy (%), reaction times (ms), and P3 amplitude (V) and latency (ms) during target trials. Cannabis measures included lifetime use of cannabis (i.e., ever used) and age at first use.\n\nResultsHigh P3 amplitude, and prolonged P3 latency and reaction time were associated with a reduced hazard of cannabis initiation (All Hazards Ratio, [H.R.s]< 0.91, ps<.008). Following initiation, cannabis use was associated with steeper declines in P3 amplitude (b=-0.29, p=0.02) and stabilized reaction time (b=0.35; p=0.005). Steeper decline in P3 amplitude (i.e., slope) was associated with greater cannabis progression (e.g., Cannabis Use Disorder, Odds Ratio, [O.R.]=2.34, p<.001), whereas steeper decline in reaction time was associated with reduced progression (O.R.=.79, p=.002).\n\nConclusionBaseline P3 indices and reaction time were associated with cannabis initiation, while cannabis use was associated with subsequent changes in P3 amplitude and reaction time trajectories. These findings indicate that accelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, may further contribute to neurocognitive changes that deepen cannabis involvement.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSAre associations between cannabis use and cognition attributable to preexisting neurodevelopmental differences, related to cannabis use, or reciprocal processes?\n\nFindingsIn this longitudinal cohort study of participants from the Collaborative Study on the Genetics of Alcoholism (COGA), high P3 amplitude and prolonged P3 latency and reaction time were associated with reduced risk of cannabis initiation. Following initiation, cannabis use was associated with steeper declines in P3 amplitude and faster but stabilized reaction time.\n\nMeaningAccelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, further contribute to neurocognitive changes that deepen cannabis involvement and make it problematic.","rel_num_authors":22,"rel_authors":[{"author_name":"Christina Garasky","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Kellyn Spychala","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Fanghong Dong","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Andrey Anokhin","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Ryan Bogdan","author_inst":"Washington University in St. Louis"},{"author_name":"Grace Chan","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Victor Hesselbrock","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Chella Kamarajan","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sivan Kinreich","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sally Kuo","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jodi Kutzner","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Alex P Miller","author_inst":"Indiana University School of Medicine"},{"author_name":"Ashwini Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Gayathri Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Martin Plawecki","author_inst":"Indiana University School of Medicine"},{"author_name":"Jessica Salvatore","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Marc Schuckit","author_inst":"University of California San Diego Medical School"},{"author_name":"Kathleen Bucholz","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Vivia McCutcheon","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Bernice Porjesz","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Jacquelyn Meyers","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Bidirectional associations between cannabis use, oddball performance, and P3 event-related potential","rel_doi":"10.64898\/2026.06.09.26355188","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355188","rel_abs":"ImportanceCannabis use remains prevalent in youth despite concerns regarding its potential impact on cognitive function. Unraveling whether the association between cannabis use and cognition is partially due to preexisting differences or primarily related to use is vital to understanding underlying mechanisms.\n\nObjectiveTo estimate the longitudinal association between cannabis initiation and cognitive trajectories, indexed by task performance and P3 event-related potential (ERP), and to estimate whether baseline cognition is associated with cannabis initiation.\n\nDesignData were analyzed from the ongoing longitudinal Collaborative Study on the Genetics of Alcoholism (COGA) cohort, which was followed up approximately every 2-5 years from 2004 to 2025.\n\nSetting6 sites across the United States.\n\nParticipantsAdolescent and young adult offspring of past COGA participants and control families who reported on their cannabis use and who had Visual Oddball (VOP) performance and P3 ERP data (N=4814; 52.4% female, 68.4% white) were grouped based on the timing of cognitive data collection relative to cannabis initiation into Pre-onset (n=2,449; [&ge;]1 assessment) and Post-onset (n=998; [&ge;]3 assessments) subsamples.\n\nMain Outcomes and MeasuresVOP measures include performance accuracy (%), reaction times (ms), and P3 amplitude (V) and latency (ms) during target trials. Cannabis measures included lifetime use of cannabis (i.e., ever used) and age at first use.\n\nResultsHigh P3 amplitude, and prolonged P3 latency and reaction time were associated with a reduced hazard of cannabis initiation (All Hazards Ratio, [H.R.s]< 0.91, ps<.008). Following initiation, cannabis use was associated with steeper declines in P3 amplitude (b=-0.29, p=0.02) and stabilized reaction time (b=0.35; p=0.005). Steeper decline in P3 amplitude (i.e., slope) was associated with greater cannabis progression (e.g., Cannabis Use Disorder, Odds Ratio, [O.R.]=2.34, p<.001), whereas steeper decline in reaction time was associated with reduced progression (O.R.=.79, p=.002).\n\nConclusionBaseline P3 indices and reaction time were associated with cannabis initiation, while cannabis use was associated with subsequent changes in P3 amplitude and reaction time trajectories. These findings indicate that accelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, may further contribute to neurocognitive changes that deepen cannabis involvement.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSAre associations between cannabis use and cognition attributable to preexisting neurodevelopmental differences, related to cannabis use, or reciprocal processes?\n\nFindingsIn this longitudinal cohort study of participants from the Collaborative Study on the Genetics of Alcoholism (COGA), high P3 amplitude and prolonged P3 latency and reaction time were associated with reduced risk of cannabis initiation. Following initiation, cannabis use was associated with steeper declines in P3 amplitude and faster but stabilized reaction time.\n\nMeaningAccelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, further contribute to neurocognitive changes that deepen cannabis involvement and make it problematic.","rel_num_authors":22,"rel_authors":[{"author_name":"Christina Garasky","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Kellyn Spychala","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Fanghong Dong","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Andrey Anokhin","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Ryan Bogdan","author_inst":"Washington University in St. Louis"},{"author_name":"Grace Chan","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Victor Hesselbrock","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Chella Kamarajan","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sivan Kinreich","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sally Kuo","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jodi Kutzner","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Alex P Miller","author_inst":"Indiana University School of Medicine"},{"author_name":"Ashwini Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Gayathri Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Martin Plawecki","author_inst":"Indiana University School of Medicine"},{"author_name":"Jessica Salvatore","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Marc Schuckit","author_inst":"University of California San Diego Medical School"},{"author_name":"Kathleen Bucholz","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Vivia McCutcheon","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Bernice Porjesz","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Jacquelyn Meyers","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Bidirectional associations between cannabis use, oddball performance, and P3 event-related potential","rel_doi":"10.64898\/2026.06.09.26355188","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355188","rel_abs":"ImportanceCannabis use remains prevalent in youth despite concerns regarding its potential impact on cognitive function. Unraveling whether the association between cannabis use and cognition is partially due to preexisting differences or primarily related to use is vital to understanding underlying mechanisms.\n\nObjectiveTo estimate the longitudinal association between cannabis initiation and cognitive trajectories, indexed by task performance and P3 event-related potential (ERP), and to estimate whether baseline cognition is associated with cannabis initiation.\n\nDesignData were analyzed from the ongoing longitudinal Collaborative Study on the Genetics of Alcoholism (COGA) cohort, which was followed up approximately every 2-5 years from 2004 to 2025.\n\nSetting6 sites across the United States.\n\nParticipantsAdolescent and young adult offspring of past COGA participants and control families who reported on their cannabis use and who had Visual Oddball (VOP) performance and P3 ERP data (N=4814; 52.4% female, 68.4% white) were grouped based on the timing of cognitive data collection relative to cannabis initiation into Pre-onset (n=2,449; [&ge;]1 assessment) and Post-onset (n=998; [&ge;]3 assessments) subsamples.\n\nMain Outcomes and MeasuresVOP measures include performance accuracy (%), reaction times (ms), and P3 amplitude (V) and latency (ms) during target trials. Cannabis measures included lifetime use of cannabis (i.e., ever used) and age at first use.\n\nResultsHigh P3 amplitude, and prolonged P3 latency and reaction time were associated with a reduced hazard of cannabis initiation (All Hazards Ratio, [H.R.s]< 0.91, ps<.008). Following initiation, cannabis use was associated with steeper declines in P3 amplitude (b=-0.29, p=0.02) and stabilized reaction time (b=0.35; p=0.005). Steeper decline in P3 amplitude (i.e., slope) was associated with greater cannabis progression (e.g., Cannabis Use Disorder, Odds Ratio, [O.R.]=2.34, p<.001), whereas steeper decline in reaction time was associated with reduced progression (O.R.=.79, p=.002).\n\nConclusionBaseline P3 indices and reaction time were associated with cannabis initiation, while cannabis use was associated with subsequent changes in P3 amplitude and reaction time trajectories. These findings indicate that accelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, may further contribute to neurocognitive changes that deepen cannabis involvement.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSAre associations between cannabis use and cognition attributable to preexisting neurodevelopmental differences, related to cannabis use, or reciprocal processes?\n\nFindingsIn this longitudinal cohort study of participants from the Collaborative Study on the Genetics of Alcoholism (COGA), high P3 amplitude and prolonged P3 latency and reaction time were associated with reduced risk of cannabis initiation. Following initiation, cannabis use was associated with steeper declines in P3 amplitude and faster but stabilized reaction time.\n\nMeaningAccelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, further contribute to neurocognitive changes that deepen cannabis involvement and make it problematic.","rel_num_authors":22,"rel_authors":[{"author_name":"Christina Garasky","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Kellyn Spychala","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Fanghong Dong","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Andrey Anokhin","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Ryan Bogdan","author_inst":"Washington University in St. Louis"},{"author_name":"Grace Chan","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Victor Hesselbrock","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Chella Kamarajan","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sivan Kinreich","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sally Kuo","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jodi Kutzner","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Alex P Miller","author_inst":"Indiana University School of Medicine"},{"author_name":"Ashwini Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Gayathri Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Martin Plawecki","author_inst":"Indiana University School of Medicine"},{"author_name":"Jessica Salvatore","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Marc Schuckit","author_inst":"University of California San Diego Medical School"},{"author_name":"Kathleen Bucholz","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Vivia McCutcheon","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Bernice Porjesz","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Jacquelyn Meyers","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Bidirectional associations between cannabis use, oddball performance, and P3 event-related potential","rel_doi":"10.64898\/2026.06.09.26355188","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355188","rel_abs":"ImportanceCannabis use remains prevalent in youth despite concerns regarding its potential impact on cognitive function. Unraveling whether the association between cannabis use and cognition is partially due to preexisting differences or primarily related to use is vital to understanding underlying mechanisms.\n\nObjectiveTo estimate the longitudinal association between cannabis initiation and cognitive trajectories, indexed by task performance and P3 event-related potential (ERP), and to estimate whether baseline cognition is associated with cannabis initiation.\n\nDesignData were analyzed from the ongoing longitudinal Collaborative Study on the Genetics of Alcoholism (COGA) cohort, which was followed up approximately every 2-5 years from 2004 to 2025.\n\nSetting6 sites across the United States.\n\nParticipantsAdolescent and young adult offspring of past COGA participants and control families who reported on their cannabis use and who had Visual Oddball (VOP) performance and P3 ERP data (N=4814; 52.4% female, 68.4% white) were grouped based on the timing of cognitive data collection relative to cannabis initiation into Pre-onset (n=2,449; [&ge;]1 assessment) and Post-onset (n=998; [&ge;]3 assessments) subsamples.\n\nMain Outcomes and MeasuresVOP measures include performance accuracy (%), reaction times (ms), and P3 amplitude (V) and latency (ms) during target trials. Cannabis measures included lifetime use of cannabis (i.e., ever used) and age at first use.\n\nResultsHigh P3 amplitude, and prolonged P3 latency and reaction time were associated with a reduced hazard of cannabis initiation (All Hazards Ratio, [H.R.s]< 0.91, ps<.008). Following initiation, cannabis use was associated with steeper declines in P3 amplitude (b=-0.29, p=0.02) and stabilized reaction time (b=0.35; p=0.005). Steeper decline in P3 amplitude (i.e., slope) was associated with greater cannabis progression (e.g., Cannabis Use Disorder, Odds Ratio, [O.R.]=2.34, p<.001), whereas steeper decline in reaction time was associated with reduced progression (O.R.=.79, p=.002).\n\nConclusionBaseline P3 indices and reaction time were associated with cannabis initiation, while cannabis use was associated with subsequent changes in P3 amplitude and reaction time trajectories. These findings indicate that accelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, may further contribute to neurocognitive changes that deepen cannabis involvement.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSAre associations between cannabis use and cognition attributable to preexisting neurodevelopmental differences, related to cannabis use, or reciprocal processes?\n\nFindingsIn this longitudinal cohort study of participants from the Collaborative Study on the Genetics of Alcoholism (COGA), high P3 amplitude and prolonged P3 latency and reaction time were associated with reduced risk of cannabis initiation. Following initiation, cannabis use was associated with steeper declines in P3 amplitude and faster but stabilized reaction time.\n\nMeaningAccelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, further contribute to neurocognitive changes that deepen cannabis involvement and make it problematic.","rel_num_authors":22,"rel_authors":[{"author_name":"Christina Garasky","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Kellyn Spychala","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Fanghong Dong","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Andrey Anokhin","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Ryan Bogdan","author_inst":"Washington University in St. Louis"},{"author_name":"Grace Chan","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Victor Hesselbrock","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Chella Kamarajan","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sivan Kinreich","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sally Kuo","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jodi Kutzner","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Alex P Miller","author_inst":"Indiana University School of Medicine"},{"author_name":"Ashwini Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Gayathri Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Martin Plawecki","author_inst":"Indiana University School of Medicine"},{"author_name":"Jessica Salvatore","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Marc Schuckit","author_inst":"University of California San Diego Medical School"},{"author_name":"Kathleen Bucholz","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Vivia McCutcheon","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Bernice Porjesz","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Jacquelyn Meyers","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Prevalence and Clinical Impact of Pathogenic Variants in Cardiomyopathy Genes Among Individuals with Cardiac Conduction Disorders","rel_doi":"10.64898\/2026.06.13.26355581","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355581","rel_abs":"ImportanceCardiac conduction disorders have traditionally been regarded as a secondary manifestation of underlying structural heart diseases. However, isolated conduction disorders may precede the onset of heart failure (HF) suggesting shared mechanisms.\n\nObjectiveTo evaluate the prevalence and clinical significance of pathogenic\/likely pathogenic (P\/LP) rare variants in cardiomyopathy genes among individuals with conduction disorders.\n\nDesign, Setting, and ParticipantsBiobank analysis of 192,834 participants with whole genome sequence data from Vanderbilts BioVU and 353,092 participants from the All of Us Research Program (AoU). Participants with primary conduction disorder (left bundle branch block [LBBB], right bundle branch block [RBBB], high-grade atrioventricular block [AVB]) were identified after excluding secondary causes.\n\nExposuresP\/LP variants in cardiomyopathy genes.\n\nMain Outcomes and MeasuresPrimary outcome was P\/LP carrier status by age and HF status. Secondary outcomes included incident HF and composite ventricular arrhythmias\/sudden cardiac death\/mortality (VA\/SCD\/mortality).\n\nResultsAmong 16,959 participants with conduction disorders in BioVU and 13,442 in AoU, 432 (2.6%) and 206 (1.5%) were P\/LP carriers, respectively. Conduction disorder was independently associated with carrier status (BioVU p<0.001; AoU p=0.005). Carrier probability varied by age at conduction disorder onset and HF status. Among participants with HF at age 30 years, predicted carrier probability for LBBB was 7.5% in BioVU and 20.2% in AoU; for high-grade AVB, 7.7% and 8.5%, respectively, compared with 3.7% and 2.9% among those with HF without conduction disorder. P\/LP carrier status among participants with conduction disorders was associated with increased risk of incident HF (BioVU p<0.001; AoU p<0.001) and ventricular arrhythmia\/sudden death\/mortality (BioVU p<0.001; AoU p<0.001). Carriers also demonstrated increased susceptibility to conduction disorder following HF diagnosis, including more than two-fold higher risk of third-degree AVB (BioVU aOR 2.48, 95% CI 1.85-3.32; AoU aOR 2.26, 95% CI 1.35-3.80).\n\nConclusionsAdults with primary conduction disorders have an increased prevalence of P\/LP variants in cardiomyopathy genes, which is most pronounced with diagnoses at early ages of adulthood. Furthermore, there is evidence of an interaction between P\/LP carrier status and conduction disorder to increase HF risk and composite cardiovascular outcomes, underscoring the potential role of genetic evaluation in patients with primary conduction disorders to inform long-term outcomes.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat is the prevalence of pathogenic\/likely pathogenic (P\/LP) variants in cardiomyopathy genes among individuals with cardiac conduction disorders, and are carriers at increased risk for adverse cardiovascular outcomes?\n\nFindingsIn this biobank study of 192,834 participants with whole genome sequence data from Vanderbilts BioVU and 353,092 participants from the All of Us Research Program, conduction disorder was independently associated with P\/LP carrier status, with predicted carrier probability reaching up to 20% among young participants with concurrent heart failure. Carriers with conduction disorder had higher risk of incident heart failure and ventricular arrhythmias, sudden cardiac death, or mortality.\n\nMeaningThese findings suggest that genetic testing may be warranted in patients with conduction disorder, particularly younger individuals, and those with heart failure.","rel_num_authors":14,"rel_authors":[{"author_name":"Temidayo A. Abe","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Favour E. Markson","author_inst":"Jefferson Health-Einstein Hospital"},{"author_name":"Quinn S. Wells","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Megan C. Lancaster","author_inst":"The Ohio State University"},{"author_name":"William G. Stevenson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Benjamin M. Shoemaker","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Luke Laws","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Majd A. El-Harasis","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Harikrishna Tandri","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Travis D. Richardson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jay A. Montgomery","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Arvindh N. Kanagasundram","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Dan M. Roden","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Giovanni E. Davogustto","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Quality Improvement Based Implementation and Evaluation of a Decision Aid for Patients with Nephrolithiasis","rel_doi":"10.64898\/2026.06.12.26355535","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355535","rel_abs":"IntroductionPatients with nephrolithiasis face challenges in making a high-quality, preference sensitive decision. Our prior work established feasibility and patient acceptance of a software-based decision aid (DA). The objectives for this study were to identify implementation strategies for the DA in routine care and determine whether DA implementation enhances decisional quality for patients.\n\nMethodsNew nephrolithiasis patients were recruited from the institutions Medical Center from June 2018 to April 2024 to receive a software-based pre-visit DA that measured care preferences and used decision analysis to rank treatments. The RE-AIM framework and Plan-Do-Study-Act (PDSA) cycles were used to improve implementation outcomes. Patients completed survey instruments evaluating decisional conflict, shared decision-making, care satisfaction, and treatment choice following their provider visit. These metrics were compared in the DA cohort (n=81) to those in a \"usual care\" cohort (n=78) with Wilcoxon rank-sum and Chi-square (or Fishers exact) tests.\n\nResultsImplementation data revealed sustained reach and progressive improvement in fidelity. The DA cohort reported higher decisional quality relative to controls (p=0.003) and reported greater support\/advice to make a choice (p=0.005). The DA cohort more often discussed options with their doctor (87.5% vs 69.2%, p=0.005) and were more likely to be promoters of their provider (p<0.001) and health system (p=0.029). The DA cohort was less likely to have switched their treatment preference post-consultation (32.1% vs 71.8%, p<0.001) suggesting greater consistency in decision-making.\n\nConclusionsSoftware-based DAs in nephrolithiasis can mitigate decisional conflict, improve SDM, and improve patient satisfaction. Further work should explore broader implementation and long-term clinical outcomes.","rel_num_authors":12,"rel_authors":[{"author_name":"Austin Lee","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Saam Kazemi","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Patrick Wilson","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Karan Thaker","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Lorna Kwan","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"John Cabri","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Kevin Li","author_inst":"Department of Urology, UCSF School of Medicine, University of California San Francisco, San Francisco, CA, United States."},{"author_name":"Matthew Dunn","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Alan Yaghoubian","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Fuad Elkhoury","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Kymora Scotland","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Christopher Saigal","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"A controlled human infection model for symptomatic pertussis in North America using the pertactin-producing clinical isolate D420","rel_doi":"10.64898\/2026.06.09.26355227","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355227","rel_abs":"BackgroundDespite widespread vaccination, pertussis remains a poorly controlled disease globally and results in substantial annual morbidity and mortality, particularly in young children. Controlled human infection models (CHIMs) using the causative agent Bordetella pertussis are promising systems to enable the study of pertussis disease pathogenesis and immunology and to rapidly assess vaccines and therapeutics. While a pertussis CHIM that produces asymptomatic infection has been established in Europe, the development of a CHIM that leads to symptomatic illness would be advantageous for evaluating vaccine efficacy against both infection and disease.\n\nMethodsHealthy participants 18-40 years of age were inoculated intranasally with one of eight doses (ranging from 104 to 108 colony forming units (CFU)) of the pertactin-producing B. pertussis isolate D420 at the challenge facility within the Canadian Center for Vaccinology (Nova Scotia, Canada). The study occurred in two stages. In stage one, the B. pertussis dose was escalated in cohort groups of five to six participants until reaching an endpoint where 70-90% of participants exhibited mild (non-severe, Grade 1 or 2) symptomatic infection, defined as the Human Infectious Dose 70-90 (HID70-90). In stage two, additional challenges were conducted for doses below, at, and above the identified HID70-90 to characterize the emerging pertussis model. For all challenge doses, participants were closely monitored during an inpatient stay of up to 24 days and post-discharge for laboratory-confirmed infection, pertussis symptoms, safety, and IgG antibody responses to four B. pertussis antigens including pertussis toxin, filamentous hemagglutinin, fimbriae, and pertactin. All participants received a five-day course of azithromycin, where timing of initiation depended on B. pertussis testing and symptoms. The study was conducted between July 4, 2022 and March 19, 2025.\n\nFindingsSeventy-five participants were inoculated with one of the eight B. pertussis D420 challenge doses and completed the inpatient stay. From the stage-one dose escalation, we found that 107 CFU of B. pertussis D420 was the lowest dose that achieved the HID70-90, where 9 of 12 participants (75{middle dot}0%) exhibited mild symptomatic infection. Following stage-two challenges, 16 of 22 total participants at 107 CFU (72{middle dot}7%) developed mild symptomatic infection, thus verifying the HID70-90. The symptomatic infection rate below the HID70-90 at 5x106 CFU of D420 was 20{middle dot}0% and above the HID70-90 at 5x107 and 108 CFU were 58{middle dot}3% and 55{middle dot}6%, respectively. Symptoms with elevated frequency for symptomatic infection (relative to background symptoms in non-infected) included nasal congestion, runny nose, fatigue, malaise, and cough. At the HID70-90, 50% of symptomatic infections included cough. Serological analyses of the four highest (stage-two) challenge doses (5x106, 107, 5x107, 108 CFU) revealed that antibody titres increased over time post-challenge. Seroconversion for at least one of the four studied antibodies was nearly twice as common for symptomatic (70{middle dot}0%) than asymptomatic (35{middle dot}7%) infection and was absent (0%) for non-infected. All infections were cleared following azithromycin treatment (100%) and there were no study-related serious adverse events.\n\nInterpretationA safe and reproducible symptomatic pertussis CHIM was achieved, providing a model for research on pertussis disease pathogenesis and immunology and for assessing vaccines and therapeutics. (Clinicaltrials.gov, NCT05136599).\n\nFundingUnited States (US) Centers for Disease Control and Prevention, US National Institutes of Health\n\nResearch in ContextO_ST_ABSEvidence before this studyC_ST_ABSBordetella pertussis, the causative agent of pertussis (whooping cough), remains a global threat despite nearly universal vaccination programs. The burden of pertussis disease is highest for infants but can also lead to complications among some adults, particularly the elderly and immunocompromised. Suboptimal vaccine efficacy and waning immunity post-vaccination have led to resurgences of pertussis in many countries and numerous outbreaks. New strategies are needed to investigate the pathophysiology and immunology of B. pertussis infection and to develop more efficacious vaccines and therapeutics. Controlled human infection models (CHIMs), the intentional exposure of human volunteers to a pathogen under closely monitored conditions, are promising platforms to address knowledge gaps on the disease and to assess the efficacy of novel vaccines. Recently, through a European collaborative effort, an asymptomatic pertussis CHIM was established using the B. pertussis isolate B1917 that showed intranasal bacterial challenge doses of 104 to 10 colony-forming units (CFU) produced infection and antibody responses, was safe, and could be eliminated with antibiotics. The development of a symptomatic pertussis CHIM would permit evaluation of vaccine efficacy against both infection and symptomatic disease, and better reflect real-world circumstances.\n\nAdded value of this studyThis study describes the establishment of a pertussis CHIM that induces mild symptomatic infection using the pertactin-producing isolate D420 at the challenge unit facilities of the Canadian Center for Vaccinology (Nova Scotia, Canada). Infection progression for participants in the study was closely monitored by testing for the pathogen in nasal washes (cultures and polymerase chain reaction (PCRs)), symptom assessments, and assays of pertussis antibodies. Using a dose-escalation design for nasal challenge with D420, we found that a B. pertussis dose of 107 CFU led to symptomatic disease in over 70% of participants. Symptoms associated with symptomatic infection included nasal congestion, runny nose, fatigue, malaise, and cough. Additional challenges below, at, and above the HID70-90 (5x106, 107, 5x107, 108 CFU) provided insights into infection rates, symptom development, antibody responses, and safety of the CHIM. Overall, all symptoms were low-grade (Grade 1 or 2), infections were cleared with azithromycin, and there were no study-related serious adverse events. We demonstrate that different rates of asymptomatic and symptomatic infection were safely achieved by titrating the challenge dose of B. pertussis.\n\nImplications of all the available evidenceThe pertussis CHIM described here provides a platform to evaluate efficacy and safety of novel vaccine candidates and therapeutics against pertussis infection and disease. The CHIM also provides a framework to advance fundamental research in pertussis disease onset and progression, including correlates of infection, symptomology, and immune protection.","rel_num_authors":20,"rel_authors":[{"author_name":"May S ElSherif","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Kara L Redden","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Joanne M Langley","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Lingyun Ye","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Wade Blanchard","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Bruce Smith","author_inst":"Department of Mathematics and Statistics, Dalhousie University, Halifax, Nova Scotia, Canada"},{"author_name":"Jun Wang","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Bahaa Abu-Raya","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Jillian H Filliter","author_inst":"Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada"},{"author_name":"Kathryn M Edwards","author_inst":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"C Buddy Creech","author_inst":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Shelly McNeil","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Todd F Hatchette","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Jason J LeBlanc","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Susan Hariri","author_inst":"Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"},{"author_name":"Lucia Pawloski","author_inst":"Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"},{"author_name":"Panagiotis Maniatis","author_inst":"Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"},{"author_name":"LeAnne M Fox","author_inst":"Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"},{"author_name":"Carrie A Whittle","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Scott A Halperin","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Midwifery Practice in Conflict Contexts: Lived Experiences from Somalia and Nigeria","rel_doi":"10.64898\/2026.06.07.26355130","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26355130","rel_abs":"BackgroundMidwives are a central cadre in the health system, particularly in conflict-affected settings where they are sometimes the primary or even only skilled providers available. Yet, despite their critical role, there is limited qualitative evidence capturing their lived experiences and how these shape workforce entry, retention, and overall well-being.\n\nMethodsDrawing on a phenomenological research methodology, this qualitative study was embedded within a larger prospective longitudinal cohort of midwifery students and graduates in Somalia and Nigeria. We conducted focus group discussions with graduate midwives (n=48 in Nigeria; n=63 in Somalia) to explore their experiences transitioning into the workforce and their realities working in health systems impacted by conflict and violent insecurity. Data were analysed using inductive thematic analysis.\n\nResultsFive themes emerged from the data: (1) job search and workforce entry, which was described as fraught with challenges and shaped by a set of formal systems in Nigeria but informal networks and structural barriers in Somalia (2) working conditions that were marked by resource scarcity, infrastructural challenges, and heavy and unreasonable workloads, (3) safety, security and coping strategies that differed across the two contexts but reflected persistent exposure to violence and a reliance on ad hoc and personal coping in lieu of systematic protection, (4) community perceptions of midwives, shaped and constrained by social and gender norms and (5) mental health and emotional wellbeing, highlighting stress, burnout and moral injury experienced by this cadre.\n\nConclusionOur findings highlight the profound challenges faced by midwives working in conflict-affected settings, and they shine a light on the urgent need to support and invest in this critical and predominantly female health workforce.","rel_num_authors":13,"rel_authors":[{"author_name":"Shatha Elnakib","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Emilia Ngozi Iwu","author_inst":"Institute of Human Virology"},{"author_name":"Asia Mohammed","author_inst":"Somali Research & Development Institute"},{"author_name":"Hawa Abdullahi Mohammed","author_inst":"Somali Research & Development Institute"},{"author_name":"Meighan Mary","author_inst":"JHU: Johns Hopkins University"},{"author_name":"Hannah Tappis","author_inst":"Johns Hopkins University"},{"author_name":"Maina Charity","author_inst":"Institute of Human Virology"},{"author_name":"Abimiku Rejoice Helma","author_inst":"Institute of Human Virology"},{"author_name":"Sussan Israel-Isah","author_inst":"Institute of Human Virology"},{"author_name":"Ayodeji Kazeem Olalekan","author_inst":"Institute of Human Virology"},{"author_name":"George Odonye","author_inst":"Institute of Human Virology"},{"author_name":"Maryan Ahmed","author_inst":"Somali Research & Development Institute"},{"author_name":"Salomine Ekambi","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Modelling the public-health impact of indoor air quality interventions on respiratory virus transmission","rel_doi":"10.64898\/2026.06.06.26355067","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26355067","rel_abs":"Respiratory virus transmission occurs in indoor settings where ventilation, occupancy, and dwell time determine exposure levels. Improving indoor air quality (IAQ) therefore could help reduce disease burden associated with respiratory viruses, yet its population-level impact remains poorly quantified. Here, we develop an individual-based transmission modelling framework that links within-location airborne dynamics to individual infection risk and population-level spread, whilst explicitly incorporating heterogeneity in ventilation and baseline indoor air quality across locations. We use this modelling approach to evaluate IAQ-improving interventions (air-quality interventions or AQIs), using hypothetical endemic and pandemic pathogen archetypes with properties similar to SARS-CoV-2 and influenza, and evaluate how effects on key epidemiological metrics (such as annualized incidence and epidemic final size) depend on AQI coverage, efficacy and allocation strategy. At 20% AQI intervention coverage and 80% efficacy, annualized incidence was reduced by approximately 7.2% for an endemic \"SARS-CoV-2-like\" respiratory virus, and 17.0% for an endemic \"influenza-like\" virus; at 60% coverage (80% efficacy) the reductions were 26.3% and 56.4%, respectively. Targeting AQI installation to the highest-risk locations outperformed random allocation: for SARS-CoV-2-like transmission, 20% coverage at 80% efficacy cut absolute incidence by 10.8% when targeted versus 7.2% when random; for influenza-like transmission, this comparison was 28.9% versus 17.0%. In epidemic scenarios, random installation at 40% coverage and 60% efficacy reduced final size by 23.7% (influenza-like) versus 6.3% (SARS-CoV-2-like). These results support treating clean indoor air as core public-health infrastructure and prioritising risk-based deployment of IAQ-improving interventions to maximise population-level benefit within budgetary and operational constraints.","rel_num_authors":14,"rel_authors":[{"author_name":"Adam Howes","author_inst":"Independent"},{"author_name":"Geetha Jeyapragasan","author_inst":"Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, USA; Computational Precision Health, Uni"},{"author_name":"Richard Williamson","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"David Carel","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"Harrison Koos","author_inst":"Department of Health Policy, Stanford University, Stanford, California, USA"},{"author_name":"Jacob L. Swett","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"James Montavon","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"Vivian Belenky","author_inst":"Center for Radiological Research, Columbia University Irving Medical Center, New York, NY, USA"},{"author_name":"Paul Lietar","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Richard Fitzjohn","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Giovanni Charles","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Serina Chang","author_inst":"Computational Precision Health, University of California, Berkeley and University of California, San Francisco, Berkeley, CA, USA; Electrical Engineering and Co"},{"author_name":"Thomas Brewer","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Charles Whittaker","author_inst":"Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, USA; Computational Precision Health, Uni"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Modelling the public-health impact of indoor air quality interventions on respiratory virus transmission","rel_doi":"10.64898\/2026.06.06.26355067","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26355067","rel_abs":"Respiratory virus transmission occurs in indoor settings where ventilation, occupancy, and dwell time determine exposure levels. Improving indoor air quality (IAQ) therefore could help reduce disease burden associated with respiratory viruses, yet its population-level impact remains poorly quantified. Here, we develop an individual-based transmission modelling framework that links within-location airborne dynamics to individual infection risk and population-level spread, whilst explicitly incorporating heterogeneity in ventilation and baseline indoor air quality across locations. We use this modelling approach to evaluate IAQ-improving interventions (air-quality interventions or AQIs), using hypothetical endemic and pandemic pathogen archetypes with properties similar to SARS-CoV-2 and influenza, and evaluate how effects on key epidemiological metrics (such as annualized incidence and epidemic final size) depend on AQI coverage, efficacy and allocation strategy. At 20% AQI intervention coverage and 80% efficacy, annualized incidence was reduced by approximately 7.2% for an endemic \"SARS-CoV-2-like\" respiratory virus, and 17.0% for an endemic \"influenza-like\" virus; at 60% coverage (80% efficacy) the reductions were 26.3% and 56.4%, respectively. Targeting AQI installation to the highest-risk locations outperformed random allocation: for SARS-CoV-2-like transmission, 20% coverage at 80% efficacy cut absolute incidence by 10.8% when targeted versus 7.2% when random; for influenza-like transmission, this comparison was 28.9% versus 17.0%. In epidemic scenarios, random installation at 40% coverage and 60% efficacy reduced final size by 23.7% (influenza-like) versus 6.3% (SARS-CoV-2-like). These results support treating clean indoor air as core public-health infrastructure and prioritising risk-based deployment of IAQ-improving interventions to maximise population-level benefit within budgetary and operational constraints.","rel_num_authors":14,"rel_authors":[{"author_name":"Adam Howes","author_inst":"Independent"},{"author_name":"Geetha Jeyapragasan","author_inst":"Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, USA; Computational Precision Health, Uni"},{"author_name":"Richard Williamson","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"David Carel","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"Harrison Koos","author_inst":"Department of Health Policy, Stanford University, Stanford, California, USA"},{"author_name":"Jacob L. Swett","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"James Montavon","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"Vivian Belenky","author_inst":"Center for Radiological Research, Columbia University Irving Medical Center, New York, NY, USA"},{"author_name":"Paul Lietar","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Richard Fitzjohn","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Giovanni Charles","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Serina Chang","author_inst":"Computational Precision Health, University of California, Berkeley and University of California, San Francisco, Berkeley, CA, USA; Electrical Engineering and Co"},{"author_name":"Thomas Brewer","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Charles Whittaker","author_inst":"Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, USA; Computational Precision Health, Uni"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Quantitative insights into the role of phages and plasmids in the persistence of nontuberculous mycobacteria in chloraminated drinking water","rel_doi":"10.64898\/2026.06.11.26355408","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355408","rel_abs":"Nontuberculous mycobacteria (NTM) are opportunistic pathogens that persist in chloraminated drinking water systems, yet the roles of phages and plasmids in their persistence remain largely unexplored. Using genome-resolved and quantitative metagenomics, we characterized NTM, phages, prophages, and plasmids in a chloraminated building plumbing system. Bacterial metagenome-assembled genomes (MAGs) and viral operational taxonomic units (vOTUs) were quantified at mean concentrations of 8.41 x 107 and 8.00 x 108 copies\/L, respectively, including seven NTM MAGs at a mean total concentration of 4.01 x 105 copies\/L. NTM concentrations were highest at the site with the lowest bacterial and viral diversity. Predicted NTM-infecting virus concentrations were inversely related to NTM concentrations across sites, suggesting complex phage-host dynamics that warrant direct experimental investigation. NTM, putative phages, prophages, and plasmids encoded functions related to disinfectant tolerance, stress response, metal resistance, and secretion. These findings identify phage interactions, prophages, and plasmids as overlooked genomic and ecological dimensions of NTM persistence in engineered water systems.","rel_num_authors":10,"rel_authors":[{"author_name":"Soojung Lee","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Kathryn Langenfeld","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Sarah Potgieter","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Sadia Marjia Ferdous","author_inst":"Case Western Reserve University"},{"author_name":"Shruti Vasagiri","author_inst":"Case Western Reserve University"},{"author_name":"G. Eric Bastien","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Melissa Duhaime","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Krista Wigginton","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Lutgarde Raskin","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Bridget Hegarty","author_inst":"Case Western Reserve University"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Recruitment, Retention Approaches and Community Engagement in the THRIVE pilot Trial: Lessons Learned from a Food is Medicine Trial","rel_doi":"10.64898\/2026.06.12.26355557","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355557","rel_abs":"BackgroundRecruitment of underrepresented populations, including Black and Hispanic populations, for Food is Medicine (FIM) and cardiovascular trials, may pose significant challenges.\n\nMethodsWe implemented a multi-component recruitment approach for the THRIVE (AdapTive personalized dietitian coacHing and messaging with pRoduce prescrIptions to improVE healthy dietary behaviors) pilot trial to engage primarily Black and Hispanic adults in a Food is Medicine for hypertension intervention. The recruitment approaches included community engagement at approximately 40 community events (cultural festivals and neighborhood gatherings); partnerships with 8 community and faith-based service hubs and food distribution sites; recruitment through safety net primary care clinics, digital outreach via the study website, and social media campaigns; and direct recruitment at places of worship. We report lessons learned from the community engagement process, recruitment efficiency, representativeness, and retention outcomes.\n\nResultsWithin 6 months, the enrollment target was exceeded by 40%, with an accrual index of 1.04. Over 1,000 individuals were reached through the direct-to-community engagement process, while faith-based partnerships engaged about 900 adults. There were 2,673 visits to the study webpage, and social media achieved 12,259 impressions with 399 clicks. About 95% of participants resided within 10 miles of the faith-based recruitment sites. Face-to-face engagement at the food distribution sites within faith-based organizations or community service hubs outperformed digital methods. Faith leader endorsements and follow-up in-person meetings (following unsuccessful email outreach) dramatically increased recruitment. Regarding retention, pre-randomization attrition was 6%, and 82% of participants completed the study.\n\nConclusionCulturally tailored, community-engaged recruitment grounded in faith-based and local community partnerships, was highly effective in engaging Black and Hispanic populations in this FIM cardiovascular trial. This provides a replicable model for implementing equitable and sustainable cardiovascular health interventions.","rel_num_authors":24,"rel_authors":[{"author_name":"Mojisola Olusola-Bello","author_inst":"Johns Hopkins University"},{"author_name":"Elohor Oborevwori","author_inst":"Johns Hopkins University School of Nursing"},{"author_name":"Khadijat Adeleye","author_inst":"University of Massachusetts Amherst - School of Nursing"},{"author_name":"Irma Irma Iribe","author_inst":"Johns Hopkins University"},{"author_name":"Adeline Assani-Uva","author_inst":"Holycross Engineering College"},{"author_name":"D?Janee Kyeremeh","author_inst":"Johns Hopkins University"},{"author_name":"Oluwatosin Tomiwa","author_inst":"Johns Hopkins University"},{"author_name":"Janice Adukwei Dugbartey","author_inst":"Johns Hopkins University"},{"author_name":"Maricielo Saldarriaga Noel","author_inst":"Johns Hopkins University"},{"author_name":"India E. Washington","author_inst":"Johns Hopkins University"},{"author_name":"Samuel Gledhill","author_inst":"Johns Hopkins University"},{"author_name":"Chelsea Akubo","author_inst":"Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Siddharth Dhadi","author_inst":"Johns Hopkins University Zanvyl Krieger School of Arts and Sciences"},{"author_name":"Mary Alawode","author_inst":"Johns Hopkins University Carey Business School"},{"author_name":"Jennifer Freeman","author_inst":"Community FarmShare"},{"author_name":"Kendra Smith","author_inst":"Kingdom Cares,  Kingdom Fellowship AME Church"},{"author_name":"Rose Bernard","author_inst":"Bread of Life Bible Church"},{"author_name":"Marie Antoinette Davis","author_inst":"Harvest Intercontinental Church"},{"author_name":"Channa Wilson","author_inst":"Harvest Intercontinental Church"},{"author_name":"Anna Maria Izquierdo Porerra","author_inst":"Tidal Health"},{"author_name":"Lisa A. Cooper","author_inst":"Johns Hopkins University"},{"author_name":"Cheryl R. Dennison Himmelfarb","author_inst":"Johns Hopkins University"},{"author_name":"Yvonne Commodore-Mensah","author_inst":"Johns Hopkins University School of Nursing"},{"author_name":"Oluwabunmi Ogungbe","author_inst":"John Hopkins School of Nursing"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Reaching out-of-school girls with HPV vaccination: A qualitative evaluation in six low- and middle-income countries using the RE-AIM framework","rel_doi":"10.64898\/2026.06.11.26355432","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355432","rel_abs":"BackgroundInfection with human papillomavirus (HPV), the primary cause of cervical cancer, disproportionately affects women in low- and middle-income countries (LMICs). While school-based vaccination of adolescent girls against HPV is highly effective, this strategy systematically excludes out-of-school (OOS) girls. Using the RE-AIM framework, we explored strategies to reach OOS girls with HPV vaccination across six African and Asian LMICs.\n\nMethodsWe conducted semi-structured key informant interviews with 32 vaccination program stakeholders from Cambodia, Cameroon, Kenya, Malawi, Mozambique, and Uganda between May and September 2024. Interviews explored countries implementation successes, challenges, and strategies to reach OOS girls with HPV vaccination and sustainability considerations. Data were analyzed using a hybrid team-based thematic analysis approach guided by the RE-AIM framework.\n\nResultsCommunity outreach-based strategies, typically integrated into routine immunization outreach, were identified as the most effective approach to reach OOS girls with HPV vaccination. Targeted strategies, such as locating outreach clinics in community venues frequented by OOS girls (e.g., churches, markets) enhanced implementation. Perceived effectiveness of these strategies varied across participants, and formal assessment of effectiveness was constrained by the absence of disaggregated vaccination coverage data by school enrollment status. Some subpopulations of OOS girls (i.e., girls in nomadic or migrant communities, urban OOS girls) were not readily reached through standard outreach approaches, prompting implementation of adapted and tailored strategies for these subpopulations. Costs associated with conducting outreach in harder-to-reach areas were major barriers to reaching OOS girls, presenting challenges to the sustainability and cost-effectiveness of these approaches.\n\nConclusionsRoutine community outreach platforms were widely perceived as most effective for reaching OOS girls. Strengthening disaggregated monitoring systems, adapting outreach for harder-to-reach subpopulations of OOS girls, and financing delivery models for tailored outreach strategies will be critical to improving equitable HPV vaccine coverage among OOS girls.","rel_num_authors":7,"rel_authors":[{"author_name":"Leanne Zhang","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Erica Rosser","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Megan  D Wysong","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Pamela  J Surkan","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Joseph  G Rosen","author_inst":"Brown University School of Public Health"},{"author_name":"Rupali  J Limaye","author_inst":"George Mason University"},{"author_name":"Soim Park","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"}],"rel_date":"2026-06-15","rel_site":"medrxiv"}]}