{"gname":"The Rockefeller University","grp_id":"2","rels":[{"rel_title":"Agentic Autodiscovery of Diastolic Dysfunction Phenotypes from Surface Electrocardiogram","rel_doi":"10.64898\/2026.06.17.26355897","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.17.26355897","rel_abs":"Background: Left ventricular diastolic dysfunction (LVDD) is a major determinant of heart failure (HF), yet its assessment relies on multiparametric echocardiography, limiting scalability. We previously demonstrated that generative artificial intelligence (AI) can synthesize tissue Doppler imaging (TDI) waveforms from the 12-lead ECG. The growing complexity of candidate architecture creates a need for automated model-discovery frameworks. Objectives: To evaluate agentic AI-based auto-discovery for ECG-based LVDD assessment using either raw ECG or synthetic TDI waveforms. Methods: Two attention-based agentic AI architectures were developed using an automated large language model-driven refinement framework that optimized transfer-learning and multimodal architectures through autonomous proposal, validation, and selection of candidate model configurations. Development was performed in 1,011 paired ECG-echocardiography studies and externally validated in 983 patients using two reference frameworks: (i) data-driven phenogroups and (ii) the 2025 ASE Diastolic Function Guidelines. External validation was performed in CODE-15% (n=219,567) for HF-related mortality and EchoNext (n=35,718) for structural heart disease associations. Results: Despite the modest cohort size, the ECG-based agentic search achieved area under the receiver operating characteristic curve (AUCs) of 0.87 (95% CI: 0.85-0.89) and 0.83 (95% CI: 0.80-0.86) for phenogroup and guideline-based LVDD severity classification. Corresponding AUCs for the synthetic TDI-based model were 0.82 (95% CI: 0.80-0.85) and 0.80 (95% CI: 0.77-0.84), respectively. In large-scale external validation, both models stratified incident HF mortality with subdistribution hazard ratios ranging 5.5 to 9.5 (Gray's p<0.001 for all). Time-dependent discrimination for incident HF mortality exceeded a publicly available convolutional neural network model (ECG2HF) ({Delta}AUC range: +0.14 to +0.20). Both models demonstrated consistent associations with structural heart disease outcomes. Conclusions: Agentic auto-discovery enabled data-efficient assessment of LVDD from surface ECG by combining physiologically informed transfer learning with autonomous architecture optimization, achieving robust external generalizability. This approach may facilitate broader access to diastolic function assessment beyond conventional echocardiography.","rel_num_authors":8,"rel_authors":[{"author_name":"Ankush Diwakar Jamthikar","author_inst":"Rutgers- The State University of New Jersey (All Campuses)"},{"author_name":"Aditya Shanmugham","author_inst":"Rutgers University"},{"author_name":"Sajeev Singh","author_inst":"Rutgers University"},{"author_name":"Aditya Radhakrishnan","author_inst":"Georgia Institute of Technology, Atlanta, GA"},{"author_name":"Jiawei Dong","author_inst":"Rutgers Universit"},{"author_name":"Kameswari Maganti","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Naveena Yanamala","author_inst":"Rutgers University"},{"author_name":"Partho Sengupta","author_inst":"Rutgers, The State University of New Jersey"}],"rel_date":"2026-06-23","rel_site":"medrxiv"},{"rel_title":"Agentic Autodiscovery of Diastolic Dysfunction Phenotypes from Surface Electrocardiogram","rel_doi":"10.64898\/2026.06.17.26355897","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.17.26355897","rel_abs":"Background: Left ventricular diastolic dysfunction (LVDD) is a major determinant of heart failure (HF), yet its assessment relies on multiparametric echocardiography, limiting scalability. We previously demonstrated that generative artificial intelligence (AI) can synthesize tissue Doppler imaging (TDI) waveforms from the 12-lead ECG. The growing complexity of candidate architecture creates a need for automated model-discovery frameworks. Objectives: To evaluate agentic AI-based auto-discovery for ECG-based LVDD assessment using either raw ECG or synthetic TDI waveforms. Methods: Two attention-based agentic AI architectures were developed using an automated large language model-driven refinement framework that optimized transfer-learning and multimodal architectures through autonomous proposal, validation, and selection of candidate model configurations. Development was performed in 1,011 paired ECG-echocardiography studies and externally validated in 983 patients using two reference frameworks: (i) data-driven phenogroups and (ii) the 2025 ASE Diastolic Function Guidelines. External validation was performed in CODE-15% (n=219,567) for HF-related mortality and EchoNext (n=35,718) for structural heart disease associations. Results: Despite the modest cohort size, the ECG-based agentic search achieved area under the receiver operating characteristic curve (AUCs) of 0.87 (95% CI: 0.85-0.89) and 0.83 (95% CI: 0.80-0.86) for phenogroup and guideline-based LVDD severity classification. Corresponding AUCs for the synthetic TDI-based model were 0.82 (95% CI: 0.80-0.85) and 0.80 (95% CI: 0.77-0.84), respectively. In large-scale external validation, both models stratified incident HF mortality with subdistribution hazard ratios ranging 5.5 to 9.5 (Gray's p<0.001 for all). Time-dependent discrimination for incident HF mortality exceeded a publicly available convolutional neural network model (ECG2HF) ({Delta}AUC range: +0.14 to +0.20). Both models demonstrated consistent associations with structural heart disease outcomes. Conclusions: Agentic auto-discovery enabled data-efficient assessment of LVDD from surface ECG by combining physiologically informed transfer learning with autonomous architecture optimization, achieving robust external generalizability. This approach may facilitate broader access to diastolic function assessment beyond conventional echocardiography.","rel_num_authors":8,"rel_authors":[{"author_name":"Ankush Diwakar Jamthikar","author_inst":"Rutgers- The State University of New Jersey (All Campuses)"},{"author_name":"Aditya Shanmugham","author_inst":"Rutgers University"},{"author_name":"Sajeev Singh","author_inst":"Rutgers University"},{"author_name":"Aditya Radhakrishnan","author_inst":"Georgia Institute of Technology, Atlanta, GA"},{"author_name":"Jiawei Dong","author_inst":"Rutgers Universit"},{"author_name":"Kameswari Maganti","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Naveena Yanamala","author_inst":"Rutgers University"},{"author_name":"Partho Sengupta","author_inst":"Rutgers, The State University of New Jersey"}],"rel_date":"2026-06-23","rel_site":"medrxiv"},{"rel_title":"Shared Polygenic Architecture Across Arteriopathies: An Integrative Cross-Trait Analysis","rel_doi":"10.64898\/2026.06.18.26356018","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26356018","rel_abs":"Background: Non-monogenic arteriopathies are often classified as distinct entities according to the arterial territory involved, yet they share clinical features and may co-occur in the same individual. This pattern suggests shared susceptibility across anatomically distinct arteriopathies, potentially driven by common biological and genetic mechanisms. Methods: We investigated the shared genetic architecture of five arteriopathies (cervical artery dissection (CeAD), intracranial aneurysm (IA), spontaneous coronary artery dissection (SCAD), aortic aneurysm and dissection (AAD), and fibromuscular dysplasia (FMD)) using LD score regression, Association analysis based on SubSETs (ASSET), pairwise Multi-Trait Analysis of Genome-wide association summary statistics (MTAG), pleiotropy mapping and Mendelian randomization (MR) to identify shared loci and prioritise candidate causal genes. Results: LD score regression identified significant positive genetic correlations between CeAD-SCAD (rg = 0.64), IA-AAD (rg = 0.33), IA-SCAD (rg = 0.37), CeAD-AAD (rg = 0.56) and SCAD-AAD (rg = 0.20). ASSET identified 37 shared independent loci, and in MTAG analyses, one novel locus was identified for CeAD and SCAD (SLC39A8) and one for IA (FGF5). 13 loci showed strong cross-trait colocalization, including PHACTR1, LRP1, and CDKN2B-AS1. Using the Genotype-Phenotype Map, we found that arteriopathy-associated variants colocalized with blood pressure- and migraine-related traits, while many showed effect directions opposite to those observed for coronary artery disease. Proteome-wide MR identified 67 circulating proteins associated with at least one trait, including ECM1 and SHISA5 for CeAD and FGF5 for IA, with 17 supported by colocalization. Transcriptome-wide MR identified 204 colocalized tissue?specific signals, of which, 14 were shared across multiple traits. Enrichment analyses implicated pathways related to vascular development, smooth muscle cell function, extracellular matrix organization, and TGF-? signaling. Conclusions: These findings support shared genetic architecture across anatomically distinct arteriopathies, implicating pathways involved in vascular structure and prioritising therapeutic targets for future mechanistic investigation.","rel_num_authors":10,"rel_authors":[{"author_name":"Stephen O Brennan","author_inst":"University of Galway School of Medicine"},{"author_name":"CADISP Consortium","author_inst":""},{"author_name":"Alexander C Tinworth","author_inst":"University of Oxford Nuffield Department of Population Health"},{"author_name":"Iyas Daghlas","author_inst":"University of California San Francisco"},{"author_name":"Quentin Le Grand","author_inst":"Universite de Bordeaux"},{"author_name":"Bastien Rioux","author_inst":"University of Montreal"},{"author_name":"Peter J Kelly","author_inst":"Mater University Hospital\/University College Dublin"},{"author_name":"Dipender Gill","author_inst":"Imperial College London"},{"author_name":"Stephanie Debette","author_inst":"Institut du Cerveau"},{"author_name":"John Joseph McCabe","author_inst":"Health Research Board Stroke Clinical Trials Network Ireland"}],"rel_date":"2026-06-23","rel_site":"medrxiv"},{"rel_title":"Acute Ischemic Stroke Detection on Non-Contrast CT: A Deep Learning Approach","rel_doi":"10.64898\/2026.06.20.26356152","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.20.26356152","rel_abs":"Acute ischemic stroke (AIS) is a leading cause of disability and death while effective treatment requires quick and accurate diagnosis. Non-contrast CT (NCCT) is widely used in the initial screening of AIS, but stroke detection is challenging because early changes on NCCT are subtle or indistinguishable. Using hyperacute NCCTs as inputs and diffusion-weighted MRI as ground truth, we trained a deep learning algorithm to classify patients with AIS and segment the stroke lesions. We hypothesized that this approach would accurately detect hyperacute tissue density changes on NCCT. For the classification task, our ResNet50 model delivered the best performance (with 98.5% accuracy, 97.4% precision, and 100% recall on an evaluation set). Classification performance remained strong when restricted to lesions smaller than 5 mL, which constituted the majority of our evaluation cases. For the segmentation task accomplished using a range of U-Net architectures, performance was acceptable for large lesions and declined sharply for smaller lesions. Together, these findings demonstrate the feasibility of deep learning for AIS detection and represent a step towards faster triage and treatment for stroke patients.","rel_num_authors":2,"rel_authors":[{"author_name":"Ansh Goyal","author_inst":"Johns Hopkins University"},{"author_name":"Robert D Stevens","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-23","rel_site":"medrxiv"},{"rel_title":"Respiratory support with Continuous Positive Airway Pressure in preterm neonates: an analysis of coverage and quality of care in 66 neonatal units in Kenya, Malawi, Nigeria and Tanzania implementing with the NEST360 Alliance","rel_doi":"10.64898\/2026.06.20.26356142","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.20.26356142","rel_abs":"Background: Prematurity is the leading cause of child deaths worldwide, with the highest neonatal mortality in sub Saharan Africa. Respiratory distress syndrome (RDS) is the leading mortality pathway in preterm neonates, but continuous positive airway pressure (CPAP) has high impact. This analysis reports CPAP coverage and quality of care for preterm neonates admitted to 66 neonatal units in Kenya, Malawi, Nigeria and Tanzania. Methods: Analyses used individually linked neonatal inpatient data and cross-sectional health systems data. All admitted neonates were eligible for inclusion (January 2021 through December 2024). Service readiness for CPAP delivery and mean CPAP coverage were described for CPAP eligible newborns (weighing <1500g and symptomatic newborns >1500g). Quality of care cascades were constructed to illustrate key indicators. Survival among CPAP eligible neonates was analysed using regression models, stratified by clinical severity scores. Results: 375,255 newborn admissions were analysed in 66 neonatal units. Functional CPAP availability varied with median 16% of days (IQR: 4 to 47%) classified as high demand (>1.5 eligible newborns per CPAP). Of 64,761 CPAP eligible neonates, 22,006 (34%, 95% CI 33 to 34%) received CPAP. All countries showed improvement in CPAP coverage, with Tanzanian hospitals recording 63% increase in mean coverage (p-value=0.001) over time. Quality of care cascades showed treatment was initiated <24 hours after birth and continued for >1 day for 42% (95% CI 41 to 43%) of eligible neonates receiving CPAP. Only 10% of neonates <1500g started CPAP within the first hour of life. Among newborns on CPAP, 55% also received KMC (from 48% in Tanzania to 88% in Nigeria). Among newborns with high clinical severity, those treated with CPAP had a higher probability of survival (32%, 95% CI 29 to 36%) than those who were not (23%, 95% CI 21 to 26%). Odds of survival were higher for CPAP eligible newborns whose mothers received antenatal corticosteroids (aOR 1.07, p=0.001). Lower aOR of survival was associated with hypoglycaemia (aOR 0.71, p<0.001), respiratory distress (aOR 0.91, p<0.001), and outborn newborns (aOR 0.72, p<0.001). Conclusion: CPAP coverage and quality are critical for premature neonates. Clinical cascades highlight quality gaps, particularly in timely prophylactic CPAP initiation and appropriate duration. Improving comprehensive care quality for newborns on CPAP, including provision of co-interventions and maternal antenatal corticosteroids, can improve survival for preterm neonates.","rel_num_authors":28,"rel_authors":[{"author_name":"Kristina Shemwell","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"John Wainaina","author_inst":"Rice360 Institute for Global Health Technologies, Rice University"},{"author_name":"Joy E. Lawn","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"Nahya Salim","author_inst":"Department of Paediatrics and Child Health, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania; Ifakara Health Institute, Dar Es Salaam"},{"author_name":"Rebecca E Penzias","author_inst":"Department of Infectious Disease Epidemiology and International Health, London School of Hygiene & Tropical Medicine, London, United Kingdom"},{"author_name":"Lucas Malla","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"Mariam Johari","author_inst":"Rice360 Institute for Global Health Technologies, Rice University"},{"author_name":"Robert Tillya","author_inst":"Ifakara Health Institute, Dar Es Salaam, Tanzania"},{"author_name":"Christine A. Bohne","author_inst":"Rice360 Institute for Global Health Technologies, Rice University"},{"author_name":"Msandeni Chiume","author_inst":"Ministry of Health, Malawi - Reproductive Health Department; School of Global and Public Health, Kamuzu University of Health Sciences, Blantyre, Malawi"},{"author_name":"Samuel K. Ngwala","author_inst":"School of Global and Public Health, Kamuzu University of Health Sciences, Blantyre, Malawi"},{"author_name":"Olabisi O. Dosumnu","author_inst":"APIN Public Health Initiatives, Abuja, Nigeria"},{"author_name":"Chinyere Ezeaka","author_inst":"Department of Paediatrics, College of Medicine, University of Lagos, Lagos, Nigeria"},{"author_name":"George Okello","author_inst":"Rice360 Institute for Global Health Technologies"},{"author_name":"William M. Macharia","author_inst":"Department of Paediatrics, Aga Khan University, Nairobi, Kenya"},{"author_name":"Natasha R. Rhoda","author_inst":"Childrens Institute, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town"},{"author_name":"Edith Gicheha","author_inst":"Rice360 Institute for Global Health Technologies, Rice University"},{"author_name":"Nebiyou Hailemariam","author_inst":"Rice360 Institute for Global Health Technologies, Rice University"},{"author_name":"Morris Ondieki Ogero","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"Junwei Chen","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Eric O. Ohuma","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"Rebecca Richards-Kortum","author_inst":"Rice360 Institute for Global Health Technologies, Rice University"},{"author_name":"Maria Oden","author_inst":"Rice360 Institute for Global Health Technologies, Rice University"},{"author_name":"James H. Cross","author_inst":"Department of Infectious Disease Epidemiology and International Health, London School of Hygiene & Tropical Medicine, London, United Kingdom"},{"author_name":"Kondwani Kawaza","author_inst":"Department of Paediatrics, Kamuzu University of Health Sciences, Blantyre, Malawi"},{"author_name":"Elizabeth M. Molyneux","author_inst":"Department of Paediatrics, Kamuzu University of Health Sciences, Blantyre, Malawi"},{"author_name":"- NEST360 Neonatal Inpatient Dataset and Data Systems Collaborative Group and Context Tracker","author_inst":"-"},{"author_name":"- NEST360 Health Facility Assessment Collaborative Group","author_inst":"-"}],"rel_date":"2026-06-23","rel_site":"medrxiv"},{"rel_title":"Multidimensional motivation in aging: a person-centred framework spanning goal-directed behaviour, social reward and pleasure","rel_doi":"10.64898\/2026.06.11.26355497","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355497","rel_abs":"Motivational changes are determinants of healthy aging, social engagement, and functional independence, and may signal early neurodegenerative risk. Existing assessment approaches in aging typically treat motivation as a unitary construct. Here, we introduce MotDem, an age-appropriate measure of motivation co-designed with people living with dementia, carers, and clinicians. Across a broad adult lifespan sample (18-80 years), MotDem revealed a robust three-domain motivational architecture encompassing goal-directed behaviour, social reward, and pleasure, with a fourth satiety factor retained as exploratory. This structure was replicated in an independent older cohort (45-80 years) from a different national context. MotDem showed strong convergence with established measures of apathy and anhedonia, alongside more modest associations with depressive symptomatology. Together, these findings show that motivational aging is multifaceted and poorly captured by traditional unitary assessment. MotDem provides a multidimensional framework for measuring distinct motivational drivers of heterogeneous aging trajectories, with implications for resilience, wellbeing, and neurodegenerative risk.","rel_num_authors":12,"rel_authors":[{"author_name":"Samuel L. Warren","author_inst":"The University of Sydney"},{"author_name":"Aria Somasundaram","author_inst":"The University of Sydney"},{"author_name":"Kristina Horne","author_inst":"The University of Sydney"},{"author_name":"Gail A. Robinson","author_inst":"The University of Queensland"},{"author_name":"Julie Behensk\u00e1","author_inst":"Sorbonne University & The University of Sydney"},{"author_name":"Kathy Nguyen","author_inst":"The University of Sydney"},{"author_name":"Anita M.Y. Goh","author_inst":"University of Melbourne"},{"author_name":"Yun-Hee Jeon","author_inst":"The University of Sydney"},{"author_name":"Lee-Fay Low","author_inst":"The University of Sydney"},{"author_name":"Chang Xu","author_inst":"The University of Sydney"},{"author_name":"Muireann Irish","author_inst":"The University of Sydney"},{"author_name":"- MotDem Consortium","author_inst":""}],"rel_date":"2026-06-23","rel_site":"medrxiv"},{"rel_title":"Oxidative Stress Biomarker Profile Dynamics across Blood and Cerebrospinal Fluid","rel_doi":"10.64898\/2026.06.19.26355411","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.19.26355411","rel_abs":"Peripheral blood measurements dominate oxidative stress research, yet whether they reflect central nervous system (CNS) redox status remains untested in humans. We simultaneously profiled five biomarkers, total antioxidant capacity (TAC), glutathione (GSH), thiobarbituric acid-reactive substances (TBARS), ferric reducing antioxidant power (FRAP), and hydroxyl radical scavenging activity (HRSA), in paired blood and cerebrospinal fluid (CSF) from 140 adults in the ALBION cohort. Only FRAP showed a significant positive cross-compartment correlation ({rho} = +0.49, FDR-p < 0.001), supporting its role as a systemic antioxidant signal. TBARS showed a significant inverse cross-compartment association ({rho} = -0.20, FDR-p = 0.042), suggesting compartmental compensation in lipid peroxidation regulation rather than parallel dynamics. TAC and GSH showed no meaningful intercompartmental alignment. Individual biomarker levels were largely stable across the 40-85 year age range in both compartments, suggesting that age effects operate through coordinated latent networks rather than single-marker trajectories. Principal component extraction with varimax rotation identified four latent factors explaining 66.6% of total variance, dominated by a coherent CSF-centred redox axis alongside multiple partially opposing peripheral components. Age stratification revealed progressive fragmentation: middle-aged adults retained four coherent cross-compartment factors, whereas older adults exhibited five more dispersed components. Sex-stratified analyses showed that females exhibited four-factor modular organisation centred on glutathione, while males showed a simpler three-factor structure with tighter cross-compartment coupling anchored by FRAP. Blood and CSF oxidative stress biomarkers are not interchangeable, a finding with direct implications for biomarker selection in clinical trials targeting neurological conditions.","rel_num_authors":10,"rel_authors":[{"author_name":"Adrian Noriega de la Colina","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Zoe Skaperda","author_inst":"University of Thessaly"},{"author_name":"Sokratis Charisis","author_inst":"National and Kapodistrian University of Athens"},{"author_name":"Eva Ntanasi","author_inst":"National and Kapodistrian University of Athens"},{"author_name":"Eirini Mamalaki","author_inst":"National and Kapodistrian University of Athens"},{"author_name":"Maria Yannakoulia","author_inst":"Harokopio University"},{"author_name":"Christopher Papandreou","author_inst":"Hospital Universitari Sant Joan de Reus"},{"author_name":"Fotios Tekos","author_inst":"University of Thessaly"},{"author_name":"Dimitrios Kouretas","author_inst":"University of Thessaly"},{"author_name":"Nikolaos Scarmeas","author_inst":"National and Kapodistrian University of Athens"}],"rel_date":"2026-06-23","rel_site":"medrxiv"},{"rel_title":"The Target ALS Global Natural History Study: Cross-platform proteomics to accelerate biofluid biomarker and drug target discovery in amyotrophic lateral sclerosis","rel_doi":"10.64898\/2026.06.13.26355379","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355379","rel_abs":"Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease of motor neurons for which therapeutics are limited. Improved biomarkers are imperative to improve patient care and therapeutic development. Here, we employed 35-plex isobaric tandem mass tag labeling based on isobutyl-proline reporter group (TMTpro) to perform unbiased proteomic analysis of cerebrospinal fluid (CSF) and plasma from control (n= 28, n= 31) and sporadic ALS (sALS) (n= 39, n= 41), from the Target ALS Global Natural History Study (TALS GNHS). We identified 2,875 proteins in CSF and 1,118 proteins in plasma and identified known and novel differentially expressed proteins (DEPs) between controls and sALS, some of which were orthogonally validated using immunoassay. Comparison of TMTpro-MS and Olink proximity extension assay proteomics revealed common and non-overlapping differentially expressed proteins illustrating strengths unique to each platform. This initial cross-sectional proteomic study of biofluids from the TALS GNHS, with unrestricted availability of study results to the research community, highlights the potential of this resource as a potent platform for ALS biomarker discovery.","rel_num_authors":28,"rel_authors":[{"author_name":"Daisuke Yasui","author_inst":"Washington University in St. Louis"},{"author_name":"Daniel Weatherill","author_inst":"Target ALS Foundation"},{"author_name":"Laura Dugom","author_inst":"Target ALS Foundation"},{"author_name":"Sophia Weiner","author_inst":"the Sahlgrenska Academy at the University of Gothenburg"},{"author_name":"Lathika Gopalakrishnan","author_inst":"Barrow Neurological Institute"},{"author_name":"Huy Tran","author_inst":"Mayo Clinic"},{"author_name":"Bj\u00f6rn Oskarsson","author_inst":"Mayo Clinic"},{"author_name":"Kyra Nagle","author_inst":"Washington University in St Louis"},{"author_name":"Timothy Miller","author_inst":"Washington University in St Louis"},{"author_name":"Gilbert Gutierrez","author_inst":"University of California, San Diego"},{"author_name":"John Ravits","author_inst":"University of California, San Diego"},{"author_name":"Benjamin Hoover","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Matthew Harms","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Neil Shneider","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Lizzi Neylon","author_inst":"Target ALS Foundation"},{"author_name":"Whitney Dailey","author_inst":"Barrow Neurological Institute"},{"author_name":"Shafeeq Ladha","author_inst":"Barrow Neurological Institute"},{"author_name":"Cassandra Holmes","author_inst":"Georgetown University Medical Center"},{"author_name":"Joseph Lee","author_inst":"Georgetown University Medical Center"},{"author_name":"Nicholas Streicher","author_inst":"Georgetown University Medical Center"},{"author_name":"Shakti Nayar","author_inst":"Georgetown University Medical Center"},{"author_name":"Brent T. Harris","author_inst":"Georgetown University Medical Center"},{"author_name":"Manish Raisinghani","author_inst":"Target ALS Foundation"},{"author_name":"Henrik Zetterberg","author_inst":"the Sahlgrenska Academy at the University of Gothenburg"},{"author_name":"Johan Gobom","author_inst":"the Sahlgrenska Academy at the University of Gothenburg"},{"author_name":"Amy Easton","author_inst":"Target ALS Foundation"},{"author_name":"Robert Bowser","author_inst":"Barrow Neurological Institute"},{"author_name":"Cindy V. Ly","author_inst":"Washington University in St Louis"}],"rel_date":"2026-06-23","rel_site":"medrxiv"},{"rel_title":"The Target ALS Global Natural History Study: Cross-platform proteomics to accelerate biofluid biomarker and drug target discovery in amyotrophic lateral sclerosis","rel_doi":"10.64898\/2026.06.13.26355379","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355379","rel_abs":"Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease of motor neurons for which therapeutics are limited. Improved biomarkers are imperative to improve patient care and therapeutic development. Here, we employed 35-plex isobaric tandem mass tag labeling based on isobutyl-proline reporter group (TMTpro) to perform unbiased proteomic analysis of cerebrospinal fluid (CSF) and plasma from control (n= 28, n= 31) and sporadic ALS (sALS) (n= 39, n= 41), from the Target ALS Global Natural History Study (TALS GNHS). We identified 2,875 proteins in CSF and 1,118 proteins in plasma and identified known and novel differentially expressed proteins (DEPs) between controls and sALS, some of which were orthogonally validated using immunoassay. Comparison of TMTpro-MS and Olink proximity extension assay proteomics revealed common and non-overlapping differentially expressed proteins illustrating strengths unique to each platform. This initial cross-sectional proteomic study of biofluids from the TALS GNHS, with unrestricted availability of study results to the research community, highlights the potential of this resource as a potent platform for ALS biomarker discovery.","rel_num_authors":28,"rel_authors":[{"author_name":"Daisuke Yasui","author_inst":"Washington University in St. Louis"},{"author_name":"Daniel Weatherill","author_inst":"Target ALS Foundation"},{"author_name":"Laura Dugom","author_inst":"Target ALS Foundation"},{"author_name":"Sophia Weiner","author_inst":"the Sahlgrenska Academy at the University of Gothenburg"},{"author_name":"Lathika Gopalakrishnan","author_inst":"Barrow Neurological Institute"},{"author_name":"Huy Tran","author_inst":"Mayo Clinic"},{"author_name":"Bj\u00f6rn Oskarsson","author_inst":"Mayo Clinic"},{"author_name":"Kyra Nagle","author_inst":"Washington University in St Louis"},{"author_name":"Timothy Miller","author_inst":"Washington University in St Louis"},{"author_name":"Gilbert Gutierrez","author_inst":"University of California, San Diego"},{"author_name":"John Ravits","author_inst":"University of California, San Diego"},{"author_name":"Benjamin Hoover","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Matthew Harms","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Neil Shneider","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Lizzi Neylon","author_inst":"Target ALS Foundation"},{"author_name":"Whitney Dailey","author_inst":"Barrow Neurological Institute"},{"author_name":"Shafeeq Ladha","author_inst":"Barrow Neurological Institute"},{"author_name":"Cassandra Holmes","author_inst":"Georgetown University Medical Center"},{"author_name":"Joseph Lee","author_inst":"Georgetown University Medical Center"},{"author_name":"Nicholas Streicher","author_inst":"Georgetown University Medical Center"},{"author_name":"Shakti Nayar","author_inst":"Georgetown University Medical Center"},{"author_name":"Brent T. Harris","author_inst":"Georgetown University Medical Center"},{"author_name":"Manish Raisinghani","author_inst":"Target ALS Foundation"},{"author_name":"Henrik Zetterberg","author_inst":"the Sahlgrenska Academy at the University of Gothenburg"},{"author_name":"Johan Gobom","author_inst":"the Sahlgrenska Academy at the University of Gothenburg"},{"author_name":"Amy Easton","author_inst":"Target ALS Foundation"},{"author_name":"Robert Bowser","author_inst":"Barrow Neurological Institute"},{"author_name":"Cindy V. Ly","author_inst":"Washington University in St Louis"}],"rel_date":"2026-06-23","rel_site":"medrxiv"},{"rel_title":"The Target ALS Global Natural History Study: Cross-platform proteomics to accelerate biofluid biomarker and drug target discovery in amyotrophic lateral sclerosis","rel_doi":"10.64898\/2026.06.13.26355379","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355379","rel_abs":"Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease of motor neurons for which therapeutics are limited. Improved biomarkers are imperative to improve patient care and therapeutic development. Here, we employed 35-plex isobaric tandem mass tag labeling based on isobutyl-proline reporter group (TMTpro) to perform unbiased proteomic analysis of cerebrospinal fluid (CSF) and plasma from control (n= 28, n= 31) and sporadic ALS (sALS) (n= 39, n= 41), from the Target ALS Global Natural History Study (TALS GNHS). We identified 2,875 proteins in CSF and 1,118 proteins in plasma and identified known and novel differentially expressed proteins (DEPs) between controls and sALS, some of which were orthogonally validated using immunoassay. Comparison of TMTpro-MS and Olink proximity extension assay proteomics revealed common and non-overlapping differentially expressed proteins illustrating strengths unique to each platform. This initial cross-sectional proteomic study of biofluids from the TALS GNHS, with unrestricted availability of study results to the research community, highlights the potential of this resource as a potent platform for ALS biomarker discovery.","rel_num_authors":28,"rel_authors":[{"author_name":"Daisuke Yasui","author_inst":"Washington University in St. Louis"},{"author_name":"Daniel Weatherill","author_inst":"Target ALS Foundation"},{"author_name":"Laura Dugom","author_inst":"Target ALS Foundation"},{"author_name":"Sophia Weiner","author_inst":"the Sahlgrenska Academy at the University of Gothenburg"},{"author_name":"Lathika Gopalakrishnan","author_inst":"Barrow Neurological Institute"},{"author_name":"Huy Tran","author_inst":"Mayo Clinic"},{"author_name":"Bj\u00f6rn Oskarsson","author_inst":"Mayo Clinic"},{"author_name":"Kyra Nagle","author_inst":"Washington University in St Louis"},{"author_name":"Timothy Miller","author_inst":"Washington University in St Louis"},{"author_name":"Gilbert Gutierrez","author_inst":"University of California, San Diego"},{"author_name":"John Ravits","author_inst":"University of California, San Diego"},{"author_name":"Benjamin Hoover","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Matthew Harms","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Neil Shneider","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Lizzi Neylon","author_inst":"Target ALS Foundation"},{"author_name":"Whitney Dailey","author_inst":"Barrow Neurological Institute"},{"author_name":"Shafeeq Ladha","author_inst":"Barrow Neurological Institute"},{"author_name":"Cassandra Holmes","author_inst":"Georgetown University Medical Center"},{"author_name":"Joseph Lee","author_inst":"Georgetown University Medical Center"},{"author_name":"Nicholas Streicher","author_inst":"Georgetown University Medical Center"},{"author_name":"Shakti Nayar","author_inst":"Georgetown University Medical Center"},{"author_name":"Brent T. Harris","author_inst":"Georgetown University Medical Center"},{"author_name":"Manish Raisinghani","author_inst":"Target ALS Foundation"},{"author_name":"Henrik Zetterberg","author_inst":"the Sahlgrenska Academy at the University of Gothenburg"},{"author_name":"Johan Gobom","author_inst":"the Sahlgrenska Academy at the University of Gothenburg"},{"author_name":"Amy Easton","author_inst":"Target ALS Foundation"},{"author_name":"Robert Bowser","author_inst":"Barrow Neurological Institute"},{"author_name":"Cindy V. Ly","author_inst":"Washington University in St Louis"}],"rel_date":"2026-06-23","rel_site":"medrxiv"},{"rel_title":"Directional information flow as a tool for analyzing protein allostery","rel_doi":"10.64898\/2026.06.22.733418","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.22.733418","rel_abs":"The ability to tune protein function through the binding of modulatory ligands enables the development of therapeutics that steer a biological system away from dysfunctional states underlying disease. Understanding the dynamic mechanisms by which allosteric ligands alter protein function remains an important open question. Dynamical network models allow us to quantify information flow between protein functional sites. However, existing network models use time-symmetric metrics for computing information from correlated residue motions extracted from molecular dynamics (MD) simulations, failing to fully capture directional information flow between sites. Here, we developed a Python library, TEntroPy, and analysis workflow using transfer entropy to generate a directional protein network from equilibrium MD trajectories. Applying this workflow to proteins with known allosteric ligands, we identified residues in both allosteric and orthosteric (primary) binding sites acting as broadcasters and receivers of information. We then computed optimal paths of directional information flow between binding sites. The presence of temporal asymmetry in residue coupling identified from simulations of the unbound (apo) state suggests that directional information flow is encoded in the intrinsic dynamics of the protein. To test this, we perturbed key binding-site residues and demonstrated that our TE-weighted network captures perturbation-induced changes in dynamics along communication routes between binding sites. Identifying residue pairs with high temporal asymmetry provides an additional tool for understanding the dynamic mechanisms of allosteric communication.","rel_num_authors":2,"rel_authors":[{"author_name":"Remy A Yovanno","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Albert Y Lau","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Surface-specific film assembly of a Vibrio cholerae adhesin peptide modulated by environmental salts","rel_doi":"10.64898\/2026.06.21.733527","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.21.733527","rel_abs":"Underwater adhesion research increasingly draws on bioinspired systems to uncover the molecular mechanisms that enable strong interfacial binding in aqueous environments. The biofilm adhesin Bap1 from Vibrio cholerae contains a short peptide motif, SYWFFGWHTK (CP), which exhibits exceptional adhesive performance, surpassing mussel foot protein mfp5 under comparable conditions. Despite its promise, the roles of ionic environments and aggregation behavior in governing CP adhesion remain unclear. In this study, we investigate how ion identity influences CP aggregation, film formation, and interfacial properties. Using dynamic light scattering, we identify the formation of micron-scale assemblies of aggregated molecular clusters (AAMCs), with size distributions modulated by salt type. Quartz crystal microbalance with dissipation and liquid atomic force microscopy reveal that CP film formation is both surface- and ion-dependent. On gold substrates, AAMCs preferentially adsorb and collapse into rigid, smooth nanofilms, consistent with hydrophobic-driven compaction. In contrast, silicate surfaces inhibit such collapse, yielding distinct morphologies and interfacial energetics. These findings demonstrate that surface chemistry and ionic conditions jointly regulate peptide aggregation and adhesion. This work provides mechanistic insight into hydrophobic-rich peptide systems and informs the rational design of next-generation wet adhesives, with broader implications for biomaterials and peptide-based formulations.","rel_num_authors":9,"rel_authors":[{"author_name":"Sixin Zhai","author_inst":"University of California Merced"},{"author_name":"Diego R Jaramillo Pinto","author_inst":"University of California Merced"},{"author_name":"Nicolas L Mendoza","author_inst":"University of California Merced"},{"author_name":"Adekunle Adewole","author_inst":"University of California Merced"},{"author_name":"Benjamin Heufner","author_inst":"University of California Merced"},{"author_name":"Andrea D Merg","author_inst":"University of California Merced"},{"author_name":"Tomas P Corrales","author_inst":"Universidad Tecnica Federico Santa Maria"},{"author_name":"Jing Yan","author_inst":"Yale University"},{"author_name":"Roberto Carlos Andresen Eguiluz","author_inst":"University of California Merced"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Evidence that the Kuenenia stuttgartiensis encapsulin does not protect against NO damage","rel_doi":"10.64898\/2026.06.22.733830","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.22.733830","rel_abs":"A paradigm shift is underway in microbiology: many prokaryotes, long considered to lack the compartmentalization present in all eukaryotic life, have been found to possess a great diversity of protein based intracellular compartments. Notably, the genomes of many marine and freshwater anaerobic ammonium oxidizing (anammox) bacteria encode one of these compartmentalization strategies; encapsulin nanocompartments. These systems structure suggests a role for anammox encapsulins in the anammox metabolism, a process of global biogeochemical significance, which results in the loss of biologically available nitrogen from aquatic environments. Here we test if the most common anammox encapsulin architecture could provide a mechanism to detoxify NO, one of the reactive intermediates produced in the core anammox metabolism. Through experiments in which the Kuenenia stuttgartiensis encapsulin was heterologously expressed by an inducible plasmid in E. coli, we show evidence that suggests the K. stuttgartiensis encapsulin provides no protection from NO.","rel_num_authors":3,"rel_authors":[{"author_name":"John C. Tracey","author_inst":"University of Chicago"},{"author_name":"Tobias Wolfgang Giessen","author_inst":"University of Michigan"},{"author_name":"Bess B Ward","author_inst":"Princeton University"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"A microbial metabolite reduces alcohol-induced inflammation via dual modulation of NF-\u03baB and Interferon pathway","rel_doi":"10.64898\/2026.06.18.733199","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733199","rel_abs":"Abstract Background and aims: Alcohol-associated hepatitis (AH) is characterized by excessive inflammation and blunted antiviral interferon (IFN) responses. We hypothesized that specific gut microbiome-derived metabolites could selectively enhance interferon signaling while limiting NF-{kappa}B mediated inflammation, thereby restoring immune balance in AH. Our goal is to identify microbiome-derived metabolites that differentially regulate the NF-{kappa}B and IFN signaling pathways. Methods and results: We used human monocytic THP1-Dual cells, which secrete reporters for NF-{kappa}B and IFN signaling, to model innate immune responses and screened a library of 152 gut microbiome-derived metabolites. From the metabolite screen, 4-hydroxyphenylacetic acid (4-HPAA) emerged as a unique immunomodulator: in LPS-challenged cells, 4-HPAA selectively increased IFN signaling with minimal NF-{kappa}B activation. 4-HPAA was evaluated in vivo using a NIAAA-model, with 4-HPAA supplementation (0.4mg\/ml) added to the diet. In the NIAAA-model, dietary 4-HPAA did not induce liver injury and was associated with enhanced interferon-stimulated gene expression. Simultaneously, 4-HPAA reduced pro-inflammatory markers such as Il1 {beta}, Ly6g and F4\/80 compared to the group exposed to ethanol alone. Metabolomic profiling of mouse cecal contents revealed 4-HPAA supplementation counteracted ethanol's metabolic effects, selectively reducing triglyceride-associated lipids that had accumulated with ethanol feeding. Conclusions: 4-HPAA enhances interferon signaling and antiviral gene induction while dampening NF-{kappa}B-driven inflammation in the presence of LPS, both in vitro and in vivo. In an acute-on-chronic alcohol injury model, 4-HPAA attenuated hepatic inflammation, reduced immune cell recruitment, and activated antioxidant defenses, reflecting a shift toward a more hepatoprotective effect. 4-HPAA treatment was associated with reduced pro-inflammatory markers and modest attenuation of ethanol-induced liver injury. Additionally, 4-HPAA reversed ethanol-induced lipid-dysregulation, particularly triglyceride accumulation, highlighting its metabolic benefit in alcohol-fed mice. In conclusion, 4-HPAA rebalances immune and metabolic pathways by enhancing IFN signaling, suppressing NF-{kappa}B inflammation, and reversing alcohol-induced hepatic injury and lipid accumulation.","rel_num_authors":7,"rel_authors":[{"author_name":"Yurui Zheng","author_inst":"Uconn Health"},{"author_name":"Nicholas Lee Handali","author_inst":"Uconn Health"},{"author_name":"Dana Moradi","author_inst":"Uconn"},{"author_name":"Colin Varnet","author_inst":"Uconn Health"},{"author_name":"Farhin Patel","author_inst":"Uconn Health"},{"author_name":"Alexander A Aksenov","author_inst":"University of Connecticut"},{"author_name":"Adam Kim","author_inst":"Uconn Health"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"replicateFest: An R Package and Shiny App for Analysis of T Cell Receptor Repertoire Data from the Functional Expansion","rel_doi":"10.64898\/2026.06.18.733036","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733036","rel_abs":"Motivation: The Functional Expansion of Specific T cell (FEST)-based assays combine short-term peptide stimulation with TCR sequencing to identify clonotypes that expand in response to specific antigens. These approaches have proven invaluable for detecting neoantigen-specific T cell responses, guiding vaccine development, and assessing checkpoint blockade efficacy. However, variability introduced by biological and technical replicates poses challenges for reproducibility and interpretation, and existing computational tools do not address replicate-level analysis in these assays. Results: We developed replicateFest, a computational framework implemented as an R package and Shiny web application, to analyze FEST-based TCR-seq data with and without replicates. replicateFest applies Fisher's exact test for non-replicate datasets and negative binomial modeling for replicate experiments, returning adjusted p-values and odds ratios to identify clonotypes significantly expanded in antigen-stimulated conditions. The framework distinguishes FEST-expanded clonotypes (relative to a no-antigen control) and FEST-positive clonotypes (expanded compared to all other conditions). Validation using synthetic datasets confirmed accurate detection of antigen-specific clonotypes. Application to published HIV-1 epitope stimulation data reproduced original findings and demonstrated replicateFest's utility for reproducibility assessment and quality control. Availability and Implementation: replicateFest is freely available under the Apache-2.0 license as an R package at https:\/\/github.com\/OncologyQS\/replicateFest and as an interactive Shiny application at http:\/\/www.stat-apps.onc.jhmi.edu\/FEST\/.","rel_num_authors":4,"rel_authors":[{"author_name":"Ludmila Danilova","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Alexander Favorov","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Kellie N Smith","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Leslie Cope","author_inst":"Johns Hopkins School of Medicine"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Representational similarity analysis of EEG reveals multiple spatiotemporal dynamics of selective attention","rel_doi":"10.64898\/2026.06.18.733142","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733142","rel_abs":"Selective attention allows listeners to follow a target speaker in complex scenes, but less is known about the neural mechanisms that control this capacity. We collected electroencephalography (EEG) during an auditory attention task encompassing spatial attention, talker-based attention, and passive listening. Time-resolved representational similarity analysis (RSA) of broadband scalp voltage and alpha-band oscillations revealed distinct representational trajectories in the two measurements: scalp voltage produced brief peaks in task discriminability shortly after the target cue and around 300 ms after target onset, whereas alpha-band power emerged more slowly and remained elevated throughout the trial. These patterns distinguish attentive from passive conditions and spatial from talker attention. Furthermore, broadband activity and alpha power encode complementary information, while other frequency bands contribute little independent explanatory power. These results demonstrate that RSA allows a unified interpretation of evoked and induced EEG measures, revealing how distinct neural computations jointly encode the spatiotemporal dynamics of selective attention.","rel_num_authors":4,"rel_authors":[{"author_name":"Jinhee Kim","author_inst":"Carnegie Mellon University"},{"author_name":"Winko W. An","author_inst":"Boston Children's Hospital"},{"author_name":"Abigail Noyce","author_inst":"Carnegie Mellon University"},{"author_name":"Barbara Shinn-Cunningham","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Ventral pallidal GABAergic neurons control hedonic feeding and obesity","rel_doi":"10.64898\/2026.06.18.733195","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733195","rel_abs":"Food intake is governed by two interacting drives. The homeostatic hunger drive regulates food intake to fulfill caloric needs while the hedonic drive promotes intake of palatable foods outside of caloric need. It is unclear which neural substrates can control the hedonic drive and thereby reduce overeating of palatable foods and associated obesity. Here, we show that ventral pallidal GABAergic neurons (VPGABA) preferentially control hedonic feeding and are necessary for diet-induced obesity in mice. Stimulating VPGABA neurons drove robust consumption of high-fat diet and liquids, but not regular laboratory chow. Despite driving intake of palatable foods, VPGABA neurons are relatively insensitive to homeostatic signals. They express few hunger-hormone receptors and are not activated by ghrelin administration or fasting. Single-cell calcium imaging revealed stronger engagement of VPGABA neurons during long vs short feeding bouts, suggesting control over bout duration, which has been linked to palatability. This was confirmed with closed-loop optogenetic stimulation. Finally, taCasp3-mediated ablation of VPGABA neurons reduced intake of palatable liquids and blocked high-fat diet-induced obesity without impacting homeostatic feeding. Together, these findings establish VPGABA neurons as a neural population that preferentially controls hedonic over homeostatic feeding and can be leveraged to block obesity in mice.","rel_num_authors":13,"rel_authors":[{"author_name":"Justin G Wang","author_inst":"Washington University in St Louis"},{"author_name":"Chang S Xu","author_inst":"Washington University in St Louis"},{"author_name":"Chantelle L Murrell","author_inst":"Washington University in St Louis"},{"author_name":"Mason R Barrett","author_inst":"Washington University in St Louis"},{"author_name":"Gargi C Basu","author_inst":"Washington University in St Louis"},{"author_name":"Lisa Z Fang","author_inst":"Washington University in St Louis"},{"author_name":"Yiru Chen","author_inst":"Washington University in St Louis"},{"author_name":"Florian Schoukroun","author_inst":"Washington University in St Louis"},{"author_name":"Thomas Topilko","author_inst":"Vibraint ApS"},{"author_name":"Johanna Perens","author_inst":"Vibraint Aps"},{"author_name":"Jacob Hecksher-Sorensen","author_inst":"Vibraint ApS"},{"author_name":"Meaghan Claire Creed","author_inst":"Washington University in St. Louis"},{"author_name":"Alexxai V Kravitz","author_inst":"Washington University in St Louis"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Automated detection of blink reflexes evoked by optogenetic stimulation of TRPV1-expressing corneal nociceptors in transgenic mice","rel_doi":"10.64898\/2026.06.18.733051","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733051","rel_abs":"Background Conventional rodent models for the study of corneal pain commonly evoke eye blink reflex using methods that indiscriminately activate polymodal nociceptors, mechanoreceptors, and thermoreceptors at temporal resolutions that don't closely match the sub-second timescale of underlying neural dynamics. New method We introduce a novel automated behavioral paradigm for detecting blink reflexes in transgenic TRPV1-ChR2-EYFP mice, enabled by cell-type-specific, millisecond-precision optogenetic stimulation of corneal nociceptors (490 nm light). Using multi-feature quantification, we achieve robust automated detection using univariate and multivariate classifiers. Results TRPV1-ChR2-EYFP mice exhibited blink reflexes to high-intensity blue light (490 nm, 10 ms pulses) in a threshold-dependent manner (N=3). Blink probability was 77.1 +\/- 17.1% at high intensity (2.77 mW\/mm2) versus 4.2 +\/- 4.2% at low intensity (0.46 mW\/mm2). Red light (638 nm) produced no intensity-dependent change. Noxious air puff evoked blinks in >95% of trials under all conditions. DeepLabCut-based pose estimation extracted six features quantifying the blink reflex, enabling automated detection with >=98% accuracy using univariate and multivariate classifiers. Comparison with existing methods Unlike conventional air puff paradigms, this optogenetic approach enables precise, cell-type-specific stimulation of corneal nociceptors, supporting automated analysis of blink responses at sub-second resolution. Conclusions This video tracking behavioral method using machine learning algorithms that accurately classify blink versus no-blink enables high-throughput and observer-independent empirical assessment of blink reflex, suggestive of corneal pain. Moreover, inducing blink reflex in TRPV1-ChR2 mice using high-intensity blue light also demonstrates nociceptive-specific behavioral responses analogous to somatosensory optogenetically-evoked hindpaw pain in the same animal genotype.","rel_num_authors":10,"rel_authors":[{"author_name":"Ki-Soo Jeong","author_inst":"Cleveland Clinic"},{"author_name":"Matthew T. McPheeters","author_inst":"Case Western Reserve University"},{"author_name":"Anagha Chandrasekharan","author_inst":"Wright State University"},{"author_name":"Ian Beeck","author_inst":"University of Michigan"},{"author_name":"Ananya Veerubhotla","author_inst":"Case Western Reserve University"},{"author_name":"Aditya Roy","author_inst":"Purdue University"},{"author_name":"Eric Y. Lu","author_inst":"Case Western Reserve University"},{"author_name":"Samer Ghosn","author_inst":"Cleveland Clinic"},{"author_name":"Michael W Jenkins","author_inst":"Case Western Reserve University"},{"author_name":"Carl Y. Saab","author_inst":"Cleveland Clinic"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Exercise training improves exercise capacity independent of AMPKa2 T172-mediated adaptations in skeletal muscle","rel_doi":"10.64898\/2026.06.18.733224","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733224","rel_abs":"Regular exercise induces adaptations in skeletal muscle and other organ systems to improve physical performance and overall health. Exercise results in phosphorylation of 5' AMP-activated protein kinase (AMPK) at threonine 172 (T172) of the a2 subunit; however, the role of this activation in cellular and functional adaptations has not been elucidated. To this end, we subjected non-activatable Ampka2(T172A) knock-in (KI) adult mice and wild-type (WT) littermates to 4 weeks of voluntary wheel running (VWR). Exercise training led to significant improvements in endurance capacity, maximal oxygen consumption (VO2max), and glucose tolerance, as well as skeletal muscle IIb-to-IIa fiber type shift in both WT and KI mice. Contrastingly, VWR resulted in increased mitochondrial OxPhos protein expression, mitochondrial volume density, and capillary density in skeletal muscle of WT but not KI mice. Exercise-induced improvements of mitochondrial respiration and conductance revealed by high-resolution respirometry of isolated mitochondria were blunted in KI mice. Therefore, for the first time, we reveal that AMPKa2 T172 activation is required for exercise training-induced mitochondrial biogenesis, improvement of mitochondrial respiratory function, and angiogenesis in skeletal muscle, but that these adaptations are not solely responsible for improved VO2max and exercise endurance capacity.","rel_num_authors":6,"rel_authors":[{"author_name":"Xuansong Mao","author_inst":"Virginia Tech"},{"author_name":"Ryan N Montalvo","author_inst":"Virginia Tech"},{"author_name":"Kenya Takahashi","author_inst":"Virginia Tech"},{"author_name":"Frank W. Booth","author_inst":"University of Missouri-Columbia"},{"author_name":"George A Brooks","author_inst":"University of California"},{"author_name":"Zhen Yan","author_inst":"Virginia Tech"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Early Tracheal and Salivary miRNAs in Extremely Preterm Infants Predict BPD-related Pulmonary Hypertension","rel_doi":"10.64898\/2026.06.17.732493","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732493","rel_abs":"Pulmonary hypertension (BPD-PH) associated with bronchopulmonary dysplasia (BPD) in preterm infants associates with high morbidity and mortality within the first two years of life. In a previous unbiased study, we identified a panel miRNAs in tracheal aspirates (TA) that were differentially expressed in extremely low gestational age newborns (ELGANs) with BPD-PH compared to those with BPD but no PH. To explore the predictive potential of these miRNAs, we studied TA exosomes from 7 days old ELGANs and analysed a curated panel of 16 miRNAs through logistic regression and calculated the predictive AUROC to diagnose BPD-PH at 36 weeks PMA. AUROC of TA miRNAs was 0.76 with sensitivity and specificity of 53% and 93%, respectively. Adding sex and gestational age to the variables improved the AUROC to 0.78 with sensitivity and specificity of 61 and 87% respectively. Due to challenges of obtaining TA in non-invasively ventilated infants, we collected saliva samples from ELGANs at 7 days of age and compared the log expression of these 16 miRNAs in both biofluids and found significant correlation in their expression (pearson r=0.92, p<0.001). We calculated the predictive AUROC of the same miRNAs to diagnose BPD-PH at 36 weeks PMA. AUROC of these miRNAs in saliva was = 0.85 with sensitivity and specificity of 82% and 72%, respectively; addition of biological sex and gestational age improved AUROC to 0.86 with sensitivity and specificity of 79% and 76% respectively. Leave-one-sample-out sensitivity analysis demonstrated stable training performance with reduced performance in testing samples, supporting the need for validation in larger independent cohorts. In conclusion, early salivary miRNAs have great potential for risk stratification of ELGANs to develop BPD-PH, while also providing the opportunity to identify target molecules and mechanisms that modulate molecular function.","rel_num_authors":10,"rel_authors":[{"author_name":"Tang Li","author_inst":"Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA"},{"author_name":"Shaoyi Zhang","author_inst":"Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA"},{"author_name":"Vincent Aluquin","author_inst":"Department of Pediatrics, Penn State Health Childrens Hospital, Hershey, PA"},{"author_name":"Ann Donnelly","author_inst":"Department of Respiratory Care, Penn State Health Milton S. Hershey Medical Center, Hershey, PA"},{"author_name":"Heather Stephens","author_inst":"Department of Nursing, Penn State Health Milton S. Hershey Medical Center, Hershey, PA"},{"author_name":"Shakshi Sharma","author_inst":"Arkansas Childrens Research Institute, Little Rock, AR"},{"author_name":"Steven D Hicks","author_inst":"Department of Pediatrics, Penn State Health Childrens Hospital, Hershey, PA"},{"author_name":"Dajiang Liu","author_inst":"Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA"},{"author_name":"Eric Austin","author_inst":"Department of Pediatrics, Vanderbilt University, Nashville, TN"},{"author_name":"Roopa Siddaiah","author_inst":"Penn State Children's Hospital"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Iron Regulates CD4 T Cell Quiescence by Controlling TGF-\u03b2 Production","rel_doi":"10.64898\/2026.06.18.733147","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733147","rel_abs":"Transforming growth factor-{beta} (TGF-{beta}) regulates CD4 T cell quiescence, activation, and regulatory T cell differentiation, but its role in T cell iron metabolism is poorly defined. Here, we investigated whether TGF-{beta} regulates iron homeostasis and how iron overload alters TGF-{beta} responsiveness. During T cell activation, TGF-{beta} enhanced survival but markedly reduced proliferation. These effects were accompanied by decreased CD71 expression and cytosolic iron availability, as well as increased mitochondrial iron accumulation. Genetic deletion of TGF{beta}R1 reversed these changes, demonstrating that TGF-{beta} regulates CD4 T cell iron homeostasis through TGF{beta}R1-dependent signaling. Iron-overloaded CD4 T cells lacking the heme exporter FLVCR1 exhibit hypersensitivity to TGF-{beta}, increased TGF-{beta} secretion, and sustained TGF{beta}R1 expression upon activation. Pharmacologic inhibition of TGF{beta}R1 restored proliferation, CD71 expression, and iron levels in FLVCR1-deficient cells. Although TGF-{beta} selectively induced total and mitochondrial ROS levels in FLVCR1-deficient cells, antioxidant treatment or Nox2 inhibition did not rescue this phenotype, suggesting that ROS is associated with, but not sufficient to explain, TGF-{beta} hypersensitivity. Acute FeSO4-induced iron overload partially recapitulated the phenotype of FLVCR1-deficient cells, although TGF{beta}R1 expression and TGF-{beta} production differed. Finally, regulatory T cells generated in vitro in the presence of TGF-{beta} displayed reduced iron acquisition, and excess iron impaired FoxP3 induction. Together, this work identifies TGF-{beta} as a context-dependent regulator of CD4 T cell iron homeostasis.","rel_num_authors":5,"rel_authors":[{"author_name":"Amber L. Siglin","author_inst":"University of Michigan"},{"author_name":"Zelong Han","author_inst":"University of Michigan"},{"author_name":"Afia Nkansah","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"WanJun Chen","author_inst":"National Institute of Health"},{"author_name":"Cheong-Hee Chang","author_inst":"University of Michigan"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Acute Slow Oscillation Power as a Biomarker of Injury Severity After Photothrombotic Stroke: Dissociation from Week 1 Functional Recovery","rel_doi":"10.64898\/2026.06.18.732981","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.732981","rel_abs":"Cortical slow oscillations (SOs; 0.1-1.0 Hz) are suppressed after ischemic stroke, and their recovery is often read as evidence of circuit reorganization and functional restoration. Whether SO recovery is coupled to behavioral improvement, and whether pre-stroke network organization shapes recovery, has not been tested within individual animals. Using longitudinal wide-field calcium imaging in Thy1-GCaMP6f mice (n = 25), we tracked ipsilateral and contralateral SO power across baseline, 24 hours, and one week after photothrombotic stroke of the left somatosensory forepaw cortex, classifying animals by the presence (STI+; n = 14) or absence (STI-; n = 11) of secondary thalamic injury (STI). Acute ipsilateral SO power was markedly suppressed and tracked concurrent behavioral deficit ({rho} = -0.718, p < 0.001), capturing dysfunction beyond lesion volume (partial {rho}= -0.448, p = 0.025). By one week SO power had recovered, yet this recovery was dissociated from forelimb use. Week 1 SO power showed no association with behavior in any region or hemisphere (all |{rho}| [&le;] 0.074, all p > 0.5), and STI+ and STI- animals recovered SO equivalently despite STI+ animals remaining more impaired (p = 0.011). In contrast, pre-stroke SO laterality predicted week 1 forelimb use independent of infarct size ({rho} = -0.518, p = 0.008; partial {rho} = -0.446, p = 0.026). Acute SO suppression thus tracks injury severity beyond infarct volume, but its recovery does not track functional recovery; instead, pre-stroke interhemispheric SO balance predicts outcome, identifying pre-injury brain state as an underappreciated prognostic factor.","rel_num_authors":3,"rel_authors":[{"author_name":"Jake Lee","author_inst":"Washington University in St. Louis"},{"author_name":"Arnav Ajay Jadav","author_inst":"Washington University in St. Louis"},{"author_name":"Eric C Landsness","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Functional Somatotopy of Lumbar Dorsal Rootlets and its Role in Selective Recruitment via Lateral Spinal Cord Stimulation","rel_doi":"10.64898\/2026.06.18.733242","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733242","rel_abs":"Objective. Lateral spinal cord stimulation (LSCS) is a promising approach for restoring somatosensory feedback in lower-limb amputees, but its spatial selectivity remains limited. Percepts often spread to unintended regions of the residual limb, and reducing electrode contact size may not improve focality. This study investigated whether the anatomical organization of lumbar dorsal rootlets (DR) imposes fundamental constraints on LSCS selectivity. Approach. Acute neurophysiology experiments were performed in six adult cats. Both LSCS and individual DR stimulation were conducted in the same animals. For DR stimulation, bipolar hook electrodes were used to stimulate individual DR, while antidromic compound action potentials (CAPs) were recorded from femoral and sciatic nerve branches instrumented with nerve cuffs. For LSCS, custom 32-contact epidural paddle electrodes were placed over the lateral surface of the spinal cord at corresponding vertebral levels. Recruitment thresholds, dynamic ranges, and response patterns were analyzed across spinal levels, and DR recruitment patterns were directly compared to those evoked by LSCS within the same animals. Main results. A clear rostrocaudal organization was observed across spinal levels during stimulation of individual DR, with femoral branches predominantly recruited at L4-L5 and sciatic branches at L6-L7. However, no somatotopic organization was found across DR within each spinal level; individual DR frequently co-activated multiple branches within the same group, and selective recruitment could only be maintained over a narrow dynamic range (median ~10 A). LSCS exhibited even a narrower dynamic range (~5 A) but closely mirrored DR recruitment patterns, indicating that LSCS activates sensory afferents in a manner determined by the organizational structure of the DR. Significance. These findings demonstrate that the limited spatial selectivity of LSCS can largely be attributed to the coarse organization of DR within each root level rather than due to limitations of epidural electrode design. Moving electrodes intradurally or reducing contact size further is unlikely to substantially improve focality. Instead, improving paddle stability to ensure consistent placement over the appropriate spinal levels may be a more effective strategy for enhancing percept localization.","rel_num_authors":9,"rel_authors":[{"author_name":"Matteo Del Brocco","author_inst":"University of Pittsburgh"},{"author_name":"Gilgal J Ansah","author_inst":"University of Pittsburgh"},{"author_name":"Manuel Duran","author_inst":"University of Pittsburgh"},{"author_name":"Sauradeep Bhowmick","author_inst":"University of Michigan"},{"author_name":"Chaitanya Gopinath","author_inst":"University of Pittsburgh"},{"author_name":"Maria K Jantz","author_inst":"Duke University"},{"author_name":"Rohit Bose","author_inst":"Case Western Reserve University"},{"author_name":"Scott  F Lempka","author_inst":"University of Michigan"},{"author_name":"Lee Fisher","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"CellOS: Learning a World Model of Cellular State through Joint Embedding Prediction","rel_doi":"10.64898\/2026.06.18.733163","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733163","rel_abs":"Foundation models learned from single-cell transcriptomes are central to the prospect of AI virtual cell that can represent, query and predict cellular state. However, most current single-cell foundation models learn from a single view of gene expression and are optimized primarily through reconstruction or next-token prediction. As a result, they capture expression abundance but can-not explicitly reconcile complementary views of cellular state. Here we present CellOS, a multi-view foundation model that learns cellular representations from paired expression and perception views. CellOS integrates complementary views through a scalable three-stage training strategy that combines causal cell-sentence language modelling, function-preserving dense-to-mixture-of-experts expansion and latent-space alignment via an LLM-JEPA objective. Using this framework, we trained a 12-billion-parameter model on 390.5 million single-cell transcriptomes. Across diverse benchmarks spanning cell-state annotation, batch integration and perturbation-response prediction, CellOS consistently outperformed state-of-the-art single-cell foundation models in cell-state annotation and perturbation-response prediction while preserving robust batch integration. Together, these results suggest that predictive alignment between complementary cellular views provides a scalable path toward representation-centric cellular world models and transferable AI virtual cells.","rel_num_authors":9,"rel_authors":[{"author_name":"Qi Zhou","author_inst":"Vitaura (Beijing) Technology Co., Ltd."},{"author_name":"Yuan Le","author_inst":"Vitaura (Beijing) Technology Co., Ltd."},{"author_name":"Xiaoning Qi","author_inst":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Shaole Chang","author_inst":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Hanshuo Lu","author_inst":"Vitaura (Beijing) Technology Co., Ltd."},{"author_name":"Yujia Wu","author_inst":"Vitaura (Beijing) Technology Co., Ltd."},{"author_name":"Haoran Wang","author_inst":"School of Advanced Interdisciplinary Sciences, University of Chinese Academy of Sciences, Beijing 100049, China"},{"author_name":"Ruoyao Ran","author_inst":"Vitaura (Beijing) Technology Co., Ltd."},{"author_name":"xin li","author_inst":"1.Vitaura (Beijing) Technology Co., Ltd. 2.State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Bei"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Electrolytic-Microbubble Dynamics Delineate Safety Thresholds During Intracortical Microstimulation with Flexible Neural Interfaces","rel_doi":"10.64898\/2026.06.17.733032","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.733032","rel_abs":"Intracortical microstimulation (ICMS) with ultraflexible neural electrodes enables low-threshold, chronically stable, and high-resolution modulation of neural circuits, providing a promising strategy for sensory restoration and closed-loop neuromodulation. However, the microscopic mechanisms delineating its safe and effective current range remain unclear. Here, we combine intravital two-photon (2P) imaging and electrophysiology in awake mice to examine the current-dependent neurovascular outcomes of charge-balanced stimulation via ultraflexible arrays. We observed gas bubbles formed along the electrode during ICMS, with bubble size increasing quadratically with current amplitude, consistent with a Faradaic bubble-growth model. Intravital 2P imaging reveals that at low-to-moderate currents (20~40 A), vascular leakage is small, spatially confined, and largely reversible, whereas higher currents ([&ge;]60 A) induce a sharp transition to extensive, field-dominated extravasation and secondary vessel disruption. This transition coincides with immediate, stimulus-locked motor responses and the onset of electrode degradation. Multiphysics simulations reproduce the observed nonlinear leakage-current relationship by incorporating gas bubble-induced electric field redistribution and voltage-dependent vessel wall permeability. The model indicates that gas bubbles act as local electric-field modulators, concentrating suprathreshold fields near the bubble boundary at lower currents while shielding more distant vessel segments; at higher currents, this confinement breaks down and the system enters a field-dominated damage regime. Collectively, these findings define a mechanistically informed safety window for ICMS with flexible neural interfaces and identify bubble-assisted vascular permeabilization as a key failure mode at high currents, crucial for the design of future bidirectional brain-computer interfaces and high-precision neuroprosthetic protocols.","rel_num_authors":9,"rel_authors":[{"author_name":"Artem Iliasov","author_inst":"State Key Laboratory of Ultra-intense Laser Science and Technology, Shanghai Institute of Optics and Fine Mechanics, Chinese Academy of Sciences, Shanghai 20180"},{"author_name":"Haoran Ma","author_inst":"State Key Laboratory of Ultra-intense Laser Science and Technology, Shanghai Institute of Optics and Fine Mechanics, Chinese Academy of Sciences, Shanghai 20180"},{"author_name":"Fangyuan Li","author_inst":"State Key Laboratory of Ultra-intense Laser Science and Technology, Shanghai Institute of Optics and Fine Mechanics, Chinese Academy of Sciences, Shanghai 20180"},{"author_name":"Zhen Chen","author_inst":"Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China"},{"author_name":"Mingliang Xu","author_inst":"Shanghai Institute of Optics and Fine Mechanics, Chinese Academy of Sciences"},{"author_name":"Chenhui Yu","author_inst":"State Key Laboratory of Ultra-intense Laser Science and Technology, Shanghai Institute of Optics and Fine Mechanics, Chinese Academy of Sciences, Shanghai 20180"},{"author_name":"Ruxin Li","author_inst":"State Key Laboratory of Ultra-intense Laser Science and Technology, Shanghai Institute of Optics and Fine Mechanics, Chinese Academy of Sciences, Shanghai 20180"},{"author_name":"Jinsong Wu","author_inst":"Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China"},{"author_name":"Fei He","author_inst":"Shanghai Inst. Opt& Fine Mech."}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Characterisation of Posterior Predominant Amyloid PET Binding Across Multiple Cohorts","rel_doi":"10.64898\/2026.06.17.733031","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.733031","rel_abs":"The standard approach to quantify amyloid (A{beta}) PET averages uptake within a single cortical mask that assumes no clinically relevant spatial heterogeneity in uptake patterns. Here, in a sample of 12,379 clinically impaired participants taken from four phenotypically diverse cohorts we use data-driven approaches to discover heterogeneous patterns of A{beta}-PET binding, uncovering a reproducible and clinically relevant pattern of posterior predominant A{beta}-PET binding. In particular, A{beta}-PET positive participants who have posterior predominant binding are less likely to be APOE-{epsilon}4 carriers, more severely impaired, have thinner cortex in posterior regions, and greater posterior tau PET burden. Furthermore, in a subsample of participants with neuropathological assessment, participants with posterior predominant A{beta} binding have a higher likelihood of having cerebral amyloid angiopathy at autopsy. These findings suggest that A{beta}-PET accumulates along two orthogonal axes with biological and clinical relevance, indicating that the standard approach to assess A{beta}-PET is insufficient to capture meaningful signal from A{beta}-PET imaging. This work has implications for the diagnosis and treatment of Alzheimers disease and extends our understanding of the mechanisms governing variable A{beta}-PET distribution and its downstream effects.","rel_num_authors":16,"rel_authors":[{"author_name":"Joseph Giorgio","author_inst":"Department of Neuroscience, University of California Berkeley"},{"author_name":"Ganna Blazhenets","author_inst":"Edward and Pearl Fein Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, Department of Neurology, University of California San"},{"author_name":"Susan Landau","author_inst":"Department of Neuroscience, University of California Berkeley"},{"author_name":"Stefania Pezzoli","author_inst":"Edward and Pearl Fein Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, Department of Neurology, University of California San"},{"author_name":"Jennifer S. Yokoyama","author_inst":"University of California, San Francisco"},{"author_name":"David Soleimani-Meigooni","author_inst":"Edward and Pearl Fein Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, Department of Neurology, University of California San"},{"author_name":"Maria Carrillo","author_inst":"Alzheimer's Association"},{"author_name":"Lea Grinberg","author_inst":"Department of Laboratory Medicine and Pathology, Mayo Clinic"},{"author_name":"William W Tenenholz Seeley","author_inst":"University of California, San Francisco"},{"author_name":"Salvatore Spina","author_inst":"University of California San Francisco"},{"author_name":"Kelly Nudelman","author_inst":"Indiana University School of Medicine"},{"author_name":"Liana Apostolova","author_inst":"Department of Neurology, Indiana University School of Medicine"},{"author_name":"Bradford Dickerson","author_inst":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School"},{"author_name":"William J Jagust","author_inst":"University of California, Berkeley"},{"author_name":"Gil Rabinovici","author_inst":"University of California, San Francisco"},{"author_name":"Renaud La Joie","author_inst":"Edward and Pearl Fein Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, Department of Neurology, University of California San"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Characterisation of Posterior Predominant Amyloid PET Binding Across Multiple Cohorts","rel_doi":"10.64898\/2026.06.17.733031","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.733031","rel_abs":"The standard approach to quantify amyloid (A{beta}) PET averages uptake within a single cortical mask that assumes no clinically relevant spatial heterogeneity in uptake patterns. Here, in a sample of 12,379 clinically impaired participants taken from four phenotypically diverse cohorts we use data-driven approaches to discover heterogeneous patterns of A{beta}-PET binding, uncovering a reproducible and clinically relevant pattern of posterior predominant A{beta}-PET binding. In particular, A{beta}-PET positive participants who have posterior predominant binding are less likely to be APOE-{epsilon}4 carriers, more severely impaired, have thinner cortex in posterior regions, and greater posterior tau PET burden. Furthermore, in a subsample of participants with neuropathological assessment, participants with posterior predominant A{beta} binding have a higher likelihood of having cerebral amyloid angiopathy at autopsy. These findings suggest that A{beta}-PET accumulates along two orthogonal axes with biological and clinical relevance, indicating that the standard approach to assess A{beta}-PET is insufficient to capture meaningful signal from A{beta}-PET imaging. This work has implications for the diagnosis and treatment of Alzheimers disease and extends our understanding of the mechanisms governing variable A{beta}-PET distribution and its downstream effects.","rel_num_authors":16,"rel_authors":[{"author_name":"Joseph Giorgio","author_inst":"Department of Neuroscience, University of California Berkeley"},{"author_name":"Ganna Blazhenets","author_inst":"Edward and Pearl Fein Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, Department of Neurology, University of California San"},{"author_name":"Susan Landau","author_inst":"Department of Neuroscience, University of California Berkeley"},{"author_name":"Stefania Pezzoli","author_inst":"Edward and Pearl Fein Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, Department of Neurology, University of California San"},{"author_name":"Jennifer S. Yokoyama","author_inst":"University of California, San Francisco"},{"author_name":"David Soleimani-Meigooni","author_inst":"Edward and Pearl Fein Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, Department of Neurology, University of California San"},{"author_name":"Maria Carrillo","author_inst":"Alzheimer's Association"},{"author_name":"Lea Grinberg","author_inst":"Department of Laboratory Medicine and Pathology, Mayo Clinic"},{"author_name":"William W Tenenholz Seeley","author_inst":"University of California, San Francisco"},{"author_name":"Salvatore Spina","author_inst":"University of California San Francisco"},{"author_name":"Kelly Nudelman","author_inst":"Indiana University School of Medicine"},{"author_name":"Liana Apostolova","author_inst":"Department of Neurology, Indiana University School of Medicine"},{"author_name":"Bradford Dickerson","author_inst":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School"},{"author_name":"William J Jagust","author_inst":"University of California, Berkeley"},{"author_name":"Gil Rabinovici","author_inst":"University of California, San Francisco"},{"author_name":"Renaud La Joie","author_inst":"Edward and Pearl Fein Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, Department of Neurology, University of California San"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"AutoBlot: deterministic single-cell western blotting reveals proteomic diversity in rare cell populations","rel_doi":"10.64898\/2026.06.22.733890","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.22.733890","rel_abs":"Single-cell western blotting (scWB) provides quantitative, molecular-mass-resolved protein measurements but relies on Poisson-limited gravity settling, requiring ~10 starting cells with <37% microwell occupancy. AutoBlot replaces stochastic loading with piezoelectric dispensing, achieving ~98% occupancy and deterministic cell-bead co-isolation from as few as 10,000 starting cells. Profiling patient-derived breast organoids (PDOs), we detect BRCA1-associated proteomic shifts, menopausal-status-dependent ER expression differences, and systematic differences between surface and intracellular lineage classification of mammary epithelial cells in organoid culture.","rel_num_authors":6,"rel_authors":[{"author_name":"Cyril Deroy","author_inst":"University of California, Berkeley"},{"author_name":"Md Nazibul Islam","author_inst":"University of California, Berkeley"},{"author_name":"Nadine Goldhammer","author_inst":"University of California, San Francisco"},{"author_name":"Lorraine Jiang","author_inst":"University of California, San Francisco"},{"author_name":"Jennifer M Rosenbluth","author_inst":"University of California, San Francisco"},{"author_name":"Amy E Herr","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"AutoBlot: deterministic single-cell western blotting reveals proteomic diversity in rare cell populations","rel_doi":"10.64898\/2026.06.22.733890","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.22.733890","rel_abs":"Single-cell western blotting (scWB) provides quantitative, molecular-mass-resolved protein measurements but relies on Poisson-limited gravity settling, requiring ~10 starting cells with <37% microwell occupancy. AutoBlot replaces stochastic loading with piezoelectric dispensing, achieving ~98% occupancy and deterministic cell-bead co-isolation from as few as 10,000 starting cells. Profiling patient-derived breast organoids (PDOs), we detect BRCA1-associated proteomic shifts, menopausal-status-dependent ER expression differences, and systematic differences between surface and intracellular lineage classification of mammary epithelial cells in organoid culture.","rel_num_authors":6,"rel_authors":[{"author_name":"Cyril Deroy","author_inst":"University of California, Berkeley"},{"author_name":"Md Nazibul Islam","author_inst":"University of California, Berkeley"},{"author_name":"Nadine Goldhammer","author_inst":"University of California, San Francisco"},{"author_name":"Lorraine Jiang","author_inst":"University of California, San Francisco"},{"author_name":"Jennifer M Rosenbluth","author_inst":"University of California, San Francisco"},{"author_name":"Amy E Herr","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Phase-tuned interfacial condensates drive transcellular access","rel_doi":"10.64898\/2026.06.22.731667","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.22.731667","rel_abs":"Life has evolved the plasma membrane as an active physicochemical interface rather than a passive barrier, one whose selectivity sustains homeostasis but excludes many therapeutic molecules. Yet most delivery strategies force molecules across this boundary, leaving the interface underused as a surface for organizing transport. Inspired by membrane-associated phase separation during endocytosis, we show that confining phase separation to the plasma-membrane interface lets cell-penetrating peptide (CPP) and silk fibroin (SF) co-condense in situ, coupling cargo recruitment, membrane wetting and entry into one continuous step. CPP-to-SF stoichiometry tunes the condensate between liquid- and solid-like states, determining whether it crosses the membrane or merely coats it. Cryo-TEM, STED, FRAP, live-cell tracking and in situ cryo-FIB\/cryo-TEM resolved the sequence from membrane nucleation within 30 s to intracellular entry within 5 min, orders of magnitude faster than previous phase-separation-based delivery. Set by phase state rather than cargo identity, the system delivered small molecules, nucleic acids and antibodies at roughly 10-fold lower CPP dose. By acquiring cytoplasmic access after entry and then re-exiting cells, the same interfacial condensates supported transcellular traversal across the intact cornea in vivo, lowering intraocular pressure with a 4.2-fold lower betaxolol dose and delivering otherwise excluded siRNA into the anterior chamber. More broadly, this establishes the membrane interface as a programmable determinant of barrier permeability, extending beyond this system to other condensate-forming partners and barriers.","rel_num_authors":6,"rel_authors":[{"author_name":"Luyi Han","author_inst":"Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University"},{"author_name":"Yue Wan","author_inst":"Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University"},{"author_name":"Zhenxi Guo","author_inst":"School of Instrumentation and Optoelectronic Engineering, Beihang University"},{"author_name":"Shuo Gao","author_inst":"School of Instrumentation and Optoelectronic Engineering, Beihang University"},{"author_name":"Ningli Wang","author_inst":"Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University"},{"author_name":"Yingyan Mao","author_inst":"Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Phase-tuned interfacial condensates drive transcellular access","rel_doi":"10.64898\/2026.06.22.731667","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.22.731667","rel_abs":"Life has evolved the plasma membrane as an active physicochemical interface rather than a passive barrier, one whose selectivity sustains homeostasis but excludes many therapeutic molecules. Yet most delivery strategies force molecules across this boundary, leaving the interface underused as a surface for organizing transport. Inspired by membrane-associated phase separation during endocytosis, we show that confining phase separation to the plasma-membrane interface lets cell-penetrating peptide (CPP) and silk fibroin (SF) co-condense in situ, coupling cargo recruitment, membrane wetting and entry into one continuous step. CPP-to-SF stoichiometry tunes the condensate between liquid- and solid-like states, determining whether it crosses the membrane or merely coats it. Cryo-TEM, STED, FRAP, live-cell tracking and in situ cryo-FIB\/cryo-TEM resolved the sequence from membrane nucleation within 30 s to intracellular entry within 5 min, orders of magnitude faster than previous phase-separation-based delivery. Set by phase state rather than cargo identity, the system delivered small molecules, nucleic acids and antibodies at roughly 10-fold lower CPP dose. By acquiring cytoplasmic access after entry and then re-exiting cells, the same interfacial condensates supported transcellular traversal across the intact cornea in vivo, lowering intraocular pressure with a 4.2-fold lower betaxolol dose and delivering otherwise excluded siRNA into the anterior chamber. More broadly, this establishes the membrane interface as a programmable determinant of barrier permeability, extending beyond this system to other condensate-forming partners and barriers.","rel_num_authors":6,"rel_authors":[{"author_name":"Luyi Han","author_inst":"Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University"},{"author_name":"Yue Wan","author_inst":"Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University"},{"author_name":"Zhenxi Guo","author_inst":"School of Instrumentation and Optoelectronic Engineering, Beihang University"},{"author_name":"Shuo Gao","author_inst":"School of Instrumentation and Optoelectronic Engineering, Beihang University"},{"author_name":"Ningli Wang","author_inst":"Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University"},{"author_name":"Yingyan Mao","author_inst":"Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"A finite element model of pregnancy derived from maternal sonography: effect of uterine and cervical structural properties on cervical mechanical loading","rel_doi":"10.64898\/2026.06.22.733744","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.22.733744","rel_abs":"Identification and treatment of pregnancies at risk for preterm birth is a central challenge in obstetric research. Many of the known causes of preterm birth originate from mechanical failure in reproductive tissues. To better understand the biomechanical environment of the gravid uterus and its potential contribution to preterm birth, this computational study presents a parametric method for modeling maternal reproductive anatomy during the early second trimester. A finite element modeling approach was built using existing sonographic measurements from early second-trimester maternal anatomy and material properties from published mechanical tests. We applied the same physiologically relevant intrauterine pressure to all models and quantified the resulting tissue stretch. The sensitivity of the stretch in the proximal cervix was explored by varying material properties and sonographic maternal anatomy dimensions. Cervical material properties, particularly the fiber stiffness modulus and ground substance Young's modulus, were found to have the greatest effect on proximal cervix stretch compared to other material properties and sonographic dimensions. Among the sonographic dimension measurements, those defining the region surrounding the proximal cervix had the greatest effect on proximal cervix stretch, including the curvature of the posterior uterine wall and the thickness of the lower uterine segment. The computational modeling approach presented here enables future patient-specific studies of gravid reproductive tissues to elucidate differences between individuals who do and do not deliver preterm. Additionally, this study is foundational for building digital twins to support future virtual clinical studies on diagnostic and therapeutic device design to prevent preterm birth.","rel_num_authors":8,"rel_authors":[{"author_name":"Erin M Louwagie","author_inst":"Columbia University"},{"author_name":"Hannah Z Haider","author_inst":"Columbia University"},{"author_name":"Camilo Duarte","author_inst":"Columbia University"},{"author_name":"Lei Shi","author_inst":"Kennesaw State University"},{"author_name":"Mirella Mourad","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Michael House","author_inst":"Tufts Medical Center"},{"author_name":"Helen Feltovich","author_inst":"North Memorial Health"},{"author_name":"Kristin  Marie Myers","author_inst":"Columbia University"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"A maximum entropy perspective reveals deviations from steady state during active diversification","rel_doi":"10.64898\/2026.06.22.733811","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.22.733811","rel_abs":"Ecosystems are rarely at steady state, yet most theory predicting universal biodiversity patterns assumes they are. Here, we test whether and how eco-evolutionary dynamics drive departures from steady state by combining arthropod community data from the geologic chronosequence of the Hawaiian Archipelago with the Maximum Entropy Theory of Ecology (METE), a minimalist steady-state framework that simultaneously predicts species abundance distributions (SADs) and individual metabolic rate distributions (IPDs). The chronosequence of the Hawaiian Archipelago has yielded insights into eco-evolutionary processes because ecosystems growing on different aged substrates offer snapshots of community assembly with different histories. We find that deviations from METE peak at geologically middle-aged sites (150 Kya - 1.4 Mya), consistent with active adaptive radiation pushing communities away from statistical steady state. Within-site {beta}-diversity, which also peaks at middle-aged sites, robustly predicts deviations from METE across all sites, while the proportion of non-native species predicts deviations only after excluding the geologically youngest site. Partitioning {beta}-diversity between native and non-native species resolves this discrepancy: at the youngest site, non-native species are distributed homogeneously and do not elevate {beta}-diversity despite their high proportional representation. Together, these results are consistent with a trajectory from young, dispersal-assembled communities near statistical steady state, through an eco-evolutionary non-steady-state transition driven by diversification, to a new stable steady state at the oldest sites. Our findings suggest that periods of active diversification create windows of ecological instability that may facilitate biological invasion, with implications for understanding invasion dynamics in biodiversity hotspots.","rel_num_authors":5,"rel_authors":[{"author_name":"Andrew J. Rominger","author_inst":"University of Hawaii at Manoa"},{"author_name":"Katie Thai","author_inst":"University of Hawaii at Manoa"},{"author_name":"Rosemary G. Gillespie","author_inst":"University of California at Berkeley"},{"author_name":"Daniel S. Gruner","author_inst":"University of Maryland"},{"author_name":"John Harte","author_inst":"University of California Berkeley"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"The Dark Ecology Dataset: Measurements of Aerial Biomass in US Weather Radar from 1995 to 2025","rel_doi":"10.64898\/2026.06.20.733536","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.20.733536","rel_abs":"The US NEXRAD radar network has monitored the aerosphere over the US and its territories continuously since the 1990s and archived nearly 300 million radar volume scans. These data contain a wealth of information about the movements of birds, bats, and insects. Historically, this biological information was difficult to access due to the amount of data and challenges in analyzing it. In the last 15 years, fueled by computational and methodological advances, large-scale aeroecology research has blossomed. However, comprehensive analyses of the NEXRAD archive remain very costly. We collected measurements of biological activity from every volume scan in the NEXRAD archive--nearly 300 million data files total--to assemble a dataset of aerial biomass over the US from 1995 to 2025. The core data are vertical profiles, which summarize biological activity at different heights above the radar station for each volume scan. We also provide time series data products that aggregate vertical profiles to point measurements at radar stations across time. These data products can support a range of aeroecology analyses at significantly reduced effort.","rel_num_authors":14,"rel_authors":[{"author_name":"Daniel Sheldon","author_inst":"University of Massachusetts Amherst"},{"author_name":"Kevin Winner","author_inst":"Yale University"},{"author_name":"Iman Deznabi","author_inst":"University of Massachusetts Amherst"},{"author_name":"Garrett Bernstein","author_inst":"Inari Agriculture"},{"author_name":"Pankaj Bhambhani","author_inst":"University of Massachusetts Amherst"},{"author_name":"Tsung-Yu Lin","author_inst":"Meta AI"},{"author_name":"Peter Desmet","author_inst":"Research Institute for Nature and Forest (INBO)"},{"author_name":"Adriaan M. Dokter","author_inst":"Cornell Lab of Ornithology"},{"author_name":"Kyle G. Horton","author_inst":"Purdue University"},{"author_name":"Cecilia Nilsson","author_inst":"Lund University"},{"author_name":"Benjamin M. Van Doren","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Andrew Farnsworth","author_inst":"Cornell Lab of Ornithology"},{"author_name":"Frank A. La Sorte","author_inst":"Yale University"},{"author_name":"Subhransu Maji","author_inst":"University of Massachusetts Amherst"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Cervical spinal cord stimulation disrupts proprioception yet improves voluntary arm reaching","rel_doi":"10.64898\/2026.06.20.733548","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.20.733548","rel_abs":"Whether proprioception is necessary for upper-limb motor control has been debated for decades. Classic studies in deafferented animals and humans suggested that proprioception may be dispensable for rapid, goal-directed movements. However, chronic sensory loss conflates the absence of proprioceptive input with years of compensatory adaptation. As a result, the field has lacked a strong causal test of proprioception's contribution to motor control. Here, we leveraged a clinical trial of cervical spinal cord stimulation (SCS) in individuals with chronic post-stroke hemiparesis to study if electrical stimulation of sensory afferents causally perturbs proprioception and affects arm reaching. We found that turning SCS ON causally impaired proprioceptive perception and postural stabilization in response to force perturbations, and enhanced adaptation to visual errors during implicit learning. Yet visually and non-visually rapid, goal-directed reaching improved in smoothness, straightness and spatial accuracy. These findings provide strong causal evidence that proprioception is not required for rapid, goal-directed action, helping resolve a decades-long debate regarding its necessity for effective movement.","rel_num_authors":15,"rel_authors":[{"author_name":"Erick Carranza","author_inst":"University of Pittsburgh"},{"author_name":"Roberto de Freitas","author_inst":"University of Pittsburgh"},{"author_name":"Nikhil Verma","author_inst":"Carnegie Mellon University"},{"author_name":"Luigi Borda","author_inst":"Carnegie Mellon University"},{"author_name":"Erynn Sorensen","author_inst":"University of Pittsburgh"},{"author_name":"Amy Boos","author_inst":"University of Pittsburgh"},{"author_name":"George F Wittenberg","author_inst":"University of Pittsburgh"},{"author_name":"Lee Fisher","author_inst":"University of Pittsburgh"},{"author_name":"Marc Powell","author_inst":"University of Pittsburgh"},{"author_name":"Peter Gerszten","author_inst":"University of Pittsburgh"},{"author_name":"Douglas Weber","author_inst":"Carnegie Mellon University"},{"author_name":"John W Krakauer","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Jonathan S Tsay","author_inst":"Carnegie Mellon University"},{"author_name":"Marco Capogrosso","author_inst":"University of Pittsburgh"},{"author_name":"Elvira Pirondini","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Cervical spinal cord stimulation disrupts proprioception yet improves voluntary arm reaching","rel_doi":"10.64898\/2026.06.20.733548","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.20.733548","rel_abs":"Whether proprioception is necessary for upper-limb motor control has been debated for decades. Classic studies in deafferented animals and humans suggested that proprioception may be dispensable for rapid, goal-directed movements. However, chronic sensory loss conflates the absence of proprioceptive input with years of compensatory adaptation. As a result, the field has lacked a strong causal test of proprioception's contribution to motor control. Here, we leveraged a clinical trial of cervical spinal cord stimulation (SCS) in individuals with chronic post-stroke hemiparesis to study if electrical stimulation of sensory afferents causally perturbs proprioception and affects arm reaching. We found that turning SCS ON causally impaired proprioceptive perception and postural stabilization in response to force perturbations, and enhanced adaptation to visual errors during implicit learning. Yet visually and non-visually rapid, goal-directed reaching improved in smoothness, straightness and spatial accuracy. These findings provide strong causal evidence that proprioception is not required for rapid, goal-directed action, helping resolve a decades-long debate regarding its necessity for effective movement.","rel_num_authors":15,"rel_authors":[{"author_name":"Erick Carranza","author_inst":"University of Pittsburgh"},{"author_name":"Roberto de Freitas","author_inst":"University of Pittsburgh"},{"author_name":"Nikhil Verma","author_inst":"Carnegie Mellon University"},{"author_name":"Luigi Borda","author_inst":"Carnegie Mellon University"},{"author_name":"Erynn Sorensen","author_inst":"University of Pittsburgh"},{"author_name":"Amy Boos","author_inst":"University of Pittsburgh"},{"author_name":"George F Wittenberg","author_inst":"University of Pittsburgh"},{"author_name":"Lee Fisher","author_inst":"University of Pittsburgh"},{"author_name":"Marc Powell","author_inst":"University of Pittsburgh"},{"author_name":"Peter Gerszten","author_inst":"University of Pittsburgh"},{"author_name":"Douglas Weber","author_inst":"Carnegie Mellon University"},{"author_name":"John W Krakauer","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Jonathan S Tsay","author_inst":"Carnegie Mellon University"},{"author_name":"Marco Capogrosso","author_inst":"University of Pittsburgh"},{"author_name":"Elvira Pirondini","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Cervical spinal cord stimulation disrupts proprioception yet improves voluntary arm reaching","rel_doi":"10.64898\/2026.06.20.733548","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.20.733548","rel_abs":"Whether proprioception is necessary for upper-limb motor control has been debated for decades. Classic studies in deafferented animals and humans suggested that proprioception may be dispensable for rapid, goal-directed movements. However, chronic sensory loss conflates the absence of proprioceptive input with years of compensatory adaptation. As a result, the field has lacked a strong causal test of proprioception's contribution to motor control. Here, we leveraged a clinical trial of cervical spinal cord stimulation (SCS) in individuals with chronic post-stroke hemiparesis to study if electrical stimulation of sensory afferents causally perturbs proprioception and affects arm reaching. We found that turning SCS ON causally impaired proprioceptive perception and postural stabilization in response to force perturbations, and enhanced adaptation to visual errors during implicit learning. Yet visually and non-visually rapid, goal-directed reaching improved in smoothness, straightness and spatial accuracy. These findings provide strong causal evidence that proprioception is not required for rapid, goal-directed action, helping resolve a decades-long debate regarding its necessity for effective movement.","rel_num_authors":15,"rel_authors":[{"author_name":"Erick Carranza","author_inst":"University of Pittsburgh"},{"author_name":"Roberto de Freitas","author_inst":"University of Pittsburgh"},{"author_name":"Nikhil Verma","author_inst":"Carnegie Mellon University"},{"author_name":"Luigi Borda","author_inst":"Carnegie Mellon University"},{"author_name":"Erynn Sorensen","author_inst":"University of Pittsburgh"},{"author_name":"Amy Boos","author_inst":"University of Pittsburgh"},{"author_name":"George F Wittenberg","author_inst":"University of Pittsburgh"},{"author_name":"Lee Fisher","author_inst":"University of Pittsburgh"},{"author_name":"Marc Powell","author_inst":"University of Pittsburgh"},{"author_name":"Peter Gerszten","author_inst":"University of Pittsburgh"},{"author_name":"Douglas Weber","author_inst":"Carnegie Mellon University"},{"author_name":"John W Krakauer","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Jonathan S Tsay","author_inst":"Carnegie Mellon University"},{"author_name":"Marco Capogrosso","author_inst":"University of Pittsburgh"},{"author_name":"Elvira Pirondini","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Programming T cells for intercellular genome editing","rel_doi":"10.64898\/2026.06.21.729417","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.21.729417","rel_abs":"Therapeutic genome editing requires delivery of editing molecules to defined cell types, but targeting specificity and efficiency are currently limited. We hypothesized that properties inherent to immune cells, including tissue infiltration and programmed cell recognition, could be harnessed to engineer a cell-based delivery system. We show here that T cells can both produce and transfer editing machinery to target cells. In response to a programmable ligand, engineered T-lymphoid cells can transfer enzymes using complex spatiotemporal logic and deliver cargo in a cell contact-dependent or -independent manner. We demonstrate feasibility of this approach in primary human T cells, establishing a customizable genetic circuit for macromolecular delivery controlled by intercellular interactions.","rel_num_authors":10,"rel_authors":[{"author_name":"Kevin M Wasko","author_inst":"University of California, Berkeley"},{"author_name":"Madeleine Maker","author_inst":"University of California, Berkeley"},{"author_name":"Wayne Ngo","author_inst":"University of California, Berkeley"},{"author_name":"Kai Chen","author_inst":"University of California, Berkeley"},{"author_name":"Enbo Ma","author_inst":"University of California, Berkeley"},{"author_name":"Rithu Pattali","author_inst":"University of California, Berkeley"},{"author_name":"Enzo Chen","author_inst":"University of California, Berkeley"},{"author_name":"Trevor Leung","author_inst":"University of California, Berkeley"},{"author_name":"Jonathan Braverman","author_inst":"University of California, Berkeley"},{"author_name":"Jennifer A Doudna","author_inst":"UC Berkeley\/HHMI"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Programming T cells for intercellular genome editing","rel_doi":"10.64898\/2026.06.21.729417","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.21.729417","rel_abs":"Therapeutic genome editing requires delivery of editing molecules to defined cell types, but targeting specificity and efficiency are currently limited. We hypothesized that properties inherent to immune cells, including tissue infiltration and programmed cell recognition, could be harnessed to engineer a cell-based delivery system. We show here that T cells can both produce and transfer editing machinery to target cells. In response to a programmable ligand, engineered T-lymphoid cells can transfer enzymes using complex spatiotemporal logic and deliver cargo in a cell contact-dependent or -independent manner. We demonstrate feasibility of this approach in primary human T cells, establishing a customizable genetic circuit for macromolecular delivery controlled by intercellular interactions.","rel_num_authors":10,"rel_authors":[{"author_name":"Kevin M Wasko","author_inst":"University of California, Berkeley"},{"author_name":"Madeleine Maker","author_inst":"University of California, Berkeley"},{"author_name":"Wayne Ngo","author_inst":"University of California, Berkeley"},{"author_name":"Kai Chen","author_inst":"University of California, Berkeley"},{"author_name":"Enbo Ma","author_inst":"University of California, Berkeley"},{"author_name":"Rithu Pattali","author_inst":"University of California, Berkeley"},{"author_name":"Enzo Chen","author_inst":"University of California, Berkeley"},{"author_name":"Trevor Leung","author_inst":"University of California, Berkeley"},{"author_name":"Jonathan Braverman","author_inst":"University of California, Berkeley"},{"author_name":"Jennifer A Doudna","author_inst":"UC Berkeley\/HHMI"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"The structure of the lipid II flippase from monoderm bacteria","rel_doi":"10.64898\/2026.06.21.733627","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.21.733627","rel_abs":"Peptidoglycan biogenesis requires membrane flippases to translocate lipid-linked precursors across the cytoplasmic membrane for processing (1). This essential step is mediated by MurJ, the lipid II flippase conserved across all peptidoglycan-producing bacteria (2). While MurJ from diderm bacteria has been structurally resolved in multiple conformational states (3-6), its monoderm homolog remains uncharacterized. Monoderm MurJ homologs exhibit substantial sequence divergence yet retain the same lipid II flipping function (7) and are promising antibiotic targets. Here we report structures of Staphylococcus aureus MurJ (SaMurJ) captured in both outward- and inward-facing conformations. These structures show that SaMurJ adopts the conserved MOP family fold and undergoes conformational transitions consistent with an alternating-access mechanism. Our findings reveal conserved and divergent features of MurJ between diderm and monoderm bacteria that are critical for lipid II flipping and provide a structural framework for probing substrate recognition and specific inhibition.","rel_num_authors":3,"rel_authors":[{"author_name":"Yancheng Evelyn Li","author_inst":"California Institute of Technology"},{"author_name":"Grace F. Baron","author_inst":"California Institute of Technology"},{"author_name":"William Clemons Jr.","author_inst":"California Institute of Technology"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Intravenous midazolam alters short-interval paired-pulse TMS responses differently in younger and older adults","rel_doi":"10.64898\/2026.06.20.733493","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.20.733493","rel_abs":"Objective: Aging is associated with changes in cortical excitability and altered responsiveness to benzodiazepines, but the effects of benzodiazepine challenge on motor cortical paired-pulse physiology in older adults remain incompletely understood. We examined whether intravenous midazolam differentially modulates corticospinal excitability and short-interval paired-pulse transcranial magnetic stimulation (TMS) responses in younger and older adults. Methods: Fifteen younger adults (18-35 years) and fifteen older adults (50-69 years) underwent single-pulse and paired-pulse TMS of the left primary motor cortex at baseline and during intravenous midazolam administration. Single-pulse motor evoked potential (MEP) amplitude was used to assess corticospinal excitability. Short-interval paired-pulse responses were quantified as the ratio of conditioned to unconditioned MEP amplitude. Results: At baseline, younger adults showed greater corticospinal excitability than older adults, reflected by larger single-pulse MEP amplitudes (adjusted p = 0.04). Younger adults demonstrated paired-pulse inhibition at baseline, reflected by a conditioned\/unconditioned MEP ratio below 1.0 (ratio = 0.73; adjusted p < 0.01), whereas older adults did not show inhibition and instead had a mean ratio above 1.0 (ratio = 1.25). Midazolam reduced single-pulse MEP amplitudes in both groups. During midazolam administration, paired-pulse inhibition was no longer observed in younger adults, and older adults continued to show no evidence of inhibition. Conclusions: Younger and older adults differed in baseline corticospinal excitability and in short-interval paired-pulse TMS responses. Intravenous midazolam reduced corticospinal excitability and altered paired-pulse response patterns, eliminating baseline paired-pulse inhibition in younger adults while producing little measurable change in older adults. These findings suggest that aging may modify the net motor cortical response to benzodiazepine challenge. The results should be interpreted in relation to the paired-pulse stimulation parameters used and support further studies using complementary approaches to characterize age-related differences in inhibitory and facilitatory motor cortical circuits.","rel_num_authors":9,"rel_authors":[{"author_name":"Keith  M. McGregor","author_inst":"University of Alabama at Birmingham"},{"author_name":"Seyed Safavynia","author_inst":"Weill Cornell Medicine"},{"author_name":"Thomas Novak","author_inst":"Emory University"},{"author_name":"Ashton Weber","author_inst":"University of Alabama at Birmingham"},{"author_name":"Jessica Wang","author_inst":"Wayne State University School of Medicine"},{"author_name":"Joe Nocera","author_inst":"Emory University School of Medicine"},{"author_name":"Anna Woodbury","author_inst":"Emory University School of Medicine"},{"author_name":"Bruce Crosson","author_inst":"Emory University School of Medicine"},{"author_name":"Paul  S Garcia","author_inst":"Columbia Presbyterian Medical Center: NewYork-Presbyterian Columbia University Medical Center"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Midlife Measures of General Cognitive Performance in the National Longitudinal Study of Adolescent to Adult Health (Add Health)","rel_doi":"10.64898\/2026.06.18.26355806","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26355806","rel_abs":"ObjectiveThe Add Health Cognitive Assessment, Physical, and Sensory Function Protocol (Add CAPS) was developed to assess cognitive, physical, and sensory function in early midlife in a nationally representative sample in the United States. Using Add CAPS, we developed two general cognitive performance measures.\n\nMethodsThe sample included 2,525 participants from Add Health Wave VI who completed an in- home assessment of cognitive performance. Confirmatory factor analysis (CFA) was used to derive two general cognitive performance (GCP) scores: (1) a five-domain score based on originally designed cognitive domains (Add CAPS GCP), and (2) a modified score aligned with the Harmonized Cognitive Assessment Protocol (HCAP) framework (Add CAPS GCP-H). We evaluated model fit using Root Mean Square Error of Approximation (RMSEA), Standardized Root Mean Square Residual (SRMR), and Comparative Fit Index (CFI) and tested factor scores for criterion validity.\n\nResultsBoth models showed good fit (Add CAPS GCP: RMSEA = 0.025, SRMR = 0.031, CFI = 0.968; Add CAPS GCP-H: RMSEA = 0.027, SRMR = 0.033, CFI = 0.962), indicating that they adequately represent the underlying GCP construct.\n\nDiscussionThe Add CAPS cognitive battery captures a robust, hierarchical structure of GCP across alternative domain specifications. The derived factor scores provide a valuable method for characterizing a persons cognitive baseline during midlife. Importantly, the Add CAPS GCP-H enhances comparability with the HCAP network, supporting cross-cohort analyses of cognitive aging.","rel_num_authors":8,"rel_authors":[{"author_name":"Allison E Aiello","author_inst":"Columbia University"},{"author_name":"Farizah I Rob","author_inst":"Columbia University"},{"author_name":"Alden L Gross","author_inst":"Johns Hopkins University"},{"author_name":"David A Bennett","author_inst":"Rush University Medical Center"},{"author_name":"Jennifer J Manly","author_inst":"Columbia University"},{"author_name":"Brenda L Plassman","author_inst":"Duke University"},{"author_name":"Jennifer Momkus","author_inst":"Columbia University"},{"author_name":"Kamaryn T Tanner","author_inst":"Columbia University"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Midlife Measures of General Cognitive Performance in the National Longitudinal Study of Adolescent to Adult Health (Add Health)","rel_doi":"10.64898\/2026.06.18.26355806","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26355806","rel_abs":"ObjectiveThe Add Health Cognitive Assessment, Physical, and Sensory Function Protocol (Add CAPS) was developed to assess cognitive, physical, and sensory function in early midlife in a nationally representative sample in the United States. Using Add CAPS, we developed two general cognitive performance measures.\n\nMethodsThe sample included 2,525 participants from Add Health Wave VI who completed an in- home assessment of cognitive performance. Confirmatory factor analysis (CFA) was used to derive two general cognitive performance (GCP) scores: (1) a five-domain score based on originally designed cognitive domains (Add CAPS GCP), and (2) a modified score aligned with the Harmonized Cognitive Assessment Protocol (HCAP) framework (Add CAPS GCP-H). We evaluated model fit using Root Mean Square Error of Approximation (RMSEA), Standardized Root Mean Square Residual (SRMR), and Comparative Fit Index (CFI) and tested factor scores for criterion validity.\n\nResultsBoth models showed good fit (Add CAPS GCP: RMSEA = 0.025, SRMR = 0.031, CFI = 0.968; Add CAPS GCP-H: RMSEA = 0.027, SRMR = 0.033, CFI = 0.962), indicating that they adequately represent the underlying GCP construct.\n\nDiscussionThe Add CAPS cognitive battery captures a robust, hierarchical structure of GCP across alternative domain specifications. The derived factor scores provide a valuable method for characterizing a persons cognitive baseline during midlife. Importantly, the Add CAPS GCP-H enhances comparability with the HCAP network, supporting cross-cohort analyses of cognitive aging.","rel_num_authors":8,"rel_authors":[{"author_name":"Allison E Aiello","author_inst":"Columbia University"},{"author_name":"Farizah I Rob","author_inst":"Columbia University"},{"author_name":"Alden L Gross","author_inst":"Johns Hopkins University"},{"author_name":"David A Bennett","author_inst":"Rush University Medical Center"},{"author_name":"Jennifer J Manly","author_inst":"Columbia University"},{"author_name":"Brenda L Plassman","author_inst":"Duke University"},{"author_name":"Jennifer Momkus","author_inst":"Columbia University"},{"author_name":"Kamaryn T Tanner","author_inst":"Columbia University"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"A Parent-Generated Framework of Early Connection: Findings from a CBPR Qualitative Study","rel_doi":"10.64898\/2026.06.12.26355487","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355487","rel_abs":"BackgroundEarly relational health (ERH) constructs are derived from research observations rather than lived experiences. This study foregrounds diverse parent voices to examine how they describe connection with their young children.\n\nMethodsUsing community-based participatory research (CBPR), this study was co-designed with parent leaders from Reach Out and Read. A semi-structured interview guide was co-designed, and parent leaders subsequently conducted and transcribed 18 interviews with parents from their networks. Researchers analyzed transcripts using Reflexive Thematic Analysis. Member checking sessions with parent leaders informed the analytic framework.\n\nResultsSix organizing principles were identified. (1) Parent-child connection begins with an instinctual sense of responsibility. (2) Connection ebbs and flows as parent and child adapt to one another through daily activities. (3) Family circumstances, including family structure, cultural expectations, and intergenerational values, directly shape this connection. (4) Parents own upbringings and past relationships indirectly shape how they connect with their child. (5) For connection to grow, parents must show up physically and emotionally for their children despite competing demands. (6) Parents grow through engaged parenting, and that growth feeds back into the connection, creating a self-sustaining cycle of relational health.\n\nConclusionsOur analysis generated two constructs underspecified in ERH frameworks. Parents described their sense of responsibility as immediate and instinctual, preceding an emotional bond. Parents demonstrated their agency in deciding what to carry forward from their relational histories, a pattern this study terms relational legacy. Integrating parent-generated language into ERH measurement research may shape a more comprehensive picture of ERH reflecting how families experience connection.","rel_num_authors":15,"rel_authors":[{"author_name":"Katrina Fuller","author_inst":"Columbia University"},{"author_name":"Sophia Duby","author_inst":"Columbia University"},{"author_name":"Diana More","author_inst":"Columbia University"},{"author_name":"Maeve Winter","author_inst":"Columbia University"},{"author_name":"Marissa Lanoff","author_inst":"Columbia University"},{"author_name":"Nicole Loveless","author_inst":"Family Network Collaborative, Nurture Connection"},{"author_name":"Jeannette Mejias","author_inst":"Statewide Parent Advocacy Network"},{"author_name":"Desarae Smalls","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Tiffany Solomon","author_inst":"THRIVE Family Health & Education Center"},{"author_name":"Deepa Srinivasavaradan","author_inst":"Statewide Parent Advocacy Network"},{"author_name":"Steven Thibert","author_inst":"Family Network Collaborative, Nurture Connection"},{"author_name":"Carly Vargas","author_inst":"Reach Out and Read, Inc."},{"author_name":"Nikki Shearman","author_inst":"Reach Out and Read, Inc."},{"author_name":"Dani Dumitriu","author_inst":"Columbia University"},{"author_name":"Andreane Lavallee","author_inst":"Columbia University"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Repeat expansions in Parkinson's disease and parkinsonism across ancestries: insights from a global genetic cohort","rel_doi":"10.64898\/2026.06.12.26354932","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26354932","rel_abs":"Expanded short tandem repeats contribute to a broad spectrum of neurodegenerative diseases, yet their roles in Parkinsons disease (PD) and parkinsonism remain incompletely characterized, especially across diverse ancestries. We analyzed short-read whole-genome (WGS) and clinical exome sequencing (CES) data from 38,365 individuals (28,861 WGS; 9,504 CES), encompassing 23,242 patients with PD, 4,729 patients with atypical parkinsonism and 10,394 healthy controls from 11 genetic ancestries. To determine carrier frequencies and characterize repeat structures across diverse ancestries, we genotyped 12 established pathogenic loci where normal, intermediate, and pathogenic alleles can be reliably differentiated using short-read sequencing data. Additionally, we conducted threshold-based associations to determine the minimum threshold associated with increased PD risk in 15,995 individuals (8,591 PD, 7,404 controls) of European ancestry.\n\nPathogenic repeat expansions were detected in 62 patients (56 PD and 6 atypical parkinsonism) and 5 controls across seven loci (AR, ATXN1, ATXN2, ATXN3, CACNA1A, HTT and THAP11), spanning seven ancestries. Among these, ATXN2 expansions were the most frequently observed in PD and were present in African, East Asian, European and Middle Eastern ancestries. Additionally, intermediate ATXN2 repeat expansions exhibited a strong, length-dependent association with PD risk in the European population, with individuals with [&ge;]32 repeats having a more than four-fold increased risk (odds ratio 4.25, 95% confidence interval 1.80-12.05). Overall, >92% of expanded alleles harbor CAA interruptions within the CAG tract. Pathogenic expansions at other loci, such as ATXN3 and THAP11, showed more ancestry-specific distributions. Clinically, individuals with pathogenic ATXN2 and ATXN3 expansions most often presented with typical PD features but frequently showed earlier disease onset and a strong family history of PD.\n\nThis large-scale, multi-ancestry study comprehensively maps the genetic landscape of pathogenic and intermediate repeat expansions in PD. Our findings confirm a length- and structure-dependent risk association for ATXN2 with PD in the European population and highlight the pleiotropic effects of repeat expansions across the parkinsonian spectrum.","rel_num_authors":40,"rel_authors":[{"author_name":"Lara M Lange","author_inst":"Laboratories of Neurogenetics, NIA\/NIH, Bethesda, MD, US"},{"author_name":"Catalina Cerquera-Cleves","author_inst":"Neurology Unit, Department of Neurosciences, Hospital Universitario San Ignacio, Bogota, Colombia"},{"author_name":"Ai-Huey Tan","author_inst":"Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Shen-Yang Lim","author_inst":"Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Njideka U Okubadejo","author_inst":"College of Medicine, University of Lagos"},{"author_name":"Chin-Hsien Lin","author_inst":"Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan"},{"author_name":"Pin-Shiuan Chen","author_inst":"Department of Neurology, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan"},{"author_name":"Jung Hwan Shin","author_inst":"Department of Neurology, Seoul National University Hospital, Seoul, South Korea"},{"author_name":"Azlina Ahmad-Annuar","author_inst":"Universiti Malaya"},{"author_name":"Laurel Screven","author_inst":"Global Parkinson's Genetics Program (GP2), Chevy Chase, MD, USA"},{"author_name":"Viorica Chelban","author_inst":"University College London, Institute of Neurology, Department of Neuromuscular Diseases, Queen Square, London, UK"},{"author_name":"Allison A. Dilliott","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Andre Fienemann","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Kamalini Ghosh Galvelis","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Henry A. Houlden","author_inst":"The MRC centre for Neuromuscular Diseases"},{"author_name":"Hirotaka Iwaki","author_inst":"DataTecnica, Washington, DC, USA"},{"author_name":"Zane Jaunmuktane","author_inst":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK"},{"author_name":"Patrick W Cullinane","author_inst":"University College London"},{"author_name":"Thomas Warner","author_inst":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK"},{"author_name":"Johanna Junker","author_inst":"University Hospital Schleswig Holstein, Campus Luebeck, Luebeck, Germany"},{"author_name":"Yuliia Kanana","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Ignacio J. Keller Sarmiento","author_inst":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Christine Klein","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Pin-Jui Kung","author_inst":"Division of Plastic Surgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan"},{"author_name":"Hampton L Leonard","author_inst":"datatecnica"},{"author_name":"Niccolo Emanuele Mencacci","author_inst":"Northwestern University"},{"author_name":"Mike A Nalls","author_inst":"Data Tecnica Int'l"},{"author_name":"Raquel Real","author_inst":"UCL Queen Square Institute of Neurology"},{"author_name":"Samia Ben Sassi","author_inst":"National Institute Mongi Ben Hamida of Neurology, Tunis, Tunisia"},{"author_name":"Joanne Trinh","author_inst":"University of Luebeck"},{"author_name":"Dan Vitale","author_inst":"Center for Alzheimer's and Related Dementias"},{"author_name":"Ana Westenberger","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Lesley Wu","author_inst":"UCL"},{"author_name":"Andrew B Singleton","author_inst":"The Global Parkinson's Genetics Program (GP2)"},{"author_name":"Huw Morris","author_inst":"UCL Institute of Neurology"},{"author_name":"Katja Lohmann","author_inst":"University of Luebeck"},{"author_name":"Cornelis Blauwendraat","author_inst":"Coalition for Aligning Science, Chevy Chase, MD, USA"},{"author_name":"Peter Heutink","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Zih-Hua Fang","author_inst":"German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany"},{"author_name":"- the Global Parkinson's Genetics Program","author_inst":"-"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Understanding and Usefulness of Effect Size and Certainty of Evidence: A Cross-sectional Survey of Evidence-Based Practice Competencies Among Registered Dietitians","rel_doi":"10.64898\/2026.06.19.26356093","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.19.26356093","rel_abs":"Introduction: Understanding of absolute and relative estimates (i.e., effect size), and certainty of evidence corresponding to those estimates, is a fundamental evidence-based practice competency to promote informed clinical decision-making. While research has been conducted in the medical profession, there is no published research on these competencies in the nutrition and dietetics profession. Methods: Among registered dietitians, our main objectives were to assess (1) their understanding and perceived usefulness of three absolute and two relative estimate approaches to assess effect size, (2) their perceived usefulness of certainty of evidence, and (3) factors influencing their understanding and perceived usefulness. We conducted a web-based, cross-sectional survey among dietitians recruited from the Academy of Nutrition and Dietetics (United States). Participants received effect estimates based on hypothetical dietary interventions vs. usual diet for reducing myocardial infarction risk. Results: Of the 11,050 dietitians who received the survey link, 210 participated (2.0% response rate), and only completers (n=114) were included in the analysis. Participants demonstrated a similar understanding of the relative (27.6%) and absolute (27.5%) estimates, with Risk Difference (30.7% correct responses) being the best understood approach and Number Needed to Treat (24.6%) being the least. The understanding of five approaches was not different than random guessing (p>0.05). While perceived usefulness scores were similar between five approaches, they were highest when data was presented as Relative Risk [mean (SD): 4.82 (1.50)]. Dietitians rated the usefulness of certainty of evidence favorably [mean (SD): 5.07 (1.83), on a 7-point scale), and no factors were associated with correct understanding. Conclusion: Dietitians may have limited understanding of how to interpret effect sizes, a finding consistent with surveys of other health professionals. To optimize informed decision-making between dietitians and clients, dietetic programs and continuing education platforms should consider additional training on interpreting effect sizes and certainty of evidence for effect sizes.","rel_num_authors":8,"rel_authors":[{"author_name":"Nirjhar Ruth Ghosh","author_inst":"Texas A and M University"},{"author_name":"Elizabeth P Neale","author_inst":"University of Wollongong"},{"author_name":"Rosa K Hand","author_inst":"Case Western Reserve University"},{"author_name":"Geoff D C Ball","author_inst":"University of Alberta"},{"author_name":"Emily Riddle","author_inst":"SUNY Oneonta"},{"author_name":"Kevin C Klatt","author_inst":"University of Toronto"},{"author_name":"Aaron Riviere","author_inst":"Texas A and M University"},{"author_name":"Bradley C Johnston","author_inst":"Texas A and M University"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Level of Physical Activity and ApoE Status - Effects on Alzheimer's Disease and on Mortality","rel_doi":"10.64898\/2026.06.18.26355781","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26355781","rel_abs":"Background: Alzheimer's disease and related dementias (ADRD) affect over 7.2 million Americans aged 65 and older, with the APOE-4 allele representing the strongest known genetic risk factor. Physical activity (PA) has been associated with reduced dementia risk, but its interaction with APOE genotype remains poorly characterized in large, genomically informed cohorts. Methods: We conducted a retrospective cohort analysis using linked genomic, survey, and longitudinal electronic health record data from the VA Million Veteran Program (MVP). Veterans aged <65 at enrollment with available APOE genotype data, at least 10 years of prior VA medical history, and a completed Lifestyle Survey were included. Individuals with a pre-existing ADRD diagnosis were excluded, yielding a final cohort of 137,593 veterans. Self-reported vigorous physical activity (PA) was ascertained from the MVP Lifestyle Survey and coded as both a four-level ordinal variable and a binary active\/inactive classification. The primary composite outcome was incident ADRD or all-cause mortality. Cox proportional hazards models were fitted adjusting for age, sex, race\/ethnicity, and baseline comorbidities. A multiplicative interaction term between APOE {varepsilon}4 allele count and PA level was included to formally test for effect modification. Results: Over a median follow-up of 84 months, 65,628 participants (47.7%) experienced the composite outcome. Each additional APOE-4 allele was associated with a 19% increase in risk (aHR = 1.19, 95% CI 1.17-1.21), while active individuals had a 33% lower risk compared to inactive individuals (aHR = 0.67, 95% CI 0.66-0.68). A statistically significant interaction between APOE-4 burden and PA was identified (p < 0.005). Stratified analyses demonstrated that the protective association of PA was present across all genotype groups, with homozygotes demonstrating a 22% risk reduction among active individuals. Conclusions: In this large veteran cohort, vigorous PA was independently and significantly associated with reduced risk of incident ADRD or death across all APOE genotype groups, with the greatest absolute benefit observed among individuals at highest genetic risk. These findings support the prioritization of PA as a targeted preventive strategy, particularly for APOE-4 carriers.","rel_num_authors":11,"rel_authors":[{"author_name":"Phillip Ma","author_inst":"George Washington University School of Medicine and Health Sciences"},{"author_name":"Yan Cheng","author_inst":"George Washington University School of Medicine and Health Sciences"},{"author_name":"Yijun Shao","author_inst":"George Washington University School of Medicine and Health Sciences"},{"author_name":"Edward Zamrini","author_inst":"George Washington University School of Medicine and Health Sciences"},{"author_name":"Xuemei Sui","author_inst":"University of South Carolina"},{"author_name":"Debby W Tsuang","author_inst":"University of Washington"},{"author_name":"Mark Logue","author_inst":"Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Ali Ahmed","author_inst":"Washington DC VA Medical Center"},{"author_name":"Peter Kokkinos","author_inst":"Rutgers University"},{"author_name":"Charles J. Faselis","author_inst":"US Department of Veteran Affairs"},{"author_name":"Qing Zeng-Treitler","author_inst":"George Washington University School of Medicine and Health Sciences"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Anterior-superior hypothalamic enlargement as specific marker in episodic migraine: converging evidence from an independent discovery-replication design","rel_doi":"10.64898\/2026.06.12.26355501","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355501","rel_abs":"BackgroundGrowing evidence implicates the hypothalamus as a key structure in migraine pathophysiology; however, our understanding of its precise role and of the specific nuclei involved remains limited. We combined MRI data from our laboratory with publicly available MRI datasets from OpenNeuro to examine hypothalamic subunit volumes in episodic migraine and assess the specificity of these alterations relative to chronic pain conditions.\n\nMethodsStructural MRI combined with an automated atlas-based segmentation algorithm and a discovery-replication design was employed to investigate cross-sectional volumetric differences across 5 bilateral hypothalamic subunits in two independent migraine cohorts: DS1-MIG (DS1-MIG-base, n = 111 patients, n = 35 controls) and DS2-MIG (n = 27 patients, n = 31 controls). The adjusted volumes were compared between groups using MANOVA as an omnibus test, followed by Welch t-tests to test univariate follow-up. Longitudinal volumetric changes were additionally assessed in DS1-MIG participants with available follow-up scans using linear mixed models. To assess the specificity of findings to migraine, the same pipeline was applied to two chronic pain datasets, one including patients with fibromyalgia (DS-FM, n = 33 patients, n = 33 controls) and the other including patients with trigeminal neuralgia (n = 119 patients, n = 55 controls).\n\nResultsMANOVA revealed significant multivariate group differences in the discovery and replication migraine cohorts (DS1-MIG-base: p = .006; DS2-MIG: p = .008). Follow-up univariate analyses identified a consistent enlargement of the left anterior-superior subunit across both cohorts (pFDR = .023 in DS1-MIG-base and pFDR = .046 in DS2-MIG), representing the only cross-cohort replication finding. Beyond this shared signature, DS2-MIG exhibited additional significant enlargements of the right anterior-inferior and right tubular-inferior subunits. Longitudinal analyses in DS1-MIG showed that hypothalamic subunit volumes remained broadly stable over time within both migraine patients and control participants. No significant volumetric alterations were detected in the fibromyalgia or trigeminal neuralgia cohorts, either in multivariate or univariate analyses, underscoring migraine-specific findings.\n\nConclusionsThese findings provide evidence for subunit-specific hypothalamic structural alterations in migraine localized in the left anterior hypothalamic subunit. The stability of these differences over time and their absence in other chronic pain conditions suggest a migraine-specific structural organisation of hypothalamic circuitry.","rel_num_authors":9,"rel_authors":[{"author_name":"Dan Liu","author_inst":"The Clinical Hospital of Chengdu Brain Science Institute, MOE-Key Lab for NeuroInformation, Brain-Apparatus Communication Institute, University of Electronic Sc"},{"author_name":"Shengkun Peng","author_inst":"Department of Radiology, Sichuan Provincial People s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China."},{"author_name":"Longlin Yin","author_inst":"Department of Radiology, Sichuan Provincial People s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China."},{"author_name":"Xueyang Wen","author_inst":"The Clinical Hospital of Chengdu Brain Science Institute, MOE-Key Lab for NeuroInformation, Brain-Apparatus Communication Institute, University of Electronic Sc"},{"author_name":"Bin Huang","author_inst":"Department of Neurology, Sichuan Provincial People s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China."},{"author_name":"Keith Maurice Kendrick","author_inst":"The Clinical Hospital of Chengdu Brain Science Institute, MOE-Key Lab for NeuroInformation, Brain-Apparatus Communication Institute, University of Electronic Sc"},{"author_name":"Benjamin Becker","author_inst":"Department of Psychology, and AI, Society and Social Dynamics, The University of Hong Kong, Hong Kong, China"},{"author_name":"Dezhong Yao","author_inst":"The Clinical Hospital of Chengdu Brain Science Institute, MOE-Key Lab for NeuroInformation, Brain-Apparatus Communication Institute, University of Electronic Sc"},{"author_name":"Stefania Ferraro","author_inst":"The Clinical Hospital of Chengdu Brain Science Institute, MOE-Key Lab for NeuroInformation, Brain-Apparatus Communication Institute, University of Electronic Sc"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Cumulative Metabolic Exposure to Hyperglycemia and Risk of Cardiovascular and Limb Events in Peripheral Artery Disease","rel_doi":"10.64898\/2026.06.18.26356017","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26356017","rel_abs":"BackgroundAlthough diabetes is a potent risk factor for the development of peripheral artery disease (PAD), the effect of cumulative metabolic exposure to hyperglycemia on risk of cardiovascular or limb events in patients with PAD remains unclear.\n\nMethodsThe Peripheral Artery Disease: Long-term Survival (PEARLS) is a longitudinal registry of Veterans with newly diagnosed PAD identified using a natural language processing approach. Included patients had ankle brachial index [&le;]0.9 or toe brachial index [&le;]0.7, and no history of lower extremity revascularization or major amputation. Among patients with diabetes in this cohort, we assessed cumulative exposure to hyperglycema based on a 24-month rolling average of hemoglobin (Hgb) A1c values, categorized as [&le;]7%, >7% to [&le;]8%, and >8%. Multivariable Cox regression models evaluated the association between categories of HgbA1c, modeled as a time-varying exposure, and risk of cardiovascular (CV: myocardial infarction or stroke) and limb (chronic limb threatening ischemia [CLTI] or major amputation) events.\n\nResultsAmong 45,109 patients with new diagnosis of PAD and pre-existing diabetes, the mean HgbA1c at baseline was 7.5%, with nearly one-third (30.4%) having HgbA1c >8%. The mean age was 70.4 years, 19.8% were Black and 4% were Hispanic. Patients with baseline HgbA1c >8% were younger and compared to those with HgbA1c [&le;]7%, more likely to have coronary disease, kidney disease, and obesity. Over a median follow up of 4.2 years, 8,306 (18.4%) patients experienced a CV event, and 8,199 (18.2%) experienced a limb event. The adjusted association between HgbA1c and hazard of CV events was 12% higher in patients exposed to HgbA1c >7% to [&le;]8% (HR 1.12; 95%CI: 1.05-1.18) and 38% higher in those exposed to HgbA1c >8% (HR 1.38; 95%CI: 1.30-1.46), compared to HgbA1c <7%. The association with limb events was even stronger, with 20% and 60% higher hazard in those exposed to >7% to [&le;]8% (HR 1.20; 95%CI: 1.13-1.28) and HgbA1c >8% (HR 1.60; 95%CI: 1.51-1.70), respectively when compared to HgbA1c [&le;]7%. These findings were consistent in subgroups based on age and severity of PAD.\n\nConclusionsAmong diabetic patients with PAD, cumulatiave metabolic exposure to hyperglycemia is associated with a markedly increased risk of clinical events, especially limb events.\n\nClinical PerspectiveO_ST_ABSWhat is new? (maximum 100 words, formatted as 2-3 bullets)C_ST_ABSO_LIAmong > 45,000 patients with diabetes and new-onset PAD in a large, multi-center registry, we found a graded positive association between cumulative metabolic exposure to hyperglycemia and risk of cardiovascular (CV) and limb events.\nC_LIO_LIPoor glycemic control was more strongly associated with limb events than CV events, and this association was consistent in older patients and those with severe PAD.\nC_LI\n\nWhat are the clinical implications? (maximum 100 words, formatted as 2-3 bullets).O_LIPatients with PAD have been underrepresented in previous trials evaluating the effect of intensive control of diabetes on CV outcomes.\nC_LIO_LIGiven the remarkably high burden of CV and limb events in those with PAD and diabetes, our findings support the need for a randomized controlled trial to evaluate the role of glycemic control in mitigating vascular disease risk in this population.\nC_LI","rel_num_authors":12,"rel_authors":[{"author_name":"Feroz James","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Qiang Li","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Medha Somisetty","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Cathy Nguyen","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Mary S Vaughan-Sarrazin","author_inst":"The University of Iowa"},{"author_name":"Brian Lund","author_inst":"Iowa City VA Medical Center"},{"author_name":"Shirling Tsai","author_inst":"Dallas VA Medical Center\/UT Southwestern Medical Center"},{"author_name":"Kim G. Smolderen","author_inst":"Yale School of Medicine"},{"author_name":"Richard M Hoffman","author_inst":"University of Iowa Hospitals and Clinics"},{"author_name":"Shipra Arya","author_inst":"Stanford University School of Medicine"},{"author_name":"Joshua A. Beckman","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Saket Girotra","author_inst":"The University of Texas Southwestern Medical Center"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Cumulative Metabolic Exposure to Hyperglycemia and Risk of Cardiovascular and Limb Events in Peripheral Artery Disease","rel_doi":"10.64898\/2026.06.18.26356017","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26356017","rel_abs":"BackgroundAlthough diabetes is a potent risk factor for the development of peripheral artery disease (PAD), the effect of cumulative metabolic exposure to hyperglycemia on risk of cardiovascular or limb events in patients with PAD remains unclear.\n\nMethodsThe Peripheral Artery Disease: Long-term Survival (PEARLS) is a longitudinal registry of Veterans with newly diagnosed PAD identified using a natural language processing approach. Included patients had ankle brachial index [&le;]0.9 or toe brachial index [&le;]0.7, and no history of lower extremity revascularization or major amputation. Among patients with diabetes in this cohort, we assessed cumulative exposure to hyperglycema based on a 24-month rolling average of hemoglobin (Hgb) A1c values, categorized as [&le;]7%, >7% to [&le;]8%, and >8%. Multivariable Cox regression models evaluated the association between categories of HgbA1c, modeled as a time-varying exposure, and risk of cardiovascular (CV: myocardial infarction or stroke) and limb (chronic limb threatening ischemia [CLTI] or major amputation) events.\n\nResultsAmong 45,109 patients with new diagnosis of PAD and pre-existing diabetes, the mean HgbA1c at baseline was 7.5%, with nearly one-third (30.4%) having HgbA1c >8%. The mean age was 70.4 years, 19.8% were Black and 4% were Hispanic. Patients with baseline HgbA1c >8% were younger and compared to those with HgbA1c [&le;]7%, more likely to have coronary disease, kidney disease, and obesity. Over a median follow up of 4.2 years, 8,306 (18.4%) patients experienced a CV event, and 8,199 (18.2%) experienced a limb event. The adjusted association between HgbA1c and hazard of CV events was 12% higher in patients exposed to HgbA1c >7% to [&le;]8% (HR 1.12; 95%CI: 1.05-1.18) and 38% higher in those exposed to HgbA1c >8% (HR 1.38; 95%CI: 1.30-1.46), compared to HgbA1c <7%. The association with limb events was even stronger, with 20% and 60% higher hazard in those exposed to >7% to [&le;]8% (HR 1.20; 95%CI: 1.13-1.28) and HgbA1c >8% (HR 1.60; 95%CI: 1.51-1.70), respectively when compared to HgbA1c [&le;]7%. These findings were consistent in subgroups based on age and severity of PAD.\n\nConclusionsAmong diabetic patients with PAD, cumulatiave metabolic exposure to hyperglycemia is associated with a markedly increased risk of clinical events, especially limb events.\n\nClinical PerspectiveO_ST_ABSWhat is new? (maximum 100 words, formatted as 2-3 bullets)C_ST_ABSO_LIAmong > 45,000 patients with diabetes and new-onset PAD in a large, multi-center registry, we found a graded positive association between cumulative metabolic exposure to hyperglycemia and risk of cardiovascular (CV) and limb events.\nC_LIO_LIPoor glycemic control was more strongly associated with limb events than CV events, and this association was consistent in older patients and those with severe PAD.\nC_LI\n\nWhat are the clinical implications? (maximum 100 words, formatted as 2-3 bullets).O_LIPatients with PAD have been underrepresented in previous trials evaluating the effect of intensive control of diabetes on CV outcomes.\nC_LIO_LIGiven the remarkably high burden of CV and limb events in those with PAD and diabetes, our findings support the need for a randomized controlled trial to evaluate the role of glycemic control in mitigating vascular disease risk in this population.\nC_LI","rel_num_authors":12,"rel_authors":[{"author_name":"Feroz James","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Qiang Li","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Medha Somisetty","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Cathy Nguyen","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Mary S Vaughan-Sarrazin","author_inst":"The University of Iowa"},{"author_name":"Brian Lund","author_inst":"Iowa City VA Medical Center"},{"author_name":"Shirling Tsai","author_inst":"Dallas VA Medical Center\/UT Southwestern Medical Center"},{"author_name":"Kim G. Smolderen","author_inst":"Yale School of Medicine"},{"author_name":"Richard M Hoffman","author_inst":"University of Iowa Hospitals and Clinics"},{"author_name":"Shipra Arya","author_inst":"Stanford University School of Medicine"},{"author_name":"Joshua A. Beckman","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Saket Girotra","author_inst":"The University of Texas Southwestern Medical Center"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Enabled Cardiac Function Estimation from Phone Videos of Echocardiograms","rel_doi":"10.64898\/2026.06.19.26356088","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.19.26356088","rel_abs":"Importance: Mobile phone-recorded echocardiogram videos are commonly used in point of care, telemedicine, and resource-limited workflows, but artificial intelligence models for left ventricular ejection fraction (LVEF) estimation have primarily been evaluated on native Digital Imaging and Communications in Medicine (DICOM) videos. Objective: To evaluate whether previously described artificial intelligence models for LVEF estimation retain performance when applied to mobile phone-recorded echocardiographic videos. Design: Multicenter model validation study comparing model-estimated LVEF with clinician reported LVEF. Setting: Three medical centers: Kaiser Permanente Northern California, Beth Israel Deaconess Medical Center through MIMIC-IV-ECHO, and Cedars-Sinai Medical Center. Participants: Source studies with clinician reported LVEF and apical 4-chamber or apical 2-chamber views, yielding 6209 phone-recorded videos from 2648 studies and 2611 patients. Exposures: Mobile phone recording of native echocardiographic videos and fine-tuning of pretrained models using mobile phone-recorded videos from the Kaiser Permanente Northern California training cohort. Main Outcomes and Measures: Mean absolute error in ejection fraction percentage points, R^2 for continuous estimation, and area under the receiver operating characteristic curve for identifying ejection fraction greater than 50%. Results: The study included 6209 mobile phone recorded echocardiographic videos from 2648 studies and 2611 patients; the weighted mean age was 68.4 years, and 1031 patients were male (39.5%). Without phone-video fine-tuning, the primary model achieved a mean absolute error of 7.00 percentage points, coefficient of determination of 0.49, and area under the receiver operating characteristic curve of 0.91 on phone-recorded videos; corresponding native DICOM performance was 6.08 percentage points, 0.60, and 0.93, respectively. On the 2396-video fine-tuning evaluation cohort, fine-tuning improved primary model performance to a mean absolute error of 6.96 percentage points, coefficient of determination of 0.61, and area under the receiver operating characteristic curve of 0.93. Fine-tuning the public EchoNet-Dynamic model improved performance from 9.36 percentage points, 0.37, and 0.84 to 7.86 percentage points, 0.50, and 0.89, respectively. Progressive central zoom preprocessing degraded model performance. Conclusions and Relevance: These findings suggest that artificial intelligence assisted left ventricular ejection fraction estimation from mobile phone-recorded echocardiograms may be feasible when native image export is unavailable, although prospective evaluation is needed before clinical deployment.","rel_num_authors":12,"rel_authors":[{"author_name":"Dhawal Modi","author_inst":"Division of Research, Kaiser Permanente Northern California"},{"author_name":"Jay Kim","author_inst":"Division of Research, Kaiser Permanente Northern California"},{"author_name":"Alexander Ye","author_inst":"National Taiwan University"},{"author_name":"Sahir Eusuff","author_inst":"Smidt Heart Institute, Cedars-Sinai Medical Center"},{"author_name":"Hirotaka Ieki","author_inst":"Division of Research, Kaiser Permanente Northern California"},{"author_name":"Andrew P Ambrosy","author_inst":"Division of Research, Kaiser Permanente Northern California"},{"author_name":"Alan C. Kwan","author_inst":"Smidt Heart Institute, Cedars-Sinai Medical Center"},{"author_name":"Bryan He","author_inst":"Stanford University"},{"author_name":"James Zou","author_inst":"Department of Computer Science, Stanford University"},{"author_name":"Susan Cheng","author_inst":"Smidt Heart Institute, Cedars-Sinai Medical Center"},{"author_name":"Euan Ashley","author_inst":"Department of Medicine, Stanford University School of Medicine"},{"author_name":"David Ouyang","author_inst":"Division of Research, Kaiser Permanente Northern California"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"AFFORDABILITY OF INTOXICATION FROM CHEAP ETHANOL: EVIDENCE FROM RETAIL ALCOHOL MARKETS IN UGANDA","rel_doi":"10.64898\/2026.06.18.26356010","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26356010","rel_abs":"Background: Alcohol affordability is a determinant of consumption and alcohol-related harm. In many low- and middle-income countries (LMICs), informal production, variable alcohol strength, and non-standard packaging complicate conventional affordability measures, limiting evidence on the economic accessibility of alcohol and the cost of intoxication. Objective: To assess the affordability of intoxication in Uganda by estimating the cost of obtaining ethanol to reach intoxication across alcohol products, packaging types, and retail contexts. Methods: Data were collected on 824 alcoholic beverages from urban, rural, and urban-slum retail markets. Ethanol-standardized pricing (price per gram of alcohol) was calculated, and the cost of consuming 60 g of ethanol was estimated. Multivariate regression identified determinants of ethanol affordability. Results: Affordability varied by product type and packaging. Opaque beers and illicit spirits provided the cheapest pathways to intoxication, with median costs of UGX 1,200-1,500 per 60 g of ethanol. Plastic packaging was associated with lower ethanol costs than glass packaging. Ethanol prices differed across formal and informal markets (p < 0.01), while rural areas and urban informal settlements had 20-25% lower costs than urban areas. Regulatory status alone did not predict affordability. Conclusions: In Ugandas diverse alcohol market, affordability is driven by access to ethanol rather than beverage price alone. Low-cost, high-strength alcohol sold through informal channels enables intoxication at minimal expense, among disadvantaged populations. Implications: Alcohol policies should target ethanol content through minimum unit pricing, alcohol-content-based taxation, and regulation of informal markets and packaging practices to reduce harmful consumption and inequities.","rel_num_authors":8,"rel_authors":[{"author_name":"Tumwine Muhamudu","author_inst":"Makerere University"},{"author_name":"Kennedy Niwagaba","author_inst":"Makerere University College of Business and Management Sciences"},{"author_name":"Simon Peter Rwakahangi","author_inst":"Makerere University Business School"},{"author_name":"Betty Kwagala","author_inst":"Makerere University College of Business and Management Sciences"},{"author_name":"Ted R Miller","author_inst":"Michigan State University Office of Health Sciences"},{"author_name":"Cosmas Zyambo","author_inst":"University of Zambia"},{"author_name":"Angela Rizzo","author_inst":"AB InBev Foundation"},{"author_name":"Tom Achoki","author_inst":"AB InBev Foundation"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"MCH-Guard: Multimodal Machine Learning Framework for Risk Stratification of Cerebral Microhemorrhage Risk in the Alzheimer's Disease Neuroimaging Initiative","rel_doi":"10.64898\/2026.06.18.26355972","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26355972","rel_abs":"BackgroundEfficient cerebral microhemorrhage (MCH) monitoring is critical for anti-amyloid therapy safety due to ARIA-H risk. We developed MCH-Guard, a multimodal machine-learning framework, to stratify MCH risk using ADNI data (N=813).\n\nMethodsNested models integrated clinical history, fluid biomarkers, and imaging to predict MCH presence, incidence, and stability.\n\nResultsThe comprehensive model detected baseline MCH with high accuracy (AUC 0.86). Notably, the \"minimal\" model (M1), utilizing only demographics and clinical history, achieved robust performance (AUC 0.82). Longitudinal models predicted time-to-onset (R2=0.68) and stratified four-year risk. Furthermore, we identified a transient vascular instability phenotype--where MCH status fluctuates-- which was strongly predicted by hepatic factors.\n\nConclusionsMCH-Guard offers a flexible clinical decision-support tool for optimizing spontaneous MCH & ARIA surveillance. The strong performance of the clinical-only M1 model supports equitable risk assessment in resource-limited settings, while the characterization of vascular instability addresses a critical confounder in safety monitoring.","rel_num_authors":5,"rel_authors":[{"author_name":"Alper Gel","author_inst":"University of California - San Francisco"},{"author_name":"Eliana Phillips","author_inst":"NCIRE"},{"author_name":"Isabella Hausle","author_inst":"NCIRE"},{"author_name":"Pamela Thropp","author_inst":"NCIRE"},{"author_name":"Duygu Tosun","author_inst":"University of California - San Francisco"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Recent antipsychotics use associated with elevated risk of Parkinson's disease","rel_doi":"10.64898\/2026.06.19.26356070","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.19.26356070","rel_abs":"IntroductionParkinsons disease is a neurodegenerative disease affecting motor and cognitive function that has a major impact on society. Epidemiological evidence has suggested that the incidence of PD may be increasing; however, the underlying etiology is unclear. Here, we investigated the role of increasingly used antipsychotics in the diagnosis of PD.\n\nMethodsWe harnessed Merative insurance claims databases to conduct a case-control study of 65,275 new cases of PD and 652,364 age-, sex-, and time-matched controls. We estimated associations between exposure and duration of use for antipsychotics adjusted for important confounders using fixed effects logistic regression. We performed sensitivity analyses stratified by the level of D2 receptor inhibition to assess dose-response relationships; a lagged exposure analysis to address confounding by indication; analysis assessing exposure of other psychiatric medications without significant D2 inhibition (bupropion, trazodone, and Z-drugs); analysis assessing exposure of non-psychiatric medications with significant (metoclopramide) or no D2 inhibition (ondansetron).\n\nResultsWe found cases with PD had elevated odds of antipsychotic exposure. Longer durations of exposure and greater affinity for the D2 receptor were associated with greater associations with PD. There was a dose-response relationship between D2 inhibition activity and increased odds of PD for a similar duration of exposure. There was a dose response relationship between duration of metoclopramide and the odds of PD; however, there was no such relationship between the non-D2 inhibiting control medications. The association between exposure to an antipsychotic and increased odds of PD was present even when the first exposure was 10 years prior to the PD diagnosis date.\n\nConclusionIf these results are causal, antipsychotic use may explain up to 2.4% of all cases of PD. Given the increasing rate of use of these medications, and the concurrent increasing age-adjusted incidence of PD, there is an urgent need for further investigation into this association and greater awareness of the potential risks of these medications in older adults.","rel_num_authors":6,"rel_authors":[{"author_name":"Lee Neilson","author_inst":"University of Iowa"},{"author_name":"Ryan Carnahan","author_inst":"University of Iowa"},{"author_name":"Susan Duffy","author_inst":"University of Iowa"},{"author_name":"Vicki Kijewski","author_inst":"University of Iowa"},{"author_name":"Nandakumar Narayanan","author_inst":"University of Iowa"},{"author_name":"Jacob E Simmering","author_inst":"University of Iowa"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Simulation-Guided Selection of a Bayesian Adaptive Phase II Design for a Nine-Arm Cilostazol-Albumin Trial in Aneurysmal Subarachnoid Hemorrhage","rel_doi":"10.64898\/2026.06.18.26356019","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26356019","rel_abs":"BackgroundThe Cilostazol Albumin Treatment in Subarachnoid Hemorrhage (CATS) trial evaluates eight active cilostazol-human albumin regimens plus control in patients with aneurysmal subarachnoid hemorrhage. We summarized the rationale for the primary statistical design, compared alternative Phase II methodologies, and evaluated reduced-arm sensitivity scenarios.\n\nMethodsThe binary primary endpoint is Common Data Elements-defined delayed cerebral ischemia within 14 days after randomization. The selected design is Bayesian adaptive, with a burn-in phase, response-adaptive randomization among active arms while maintaining fixed control allocation, four interim analyses, early stopping for expected success or futility, and a two-dimensional normal dynamic linear model. Primary operating characteristics were obtained from 1,000 virtual trials per scenario using Fixed and Adaptive Clinical Trial Simulator version 7.0.0. Exploratory simulations evaluated six-, four-, and two-active-arm configurations and simplified alternative designs.\n\nResultsCompared with fixed equal allocation, the Bayesian adaptive design preserved an approximately 10% false-success probability under the global null while improving probability of success and efficiency in clinically relevant scenarios. Under the Realistic scenario, probability of success increased from 0.61 to 0.86, expected sample size decreased from 400 to 308, and expected duration decreased from 235 to 187 weeks. Under common thresholds, null probability of success was 0.098 for the full anchor and 0.073 for Reduced-6; Reduced-6 probabilities of success were 0.774 and 0.765 in the Realistic and Realistic2 scenarios. However, Reduced-6 omitted two monotherapy anchors and was less robust in Backwards2. In the comparator simulation, the selected design had probability of success of 0.858 and expected sample size of 308.3 under the Realistic scenario, compared with 0.624 to 0.845 and approximately 352 to 400 for simplified comparators.\n\nConclusionsFor identifying the most promising cilostazol-human albumin regimen for Phase III rather than confirming efficacy, the Bayesian response-adaptive design with two-dimensional normal dynamic linear model borrowing is more efficient and better aligned than simplified comparators. The full nine-arm design remains preferable because it preserves the complete therapeutic discovery space and is more robust to misspecified or non-smooth response surfaces.","rel_num_authors":7,"rel_authors":[{"author_name":"Adnan I. Qureshi","author_inst":"University of Missouri"},{"author_name":"Hassan Raza","author_inst":"University of Missouri"},{"author_name":"Naima Alam","author_inst":"University of Kansas Medical Center"},{"author_name":"Jonathan Beall","author_inst":"Medical University of South Carolina"},{"author_name":"Byron J. Gajewski","author_inst":"University of Kansas Medical Center"},{"author_name":"Renee L. Martin","author_inst":"Medical University of South Carolina"},{"author_name":"Jose I. Suarez","author_inst":"The Johns Hopkins University School of Medicine"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Simulation-Guided Selection of a Bayesian Adaptive Phase II Design for a Nine-Arm Cilostazol-Albumin Trial in Aneurysmal Subarachnoid Hemorrhage","rel_doi":"10.64898\/2026.06.18.26356019","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26356019","rel_abs":"BackgroundThe Cilostazol Albumin Treatment in Subarachnoid Hemorrhage (CATS) trial evaluates eight active cilostazol-human albumin regimens plus control in patients with aneurysmal subarachnoid hemorrhage. We summarized the rationale for the primary statistical design, compared alternative Phase II methodologies, and evaluated reduced-arm sensitivity scenarios.\n\nMethodsThe binary primary endpoint is Common Data Elements-defined delayed cerebral ischemia within 14 days after randomization. The selected design is Bayesian adaptive, with a burn-in phase, response-adaptive randomization among active arms while maintaining fixed control allocation, four interim analyses, early stopping for expected success or futility, and a two-dimensional normal dynamic linear model. Primary operating characteristics were obtained from 1,000 virtual trials per scenario using Fixed and Adaptive Clinical Trial Simulator version 7.0.0. Exploratory simulations evaluated six-, four-, and two-active-arm configurations and simplified alternative designs.\n\nResultsCompared with fixed equal allocation, the Bayesian adaptive design preserved an approximately 10% false-success probability under the global null while improving probability of success and efficiency in clinically relevant scenarios. Under the Realistic scenario, probability of success increased from 0.61 to 0.86, expected sample size decreased from 400 to 308, and expected duration decreased from 235 to 187 weeks. Under common thresholds, null probability of success was 0.098 for the full anchor and 0.073 for Reduced-6; Reduced-6 probabilities of success were 0.774 and 0.765 in the Realistic and Realistic2 scenarios. However, Reduced-6 omitted two monotherapy anchors and was less robust in Backwards2. In the comparator simulation, the selected design had probability of success of 0.858 and expected sample size of 308.3 under the Realistic scenario, compared with 0.624 to 0.845 and approximately 352 to 400 for simplified comparators.\n\nConclusionsFor identifying the most promising cilostazol-human albumin regimen for Phase III rather than confirming efficacy, the Bayesian response-adaptive design with two-dimensional normal dynamic linear model borrowing is more efficient and better aligned than simplified comparators. The full nine-arm design remains preferable because it preserves the complete therapeutic discovery space and is more robust to misspecified or non-smooth response surfaces.","rel_num_authors":7,"rel_authors":[{"author_name":"Adnan I. Qureshi","author_inst":"University of Missouri"},{"author_name":"Hassan Raza","author_inst":"University of Missouri"},{"author_name":"Naima Alam","author_inst":"University of Kansas Medical Center"},{"author_name":"Jonathan Beall","author_inst":"Medical University of South Carolina"},{"author_name":"Byron J. Gajewski","author_inst":"University of Kansas Medical Center"},{"author_name":"Renee L. Martin","author_inst":"Medical University of South Carolina"},{"author_name":"Jose I. Suarez","author_inst":"The Johns Hopkins University School of Medicine"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Wearable sensing for quantifying cognitive and balance functions in naturalistic movements of older adults with mild cognitive impairment in therapeutic environments","rel_doi":"10.64898\/2026.06.18.26355980","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26355980","rel_abs":"Mild cognitive impairment (MCI) is a clinically important stage preceding Alzheimers disease and related dementias, in which cognitive and balance functions are commonly evaluated using standard clinical assessments such as the Montreal Cognitive Assessment (MoCA) and Mini-Balance Evaluation Systems Test (Mini-BESTest). These assessments are administered episodically by clinicians and may miss functional changes during everyday movement. Recent studies and prior work in the Charlie and Harriet Shaffer Cognitive Empowerment Program (CEP), a therapeutic environment supporting lifestyle intervention and naturalistic social interaction, suggest that wearable and passive behavioral sensing can monitor movement patterns associated with cognitive and balance function in older adults with MCI. However, it remains unclear whether passive waist-mounted IMU data collected during naturalistic movement and social interaction can quantify clinician-rated cognitive and balance outcomes, particularly at the subdomain level, in an interpretable and demographically fair manner. To address this gap, we analyzed weekly IMU recordings collected over 6 months from 44 older adults with MCI in the CEP and trained tree-based ensemble regression models to estimate MoCA and Mini-BESTest total and subdomain scores, with interpretability and demographic fairness evaluation. Our models achieved RMSEs of 3.677 for MoCA and 3.672 for Mini-BESTest, benchmarked against Minimal Detectable Change and Minimal Clinically Important Difference thresholds. Feature importance analysis showed distinct movement signal properties across assessments, with general movement intensity features most informative for MoCA and temporal gait features led by cadence most informative for Mini-BESTest. Demographic bias analysis identified sex-related model bias, mitigated through post-processing while maintaining performance. This study supports the feasibility of wearable-based estimation of clinical assessment scores in older adults with MCI during naturalistic activity, with comparable performance between sexes after bias mitigation. This advances the validation of passive sensing for home monitoring to support clinical decision-making and personalized interventions.\n\nAuthor summaryMild cognitive impairment (MCI) is an early stage of cognitive decline that may precede Alzheimers disease and related dementias. Cognitive and balance changes are usually evaluated during clinical visits, but clinical assessments may miss functional changes that occur during everyday movement. In this study, we examined whether waist-worn motion sensors could be used to estimate standard cognitive and balance assessment scores in older adults with MCI during naturalistic activity in a therapeutic program. We used machine learning models to analyze movement patterns collected over six months and evaluated whether the models could estimate total and subdomain scores from the Montreal Cognitive Assessment and Mini-Balance Evaluation Systems Test. We also examined which movement features were most informative, whether estimations differed by sex or race, and whether post-processing bias mitigation reduced these differences. Our findings suggest that passive wearable sensing may provide useful information about cognitive and balance function of older adults with MCI in naturalistic settings. With further validation, this approach could support future monitoring and triage tools by helping identify individuals with MCI who exhibit concerning movement or balance changes and may benefit from more detailed clinical evaluation.","rel_num_authors":9,"rel_authors":[{"author_name":"Jangwon Lim","author_inst":"Emory University"},{"author_name":"Rahul Islam","author_inst":"Emory University School of Medicine"},{"author_name":"Dharini Raghavan","author_inst":"Georgia Institute of Technology"},{"author_name":"Bolaji Omofojoye","author_inst":"Emory University School of Medicine"},{"author_name":"Amy D. Rodriguez","author_inst":"Emory University School of Medicine, Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center"},{"author_name":"Yashar Kiarashi","author_inst":"Emory University School of Medicine"},{"author_name":"Rachel Hershenberg","author_inst":"Emory University School of Medicine"},{"author_name":"Gari D. Clifford","author_inst":"Emory University School of Medicine, Georgia Institute of Technology"},{"author_name":"Hyeokhyen Kwon","author_inst":"Emory University School of Medicine"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Subtle language deficits in WAB-recovered patients at 12 months after left-hemisphere stroke","rel_doi":"10.64898\/2026.06.19.26356022","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.19.26356022","rel_abs":"BackgroundThe Western Aphasia Battery-Revised (WAB-R) Aphasia Quotient is the most widely used standardized post-stroke aphasia measure; its conventional 93.8 cutoff has limited sensitivity to mild residual impairment. Beyond the cutoff, it offers limited objective discourse assessment, no action-naming assessment, and naming tests limited to very common objects.\n\nAimsWe sought short tests capturing subtle aphasia in patients recovered above the WAB-R threshold, then its demographic and lesion correlates.\n\nMethods & ProceduresSixty-seven patients with acute left-hemisphere ischemic stroke completed acute structural MRI and a 12-month language battery comprising the WAB-R, Boston Naming Test (BNT), Hopkins Action Naming Assessment (HANA), and Modern Cookie Theft (MCT) picture description. Hierarchical logistic (binary deficit) and linear (control-referenced composite z-score) regressions evaluated acute aphasia history, sex, education, age, acute depression (PHQ-9), and residualized regional lesion load.\n\nOutcomes & ResultsOf 67 participants, 45 (67%) recovered above the WAB-R threshold. Of these, 18 (40%) had residual deficits on at least one supplemental test (\"subtle aphasia\"). BNT plus MCT content-unit count captured all 18 (100%); HANA added none beyond these two. The binary model discriminated deficit from no-deficit at AUC = 0.80 (95% CI [0.70, 1.00]); higher education significantly lowered deficit odds (OR = 0.80\/year, 95% CI [0.64, 1.00], p = .049). On the continuous composite, acute PHQ-9 independently predicted 12-month outcome ({beta} = -0.13 per point, 95% CI [-0.22, -0.04], p = .006, cumulative R{superscript 2} = 0.38). Applying the Senthilkumar et al. (2026) stricter cutoff (WAB-AQ [&ge;] 96.7) reclassified 12 of 45 (27%) out of recovery, capturing 8 of 18 (44%) subtle-aphasia patients. Composite residualized lesion load did not differentiate the groups when adjusted.\n\nConclusionsAbove the WAB-R recovery threshold, subtle aphasia is present on the BNT or MCT in [~]40%, with higher education associated with lower odds at 12 months; acute depression emerged as a candidate correlate but did not survive removal of a single high-influence observation, warranting replication in larger samples. Regional lesion variables informative at greater stroke severity contribute little as large lesions cluster in the persistently aphasic group, reducing lesion variance within the recovered subgroup and its discrimination of subtle deficits. This adds to evidence that clinicians should not infer complete language recovery from the WAB-AQ alone, and that identifying residual deficits may require greater investment in behavioral assessment and consideration of alternative WAB-AQ cutoffs. Structural anatomical information, by contrast, appears to add little discriminative value at the upper performance range.","rel_num_authors":8,"rel_authors":[{"author_name":"Manuel Jose Marte","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Mathew Chaves","author_inst":"Department of Neuroscience, Krieger School of Arts and Sciences, Johns Hopkins University"},{"author_name":"Lindsey Kelly","author_inst":"Department of Neurology, Cerebrovascular Division, Johns Hopkins University School of Medicine"},{"author_name":"Isidora Diaz-Carr","author_inst":"Department of Neurology, Cerebrovascular Division, Johns Hopkins University School of Medicine"},{"author_name":"Voss Neal","author_inst":"Department of Neurology, Cerebrovascular Division, Johns Hopkins University School of Medicine"},{"author_name":"Andreia V. Faria","author_inst":"Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine"},{"author_name":"Melissa D. Stockbridge","author_inst":"Department of Neurology, Cerebrovascular Division, Johns Hopkins University School of Medicine"},{"author_name":"Argye E. Hillis","author_inst":"Department of Neurology, Cerebrovascular Division, Johns Hopkins University School of Medicine"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"High-Density Surface Electromyography Reveals Shared Baseline Spatial Organization and Heterogeneous Fatigue Responses in Amyotrophic Lateral Sclerosis","rel_doi":"10.64898\/2026.06.18.26355984","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26355984","rel_abs":"Introduction\/AimsAmyotrophic lateral sclerosis (ALS) causes progressive motor neuron degeneration, denervation, collateral reinnervation, and altered motor unit organization. Clinical assessments track functional decline but provide limited information about the physiological remodeling that precedes or accompanies weakness. High-density surface electromyography (HD-sEMG) can noninvasively measure motor unit morphology, fatigue-related signal behavior, and spatial patterns of muscle activation.\n\nMethodsWe recorded HD-sEMG from the biceps brachii and tibialis anterior in participants with ALS and healthy controls during sustained isometric contractions at 30% and 50% maximum voluntary contraction. Features were extracted from four domains: fatigue dynamics, motor unit morphology, propagation, and spatial organization. Principal component analysis (PCA) was used to test whether the dominant HD-sEMG feature structure was shared or reorganized differently between groups at baseline and during fatigue.\n\nResultsBaseline PCA showed highly similar HD-sEMG structure in healthy and ALS muscles. Baseline loading profiles were strongly spatial in both groups, with spatial features contributing 91.1% of loading weight in healthy observations and 89.9% in ALS observations. During fatigue, the composite did not significantly separate groups, but ALS showed a larger shift in loading structure and greater score variability than controls. The fatigue-change composite did not scale linearly with limb function. Exploratory binned analysis showed the greatest variability in the moderate impairment group.\n\nDiscussionHD-sEMG captured strong spatial organization in both groups during baseline contraction. Sustained contraction exposed more variable ALS responses involving amplitude and spectral dynamics, rather than a single uniform fatigue pattern.","rel_num_authors":7,"rel_authors":[{"author_name":"Ernesto H Bedoy","author_inst":"Carnegie Mellon University"},{"author_name":"Maia Brown","author_inst":"University of Pittsburgh"},{"author_name":"Michael Christofidis","author_inst":"University of Pittsburgh"},{"author_name":"Breanna Sullivan","author_inst":"University of Pittsburgh"},{"author_name":"Tawfiq Al-lahham","author_inst":"University of Pittsburgh"},{"author_name":"Douglas Weber","author_inst":"Carnegie Mellon University"},{"author_name":"Christi Kolarcik","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Isolated great saphenous vein stripping for the treatment of varicose veins in lower limbs: a prospective study","rel_doi":"10.64898\/2026.06.17.26355878","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.17.26355878","rel_abs":"Background: Endovenous techniques are considered the gold standard for treating great saphenous vein (GSV) insufficiency, but access remains limited in low- and middle-income countries. In such contexts, simplified conventional surgeries may represent viable alternatives. This study aimed to compare outcomes of isolated GSV stripping with conventional surgery (stripping plus varicose vein resection) in patients with varicose veins (VV) associated with GSV insufficiency. Methods: A prospective interventional study was conducted including 34 patients with VV (CEAP C2-C6), divided into two groups: Conventional (C, n=17) and Isolated Saphenectomy (IS, n=17). Quality of life was assessed preoperatively and at 2 and 6 months postoperatively using the Venous Clinical Severity Score (VCSS) and VEINES-QoL\/Sym questionnaires. Varicose vein evolution in the IS group was quantified using a standardized visual scoring system. Statistical analyses included Students t-test, chi-square, and generalized estimating equations (p[&le;]0.05). Results: Both groups were demographically comparable. Surgical treatment significantly improved VCSS and VEINES scores in both groups (p<0.005), with no intergroup difference at 6 months. In the IS group, the mean reduction in visible VV was 46% (range 20-90%). CEAP classification improved in both groups, with migration toward less severe categories postoperatively. No major complications were reported. Conclusion: Isolated GSV stripping yields comparable short- and mid-term improvements in symptoms and quality of life to conventional surgery, while reducing operative extent. In resource-limited settings, this abbreviated technique may expand access to treatment for VV, improving patient outcomes and reducing healthcare costs without compromising clinical efficacy.","rel_num_authors":8,"rel_authors":[{"author_name":"Felipe Soares Oliveira Portela","author_inst":"Hospital Israelita Albert Einstein"},{"author_name":"Andressa Cristina Sposato Louzada","author_inst":"Hospital Israelita Albert Einstein"},{"author_name":"Maria Fernanda Cassino Portugal","author_inst":"Hospital Israelita Albert Einstein"},{"author_name":"Marcelo Fiorelli Alexandrino da Silva","author_inst":"Hospital Israelita Albert Einstein"},{"author_name":"Lucas Lembranca Pinheiro","author_inst":"Hospital Israelita Albert Einstein"},{"author_name":"Bruno Fabricio Feio Antunes","author_inst":"Hospital Israelita Albert Einstein"},{"author_name":"Alexandre Fioranelli","author_inst":"Hospital Israelita Albert Einstein"},{"author_name":"Nelson Wolosker","author_inst":"Hospital Israelita Albert Einstein"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Patterns of Muscle Health in Single- and Multi-Site Chronic Pain: A UK Biobank Normative Modeling Study","rel_doi":"10.64898\/2026.06.19.26356062","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.19.26356062","rel_abs":"Background: Chronic pain is associated with impaired muscle health, but whether these changes reflect site-specific factors, broader systemic factors, or both remains unclear. The purpose of this study is to determine whether normative markers of muscle health derived from MRI show site-specific patterns in chronic pain. Methods: UK Biobank participants who underwent whole-body MRI from 2006 to 2010 were included in this retrospective cross-sectional study. The MuscleMap Toolbox quantified volume and intramuscular fat (IMF) in 42 muscles of the abdomen, pelvis, and thigh. Normative models trained on a no pain group generated muscle-specific deviations from normal (i.e., Z-scores) for single- and multi-site chronic and acute pain. Results: Of 17,843 participants, the primary site-specific analysis included 9,704 no pain, 885 single-site chronic back pain (CBP), 438 single-site chronic hip pain (CHP), and 1,315 single-site chronic knee pain (CKP) participants (n=12,342; mean age 63.7{+\/-}7.5 years; 52.7% female). Additional analyses included single-site chronic neck\/shoulder pain, acute pain, and multi-site chronic pain groups. In CBP, deviations were localized to abdominal muscles, with decreased volume in 6\/8 and increased IMF in 6\/8. In CHP, deviations were broad, with decreased volume in 3\/8 of the abdominal and 14\/26 of the thigh muscles, and increased IMF in 6\/8 of the abdominal, 5\/8 of the pelvic, and 4\/26 of the thigh muscles. In CKP, deviations were localized to thigh muscles, with decreased volume in 8\/26 and increased IMF in 6\/26. Acute pain groups showed no significant differences except for decreased volume in one thigh muscle in acute knee pain. With each additional chronic pain site, volume decreased ({beta}=-.078;IQR:-0.100-0.051), and IMF increased ({beta}=.085;IQR:0.066-0.101). Combined Z-scores classified chronic pain groups better than chance (accuracy: 48.6%;p<.001), but not acute pain groups (accuracy: 39.0%;p=.20). Conclusions: Whole-body MRI combined with AI-driven muscle segmentation and normative modeling revealed site-specific patterns of muscle health in single-site chronic pain.","rel_num_authors":41,"rel_authors":[{"author_name":"Merve Kaptan","author_inst":"Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Yiyu Wang","author_inst":"Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Augustijn A. A. de Boer","author_inst":"Donders Institute for Cognition, Brain and Behavior, Radboud University, Nijmegen, The Netherlands; Department of Cognitive Neuroscience, Radboud University Med"},{"author_name":"Ananya Goyal","author_inst":"Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA; Department of Bioengineering, Stanford University, CA, USA"},{"author_name":"Skylar Holmes","author_inst":"Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Kerem Ozkan","author_inst":"Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Sandrine Bedard","author_inst":"NeuroPoly Lab, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, Quebec, Canada"},{"author_name":"Teresa Indriolo","author_inst":"Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Christine S W Law","author_inst":"Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Dario Pfyffer","author_inst":"Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Joel Fundaun","author_inst":"Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Estifanos Berhe","author_inst":"Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Garry E. Gold","author_inst":"Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Akshay Chaudhari","author_inst":"Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Anoosha Pai S","author_inst":"Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA; Department of Bioengineering, Stanford University, CA, USA"},{"author_name":"Anthony A. Gatti","author_inst":"Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Feliks Kogan","author_inst":"Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Brian A. Hargreaves","author_inst":"Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Scott L. Delp","author_inst":"Department of Bioengineering and Mechanical Engineering, Stanford University, Palo Alto, CA, USA"},{"author_name":"John Ratliff","author_inst":"Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Serena Hu","author_inst":"Department of Orthopaedic Surgery, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Anand Veeravagu","author_inst":"Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Atman Desai","author_inst":"Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Suzanne Tharin","author_inst":"Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Todd Alamin","author_inst":"Department of Orthopaedic Surgery, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Andrew C. Smith","author_inst":"Physical Therapy Program, Department of Physical Medicine and Rehabilitation, School of Medicine, University of Colorado, Aurora, CO, USA"},{"author_name":"Marnee J. McKay","author_inst":"The Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia"},{"author_name":"Brian Kim","author_inst":"Northern Sydney Local Health District, The Kolling Institute, St. Leonards, NSW, Australia; The Faculty of Medicine and Health, The University of Sydney, Camper"},{"author_name":"Robert Walsh","author_inst":"Department of Integrated Primary Care, VA Palo Alto, Palo Alto, CA, USA"},{"author_name":"Alec Schielke","author_inst":"Department of Integrated Primary Care, VA Palo Alto, Palo Alto, CA, USA"},{"author_name":"Dean Dennis","author_inst":"Department of Integrated Primary Care, VA Palo Alto, Palo Alto, CA, USA"},{"author_name":"Johannes Decker","author_inst":"Division of Neuroimaging and Neurointervention, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Benjamin De Leener","author_inst":"NeuroPoly Lab, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, Quebec, Canada; Department of Computer Science, Polytechnique Montreal, Mo"},{"author_name":"Julien Cohen-Adad","author_inst":"NeuroPoly Lab, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, Quebec, Canada; Research Center, Ste-Justine Hospital University Centre, M"},{"author_name":"Zachary A. Smith","author_inst":"Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA"},{"author_name":"Fauziyya Muhammad","author_inst":"Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA"},{"author_name":"James M. Elliott","author_inst":"Northern Sydney Local Health District, The Kolling Institute, St. Leonards, NSW, Australia; The Faculty of Medicine and Health, The University of Sydney, Camper"},{"author_name":"Andre F. Marquand","author_inst":"Donders Institute for Cognition, Brain and Behavior, Radboud University, Nijmegen, The Netherlands; Department of Cognitive Neuroscience, Radboud University Med"},{"author_name":"Sean Mackey","author_inst":"Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Evert Onno Wesselink","author_inst":"Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, USA"},{"author_name":"Kenneth A. Weber II","author_inst":"Division of Pain Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, USA"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Impact of Connecticut's 2021 Repeal of Religious Vaccine Exemptions on Kindergarten Vaccine Coverage","rel_doi":"10.64898\/2026.06.19.26356105","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.19.26356105","rel_abs":"Importance: Religious vaccine exemptions remain central to debates over school-entry immunization mandates, but evidence on exemption repeal outside outbreak-driven policy responses and across communities with different religious contexts remains limited. Objective: To estimate changes in kindergarten vaccination coverage associated with Connecticut's 2021 repeal of religious vaccine exemptions, examine variation by school type and local religious congregation density, and compare trends with states that retained exemptions. Design\/Setting\/Participants: Interrupted time series analysis using kindergarten vaccination data from 2012-2025. Vaccine coverage trends in Connecticut were compared to Arizona, Louisiana, and Oregon, which retained religious exemptions during the study period. Intervention: The intervention studied was Public Act 21-6, which eliminated religious vaccine exemptions from school-entry immunization requirements. Main Outcomes and Measures: Outcomes included annual coverage for measles-mumps-rubella (MMR), varicella, diphtheria-tetanus-acellular pertussis (DTaP), polio, and hepatitis B vaccines. Models estimated pre-policy trends, immediate level changes, and post-policy slope changes. Analyses were stratified by public and private schools and by county-level religious congregation density. Results: Before policy implementation, kindergarten vaccination coverage in Connecticut declined across all vaccines by 0.16-0.20% per year (p < 0.001). Repeal of the religious exemptions occurred during a period of increasing religious congregation density and was associated with improved school-entry vaccination coverage, with annual coverage increasing 0.88-1.02% per year (p < 0.001). Coverage increased in both public and private schools, with larger post-policy gains in private schools. Coverage increases did not differ significantly between high- and low-religiosity counties. In segmented regression analyses, Connecticut's post-policy MMR slope was significantly higher than those of Arizona, Oregon, and Louisiana by 1.36, 1.71, and 1.15 percentage points per year, respectively (p < 0.001). By 2024\/25, Connecticut MMR coverage reached 98.2%, exceeding coverage in comparison states by 5.6-9.6%. Cumulatively, the model-estimated policy impact represented an estimated 2,579 additional kindergarteners immunized against MMR compared with the no-policy counterfactual. Conclusions and Relevance: Connecticut's repeal of religious vaccine exemptions was associated with increases in kindergarten vaccination coverage across public and private schools, independent of local religious congregation density. These findings suggest that removal of religious vaccine exemptions may be an effective policy approach to improve childhood immunization coverage.","rel_num_authors":8,"rel_authors":[{"author_name":"Casey Leigh Benzaken","author_inst":"Yale New Haven Children's Hospital"},{"author_name":"J\u00falia Moniz Ganem","author_inst":"Yale University School of Medicine"},{"author_name":"Barbara L Araujo","author_inst":"Yale University School of Medicine"},{"author_name":"Camila Aparicio-Llorente","author_inst":"Yale University School of Medicine"},{"author_name":"Isabela Oliva","author_inst":"Yale University School of Medicine"},{"author_name":"Aanchal Leigh Wats","author_inst":"Yale University School of Medicine"},{"author_name":"Diego R Hijano","author_inst":"St. Jude Children's Research Hospital; University of Tennessee Health Science Center"},{"author_name":"Carlos R Oliveira","author_inst":"Yale University School of Medicine"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Digital Health Misinformation and HPV Vaccine Awareness Among U.S. Adults: A National HINTS Analysis","rel_doi":"10.64898\/2026.06.19.26356030","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.19.26356030","rel_abs":"BackgroundHuman papillomavirus (HPV) vaccination is an effective cancer prevention strategy, yet HPV vaccine awareness remains uneven across sociodemographic groups. In the current digital information environment, awareness may be shaped not only by access to health information but also by exposure to false or misleading health information, difficulty evaluating information accuracy, and echo-chamber dynamics on social media.\n\nObjectiveThis study examined associations between perceived exposure to false or misleading health information on social media, difficulty determining whether social media health information is true or false, perceived echo-chamber exposure, and HPV vaccine awareness among U.S. adults.\n\nMethodsWe analyzed nationally representative Health Information National Trends Survey data using survey-weighted descriptive statistics and logistic regression models. The analytic sample included 2,371 respondents, representing a weighted population of 49.2 million U.S. adults. The outcome was HPV vaccine awareness. Primary predictors included perceived exposure to false or misleading health information on social media, difficulty determining whether social media health information was true or false, and perceived same-view health network exposure on social media. Models adjusted for age, sex, race\/ethnicity, education, household income, rurality, and Census division.\n\nResultsOverall, 60.37% of respondents reported HPV vaccine awareness. Most respondents reported encountering false or misleading health information on social media, with 45.57% reporting \"some\" and 32.83% reporting \"a lot.\" In unadjusted models, greater perceived exposure to false or misleading health information was associated with higher odds of HPV vaccine awareness. After adjustment, respondents reporting \"some\" false or misleading health information had significantly higher odds of HPV vaccine awareness compared with those reporting none (AOR=2.40, 95% CI: 1.06-5.43), while the association for \"a lot\" was marginal (AOR=2.29, 95% CI: 0.97-5.38). Difficulty identifying true versus false social media health information and perceived echo-chamber exposure were associated with HPV vaccine awareness in unadjusted models but were attenuated after adjustment. HPV vaccine awareness was substantially higher among females and respondents with higher educational attainment, and lower among Hispanic, non-Hispanic Asian, and non-Hispanic other respondents compared with non-Hispanic White respondents.\n\nConclusionsHPV vaccine awareness is associated with both digital health information exposure and persistent sociodemographic inequities. Greater perceived exposure to misleading health information may reflect broader engagement with health-related content on social media, where accurate and inaccurate information coexist. Public health communication strategies should address misinformation vulnerability while expanding accurate, culturally responsive HPV vaccine messaging across digital platforms.","rel_num_authors":8,"rel_authors":[{"author_name":"Jingjing Gao","author_inst":"The University of Texas Health Science Center at Houston School of Public Health"},{"author_name":"Jason  H. Windett","author_inst":"UNC Charlotte College of Liberal Arts and Sciences"},{"author_name":"Lilian  O. Ademu","author_inst":"Texas A&M University"},{"author_name":"Zhi Li","author_inst":"University of Illinois College of Medicine Rockford"},{"author_name":"Muinat  Abolore Idris","author_inst":"The University of Texas Health Science Center at Houston School of Public Health"},{"author_name":"Bryan  Colby Griffin","author_inst":"The University of Texas Health Science Center at Houston School of Public Health"},{"author_name":"Yue Zhang","author_inst":"The University of Texas Health Science Center at Houston School of Public Health"},{"author_name":"Benjamin  J. Radford","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Resilience factors, pain, and physical activity in adolescent chronic musculoskeletal pain: design and protocol of a pilot phase 2 single-group, non-randomized clinical trial","rel_doi":"10.64898\/2026.06.19.26356029","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.19.26356029","rel_abs":"Introduction  Chronic musculoskeletal pain (CMSKP) in adolescence is associated with physical, psychological, social, and academic impairment and increased risk for chronic pain in adulthood. Although physical activity interventions are an evidence-based approach for managing pediatric chronic pain, many adolescents with CMSKP avoid physical activity due to fear of increased pain, low confidence in physical functioning, and other pain-avoidance behaviors. Resilience-focused interventions targeting self-efficacy, motivation, and mental flexibility may improve engagement in valued activities despite pain. This study describes the design and protocol of the Pain REsilience Promotion for Youth (PREP-Y) intervention, a resilience-focused physical activity intervention for adolescents with CMSKP.  Methods and analysis  This single-site, pilot phase 2, single-group, non-randomized clinical trial will enroll 40 adolescents aged 12-17 years with CMSKP from Nationwide Childrens Hospital in Columbus, Ohio, USA. Participants complete questionnaires, objective physical functioning assessments, and physical activity monitoring using activPAL devices as baseline measures. Participants then complete 4 virtual resilience-focused intervention sessions targeting pain resilience, self-efficacy, motivation, and adaptive coping related to physical activity. Garmin watches are used to track activity during the intervention period. Follow-up assessments occur post-intervention and at 3 months post-intervention. Primary outcomes include feasibility and acceptability, assessed through recruitment, retention, attendance, intervention fidelity, and completion of study measures. Exploratory outcomes include physical activity, sedentary behavior, pain-related functioning, pain catastrophizing, kinesiophobia, self-efficacy, and resilience-related constructs.  Ethics and dissemination  The study was approved by the Nationwide Childrens Hospital Institutional Review Board. Findings will inform a future randomized clinical trial.  This manuscript reflects protocol version 5.0 dated 23 March 2026.  Trial registration  ClinicalTrials.gov: NCT06923891.","rel_num_authors":7,"rel_authors":[{"author_name":"Faith Logan","author_inst":"Abigail Wexner Research Institute at Nationwide Children's Hospital"},{"author_name":"Madeline Marsh","author_inst":"Abigail Wexner Research Institute at Nationwide Children's Hospital"},{"author_name":"Adam Hively","author_inst":"Abigail Wexner Research Institute at Nationwide Children's Hospital"},{"author_name":"Jacqueline Warner","author_inst":"Abigail Wexner Research Institute at Nationwide Children's Hospital"},{"author_name":"Ann Davis","author_inst":"University of Kansas Medical Center"},{"author_name":"Jamie  L Jackson","author_inst":"Abigail Wexner Research Institute at Nationwide Children's Hospital"},{"author_name":"William Black","author_inst":"Abigail Wexner Research Institute at Nationwide Children's Hospital"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Integration of lung tissue proteomics and genome-wide association data to identify lung cancer susceptibility proteins and potential drug targets","rel_doi":"10.64898\/2026.06.18.26355973","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26355973","rel_abs":"BackgroundProteins directly impact disease development and act as drug targets. Therefore, we integrated genomic and lung tissue proteomics data to identify lung cancer susceptibility proteins, elucidating genetic mechanisms and candidate drug targets.\n\nMethodWe profiled the proteome and genome in non-neoplastic lung tissue from 200 lung cancer patients. Using this data, we constructed genetic models to predict abundance across the proteome in lung tissue. We applied these models to genome-wide association study (GWAS) data from 55,174 lung cancer cases and 1,294,174 controls to evaluate their associations with the risk of lung cancer, overall and by major histological subtypes. Bayesian colocalization and Mendelian randomization (MR) analyses were used to prioritize putative causal proteins, which were cross-referenced with three main drug-protein databases to identify potential therapeutic targets.\n\nResultsWe identified 29 proteins associated with lung cancer risk at a false discovery rate < 5%, including 25 for overall lung cancer, two (AQP3 and IL18) specifically for adenocarcinoma, and another two (HMGN2 and HLA-DMB) for squamous cell carcinoma. Of them, genes encoding 17 proteins reside at least 2Mb away from any known GWAS risk loci, including 14 for overall lung cancer (HYI, GPX1, GMPPB, DSP, HDDC2, MTCH2, SUOX, JMJD7, PDIA3, IL16, IQGAP1, SULT1A2, ARHGAP27, and TYMP) and three for subtypes (AQP3, IL18, and HMGN2). Among the 12 proteins located within the known risk loci, EPHX2, CLDN18, PSMD5, and CYP2S1 proteins showed an association independent of the proximal GWAS-identified lead variant. Colocalization and\/or MR analysis suggested 11 potential causal proteins. Five of these candidate causal proteins (DSP, CLDN18, IQGAP1, IL18 and TYMP) are targeted by nine drugs already approved by the FDA or in phase III trials.\n\nConclusionOur study identified novel lung cancer susceptibility proteins and potential drug targets, offering valuable insights into lung cancer biology and future translational utilities.","rel_num_authors":15,"rel_authors":[{"author_name":"Shuai Xu","author_inst":"Vanderbilt University"},{"author_name":"Jiajun Shi","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Xiao-Ou Shu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ran Tao","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Yongchao Dou","author_inst":"Baylor College of Medicine"},{"author_name":"Xingyi Guo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Wanqing Wen","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Yaohua Yang","author_inst":"University of Virginia School of Medicine"},{"author_name":"Bing Zhang","author_inst":"Baylor College of Medicine"},{"author_name":"Jie Wu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Stephen A. Deppen","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Bingshan Li","author_inst":"Vanderbilt University"},{"author_name":"Wei Zheng","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jirong Long","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Qiuyin Cai","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Survival differences and artemisinin resistance in severe malaria among HIV coinfected patients: data from Mozambique","rel_doi":"10.64898\/2026.06.19.26356090","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.19.26356090","rel_abs":"Abstract Background Malaria remains a significant cause of morbidity and mortality, especially in sub-Saharan Africa, where rates of HIV coinfection are high. This study aimed to determine whether Plasmodium falciparum malaria treatment outcomes and rates of antimalarial resistance markers differ according to HIV serostatus in Mozambique. Methodology We conducted an observational study of non-pregnant adults, with and without HIV coinfection, admitted to the Hospital Central de Maputo for treatment of severe malaria. Plasmodium falciparum DNA was extracted from whole blood and sequenced to identify single-nucleotide polymorphisms. Statistical analyses to compare clinical outcomes and rates of nonsynonymous mutations in genes associated with drug resistance were performed in R version 4.2. Results We recruited 149 study participants aged between 18-62 years, 72 (48.3%) were female, and 59 (39.6%) were infected with HIV. Comparing clinical outcomes, we found a significant difference in anemia (hemoglobin <5 mg\/dl: P-value = 0.01248) but no other predefined clinical characteristics including fever, renal dysfunction, or pulmonary edema in those with and without HIV coinfection. We found significantly higher in hospital mortality in those with HIV coinfection (P-value = 0.03416, and at 30 days post discharge P-value = 0.007526). Mortality correlated inversely with CD4 count. Overall mortality at the end of the study was 20.1%. We did not find a significant increase in the number of nonsynonymous mutations in known antimalarial resistance associated genes pfmdr1, pfcrt, pfdhfr, pfdhps, in patients who reported taking antimalarials prior to admission or in those with HIV coinfection. However, we did find an increase in rates of K189T pfkelch mutations (21.2% vs 2.7%, p = 0.022) in HIV infected patients. We found no increase in rates of nonsynonymous mutations in pfdhfr in HIV infected patients taking TMP-SMX prophylaxis: pfdhfr-pfdhps quintuple mutations were found in almost 100% of the parasite population. Conclusions We find a higher mortality rate in patients with malaria-HIV coinfection, further emphasizing the importance of effective treatment for this vulnerable population. We also provide an important baseline for the rate of resistance-conferring mutations in a population at risk of harboring resistant parasites in Mozambique, highlighting the need for continued surveillance.","rel_num_authors":13,"rel_authors":[{"author_name":"Emilia Virginia Noormahomed","author_inst":"Eduardo Mondlane University"},{"author_name":"Irina Mendes de Sousa","author_inst":"Eduardo Mondlane University"},{"author_name":"Erin McArthur","author_inst":"University of California San Diego"},{"author_name":"Lucia Chambal","author_inst":"Maputo Central Hospital: Hospital Central de Maputo"},{"author_name":"Kevan Akrami","author_inst":"University of California San Diego"},{"author_name":"Anne Cowell","author_inst":"University of California San Diego"},{"author_name":"Titos Paulo Buene","author_inst":"Eduardo Mondlane University"},{"author_name":"Robert Schooley","author_inst":"UCSD"},{"author_name":"Bharti Ajay","author_inst":"University of California San Diego"},{"author_name":"Constance Benson","author_inst":"University of California San Diego"},{"author_name":"Ana Paula Arez","author_inst":"Universidade Nova de Lisboa"},{"author_name":"Marcelo Ferreira","author_inst":"Universidade de Sao Paulo"},{"author_name":"Elizabeth Winzeler","author_inst":"University of California San Diego"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"AI-Assisted Longitudinal Analyses of Environmental and Psychosocial Determinants of Subjective Cognitive Difficulties","rel_doi":"10.64898\/2026.06.18.26355982","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26355982","rel_abs":"Short-term environmental exposures have been linked to cognitive and behavioral outcomes, although many reported associations may reflect broader geographic and contextual differences. Using longitudinal data from the All of Us Research Program (2018--2024), we linked daily weather and air-pollution exposures to repeated attention-related and subjective cognitive outcomes. Associations were evaluated using pooled, fixed-effects, lagged, and event-study analyses. Additional machine-learning analyses were conducted to explore potential heterogeneity and latent psychosocial structure. Replication analyses were performed using the 2024 Behavioral Risk Factor Surveillance System (BRFSS). Several environmental exposure measures showed small associations with cognitive outcomes in pooled analyses, but most attenuated substantially after accounting for within-location temporal variation. Mediation, sensitivity, and machine-learning analyses yielded similar conclusions. In contrast, mental-health burden, loneliness, and social functioning were consistently associated with subjective cognitive difficulty and exhibited substantially larger effect sizes than environmental exposures. Similar patterns were observed in BRFSS. Exploratory AI-assisted analyses yielded findings broadly consistent with the primary longitudinal analyses. These findings suggest that short-term environmental perturbations may have limited associations with cognitive outcomes after accounting for within-location variation, whereas psychosocial factors appear to be more consistently associated with subjective cognitive burden.","rel_num_authors":2,"rel_authors":[{"author_name":"Shuangge Ma","author_inst":"Yale School of Public Health"},{"author_name":"Cong Cao","author_inst":"Yale School of Public Health"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"AI-driven Multimodal Representation Learning for Latent Mediation Structure Discovery of Socioeconomic Disadvantage, Psychosocial Factors, and Cardiometabolic Multimorbidity","rel_doi":"10.64898\/2026.06.17.26355907","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.17.26355907","rel_abs":"Social disadvantage is associated with multimorbidity, but the pathways linking social conditions to disease burden remain poorly understood. We developed an AI-driven multimodal mediation framework that integrates socioeconomic, psychosocial, clinical, laboratory, behavioral, and genomic data from the All of Us Research Program. Modality-specific variational autoencoders were used to derive latent representations of each data domain, and mediation analyses were subsequently performed in latent space to evaluate indirect associations between socioeconomic disadvantage, psychosocial factors, and multimorbidity. The final analytic cohort included 20,804 participants with complete multimodal data. Across 800 exposure--mediator--outcome combinations, mediation signals were concentrated within a small number of latent dimensions. The strongest indirect association linked a socioeconomic disadvantage dimension, a psychosocial vulnerability dimension, and a cardiometabolic multimorbidity dimension (NIE = 0.002517). The psychosocial dimension was characterized by poorer mental health, greater loneliness, lower social well-being, and lower health literacy, whereas the outcome dimension was associated with hypertension, diabetes, hyperlipidemia, obesity, chronic kidney disease, and heart disease. Bootstrap analyses supported the stability of the leading pathway. These findings suggest that psychosocial vulnerability may contribute to the association between socioeconomic disadvantage and cardiometabolic multimorbidity. More broadly, the proposed framework illustrates how AI-based representation learning can be used to investigate complex relationships across high-dimensional multimodal health data.","rel_num_authors":2,"rel_authors":[{"author_name":"Shuangge Ma","author_inst":"Yale university"},{"author_name":"Cong Cao","author_inst":"Yale university"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Substantia Nigra and Subthalamic Nucleus Deep Brain Stimulation Exert Opposing Effects on Novelty Recognition in Parkinson's Disease","rel_doi":"10.64898\/2026.06.17.26355856","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.17.26355856","rel_abs":"Episodic memory plays a critical role in supporting adaptive behavior; however, whether it can be causally regulated in humans via deep subcortical stimulation remains unclear. In the present study, we investigated the differential effects of substantia nigra (SN) and subthalamic nucleus (STN) stimulation on episodic memory, as well as the underlying mechanisms of its associated brain networks, using a recognition memory task combined with concurrent functional magnetic resonance imaging in patients with Parkinsons disease. SN-DBS increased recognition sensitivity and reduced false alarms at both frequencies, whereas 10 Hz STN-DBS reduced sensitivity and increased false alarms. Functional connectivity analyses in the absence of DBS stimulation identified a false recognition-related network linking nigral, pallidal, subthalamic, medial temporal, frontal, and occipital regions. SN-DBS-related false alarm reduction tracked modulation of this circuit and was marked by its baseline vulnerability state. These behavioral effects mapped onto target-dependent parieto-occipital and SN-visual retrieval pathways, supporting a model in which DBS bidirectionally regulates recognition memory through target- and frequency-dependent subcortical-cortical circuits.","rel_num_authors":16,"rel_authors":[{"author_name":"Bingxin Li","author_inst":"Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Beijing Neurosurgical Institute, Capital Medical University, Beijing, China"},{"author_name":"Chenguan Jiang","author_inst":"Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"author_name":"Yan Liu","author_inst":"Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"author_name":"Zhou Yang","author_inst":"Beijing Neurosurgical Institute, Capital Medical University, Beijing, China"},{"author_name":"Anbang Yao","author_inst":"Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"author_name":"Xiaoyu Zhang","author_inst":"Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"author_name":"Yuye Liu","author_inst":"Beijing Neurosurgical Institute, Capital Medical University, Beijing, China"},{"author_name":"Hutao Xie","author_inst":"Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"author_name":"Barbara Hollunder","author_inst":"Center for Brain Circuit Therapeutics, Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA"},{"author_name":"Bryan Strange","author_inst":"Laboratory for Clinical Neuroscience, Centre for Biomedical Technology, Universidad Politecnica de Madrid, Spain"},{"author_name":"Anchao Yang","author_inst":"Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"author_name":"Fangang Meng","author_inst":"Beijing Neurosurgical Institute, Capital Medical University, Beijing, China"},{"author_name":"Jianguo Zhang","author_inst":"Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"author_name":"Changming Wang","author_inst":"Beijing Luhe Hospital, Capital Medical University, China"},{"author_name":"Ningfei Li","author_inst":"School of Artificial Intelligence, Northwestern Polytechnical University, Xi'an, China; Institute for Network Stimulation, Department of Stereotactic and Functi"},{"author_name":"Lin Shi","author_inst":"Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Beijing Neurosurgical Institute, Capital Medical University, Beijing, China"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Histologically validated diffusion MRI signatures of neuroinflammation and neurodegeneration in Alzheimer disease","rel_doi":"10.64898\/2026.06.11.26354743","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26354743","rel_abs":"Noninvasive neuroinflammation measurement remains a major barrier for Alzheimer disease (AD) therapeutics. We present generalized diffusion basis spectrum imaging (g-DBSI), a diffusion MRI framework that decomposes the tissue signal into biologically interpretable microstructural compartments. In postmortem Knight ADRC brains, g-DBSI-derived restricted isotropic fraction (RIF) and restricted anisotropic fraction (RAF) mapped cellularity and neurofilament density, while their ratio (RIF\/RAF) tracked inflammatory cell density and peri-plaque amyloid-beta with higher specificity and regional consistency than RIF alone. In 112 living Knight ADRC participants stratified by PET amyloid, g-DBSI metrics showed amyloid-dependent trajectories: in low-amyloid individuals, RIF and RAF rose together with amyloid, consistent with early neuropil expansion and glial elaboration, whereas in high-amyloid individuals, RIF\/RAF increased, and RAF declined, indicating established neuroinflammatory remodeling and neurofilament loss. CSF proteomics linked RIF\/RAF to glia-enriched immune and vascular pathways, supporting g-DBSI as a clinically compatible MRI biomarker of neuroinflammation and neurodegeneration in AD.\n\nTeaserg-DBSI provides noninvasive MRI biomarkers of neuroinflammation and neurodegeneration in AD, validated by histopathology and CSF proteomics.","rel_num_authors":12,"rel_authors":[{"author_name":"Qing Wang","author_inst":"Washington University in St. Louis"},{"author_name":"Meng Jiang","author_inst":"Washington University in St. Louis"},{"author_name":"Aime Luna","author_inst":"Washington University in St. Louis"},{"author_name":"Xuan Niu","author_inst":"Washington University in St. Louis"},{"author_name":"Yuan Nan","author_inst":"Washington University in St. Louis"},{"author_name":"Qiuchang Sun","author_inst":"Washington University in St. Louis"},{"author_name":"Richard J Perrin","author_inst":"Washington University in St. Louis"},{"author_name":"Erin Franklin","author_inst":"Washington University in St. Louis"},{"author_name":"Carlos Cruchaga","author_inst":"Washington University in St. Louis"},{"author_name":"Shaney Flores","author_inst":"Washington University in St. Louis"},{"author_name":"Tammie L.S. Benzinger","author_inst":"Washington University in St. Louis"},{"author_name":"Yong Wang","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Effectiveness of Stress Management to Reduce Stress Eating for Women: A Systematic Review and Meta-analysis of Intervention Studies","rel_doi":"10.64898\/2026.06.11.26355007","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355007","rel_abs":"ObjectiveThis systematic review and meta-analysis examined 1) the effects of stress management interventions on changes in stress eating for women, and 2) the longevity of these effects, by summarizing and assessing evidence from controlled and non-equivalent pretest-posttest intervention studies.\n\nMethodFive databases (PsycINFO, PubMed, Medline, Web of Science, CINAHL), existing sources, and grey literature were searched (February - June 2025). Studies that assessed stress eating or emotional eating, included a stress management intervention, and comprised at least 70% women were included. The primary outcome was reduction in stress eating. Data were pooled in meta-analyses using multi-level random-effects models and subset by follow-up period. Risk of bias was assessed via funnel plots and sensitivity analyses.\n\nResultsSixty studies with 119 effect size estimates were included in the primary analysis. Pooled estimates indicated that stress management interventions significantly reduced stress eating (Hedges g = -0.4174, p < 0.001), with pre-post designs having larger effects than controlled trials. Subgroup analyses of follow-up periods found small effects in the short-term (before 3 months; Hedges g = -0.4202, p < 0.0001) and moderate effects for mid-term (3-6 months; Hedges g = -0.5886, p < 0.0001). Effects beyond 6 months were small and nonsignificant (Hedges g = -0.4370, p = 0.0660).\n\nConclusion and RelevanceStress management interventions appear to be effective for reducing stress eating for women, suggesting the potential to incorporate stress management in interventions targeting obesity. Effects may be only sustained 6 months post-intervention, suggesting the need for strategies to bolster long-term effectiveness.","rel_num_authors":10,"rel_authors":[{"author_name":"Vanessa V Volpe","author_inst":"North Carolina State University"},{"author_name":"Abbey N Collins","author_inst":"North Carolina State University"},{"author_name":"Elizabeth M Davis","author_inst":"University of Michigan"},{"author_name":"Oreoluwa O Badejoh","author_inst":"North Carolina State University"},{"author_name":"MarQia Allen","author_inst":"North Carolina State University"},{"author_name":"Melissa C Holland","author_inst":"North Carolina State University"},{"author_name":"Julia M Ross","author_inst":"North Carolina State University"},{"author_name":"Abby Braden","author_inst":"Bowling Green State University"},{"author_name":"Keri F Kirk","author_inst":"Georgetown University and MedStar Hospital"},{"author_name":"Emily C Hector","author_inst":"University of Michigan"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Toward less intrusive pubertal assessment: longitudinal evaluation of tanner and non-tanner metrics in East African adolescents","rel_doi":"10.64898\/2026.06.17.26355904","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.17.26355904","rel_abs":"BackgroundAccurate pubertal assessment is essential in pediatric endocrinology and adolescent health research. While Tanner staging remains the gold standard, its subjective nature and invasive genital examination limit feasibility and acceptability, especially in longitudinal studies and culturally sensitive settings. This study evaluated less intrusive pubertal assessment combinations that maintain discriminative accuracy.\n\nMethodsWe conducted a longitudinal study among 200 uncircumcised, sexually naive males aged 15-17 years in Southwestern Uganda, with quarterly follow-up over three years. Clinicians assessed Tanner staging metrics (pubic hair, testicular volume, penile length, scrotal color), axillary hair, and serum testosterone. Markov transition models estimated Tanner stage progression. Ordinal logistic regression and area under the receiver operating characteristic curve (AUC) analyses quantified discriminative performance of individual and combined metrics.\n\nResultsAt baseline, participants were distributed across Tanner stages II (6.0%), III (13.5%), IV (55.0%), and V (25.5%). Among individual metrics, pubic hair distribution best predicted overall Tanner stage (AUC=0.867), while penile length was least predictive (AUC=0.833). The full four-metric Tanner model achieved high discrimination (AUC=0.993). However, a less intrusive combination of pubic hair and scrotal color achieved comparable discrimination (AUC=0.942), improving to AUC=0.953 with axillary hair and age. Markov modeling demonstrated frequent bidirectional transitions between Tanner stages IV and V, reflecting variability in longitudinal staging.\n\nConclusionsA minimally intrusive assessment combining pubic hair, scrotal color, axillary hair, and age reliably predicts pubertal stage, offering an acceptable alternative to traditional Tanner staging for research and surveillance contexts where genital manipulation is impractical or unethical.","rel_num_authors":17,"rel_authors":[{"author_name":"Job  Job Anok","author_inst":"RHSP: Rakai Health Sciences Program"},{"author_name":"Jessica  L Prodger","author_inst":"Schulich School of Medicine and Dentistry: Western University Schulich School of Medicine & Dentistry"},{"author_name":"Jodie  L White","author_inst":"Johns Hopkins University Department of Pathology"},{"author_name":"Ping Yang","author_inst":"Johns Hopkins University Department of Pathology"},{"author_name":"Daniel  E Park","author_inst":"The George Washington University Milken Institute of Public Health"},{"author_name":"Simon Peter Bukenya","author_inst":"Rakai Health Sciences Program"},{"author_name":"Stephen Kiboneka","author_inst":"Rakai Health Sciences Program"},{"author_name":"Mathias Agaba","author_inst":"Rakai Health Sciences Program"},{"author_name":"Mary  J Nalubowa","author_inst":"Rakai Health Sciences Program"},{"author_name":"James Nnamutete","author_inst":"Rakai Health Sciences Program"},{"author_name":"Edward  N Kankaka","author_inst":"Rakai Health Sciences Program"},{"author_name":"Nathan  O Weber","author_inst":"The George Washington University Milken Institute of Public Health"},{"author_name":"Cindy  M Liu","author_inst":"The George Washington University Milken Institute of Public Health"},{"author_name":"Rupert Kaul","author_inst":"University of Toronto Department of Medicine"},{"author_name":"Godfrey Kigozi","author_inst":"Rakai Health Sciences Program"},{"author_name":"Aaron  AR Tobian","author_inst":"Johns Hopkins University Department of Pathology"},{"author_name":"Ronald  M Galiwango","author_inst":"Rakai Health Sciences Program"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Sex-specific multimorbidity clusters and all-cause mortality in relatively healthy older adults: findings from the ASPREE cohort","rel_doi":"10.64898\/2026.06.18.26355909","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.18.26355909","rel_abs":"BackgroundMultimorbidity is common in older adults, but sex differences in chronic condition clustering remain unclear. This study explored multimorbidity clusters and their associations with all-cause mortality among community-dwelling adults aged 70 years and over.\n\nMethodsThis was a secondary analysis of data from 16,095 Australian ASPREE participants aged [&ge;]70 years without prior dementia or cardiovascular disease. Fifteen baseline chronic conditions were grouped using latent class analysis (LCA). Observed-to-expected (O\/E) ratios characterised conditions over-represented within clusters, and Cox proportional hazards models assessed associations with all-cause mortality.\n\nResultsAmong 16,095 participants (mean age 74 years), 88.3% had multimorbidity at baseline; 4,217 deaths occurred over a median follow-up of 10.85 years. Five clusters were identified overall: hypertension & dyslipidemia (52.1%), gout & metabolic (14.4%), depressive symptoms, osteoporosis & frailty (10.0%), anaemia & kidney disease (10.2%), and hypotension, thyroid disorder & past cancer (13.3%). Sex-stratified analyses revealed three clusters in males and four in females. The frailty, depressive symptoms & osteoporosis cluster was associated with higher mortality in both sexes (aHR 1.56 [95% CI 1.40-1.73] in males; 1.68 [1.49-1.89] in females). Higher mortality was also observed for the metabolic, gout & kidney disease cluster in males (aHR 1.63 [1.47-1.81]) and the gout, anaemia & kidney disease cluster in females (aHR 1.96 [1.74-2.21]).\n\nConclusionsDistinct multimorbidity clusters differed by sex and were associated with increased all-cause mortality. These findings may support risk stratification, targeted screening, and more person-centred management of older adults with multimorbidity.","rel_num_authors":8,"rel_authors":[{"author_name":"Rong Du","author_inst":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"},{"author_name":"Swarna Vishwanath","author_inst":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"},{"author_name":"Zimu Wu","author_inst":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"},{"author_name":"Aung Zaw Zaw Phyo","author_inst":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"},{"author_name":"Suzanne G Orchard","author_inst":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"},{"author_name":"Kerry Sheets","author_inst":"Geriatric Medicine Division, Department of Medicine, Hennepin Healthcare, Minneapolis, Minnesota, USA"},{"author_name":"Michael E Ernst","author_inst":"Department of Pharmacy Practice and Science, College of Pharmacy, The University of Iowa, Iowa City, Iowa, USA; Department of Family Medicine, Carver College of"},{"author_name":"Joanne Ryan","author_inst":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Why drinking episodes escalate differently: Event-level pathways linking hazardous alcohol consumption and sexual risk","rel_doi":"10.64898\/2026.06.17.26355906","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.17.26355906","rel_abs":"BackgroundAlcohol-involved drinking episodes vary in whether they involve hazardous alcohol consumption alone, near-miss sexual risk, or sexual risk behavior, but the within-event mechanisms underlying this variability remain unclear.\n\nMethodsGuided by syndemic theory, we conducted a qualitative event-level analysis using modified grounded theory among adults in the San Francisco Bay Area who reported hazardous alcohol consumption, defined as an Alcohol Use Disorder Identification Test score [&ge;]16. In-depth interviews elicited narratives of recent heavy drinking episodes and yielded 64 discrete drinking events across 22 participants. We focused on 35 events with evidence of within-event interaction between biopsychosocial and contextual factors. Using constant comparison, we identified escalation pathways, characterized interruption, and examined how events diverge into three outcomes: hazardous alcohol consumption only, hazardous alcohol consumption with near-miss sexual risk (when risk was plausible but not enacted), and hazardous alcohol consumption with sexual risk behavior.\n\nResultsTwo primary escalation pathways emerged. Dose-driven escalation involved cumulative alcohol or substance exposure that progressively impaired awareness and self-regulation. Meaning-driven escalation involved prioritizing connection, intimacy, or belonging despite awareness of risk. Time-driven continuation extended exposure across contexts and amplified both pathways. Hazardous alcohol consumption-only events more often followed dose-driven pathways, whereas events involving sexual risk behavior more often followed meaning-driven pathways. Near-miss events occurred across both pathways and illustrated how interruption before the escalation constraint point, when the capacity to modify behavior became reduced, could redirect escalation before sexual risk behavior occurred. Across events with similar levels of intoxication narratives, outcomes diverged according to when the interruption occurred and whether it altered escalation.\n\nConclusionHazardous drinking episodes diverge into different outcomes based on escalation pathways and the timing and effectiveness of interruption. Early and effective interruption before the escalation constraint point may represent a key target for harm-reduction strategies to prevent progression to sexual risk behavior.","rel_num_authors":3,"rel_authors":[{"author_name":"Thye Peng Ngo","author_inst":"University of Michigan School of Nursing"},{"author_name":"Alexandrea  Elizabeth Dunham","author_inst":"University of California Berkeley"},{"author_name":"Glenn-Milo Santos","author_inst":"University of California San Francisco School of Nursing"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Multisite Real-World Validation of an Electronic Health Record-Integrated Generative Artificial Intelligence Tool for Venous Thromboembolism Risk Stratification","rel_doi":"10.64898\/2026.06.17.26355819","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.17.26355819","rel_abs":"Background: Guiding risk-appropriate inpatient thromboprophylaxis requires venous thromboembolism (VTE) risk stratification; however, reliable risk determination remains inconsistent in routine care. Health systems increasingly pilot artificial intelligence (AI) tools, yet few studies demonstrate rigorous evaluation in the context of a learning health system (LHS). We evaluated the performance of a pilot electronic health record (EHR)-integrated generative AI (GenAI) system, inHealth General Reasoner (iHGR), for VTE risk stratification versus clinician order set classifications and physician-adjudicated chart review. Methods: This multisite retrospective validation study included adult inpatient admissions at Johns Hopkins Medicine between June 21, 2025, and Dec 18, 2025 (checklist-based order set from June 21, 2025 - November 19, 2025, and clinician judgement-based order set from November 29 - December 18, 2025). From 758 eligible admissions, we randomly sampled 500 balanced by site and order set periods. iHGR and clinician-selected order set classifications were compared with the reference standard (RS). Primary outcomes were iHGR sensitivity and specificity. Secondary analyses compared the order sets with the same RS to evaluate workflow comparators and error patterns. Results: iHGR achieved 81.8% sensitivity (95% CI 77.3-85.6) and 70.9% specificity (63.6-77.3). The checklist-based order set had 61.3% sensitivity (53.7-68.5) and 86.2% specificity (77.4-91.9). The clinician judgement-based order set had 78.1% sensitivity (71.3-83.7) and 65.4% specificity (54.3-75.0). False-negative iHGR classifications were associated with missed narrative risk factors. Conclusion: iHGR showed higher sensitivity for VTE risk than checklist-based order sets and clinician judgement without introducing systematic bias. In silico evaluation of pilot AI systems within LHSs can identify clinically important performance trade-offs and implementation targets before operational scale-up. Narrative clinical data abstraction remained a key limitation, supporting the use of GenAI to support rather than supplant clinician judgement.","rel_num_authors":16,"rel_authors":[{"author_name":"Derek J. Baughman","author_inst":"Biomedical Informatics and Data Science, Johns Hopkins School of Medicine"},{"author_name":"Star Liu","author_inst":"Biomedical Informatics and Data Science, Johns Hopkins School of Medicine"},{"author_name":"Sangho Jee","author_inst":"Department of Medicine, Johns Hopkins School of Medicine"},{"author_name":"Chase Young","author_inst":"Health IT, Johns Hopkins Medicine"},{"author_name":"Amy M. Knight","author_inst":"Department of Medicine, Johns Hopkins School of Medicine"},{"author_name":"Andrew Davis","author_inst":"Department of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine"},{"author_name":"Srinivasan Yegnasubramanian","author_inst":"inHealth Precision Medicine, Johns Hopkins Medicine; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine"},{"author_name":"Peter Najjar","author_inst":"Department of Surgery, Johns Hopkins School of Medicine; Armstrong Institute for Patient Safety and Quality, Johns Hopkins Medicine"},{"author_name":"James J. Whitbread Jr.","author_inst":"Department of Surgery, Johns Hopkins School of Medicine; Armstrong Institute for Patient Safety and Quality, Johns Hopkins Medicine"},{"author_name":"Luis Ahumada","author_inst":"Johns Hopkins University School of Medicine; Center for Pediatric Data Science and Analytic Methodology, Johns Hopkins All Children's Hospital"},{"author_name":"Amy Chused","author_inst":"Department of Medicine, Johns Hopkins Sibley Memorial Hospital"},{"author_name":"Elliott R. Haut","author_inst":"Department of Surgery, Johns Hopkins School of Medicine; Armstrong Institute for Patient Safety and Quality, Johns Hopkins Medicine; Department of Anesthesiolog"},{"author_name":"Brandyn D. Lau","author_inst":"Armstrong Institute for Patient Safety and Quality, Johns Hopkins Medicine; Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public"},{"author_name":"Anirudh Sridharan","author_inst":"Department of Medicine, Johns Hopkins Howard County General Hospital"},{"author_name":"Michael Streiff","author_inst":"Department of Medicine, Johns Hopkins School of Medicine; Armstrong Institute for Patient Safety and Quality, Johns Hopkins Medicine;"},{"author_name":"Khyzer B. Aziz","author_inst":"Biomedical Informatics and Data Science, Johns Hopkins School of Medicine; inHealth Precision Medicine, Johns Hopkins Medicine; Department of Pediatrics, Johns "}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Assessment of adaptive functioning in Angelman syndrome using the Vineland Adaptive Behavior Scales, Third Edition","rel_doi":"10.64898\/2026.06.11.26355399","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355399","rel_abs":"PurposeThis study examined longitudinal trajectories of adaptive functioning in 331 individuals with Angelman syndrome (AS) using the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) and examined differences by molecular subtype.\n\nMethodsA total of 331 individuals (156 females, 47%) with genetically confirmed AS (ages 6 months to 52 years) were assessed between 2018 and 2025, including 207 with a deletion subtype, 63 with uniparental disomy or imprinting defect, and 61 with a UBE3A point mutation. Growth scale values were analyzed using linear mixed-effects models with log2-transformed age.\n\nResultsIndividuals with deletion subtypes demonstrated significantly lower adaptive functioning across domains compared to those with non-deletion subtypes. Adaptive skills across all Vineland-3 subdomains increased nonlinearly with age, showing faster growth early in life that slowed over time, with largely parallel trajectories across subtypes.\n\nConclusionIndividuals with AS demonstrate slow but steady growth in adaptive functioning that continues into adulthood, with progress varying by molecular subtype. These findings provide updated natural history benchmarks and demonstrate the utility of the Vineland-3 for clinical trials.","rel_num_authors":25,"rel_authors":[{"author_name":"Sarah Nelson Potter","author_inst":"RTI International"},{"author_name":"Julia Zhang","author_inst":"RTI International"},{"author_name":"Batsheva Friedman","author_inst":"Boston Children's Hospital"},{"author_name":"Julia Gable","author_inst":"RTI International"},{"author_name":"Nadia Ali","author_inst":"Emory University School of Medicine"},{"author_name":"Rene L. Barbieri-Welge","author_inst":"Rady Children's Hospital-San Diego"},{"author_name":"Ayala Ben-Tall","author_inst":"Rady Children's Hospital-San Diego"},{"author_name":"Kelly E. Caravella","author_inst":"Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill School of Medicine"},{"author_name":"Margaret DeRamus","author_inst":"Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill School of Medicine"},{"author_name":"Dea Garic","author_inst":"Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill School of Medicine"},{"author_name":"Margot MacKay","author_inst":"BC Children's Hospital"},{"author_name":"Kara Murias","author_inst":"Alberta Children's Hospital Research Institute, University of Calgary"},{"author_name":"Sarika U. Peters","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kimberly Smyth","author_inst":"Alberta Children's Hospital Research Institute, University of Calgary"},{"author_name":"Jane Summers","author_inst":"The Hospital for Sick Children, University of Toronto"},{"author_name":"Angel Wang","author_inst":"Rush University Medical Center"},{"author_name":"Mark D. Shen","author_inst":"Carolina Institute for Developmental Disabilities, Neuroscience Center, University of North Carolina at Chapel Hill School of Medicine"},{"author_name":"Joerg F. Hipp","author_inst":"F. Hoffmann-La Roche Ltd."},{"author_name":"Julian Tillmann","author_inst":"F. Hoffmann-La Roche Ltd."},{"author_name":"Jorrit Tjeertes","author_inst":"Oak Hill Bio Ltd."},{"author_name":"Brenda Vincenzi","author_inst":"Oak Hill Bio Ltd."},{"author_name":"Lynne M. Bird","author_inst":"Rady Children's Hospital-San Diego"},{"author_name":"Wen-Hann Tan","author_inst":"Boston Children's Hospital"},{"author_name":"Anne C. Wheeler","author_inst":"RTI International"},{"author_name":"Anjali Sadhwani","author_inst":"Boston Children's Hospital"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"GCH1 p.Ser80Asn Confers Risk for Parkinson's Disease in East Asian Populations","rel_doi":"10.64898\/2026.06.11.26354827","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26354827","rel_abs":"Introduction: GCH1 has been implicated in Parkinson's disease (PD), but its risks variants and associations are not well defined. Objectives: To investigate the clinical relevance and PD risk associated with the GCH1 p.Ser80Asn variant. Methods: We first identified a segregating GCH1 p.Ser80Asn variant in a Malaysian Chinese PD family via whole genome sequencing (WGS). We assessed its risk association using multi-ancestry WGS data from the Global Parkinson's Genetics Program (GP2) (n=22,372PD vs n=8,826Controls) and meta-analysis of East Asian (EAS) cohorts (n=4,712PD vs 38,733Controls). Clinico-demographic details of affected variant carriers were collated. Results: The GCH1 p.Ser80Asn variant was enriched in GP2 EAS PD populations (n=9\/2,757; 0.33%) but not detected in other ancestries. Meta-analysis revealed increased PD risk in EAS populations (odds ratio:5.1; 95%CI:2.3-10.7; p=2.89x10-5). Affected carriers (mean age at onset:56.3+-12.5 years) had additional occurrence of dystonia, while dementia was rare. Conclusions: The GCH1 p.Ser80Asn variant is a rare, EAS-enriched risk variant for PD.","rel_num_authors":37,"rel_authors":[{"author_name":"Yi Wen Tay","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Andrew Leslie Lee","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Jie Ping Schee","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Chin Hsien Lin","author_inst":"National Taiwan University Hospital Taipei, Taipei, Taiwan"},{"author_name":"Eng King Tan","author_inst":"Duke-National University of Singapore Medical School, Singapore"},{"author_name":"Jung Hwan Shin","author_inst":"Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea"},{"author_name":"Pin-Shiuan Chen","author_inst":"National Taiwan University Hospital Bei-Hu branch, Taipei, Taiwan"},{"author_name":"Sung-Pin Fan","author_inst":"National Taiwan University Hospital Taipei, Taipei, Taiwan"},{"author_name":"Cheng-Hsuan Li","author_inst":"National Taiwan University Hospital Taipei, Taipei, Taiwan"},{"author_name":"Ebonne Yu Lin Ng","author_inst":"National Neuroscience Institute, Singapore General Hospital, Singapore"},{"author_name":"Han Joon Kim","author_inst":"Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea"},{"author_name":"Beomseok Jeon","author_inst":"Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea"},{"author_name":"Sulev Koks","author_inst":"Health Futures Institute, Murdoch University, Perth, Australia"},{"author_name":"Kin Ying Mok","author_inst":"The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China"},{"author_name":"Yi Ting Lim","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Mohd Salahuddin Kamaruddin","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Tzi Shin Toh","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Hans Xing Ding","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Anis Nadhirah Khairul Anuar","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Norlisah Ramli","author_inst":"Subang Jaya Medical Centre, Selangor, Malaysia"},{"author_name":"Ignacio Juan Keller Sarmiento","author_inst":"Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA"},{"author_name":"Maria Teresa Perinan","author_inst":"Queen Mary University of London, London, United Kingdom"},{"author_name":"Zih-Hua Fang","author_inst":"DataTecnica LLC, Washington, DC 20037, USA"},{"author_name":"Lara M Lange","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Kishore R. Kumar","author_inst":"The University of Sydney, Sydney, New South Wales, Australia"},{"author_name":"Soraya Bardien","author_inst":"Stellenbosch University, Cape Town, South Africa"},{"author_name":"Joanne Trinh","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Enza Maria Valente","author_inst":"University of Pavia, 27100 Pavia, Italy"},{"author_name":"- SG10K_Health Consortium","author_inst":"-"},{"author_name":"- Global Parkinson's Genetics Program (GP2)","author_inst":"-"},{"author_name":"Peter Heutink","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Katja Lohmann","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Christine Klein","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Niccolo E Mencacci","author_inst":"Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA"},{"author_name":"Shen-Yang Lim","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Azlina Ahmad-Annuar","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Ai Huey Tan","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"GCH1 p.Ser80Asn Confers Risk for Parkinson's Disease in East Asian Populations","rel_doi":"10.64898\/2026.06.11.26354827","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26354827","rel_abs":"Introduction: GCH1 has been implicated in Parkinson's disease (PD), but its risks variants and associations are not well defined. Objectives: To investigate the clinical relevance and PD risk associated with the GCH1 p.Ser80Asn variant. Methods: We first identified a segregating GCH1 p.Ser80Asn variant in a Malaysian Chinese PD family via whole genome sequencing (WGS). We assessed its risk association using multi-ancestry WGS data from the Global Parkinson's Genetics Program (GP2) (n=22,372PD vs n=8,826Controls) and meta-analysis of East Asian (EAS) cohorts (n=4,712PD vs 38,733Controls). Clinico-demographic details of affected variant carriers were collated. Results: The GCH1 p.Ser80Asn variant was enriched in GP2 EAS PD populations (n=9\/2,757; 0.33%) but not detected in other ancestries. Meta-analysis revealed increased PD risk in EAS populations (odds ratio:5.1; 95%CI:2.3-10.7; p=2.89x10-5). Affected carriers (mean age at onset:56.3+-12.5 years) had additional occurrence of dystonia, while dementia was rare. Conclusions: The GCH1 p.Ser80Asn variant is a rare, EAS-enriched risk variant for PD.","rel_num_authors":37,"rel_authors":[{"author_name":"Yi Wen Tay","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Andrew Leslie Lee","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Jie Ping Schee","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Chin Hsien Lin","author_inst":"National Taiwan University Hospital Taipei, Taipei, Taiwan"},{"author_name":"Eng King Tan","author_inst":"Duke-National University of Singapore Medical School, Singapore"},{"author_name":"Jung Hwan Shin","author_inst":"Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea"},{"author_name":"Pin-Shiuan Chen","author_inst":"National Taiwan University Hospital Bei-Hu branch, Taipei, Taiwan"},{"author_name":"Sung-Pin Fan","author_inst":"National Taiwan University Hospital Taipei, Taipei, Taiwan"},{"author_name":"Cheng-Hsuan Li","author_inst":"National Taiwan University Hospital Taipei, Taipei, Taiwan"},{"author_name":"Ebonne Yu Lin Ng","author_inst":"National Neuroscience Institute, Singapore General Hospital, Singapore"},{"author_name":"Han Joon Kim","author_inst":"Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea"},{"author_name":"Beomseok Jeon","author_inst":"Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea"},{"author_name":"Sulev Koks","author_inst":"Health Futures Institute, Murdoch University, Perth, Australia"},{"author_name":"Kin Ying Mok","author_inst":"The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China"},{"author_name":"Yi Ting Lim","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Mohd Salahuddin Kamaruddin","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Tzi Shin Toh","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Hans Xing Ding","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Anis Nadhirah Khairul Anuar","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Norlisah Ramli","author_inst":"Subang Jaya Medical Centre, Selangor, Malaysia"},{"author_name":"Ignacio Juan Keller Sarmiento","author_inst":"Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA"},{"author_name":"Maria Teresa Perinan","author_inst":"Queen Mary University of London, London, United Kingdom"},{"author_name":"Zih-Hua Fang","author_inst":"DataTecnica LLC, Washington, DC 20037, USA"},{"author_name":"Lara M Lange","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Kishore R. Kumar","author_inst":"The University of Sydney, Sydney, New South Wales, Australia"},{"author_name":"Soraya Bardien","author_inst":"Stellenbosch University, Cape Town, South Africa"},{"author_name":"Joanne Trinh","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Enza Maria Valente","author_inst":"University of Pavia, 27100 Pavia, Italy"},{"author_name":"- SG10K_Health Consortium","author_inst":"-"},{"author_name":"- Global Parkinson's Genetics Program (GP2)","author_inst":"-"},{"author_name":"Peter Heutink","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Katja Lohmann","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Christine Klein","author_inst":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"},{"author_name":"Niccolo E Mencacci","author_inst":"Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA"},{"author_name":"Shen-Yang Lim","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Azlina Ahmad-Annuar","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"Ai Huey Tan","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Virtual Responsive Neurostimulation Implantation: From Intracranial Connectivity to Optimized Lead Placement","rel_doi":"10.64898\/2026.06.17.26355892","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.17.26355892","rel_abs":"Responsive neurostimulation (RNS) is an implanted device that delivers direct brain stimulation for drug-resistant focal epilepsy. Individual responses are highly variable, and no validated framework exists to predict outcome or guide lead placement before implantation. We hypothesized that this variability is partly explained by lead placement in relation to patterns of functional connectivity in brain networks.\n\nFourty-nine patients with drug-resistant focal epilepsy who underwent pre-implantation intracranial EEG (iEEG) and RNS implantation across three independent epilepsy centers were retrospectively studied. We developed a composite functional connectivity score, based on simple Spearman correlation, combining the standard deviation and kurtosis of interictal iEEG connectivity distributions to predict the response outcome in a training cohort (HUP, n=18) and validated in two independent cohorts (NYU, n=17; UCSF, n=14). We accounted for a spatial mismatch between iEEG and RNS electrodes with a distance-based correction. The score was extended to generate patient-specific 3D maps of predicted RNS efficacy across 200 simulated, or \"virtual RNS\", lead configurations.\n\nAccuracy of the score in predicting clinical outcome was 72% at the group level, 61% at the individual patient level, and, after distance-based optimization, 100% in patients with RNS electrodes placed close to location of iEEG electrodes. Applied to the validation cohort, the same score reached 68% accuracy (71% balanced accuracy, 55% sensitivity, 88% specificity). The spatial combination of the scores at different SEEG contacts localization gives a spatial score for each patient. Responders showed significantly higher spatial scores than non-responders, supporting that actual RNS lead placement in responders was located in map-identified favorable regions.\n\nInterictal iEEG functional connectivity predicts individual RNS response across independent epilepsy centers, and patient-specific 3D maps derived from this biomarker could prospectively guide lead implantation toward favorable network regions, opening a promising avenue toward network-informed RNS surgical planning.","rel_num_authors":17,"rel_authors":[{"author_name":"Odile Feys","author_inst":"University of Pennsylvania"},{"author_name":"Katherine G Walsh","author_inst":"University of Pennsylvania"},{"author_name":"Kerry C Nix","author_inst":"University of Pennsylvania"},{"author_name":"Mariam Josyula","author_inst":"University of Pennsylvania"},{"author_name":"Nishant Sinha","author_inst":"University of Pennsylvania"},{"author_name":"Sarah B Lavelle","author_inst":"University of Pennsylvania"},{"author_name":"Joost Wagenaar","author_inst":"University of Pennsylvania"},{"author_name":"Andrew Michalak","author_inst":"New York University"},{"author_name":"Martha J Morrell","author_inst":"Neuropace Inc"},{"author_name":"Jay Jeschke","author_inst":"New York University"},{"author_name":"Ankit N Khambhati","author_inst":"University of California San Francisco"},{"author_name":"Erin C Conrad","author_inst":"University of Pennsylvania"},{"author_name":"Jonathan K Kleen","author_inst":"University of California San Francisco"},{"author_name":"Brian Litt","author_inst":"University of Pennsylvania"},{"author_name":"Vikram R Rao","author_inst":"University of California San Francisco"},{"author_name":"Daniel Friedman","author_inst":"New York University"},{"author_name":"Kathryn Adamiak Davis","author_inst":"University of Pennsylvania"}],"rel_date":"2026-06-22","rel_site":"medrxiv"},{"rel_title":"Simulation of cell-size systems at long timescales with flexible protein structures","rel_doi":"10.64898\/2026.06.20.733545","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.20.733545","rel_abs":"Protein behavior inside cells is dominated by the crowded nature of the intracellular environment. Progress in structure determination of proteins and protein complexes, based on advances in Artificial Intelligence, provides an opportunity for structure-based modeling of cellular phenomena. Such modeling at the atomic resolution has been advanced by the traditional simulation techniques, e.g. molecular dynamics. A recently developed docking-based approach implements Markov Chain Monte Carlo sampling of intermolecular energy landscapes, offering several orders of magnitude faster simulation protocols. The approach allows addressing much longer trajectories of macromolecular systems in the crowded intracellular environment at atomic resolution. The sampling by design avoids low-probability (high-energy) states, which greatly accelerates the simulation process. A notable feature of this docking-based approach is the rigid body approximation of protein structures. The rigid-body approximation had been the primary direction in the protein docking field up until recent developments in deep learning. The rigid-body approach should be quite robust for the higher energy transient interactions that dominate the highly crowded cellular environment, as they likely involve relatively small conformational change. However, it is less applicable to the low-energy protein-protein complexes, especially those involving flexible regions. We addressed this problem by incorporating AlphaFold3 top models of the protein complexes in the mapping of the intermolecular energy landscape, as representative of the low-energy configurations of the protein assembly. By the nature of the AlphaFold predictions, these models involve appropriate conformational change between unbound and bound structures. These low-energy docking poses are combined with the rigid-body docking predictions that cover the multiplicity of the transient interactions. Such combination directly addresses the conformational flexibility of proteins upon binding along with the multiplicity of the transient protein encounters in the crowded cellular environment.\n\nSIGNIFICANCEProtein behavior inside cells is dominated by the crowded nature of intracellular environment. A recently developed approach allowed addressing long simulation trajectories of macromolecular systems in such environment at atomic resolution. A notable feature of this approach is the rigid body approximation in representation of the protein structures, which had been popular in the field up until the recent developments in artificial intelligence. However, such approximation is less applicable to stable protein-protein complexes, especially those involving flexible regions. We addressed this problem head-on by incorporating top deep learning-generated models of protein complexes. The new approach directly accounts for the flexibility of protein structures upon binding, along with the multiplicity of the transient protein encounters in the crowded cellular environment.","rel_num_authors":9,"rel_authors":[{"author_name":"Kamila Yunas","author_inst":"Computational Biology Program, The University of Kansas, Lawrence, KS 66045, USA"},{"author_name":"Amar Singh","author_inst":"Computational Biology Program, The University of Kansas, Lawrence, KS 66045, USA"},{"author_name":"Matthew M Copeland","author_inst":"Computational Biology Program, The University of Kansas, Lawrence, KS 66045, USA"},{"author_name":"Andrii M Tytarenko","author_inst":"Institute for Applied System Analysis at the Igor Sikorsky Kyiv Polytechnic Institute, Kyiv 03056, Ukraine"},{"author_name":"Petras J Kundrotas","author_inst":"Computational Biology Program, The University of Kansas, Lawrence, KS 66045, USA"},{"author_name":"Randal Halfmann","author_inst":"Stowers Institute for Medical Research, Kansas City, MO 64110, USA"},{"author_name":"Pavlo O Kasyanov","author_inst":"Institute for Applied System Analysis at the Igor Sikorsky Kyiv Polytechnic Institute, Kyiv 03056, Ukraine"},{"author_name":"Eugene A Feinberg","author_inst":"Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, 11794, USA"},{"author_name":"Ilya A Vakser","author_inst":"Computational Biology Program, The University of Kansas, Lawrence, KS 66045, USA"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Simulation of cell-size systems at long timescales with flexible protein structures","rel_doi":"10.64898\/2026.06.20.733545","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.20.733545","rel_abs":"Protein behavior inside cells is dominated by the crowded nature of the intracellular environment. Progress in structure determination of proteins and protein complexes, based on advances in Artificial Intelligence, provides an opportunity for structure-based modeling of cellular phenomena. Such modeling at the atomic resolution has been advanced by the traditional simulation techniques, e.g. molecular dynamics. A recently developed docking-based approach implements Markov Chain Monte Carlo sampling of intermolecular energy landscapes, offering several orders of magnitude faster simulation protocols. The approach allows addressing much longer trajectories of macromolecular systems in the crowded intracellular environment at atomic resolution. The sampling by design avoids low-probability (high-energy) states, which greatly accelerates the simulation process. A notable feature of this docking-based approach is the rigid body approximation of protein structures. The rigid-body approximation had been the primary direction in the protein docking field up until recent developments in deep learning. The rigid-body approach should be quite robust for the higher energy transient interactions that dominate the highly crowded cellular environment, as they likely involve relatively small conformational change. However, it is less applicable to the low-energy protein-protein complexes, especially those involving flexible regions. We addressed this problem by incorporating AlphaFold3 top models of the protein complexes in the mapping of the intermolecular energy landscape, as representative of the low-energy configurations of the protein assembly. By the nature of the AlphaFold predictions, these models involve appropriate conformational change between unbound and bound structures. These low-energy docking poses are combined with the rigid-body docking predictions that cover the multiplicity of the transient interactions. Such combination directly addresses the conformational flexibility of proteins upon binding along with the multiplicity of the transient protein encounters in the crowded cellular environment.\n\nSIGNIFICANCEProtein behavior inside cells is dominated by the crowded nature of intracellular environment. A recently developed approach allowed addressing long simulation trajectories of macromolecular systems in such environment at atomic resolution. A notable feature of this approach is the rigid body approximation in representation of the protein structures, which had been popular in the field up until the recent developments in artificial intelligence. However, such approximation is less applicable to stable protein-protein complexes, especially those involving flexible regions. We addressed this problem head-on by incorporating top deep learning-generated models of protein complexes. The new approach directly accounts for the flexibility of protein structures upon binding, along with the multiplicity of the transient protein encounters in the crowded cellular environment.","rel_num_authors":9,"rel_authors":[{"author_name":"Kamila Yunas","author_inst":"Computational Biology Program, The University of Kansas, Lawrence, KS 66045, USA"},{"author_name":"Amar Singh","author_inst":"Computational Biology Program, The University of Kansas, Lawrence, KS 66045, USA"},{"author_name":"Matthew M Copeland","author_inst":"Computational Biology Program, The University of Kansas, Lawrence, KS 66045, USA"},{"author_name":"Andrii M Tytarenko","author_inst":"Institute for Applied System Analysis at the Igor Sikorsky Kyiv Polytechnic Institute, Kyiv 03056, Ukraine"},{"author_name":"Petras J Kundrotas","author_inst":"Computational Biology Program, The University of Kansas, Lawrence, KS 66045, USA"},{"author_name":"Randal Halfmann","author_inst":"Stowers Institute for Medical Research, Kansas City, MO 64110, USA"},{"author_name":"Pavlo O Kasyanov","author_inst":"Institute for Applied System Analysis at the Igor Sikorsky Kyiv Polytechnic Institute, Kyiv 03056, Ukraine"},{"author_name":"Eugene A Feinberg","author_inst":"Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, 11794, USA"},{"author_name":"Ilya A Vakser","author_inst":"Computational Biology Program, The University of Kansas, Lawrence, KS 66045, USA"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Thrombospondin-2 deficiency primes the synovial joint for aberrant tissue remodeling and injury response","rel_doi":"10.64898\/2026.06.18.732872","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.732872","rel_abs":"Objective. This study investigates joint injury-induced angiogenesis and the effects of genetic deficiency of thrombospondin-2 (TSP2), an anti-angiogenic factor, in joint homeostasis and post-traumatic osteoarthritis (PTOA). Method. We utilized a murine non-invasive anterior cruciate ligament rupture (ACLR) model of PTOA and mined published synovial transcriptomics datasets to investigate injury-induced synovial angiogenesis. Spatial transcriptomics and flow cytometry of TSP2-GFP reporter mice were used to assess injury-induced thrombospondin-2 and its cellular origins in synovium. Global TSP2 knockout mice (TSP2-KO) were used to assess the effect of TSP2 deficiency on early and late stages of PTOA development via molecular imaging of inflammation and angiogenesis, histopathology, micro-computed tomography, Raman spectroscopy, and synovium bulk RNA-sequencing. Results. Intra-articular angiogenesis peaked at 7d post-ACLR and declined but remained elevated above baseline at 28d post-ACLR. We identified synovial crosstalk between endothelial cells and sublining fibroblasts as a key driver of angiogenesis and source of thrombospondin-2 signaling, with TSP2 primarily upregulated in sublining fibroblasts. TSP2-KO mice exhibited increased peri-articular inflammation at 7d post-ACLR and inferior bone quality. Histopathology revealed greater PTOA severity but paradoxically lower synovitis in TSP2-KOs. Additionally, aberrant structural remodeling of the entire knee joint was observed in uninjured and ACLR TSP2-KO limbs. The uninjured TSP2-KO synovial transcriptome demonstrated elevated immune, fibrotic, and angiogenic activation; however, TSP2-KO and WT synovial transcriptomes partially converged upon injury. Conclusion. TSP2 is essential for joint homeostasis and trauma response. Global TSP2 deficiency causes premature OA and worsened PTOA, suggesting that therapeutic targeting with TSP2 mimetic could be used to prevent OA.","rel_num_authors":16,"rel_authors":[{"author_name":"Lindsey Lammlin","author_inst":"ETH Zurich"},{"author_name":"Lucas M Junginger","author_inst":"University of Michigan"},{"author_name":"Alexander J Knights","author_inst":"Washington University St. Louis"},{"author_name":"Michael D Newton","author_inst":"University of Michigan"},{"author_name":"Henry Dai","author_inst":"University of Michigan"},{"author_name":"Carlisle R DeJulius","author_inst":"ETH Zurich"},{"author_name":"Aanya Mohan","author_inst":"ETH Zurich"},{"author_name":"Isabelle J Smith","author_inst":"University of Michigan"},{"author_name":"Scarlet C Howser","author_inst":"University of Michigan"},{"author_name":"Gurjit S Mandair","author_inst":"University of Michigan"},{"author_name":"Sunghun Cheong","author_inst":"University of Michigan"},{"author_name":"Paul F Lais","author_inst":"University of Michigan"},{"author_name":"Sofia Gonzalez-Nolde","author_inst":"University of Michigan"},{"author_name":"Andrea I Alford","author_inst":"University of Michigan"},{"author_name":"Kurt D Hankenson","author_inst":"University of Michigan"},{"author_name":"Tristan Maerz","author_inst":"ETH Zurich"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Cholinergic interneuron control of GABAergic circuits targeting spiny projection neurons is disrupted in parkinsonian models","rel_doi":"10.64898\/2026.06.17.732978","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732978","rel_abs":"Parkinsons disease (PD) is known to alter the intrinsic properties of striatal cholinergic interneurons (ChIs). However, how PD shapes ChI control of intrastriatal GABAergic circuits regulating principal spiny projection neurons (SPNs) is unknown. To fill this gap, striatal circuits in healthy and parkinsonian mice were interrogated. In ex vivo brain slices from healthy mice, optogenetic stimulation of ChIs evoked GABAA receptor currents in both indirect and direct pathway SPNs that were attributable to nicotinic acetylcholine receptor (nAChR)-mediated activation of GABAergic interneurons (GIs). Simulations suggested that this circuit exerts a state-dependent control of SPN dendritic integration that was modulated by concomitant muscarinic receptor signaling. Surprisingly, in mouse models of prodromal and parkinsonian states, the ability of ChIs to engage this intrastriatal circuitry was disrupted because interneurons down-regulated nicotinic AChRs. Taken together, these studies suggest that impaired ChI control of GABAergic interneurons contributes to behavioral deficits in both prodromal and clinical PD states.","rel_num_authors":13,"rel_authors":[{"author_name":"Marziyeh Belal","author_inst":"Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Aligning Science Across Parkinson's (ASAP) Collaborati"},{"author_name":"Tamara Perez-Rosello","author_inst":"Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Aligning Science Across Parkinson's (ASAP) Collaborati"},{"author_name":"Elif B. Guven","author_inst":"Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ, USA"},{"author_name":"Samet Kocaturk","author_inst":"School of Biosciences, Cardiff University, Cardiff, UK"},{"author_name":"Zhong Xie","author_inst":"Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Aligning Science Across Parkinson's (ASAP) Collaborati"},{"author_name":"Ema Ilijic","author_inst":"Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Aligning Science Across Parkinson's (ASAP) Collaborati"},{"author_name":"Tatiana Tkatch","author_inst":"Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Aligning Science Across Parkinson's (ASAP) Collaborati"},{"author_name":"Jay Li","author_inst":"Department of Internal Medicine, University of Michigan Medical School. Ann Arbor, MI, USA"},{"author_name":"William Dauer","author_inst":"Peter O'Donnell Jr. Brain Institute, Departments of Neurology and Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Maxime Assous","author_inst":"School of Biosciences, Cardiff University, Cardiff, UK"},{"author_name":"James M. Tepper","author_inst":"Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ, USA"},{"author_name":"Vernon R. J. Clarke","author_inst":"Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Aligning Science Across Parkinson's (ASAP) Collaborati"},{"author_name":"D. James Surmeier","author_inst":"Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Aligning Science Across Parkinson's (ASAP) Collaborati"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Individual differences in ethanol drinking meal structure are shaped by social environments","rel_doi":"10.64898\/2026.06.17.732974","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732974","rel_abs":"Alcohol use disorder (AUD) is marked by substantial heterogeneity in drinking behaviors and health outcomes, underscoring the need for preclinical models that capture interindividual variability. We recently developed open-source capacitive lickometer systems for high-resolution monitoring of mouse fluid intake. Using LIQ PARTI and LIQ HD, we found substantial individual differences in alcohol intake that varied across sex and housing status in C57Bl6\/J mice. Here, we conducted a secondary analysis of this continuous access ethanol drinking data to quantify behavioral variability in group and singly housed mice. We introduce a fluid \"meal\" pattern analysis that integrates drinking across ethanol and water sippers to define discrete drinking episodes. Using this approach, we observed sex- and housing-dependent reorganization of drinking structure across group and single-housed settings, with group-housed male mice exhibiting fewer but faster liquid meals. To further characterize multidimensional drinking patterns, we applied principal component analysis to meal variables and identified a \"distributed meal\" phenotype defined by increased meal number, reduced meal size, earlier onset of drinking, and higher ethanol preference. Considering factors that influence behaviors in a social environment, we next examined whether social hierarchy was associated with these patterns using a tube test dominance assay. Social rank was unrelated to ethanol and meal measures; however, offensive dominance behavior positively correlated with principal component scores in males. Together, these findings demonstrate that high-resolution, longitudinal analysis of ethanol drinking reveals distinct behavioral phenotypes that are associated with key components of social behaviors, providing a potential framework for understanding heterogeneity in AUD-related drinking.\n\nHighlightsO_LILIQ PARTI and HD enable high-resolution analysis of ethanol drinking patterns.\nC_LIO_LIFluid meal analysis captures sex- and housing-dependent drinking structures.\nC_LIO_LIBehavioral phenotyping reveals individual differences beyond total ethanol intake.\nC_LIO_LIPCA identifies a meal phenotype associated with male offensive dominance behavior.\nC_LI","rel_num_authors":6,"rel_authors":[{"author_name":"Marie A. Doyle","author_inst":"UMass Chan Medical School"},{"author_name":"Caitlyn M. Edwards","author_inst":"University of Massachussetts Medical School"},{"author_name":"Sabrina D. Hallal","author_inst":"UMass Chan Medical School"},{"author_name":"Samuel M. Bond","author_inst":"UMass Chan Medical School"},{"author_name":"Nicholas Petersen","author_inst":"Vanderbilt University"},{"author_name":"Danny G. Winder","author_inst":"UMass Chan Medical School"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Individual differences in ethanol drinking meal structure are shaped by social environments","rel_doi":"10.64898\/2026.06.17.732974","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732974","rel_abs":"Alcohol use disorder (AUD) is marked by substantial heterogeneity in drinking behaviors and health outcomes, underscoring the need for preclinical models that capture interindividual variability. We recently developed open-source capacitive lickometer systems for high-resolution monitoring of mouse fluid intake. Using LIQ PARTI and LIQ HD, we found substantial individual differences in alcohol intake that varied across sex and housing status in C57Bl6\/J mice. Here, we conducted a secondary analysis of this continuous access ethanol drinking data to quantify behavioral variability in group and singly housed mice. We introduce a fluid \"meal\" pattern analysis that integrates drinking across ethanol and water sippers to define discrete drinking episodes. Using this approach, we observed sex- and housing-dependent reorganization of drinking structure across group and single-housed settings, with group-housed male mice exhibiting fewer but faster liquid meals. To further characterize multidimensional drinking patterns, we applied principal component analysis to meal variables and identified a \"distributed meal\" phenotype defined by increased meal number, reduced meal size, earlier onset of drinking, and higher ethanol preference. Considering factors that influence behaviors in a social environment, we next examined whether social hierarchy was associated with these patterns using a tube test dominance assay. Social rank was unrelated to ethanol and meal measures; however, offensive dominance behavior positively correlated with principal component scores in males. Together, these findings demonstrate that high-resolution, longitudinal analysis of ethanol drinking reveals distinct behavioral phenotypes that are associated with key components of social behaviors, providing a potential framework for understanding heterogeneity in AUD-related drinking.\n\nHighlightsO_LILIQ PARTI and HD enable high-resolution analysis of ethanol drinking patterns.\nC_LIO_LIFluid meal analysis captures sex- and housing-dependent drinking structures.\nC_LIO_LIBehavioral phenotyping reveals individual differences beyond total ethanol intake.\nC_LIO_LIPCA identifies a meal phenotype associated with male offensive dominance behavior.\nC_LI","rel_num_authors":6,"rel_authors":[{"author_name":"Marie A. Doyle","author_inst":"UMass Chan Medical School"},{"author_name":"Caitlyn M. Edwards","author_inst":"University of Massachussetts Medical School"},{"author_name":"Sabrina D. Hallal","author_inst":"UMass Chan Medical School"},{"author_name":"Samuel M. Bond","author_inst":"UMass Chan Medical School"},{"author_name":"Nicholas Petersen","author_inst":"Vanderbilt University"},{"author_name":"Danny G. Winder","author_inst":"UMass Chan Medical School"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"An Integrated muti-omics cell atlas of the human trabecular meshwork and ciliary body","rel_doi":"10.64898\/2026.06.17.732980","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732980","rel_abs":"The trabecular meshwork (TM) and ciliary body (CB) regulate aqueous humor dynamics and intraocular pressure (IOP), and TM\/Schlemms canal (SC) dysfunction underlies glaucoma. Here, we present a spatially resolved multi-omics atlas of human TM and CB, integrating snRNA-seq, scRNA-seq, and snATAC-seq from over one million cells and nuclei across 112 donors with Xenium spatial transcriptomics. We identified 9 major cell classes and 21 cell types, revealing heterogeneity, including undercharacterized fibroblast and epithelial subpopulations. Spatial mapping supported TM fibroblast zonation and CB epithelial organization. Regulatory analyses identified cell type-specific programs, including OTX\/PAX networks in CB epithelium and SMAD3\/TGF-{beta} signaling in fibroblasts. Integration with glaucoma loci showed enrichment of non-coding variants in regulatory elements associated with POAG and PACG. Age- and ancestry-associated remodeling revealed divergent fibroblast aging with increased PIEZO1, suggesting impaired outflow and elevated IOP. Together, this high-resolution atlas links cellular, regulatory, and genetic variation to anterior segment function and glaucoma susceptibility.","rel_num_authors":23,"rel_authors":[{"author_name":"Jinjing Jian","author_inst":"Baylor College of Medicine"},{"author_name":"Xuan Bao","author_inst":"University of California, Irvine"},{"author_name":"Jun Wang","author_inst":"Baylor College of Medicine"},{"author_name":"Ye Zheng","author_inst":"University of California, Irvine"},{"author_name":"Jin Li","author_inst":"University of California, Irvine"},{"author_name":"Jianming Shao","author_inst":"Baylor College of Medicine"},{"author_name":"Tingting Yang","author_inst":"Baylor College of Medicine"},{"author_name":"Ismail Yaman","author_inst":"Baylor College of Medicine"},{"author_name":"Jean Li","author_inst":"University of California, Irvine"},{"author_name":"Han Chen","author_inst":"New York University"},{"author_name":"Nicholas Tolman","author_inst":"Columbia University"},{"author_name":"Richard H. Scheuermann","author_inst":"National Institutes of Health"},{"author_name":"Jie J. Zheng","author_inst":"University of California, Los Angeles"},{"author_name":"Carl Sheridan","author_inst":"University of Liverpool"},{"author_name":"Yutao Liu","author_inst":"Mayo Clinic"},{"author_name":"Yiqin Du","author_inst":"University of South Florida"},{"author_name":"Revathi Balasubramanian","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Gulab S. Zode","author_inst":"University of California, Irvine"},{"author_name":"Simon John","author_inst":"Columbia University Irving Medical Center"},{"author_name":"J Timothy Stout","author_inst":"Baylor College of Medicine"},{"author_name":"Dan Stamer","author_inst":"Duke University"},{"author_name":"Yumei Li","author_inst":"University of California, Irvine"},{"author_name":"Rui Chen","author_inst":"University of California, Irvine"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Interaction forces reflect the perception of texture during active exploration","rel_doi":"10.64898\/2026.06.17.732939","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732939","rel_abs":"We are constantly exploring the world around us through touch. Active touch depends on coordination of movement and force, yet the forces used during natural exploration and their relationship with perception is largely unexplored. Here we measured exploration forces together with fingertip motion while 17 participants explored 14 textures and rated their perceived hardness, slipperiness, or roughness. Exploration strategies differed systematically across tasks: hardness judgments involved relatively stationary pressing with larger and more variable normal forces, whereas slipperiness and roughness judgments relied more on sweeping movements. Within tasks, interaction forces covaried with perceptual ratings: harder textures elicited larger maximum tangential forces, consistent with diagonal pressing, while more slippery textures were explored with faster fingertip motion and lower forces. Estimated dynamic friction was negatively correlated with perceived slipperiness but not roughness. At the same time perceived roughness was strongly related to vibrations in the force, indicating distinct physical bases for these perceptual dimensions. These results show that humans actively tailor contact mechanics to perceptual goals during active exploration, supporting a sensorimotor account of texture perception.","rel_num_authors":5,"rel_authors":[{"author_name":"Neema Darabi","author_inst":"University of Chicago"},{"author_name":"Benoit P Delhaye","author_inst":"UCLouvain"},{"author_name":"Sliman J Bensmaia","author_inst":"University of Chicago"},{"author_name":"Stephanie E Palmer","author_inst":"University of Chicago"},{"author_name":"Anton R Sobinov","author_inst":"University of Chicago"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Targeting pathogenic VWF\/ADAMTS13 dysregulation attenuates CTEPH progression","rel_doi":"10.64898\/2026.06.17.732997","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732997","rel_abs":"Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening pulmonary vascular disease, characterized by persistent thrombotic obstruction and progressive pulmonary vascular remodeling, yet the molecular mechanisms linking persistent thrombosis to vascular remodeling remain incompletely understood. Clinical studies have reported elevated plasma von Willebrand factor (VWF) levels and reduced ADAMTS13 in patients with CTEPH, but whether VWF\/ADAMTS13 dysregulation contributes directly to disease pathogenesis remains unclear. Here, using newly established rat models of CTEPH, we identify a causative role for dysregulation of the VWF-ADAMTS13 axis in chronic thromboembolic progression. CTEPH rats developed persistent, unresolved VWF- and fibrin-rich thrombi accompanied by markedly increased endothelial VWF deposition. In contrast, ADAMTS13 expression and activity were significantly reduced in CTEPH rats. Consistent with these findings, genetic Adamts13 deficiency further exacerbates pulmonary microvascular thrombosis and accelerated early mortality following disease induction. Mechanistically, ultra-large (UL)-VWF accumulated on the pulmonary endothelial surface, promoting robust platelet recruitment under shear. This platelet-VWF interaction stimulated the release of platelet-derived pro-remodeling mediators, including TGF-{beta}1 and PDGF-BB. Genetic ablation of Vwf markedly reduced in situ microvascular thrombosis within pulmonary arterioles, attenuated pulmonary arterial remodeling, and improved pulmonary hemodynamics. Moreover, treatment with recombinant ADAMTS13 reduced endothelial UL-VWF accumulation, suppressed platelet activation, and effectively prevented thrombosis and platelet-driven pro-remodeling signaling in CTEPH rats. Collectively, these findings identify dysregulation of the VWF-ADAMTS13 axis as a key driver of pulmonary thrombosis and vascular remodeling in CTEPH and support therapeutic targeting of this pathway as a potential disease-modifying strategy.\n\nKey PointsO_LIVWF-ADAMTS13 dysregulation promotes persistent pulmonary thrombosis and platelet-driven arterial remodeling within pulmonary arterioles.\nC_LIO_LIRecombinant ADAMTS13 treatment or VWF ablation abrogates pulmonary arterial thrombosis and halts vascular remodeling in CTEPH.\nC_LI","rel_num_authors":11,"rel_authors":[{"author_name":"Zhijian Wu","author_inst":"University of Kansas Medical Center"},{"author_name":"Huan Dong","author_inst":"University of Kansas Medical Center"},{"author_name":"Quan Zhang","author_inst":"University of Kansas Medical Center"},{"author_name":"Zhirong Chai","author_inst":"University of Kansas Medical Center"},{"author_name":"Anlun li","author_inst":"University of Kansas Medical Center"},{"author_name":"Esteban M Dominguez","author_inst":"University of Kansas Medical Center"},{"author_name":"Xinyang Zhao","author_inst":"The University of Kansas Medical center"},{"author_name":"Leslie Spikes","author_inst":"University of Kansas Medical Center"},{"author_name":"Michael Soares","author_inst":"University of Kansas Medical Center"},{"author_name":"X. Long Zheng","author_inst":"The University of Kansas Medical Center"},{"author_name":"Liang Zheng","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Genetic susceptibility to obesity-related asthma and its modulation by sequelae of obesity","rel_doi":"10.64898\/2026.06.16.731769","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.731769","rel_abs":"Rationale Asthma is a multifactorial disease with a role of genetic susceptibility and environmental exposures. These aspects are poorly understood for pediatric obesity-related asthma, a phenotype of non-allergic asthma. Objective To quantify gene by environment interactions in obesity-related asthma Methods Using expression quantitative trait loci (eQTLs) as measure of genetic susceptibility, and obesity-mediated effects on anthropometrics, metabolic measures, and T helper cell proportions as biological sequelae of obesogenic environment, we quantified the association of eQTLs with asthma burden, and its modulation by obesity-mediated effects, in primary cohort of 144 children, and validation cohort of 101 children. Measurements and Main Results Of the 3,904 eQTLs associated with gene expression, up to 30% were associated with pulmonary function indices, including FVC, FEV1, TLC, FRC and IC, and were enriched for African ancestry. These eQTLs encoded for antigen presentation, cell mobility, autophagy, small GTPase signal transduction, fatty acid metabolism, and chromosome segregation pathways. Neck and waist circumference, insulin resistance, leptin and adiponectin levels, and T helper 1 and 17 cell proportions attenuated association of up to 51% eQTLs with pulmonary function, which encoded for all but fatty acid metabolism and chromosome segregation pathways. eQTLs associated with ATF6 and MEI1 retained significance. eQTLs for RNASET2, FBLN5, STX2, HEATR3 and SERPINB6 genes were associated with pulmonary function in the validation cohort. Conclusions We report novel genetic susceptibility markers of asthma burden in pediatric obesity-related asthma that are enriched for African ancestry and are partly attenuated by truncal fat load and obesity-mediated inflammation and metabolic dysregulation.","rel_num_authors":5,"rel_authors":[{"author_name":"David Thompson","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Yvonne Wabara","author_inst":"Children's National Hospital, George Washington University"},{"author_name":"Sarai Duran","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Anna Reichenbach","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Deepa Rastogi","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Altered Lighting Conditions Elicit Sex-Specific Circadian Behaviors in Diurnal Grass Rats","rel_doi":"10.64898\/2026.06.17.732698","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732698","rel_abs":"Circadian rhythms are crucial to biological functions, and cognitive functions such as attention, choice, and preference-related behaviors are modulated by circadian rhythms and disrupted in mood disorders such as Seasonal Affective Disorder (SAD) and Major Depressive Disorder (MDD). These neuropsychiatric diseases can be induced or worsened by alterations to daily light patterns and can also be treated with circadian-timed bright-light therapy, suggesting modulatory effects of light brightness on mood and behavior. While most laboratory rodents are nocturnal, the Nile grass rat Arvicanthis niloticus) is diurnal, offering a unique model to study light modulation effects relevant to humans. In this work, we track daily activity in male and female grass rats under varied lighting for several weeks, revealing sex-specific circadian patterns and responses. These findings establish a foundation for mechanistic studies of light effects on mood-related brain circuits in diurnal animals.","rel_num_authors":8,"rel_authors":[{"author_name":"Jeremiah P. Hartner","author_inst":"University of Michigan"},{"author_name":"Noah Muscat","author_inst":"University of Michigan"},{"author_name":"Mujtaba Khan","author_inst":"University of Michigan"},{"author_name":"Katrina Linning-Duffy","author_inst":"Michigan State University"},{"author_name":"Diksha Zutshi","author_inst":"University of Michigan"},{"author_name":"Nicolette Ognjanovski","author_inst":"University of Michigan"},{"author_name":"Lily Yan","author_inst":"Michigan State University"},{"author_name":"Brendon O Watson","author_inst":"University of Michigan"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"ResXR: validated infrastructure for reproducible studies of human behavior in Extended Reality","rel_doi":"10.64898\/2026.06.17.732869","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732869","rel_abs":"Extended Reality (XR) combines experimental control and ecological validity, yet behavioral XR research lacks shared infrastructure: building immersive experiments demands specialized engineering, and custom tools yield data in custom formats that other laboratories cannot readily reanalyze. We present ResXR (Research with XR), an open-source toolkit providing a path from immersive experiment to standardized dataset and quality report, running on standalone headsets. A Unity template records synchronized head, hand, eye, and face tracking with per-sample hardware timestamps; an independent Python pipeline validates quality, masks flagged intervals, and exports raw and derivative datasets in Motion-BIDS format with self-contained quality reports. Three ready-to-run paradigms span common behavioral designs. ResXR is an idea new to XR research: sensor data from consumer headsets must be empirically validated rather than taken from vendor documentation, grounding its schema and quality flags in stress-tested sensor behavior. Its aim is a transparent, community-extensible foundation for reproducible XR experimentation.","rel_num_authors":5,"rel_authors":[{"author_name":"Yehuda Bergstein","author_inst":"Tel Aviv University"},{"author_name":"Noa Barel","author_inst":"Tel Aviv University"},{"author_name":"Galia Shai Basson","author_inst":"Tel Aviv University"},{"author_name":"Omri Bromberg","author_inst":"Tel Aviv University"},{"author_name":"Tom Schonberg","author_inst":"Tel Aviv University"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Inhalation of nanoparticles during pregnancy enhances placental glucose transport in rats","rel_doi":"10.64898\/2026.06.16.732724","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732724","rel_abs":"Fetal health is heavily dictated by the maternal environment. Inhaling airborne pollutants, like particulate matter, is associated with pregnancy complications and fetal developmental pathologies, including fetal growth restriction (FGR). Because fetal growth is dependent on the placental transfer of nutrients from the maternal circulation, particularly glucose, investigating glucose transport capacity is critical to understanding the development of FGR associated with gestational inhalation of particulate matter. Pregnant Sprague Dawley rats were exposed to titanium dioxide nanoparticles (9.8{+\/-}1.0 mg\/m3) as a proxy for ultrafine particulate matter, from gestational day (GD) 5 to GD 19 via whole-body inhalation. Glucose transporters (GLUTs) 1, 3 and 4 were evaluated in term placentas on GD 20 and ex vivo placental perfusion was conducted as a functional assessment of glucose transport. Exposure resulted in a reduction in Glut3 mRNA and GLUT1 protein. However, exposed placentas exhibited an adaptation, characterized by increased GLUT4 expression and membrane localization of both GLUT1 and GLUT4. Placental perfusion confirmed these molecular changes, revealing increased glucose flux in exposed placentas compared to control (AUC 95% CI: 77.4 to 127.5 vs 39.1 to 73.6, respectively). Contrary to our hypothesis, exposure to these nanoparticles enhanced glucose transport across the placenta. Here we have demonstrated that inhaling airborne pollutants during pregnancy modulates placental function and nutrient transport mechanisms, which can have direct effects on fetal development. Furthermore, we provide evidence for targeted interventions, aimed at mitigating fetal developmental pathologies.\n\nHighlightsO_LIGestational inhalation of nanoparticles decreases GLUT1 expression in the placenta.\nC_LIO_LIThe placenta adapts to gestational nanoparticle inhalation by enhancing GLUT4 expression and GLUT1 and GLUT4 membrane localization.\nC_LIO_LIEx vivo placental perfusion demonstrated increased glucose flux across to the placenta to the fetus following gestational inhalation of nanoparticles.\nC_LI","rel_num_authors":6,"rel_authors":[{"author_name":"Talia Seymore","author_inst":"Rutgers University"},{"author_name":"Sara Hoffmann","author_inst":"Bucknell University"},{"author_name":"Pedro Louro","author_inst":"Rutgers University"},{"author_name":"Carol Gardner","author_inst":"Rutgers University"},{"author_name":"Michael Goedken","author_inst":"Rutgers University"},{"author_name":"Phoebe Stapleton","author_inst":"Rutgers University"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Benchmarking cell type annotation in spatial transcriptomics: resolving cellular hierarchies, biological fidelity, and dynamic cell states","rel_doi":"10.64898\/2026.06.16.732716","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732716","rel_abs":"Spatial transcriptomics enables the quantification of gene expression within its native tissue context, providing unprecedented insight into tissue architecture, cellular ecosystems, and local cell-cell interactions at regional and single-cell resolution. Accurate cell type annotation is a critical prerequisite for interpreting these data and is often the first and most essential step in downstream analysis. Despite rapid advances in computational methods, cell type annotation remains challenging and frequently requires extensive expert-driven manual curation based on marker-gene expression, spatial context, and prior biological knowledge. While early approaches relied primarily on transcriptional similarity, newer methods increasingly incorporate spatial information, histological features, and multimodal data to improve annotation accuracy. Nevertheless, reliable annotation remains difficult when biological interpretation requires fine-grained subtype resolution, particularly for platforms with limited gene panels, tissues undergoing dynamic cellular state transitions, and studies in which reference and query datasets differ substantially in biological context or technical modality. Here, we present a systematic benchmark of 20 state-of-the-art cell type annotation methods across four spatial transcriptomics datasets spanning diverse technologies, experimental conditions, cell numbers, and gene panel sizes. Importantly, all benchmark datasets contain expert-curated cell type labels, including well-resolved cell populations and subtype annotations, providing high-quality biological ground truth for evaluation. The benchmark encompasses both reference-based and reference-free methods representing a broad range of computational frameworks. Performance was assessed using conventional classification metrics, including accuracy and F1-based measures, together with structure-aware metrics that evaluate both cell-level annotation accuracy and preservation of higher-order biological organization. Across datasets, annotation performance varied substantially according to tissue context, reference-query similarity, and annotation granularity. Fine-grained subtype annotation and recovery of rare cell populations remained challenging for many methods, particularly in datasets capturing injury, repair, developmental, and regenerative processes characterized by continuous cellular state transitions. Notably, high classification accuracy did not necessarily correspond to preservation of global cellular relationships or biologically coherent downstream pathway and gene-set enrichment analyses. Overall, scANVI, Seurat, and TACCO consistently ranked among the top-performing methods, although their relative advantages were context dependent. Together, our results provide a comprehensive assessment of current annotation strategies for spatial transcriptomics and offer practical guidance for selecting methods that best align with specific biological questions, dataset characteristics, and analytical priorities.","rel_num_authors":12,"rel_authors":[{"author_name":"Yuling Zhu","author_inst":"Department of Biomedical Engineering"},{"author_name":"Yunfei Hu","author_inst":"Department of Computer Science"},{"author_name":"Manfei Bella Xie","author_inst":"Department of Biomedical Engineering"},{"author_name":"Haoran Qin","author_inst":"Department of Computer Science"},{"author_name":"Zuzanna J Szul","author_inst":"Department of Computer Science"},{"author_name":"Derek M Young","author_inst":"Department of Biomedical Engineering"},{"author_name":"Weiman Yuan","author_inst":"Department of Biomedical Engineering"},{"author_name":"Qimeng Wang","author_inst":"Department of Pharmacology"},{"author_name":"Yichen Henry Liu","author_inst":"Department of Computer Science"},{"author_name":"Wenjun Shen","author_inst":"Department of Bioinformatics"},{"author_name":"Shan Meltzer","author_inst":"Department of Pharmacology"},{"author_name":"Xin Maizie Zhou","author_inst":"Department of Biomedical Engineering"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"CellTosg2Sequence: A Unified Text-Omics-Signaling-Graph Large Language Model for Single-Cell Analysis","rel_doi":"10.64898\/2026.06.16.732397","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732397","rel_abs":"bioRxivLaTeXUnicodeabstract --- In single-cell (sc)-based scientific discovery, text-formatted biomedical prior knowledge and signaling graphs are essential for annotating and interpreting numeric sc-omics data and for generating novel testable hypotheses. A major limitation of existing single-cell large language models (scLLMs) is that they rely on numeric expression data with gene names as the only textual signal, while comprehensive biomedical priors -- cellular localization, gene function, disease associations, and signaling interaction patterns -- remain absent from the model input. We introduce CellTosg2Sequence, a textual-prior- and signaling-graph-augmented cell-omics-sentence language model. A lightweight heterogeneous graph encoder maps a curated 62,507-node biomedical knowledge graph (KG) into compact virtual tokens that are prepended to each cell sentence, allowing the language model to condition on biological structure with minimal sequence-length overhead. We train CellTosg2Sequence with a three-stage objective: Stage I anchors the KG channel under autoregressive language-model pretraining, leveraging Qwen2.5-32B's own language reasoning for rapid KG alignment; Stage II aligns labels via supervised fine-tuning with KG-anchored InfoNCE; Stage III applies Group Relative Policy Optimization (GRPO) with an ontology-hierarchy reward, enabling free-generation cell-type prediction that generalizes beyond the closed training vocabulary. Across multiple benchmarks and ablation experiments, CellTosg2Sequence outperforms strong baselines. All results are achieved with lightweight LoRA training and a single unified checkpoint.","rel_num_authors":10,"rel_authors":[{"author_name":"weihang chen","author_inst":"Washington University in St. Louis"},{"author_name":"Mingrui Ye","author_inst":"Washington University in St. Louis"},{"author_name":"Tianqi Xu","author_inst":"Washington University in St. Louis"},{"author_name":"Di Huang","author_inst":"Washington University in St. Louis"},{"author_name":"Heming Zhang","author_inst":"Washington University in St. Louis"},{"author_name":"Hao Li","author_inst":"Washington University in St. Louis"},{"author_name":"Wenyu Li","author_inst":"Washington University in St. Louis"},{"author_name":"Yixin Chen","author_inst":"Washington University in St. Louis"},{"author_name":"Philip R Payne","author_inst":"Washington University in St. Louis"},{"author_name":"Fuhai Li","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Metabolomic Network Analysis Reveals Reorganization of Lipid and Steroid Programs Linked to Right Ventricular-Pulmonary Vascular Function in Pulmonary Hypertension","rel_doi":"10.64898\/2026.06.16.732773","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732773","rel_abs":"BackgroundPulmonary arterial hypertension (PAH) is characterized by circulating metabolic alterations, but whether these reflect disease-specific metabolic programs or reorganization of normal metabolic architecture, and how they relate to right ventricular-pulmonary vascular function (RV-PV), remains unclear. We hypothesized that the PAH metabolome is organized into biologically coherent, co-regulated metabolic modules whose relationships to RV-PV function would provide insight into known and novel metabolic pathways.\n\nMethodsWe applied weighted gene co-expression network analysis (WGCNA) to untargeted metabolomic data from 412 PAH patients enrolled in the multicenter PVDOMICS study. Module preservation analysis was performed in 85 healthy controls, with external replication in an independent single-center pulmonary hypertension cohort of 89 patients.\n\nResultsWGCNA identified 16 distinct metabolic modules organized around biologically coherent programs. A coherent fatty acid axis, spanning substrate pools, {beta}-oxidation intermediates, and conjugated fatty acid disposal products, formed a central organizing structure, with downstream fatty acid oxidation modules strongly associated with adverse hemodynamics and worse RV-pulmonary artery (PA) coupling. Acylcholine-enriched and 5-reduced androgen metabolite modules were associated with favorable hemodynamic indices. Module architecture was largely preserved in healthy controls, with subtle disease-associated modular reorganization, rather than emergence of novel modules, observed in PAH. Core modules were recovered in the replication cohort with conserved hub metabolites.\n\nConclusionsThese findings establish a systems-level framework demonstrating that PAH involves structured intensification and reorganization of interconnected metabolic programs associated with favorable and adverse RV-PV phenotypes. This work provides new insight into the metabolic architecture underlying PAH and identifies coordinated metabolic pathways linked to pulmonary vascular and right ventricular function.","rel_num_authors":26,"rel_authors":[{"author_name":"Ivor Clinton","author_inst":"Johns Hopkins University"},{"author_name":"- PVDOMICS Study Group","author_inst":"-"},{"author_name":"Julie Coursen","author_inst":"Johns Hopkins University"},{"author_name":"Darin Rosen","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Karthik Suresh","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Aparna Balasubramanian","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Todd Matthew Kolb","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Rachel L Damico","author_inst":"University of Miami"},{"author_name":"Stephen C Mathai","author_inst":"Johns Hopkins Medical Institutions, Baltimore, MD"},{"author_name":"Steven Hsu","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Monica Mukherjee","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"J. Emanuel Finet","author_inst":"Cleveland Clinic"},{"author_name":"Gabriele Grunig","author_inst":"New York University Grossman School of Medicine"},{"author_name":"John Barnard","author_inst":"Cleveland Clinic"},{"author_name":"Anna R. Hemnes","author_inst":"Vanderbilt University"},{"author_name":"Jane A. Leopold","author_inst":"Brigham and Women's Hospital"},{"author_name":"Evelyn M Horn","author_inst":"Weill Cornell Medical College"},{"author_name":"Erika B. Rosenzweig","author_inst":"Westchester Medical Center"},{"author_name":"Franz Rischard","author_inst":"University of Arizona"},{"author_name":"Robert P Frantz","author_inst":"Mayo Clinic"},{"author_name":"Serpil Erzurum","author_inst":"Cleveland Clinic"},{"author_name":"Wendy King","author_inst":"Cleveland Clinic"},{"author_name":"Gerald Beck","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Nicholas S. Hill","author_inst":"Tufts University School of Dental Medicine"},{"author_name":"Paul Hassoun","author_inst":"Johns Hopkins University"},{"author_name":"Catherine E. Simpson","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Metabolomic Network Analysis Reveals Reorganization of Lipid and Steroid Programs Linked to Right Ventricular-Pulmonary Vascular Function in Pulmonary Hypertension","rel_doi":"10.64898\/2026.06.16.732773","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732773","rel_abs":"BackgroundPulmonary arterial hypertension (PAH) is characterized by circulating metabolic alterations, but whether these reflect disease-specific metabolic programs or reorganization of normal metabolic architecture, and how they relate to right ventricular-pulmonary vascular function (RV-PV), remains unclear. We hypothesized that the PAH metabolome is organized into biologically coherent, co-regulated metabolic modules whose relationships to RV-PV function would provide insight into known and novel metabolic pathways.\n\nMethodsWe applied weighted gene co-expression network analysis (WGCNA) to untargeted metabolomic data from 412 PAH patients enrolled in the multicenter PVDOMICS study. Module preservation analysis was performed in 85 healthy controls, with external replication in an independent single-center pulmonary hypertension cohort of 89 patients.\n\nResultsWGCNA identified 16 distinct metabolic modules organized around biologically coherent programs. A coherent fatty acid axis, spanning substrate pools, {beta}-oxidation intermediates, and conjugated fatty acid disposal products, formed a central organizing structure, with downstream fatty acid oxidation modules strongly associated with adverse hemodynamics and worse RV-pulmonary artery (PA) coupling. Acylcholine-enriched and 5-reduced androgen metabolite modules were associated with favorable hemodynamic indices. Module architecture was largely preserved in healthy controls, with subtle disease-associated modular reorganization, rather than emergence of novel modules, observed in PAH. Core modules were recovered in the replication cohort with conserved hub metabolites.\n\nConclusionsThese findings establish a systems-level framework demonstrating that PAH involves structured intensification and reorganization of interconnected metabolic programs associated with favorable and adverse RV-PV phenotypes. This work provides new insight into the metabolic architecture underlying PAH and identifies coordinated metabolic pathways linked to pulmonary vascular and right ventricular function.","rel_num_authors":26,"rel_authors":[{"author_name":"Ivor Clinton","author_inst":"Johns Hopkins University"},{"author_name":"- PVDOMICS Study Group","author_inst":"-"},{"author_name":"Julie Coursen","author_inst":"Johns Hopkins University"},{"author_name":"Darin Rosen","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Karthik Suresh","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Aparna Balasubramanian","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Todd Matthew Kolb","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Rachel L Damico","author_inst":"University of Miami"},{"author_name":"Stephen C Mathai","author_inst":"Johns Hopkins Medical Institutions, Baltimore, MD"},{"author_name":"Steven Hsu","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Monica Mukherjee","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"J. Emanuel Finet","author_inst":"Cleveland Clinic"},{"author_name":"Gabriele Grunig","author_inst":"New York University Grossman School of Medicine"},{"author_name":"John Barnard","author_inst":"Cleveland Clinic"},{"author_name":"Anna R. Hemnes","author_inst":"Vanderbilt University"},{"author_name":"Jane A. Leopold","author_inst":"Brigham and Women's Hospital"},{"author_name":"Evelyn M Horn","author_inst":"Weill Cornell Medical College"},{"author_name":"Erika B. Rosenzweig","author_inst":"Westchester Medical Center"},{"author_name":"Franz Rischard","author_inst":"University of Arizona"},{"author_name":"Robert P Frantz","author_inst":"Mayo Clinic"},{"author_name":"Serpil Erzurum","author_inst":"Cleveland Clinic"},{"author_name":"Wendy King","author_inst":"Cleveland Clinic"},{"author_name":"Gerald Beck","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Nicholas S. Hill","author_inst":"Tufts University School of Dental Medicine"},{"author_name":"Paul Hassoun","author_inst":"Johns Hopkins University"},{"author_name":"Catherine E. Simpson","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Upregulation of ATP-purinergic P2x2 receptors in the cochlea over-amplifies hearing sensitivity leading to hyperacusis and attenuation by antagonists","rel_doi":"10.64898\/2026.06.17.733049","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.733049","rel_abs":"Hearing hypersensitivity (hyperacusis) is a common hearing stress and can cause many psychological diseases, e.g., anxiety, learning disabilities, and attention-deficit\/hyperactivity disorder (ADHD). Here, we report an unexpected finding that the upregulation of P2x2 ATP-purinergic receptors in the cochlea links to hyperacusis generation. We found that P2x2 expression in the cochlea but not in auditory centers was upregulated in the hyperacusis generated by Cx26 deficiency. Overexpression of P2x2 in the cochlea also caused hyperacusis. Conversely, downregulation of P2x2 expression or administration of P2x2 antagonists attenuated hyperacusis. We further found that upregulation of P2x2 receptors in the cochlea increased outer hair cell (OHC) electromotility through the post-transcription functional modulation to potentiate active cochlear amplification leading to hearing hypersensitivity. Such enhancements in OHC electromotility and active cochlear amplification were also suppressed by P2x2 receptor antagonists. Overall, these findings demonstrate that P2x2-mediated ATP-purinergic signaling in the cochlea plays a critical role in hyperacusis generation; targeting P2x2 receptors can attenuate hyperacusis stress, which may also offer a therapeutic strategy for other related psychological comorbidities.\n\nSignificance statementHearing hypersensitivity is a common hearing stress and can cause many other psychological disorders. However, little is known about the underlying genetic and cellular mechanisms. Also, it lacks efficient drugs for their treatments in the clinic. In this study, we found that upregulation of P2x2 ATP-purinergic receptors in the cochlea can potentiate outer hair cell electromotility, which is an active cochlear amplifier in mammals and can increase hearing sensitivity and frequency selectivity, through post-transcription functional modulation to enhance active cochlear amplification leading to hearing hypersensitivity. These enhancements can be inhibited by administrations of P2x2 receptor antagonists both in vitro and in vivo. These findings revealed a new genetic and cellular mechanism underlying hyperacusis generation and opened a new avenue to develop an efficient therapy for this common hearing stress and other associated psychological comorbidities.","rel_num_authors":8,"rel_authors":[{"author_name":"Tian-Ying Zhai","author_inst":"Yale University School of Medicine"},{"author_name":"Chun Liang","author_inst":"Yale University School of Medicine"},{"author_name":"Jin Chen","author_inst":"Yale University School of Medicine"},{"author_name":"Jie Yang","author_inst":"Yale University School of Medicine"},{"author_name":"Yong Kong","author_inst":"Yale University School of Public Health"},{"author_name":"Yan Zhu","author_inst":"University of Kentucky Medical Center"},{"author_name":"Ning Yu","author_inst":"University of Kentucky Medical Center"},{"author_name":"Hong-Bo Zhao","author_inst":"Yale University School of Medicine"}],"rel_date":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Seeing the world in a grain of sand: Fine global and local representations in foveal and parafoveal vision","rel_doi":"10.64898\/2026.06.16.732548","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732548","rel_abs":"Foveal vision enables primates to perceive small objects with remarkable precision by resolving both global form and fine local detail. Here, we challenge current frameworks of coarse-to-fine spatial analysis and local-to-global feature integration, which posit that V1 encodes fine local detail, whereas IT represents global. We found that fine-global structure and fine-local detail are jointly encoded neuronally as early as V1 and preserved across V2, V4 and IT across both foveal (1{degrees}-2{degrees}) and parafoveal (2{degrees}-6{degrees}) retinal eccentricities. By contrast, coarse-global features dominated parafoveal vision and higher cortical areas. Response latencies revealed a rapid processing sequence, with 2-6 ms separating coarse-global, fine-local, and fine-global processing within parafoveal V1, V2 and V4. These findings establish a neuronal framework supporting fine-scale visual perception and behavior.","rel_num_authors":21,"rel_authors":[{"author_name":"Jiapeng Yin","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":"Zheyuan 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":"Yizhejun Li","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":"Wenheng Xie","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":"Weibin Song","author_inst":"Peking University School of Life Sciences"},{"author_name":"Tianye Wang","author_inst":"Peking University School of Life Sciences; IDG\/McGovern Institute for Brain Research at Peking University"},{"author_name":"Ye Liu","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":"Yingfan Liu","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":"Hetian Cao","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":"Xiaotao Wang","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":"Yongyu Wang","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":"Lixuan Liu","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":"Jinghao Ge","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":"Xiaohong Li","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":"Lothar Spillmann","author_inst":"University Hospital Freiburg"},{"author_name":"Stewart Shipp","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":"Niall McLoughlin","author_inst":"Division of Pharmacy & Optometry, University of Bradford"},{"author_name":"Ian Max Andolina","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":"Yiliang Lu","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":"Shiming Tang","author_inst":"Peking University School of Life Sciences; IDG\/McGovern Institute for Brain Research at Peking University"},{"author_name":"Wei Wang","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":"2026-06-22","rel_site":"biorxiv"},{"rel_title":"Validation of an Artificial Intelligence-Assisted Mobile Application for Dietary Oxalate Assessment in Kidney Stone Prevention","rel_doi":"10.64898\/2026.06.16.26355631","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355631","rel_abs":"BackgroundCalcium oxalate nephrolithiasis is the most common type of kidney stone disease. Dietary oxalate intake is an important modifiable factor. Assessing dietary oxalate exposure in clinical practice poses challenges due to limitations of traditional dietary recall tools and variability in food composition data. Artificial intelligence (AI) applications in mobile health may offer scalable solutions for better dietary monitoring and kidney stone prevention. We examined the ability of StoneFree AI to estimate dietary oxalate from verbal and image-based food inputs.\n\nObjectiveTo evaluate the accuracy and limitations of StoneFree AI, for estimating dietary oxalate intake from verbal food descriptions and meal images, and to evaluate errors from entries that may inform future clinical use in kidney stone prevention.\n\nMethodsStoneFree AI is a cross-platform mobile application that uses a multimodal large language model (Google Gemini) to interpret verbal food descriptions and visual food images. The identified foods were mapped to oxalate values using the Harvard Oxalate Database. System performance was evaluated using 804 verbal food entries and 276 portion-size food images obtained from the ASA24 dietary assessment database. Verbal inputs were compared with reference oxalate values using absolute error and predefined agreement thresholds ({+\/-}1, {+\/-}5, {+\/-}10 mg). Image-based inputs were evaluated against mutually exclusive primary error categories, including food identification, portion estimation, ingredient recognition, oxalate reference selection, and non-analyzable cases.\n\nResultsFor verbal food entries, the AI system showed strong agreement with reference oxalate values. Overall, 82.1% of estimates were within {+\/-}1 mg, 91.5% within {+\/-}5 mg, and 94.5% within {+\/-}10 mg of reference values. The mean absolute error was 3.32 mg, the median absolute error was 0.10 mg, and the concordance correlation coefficient (CCC) was 0.860. Image-based inputs showed a higher overall error rate of 63.0%, primarily due to food identification errors (33.0%), inaccurate portion estimation (11.0%), and ingredient recognition errors (9.8%). Most errors occurred with visually complex meals, such as mixed dishes and grain-based foods.\n\nConclusionsAI-assisted estimation of dietary oxalate intake demonstrated high accuracy when structured verbal inputs were used but was less reliable for image-based meal analysis. These findings suggest AI-enabled mobile tools may support dietary monitoring for kidney stone prevention, particularly when user input is structured. Further refinement of computer vision models and prospective clinical validation are required before widespread clinical implementation.","rel_num_authors":8,"rel_authors":[{"author_name":"Kymora B. Scotland","author_inst":"Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California"},{"author_name":"Olumide A Ojo","author_inst":"Charles R Drew University College Of Medicine"},{"author_name":"Ferdinand Anokwuru","author_inst":"Charles R. Drew University College of Medicine, Los Angeles, California"},{"author_name":"Jessica Javaherforoush","author_inst":"University of California, Los Angeles"},{"author_name":"Janelly Jimenez","author_inst":"Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California"},{"author_name":"Andersen Teoh","author_inst":"MarinHealth Urology | A UCSF Health Clinic, Greenbrae, California"},{"author_name":"Bhushan Suryavanshi","author_inst":"The Wharton School, University of Pennsylvania | Philadelphia, PA"},{"author_name":"Robert Chan","author_inst":"MarinHealth Urology | A UCSF Health Clinic, Greenbrae, California"}],"rel_date":"2026-06-19","rel_site":"medrxiv"},{"rel_title":"Fine-Tuning SAM2 for Coronary Artery Segmentation in X-Ray Fluoroscopy","rel_doi":"10.64898\/2026.06.16.26355803","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355803","rel_abs":"SAM2 [Ravi et al., 2024] (Meta, 2024) provides a strong starting point for segmentation, but given the unique challenges in medical imaging (noise from patient movement, the projection-based nature of X-ray fluoroscopy, and low contrast between vessels and background), direct application is difficult. We fine-tune MedSAM2 [Ma et al., 2025] on annotated coronary angiograms and apply it to video data for point-of-care use. On the ARCADE validation set [Popielarski et al., 2024] (200 images), the fine-tuned model achieves Dice 0.767 {+\/-} 0.082 compared to 0.033 zero-shot. In 10 fluoroscopic video studies from CoronaryDominance [Danilov et al., 2025], it tracks vessels coherently and avoids false segmenting of ribs, stents, and bypass grafts in 9 of 10 studies. Code is available here and the fine-tuned checkpoint here.","rel_num_authors":1,"rel_authors":[{"author_name":"Elakiya Sivakumar","author_inst":"Columbia University"}],"rel_date":"2026-06-19","rel_site":"medrxiv"}]}