{"gname":"University of California, San Francisco","grp_id":"10","rels":[{"rel_title":"A ReAct Agentic AI System for Natural Language Querying and Statistical Analysis of The Cancer Genome Atlas Clinical Data","rel_doi":"10.64898\/2026.07.15.26358188","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.15.26358188","rel_abs":"The Cancer Genome Atlas (TCGA) holds clinical data for over 11,000 patients across 33 cancer types, but access is hard because of complex file structures, heterogeneous formats, and the need for programming. We present an agentic system for natural language querying and statistical analysis of TCGA clinical data. The system uses a large language model as an autonomous ReAct agent that selects from eight computational tools, including data extraction, descriptive statistics, Kaplan-Meier survival analysis with log-rank tests, hypothesis testing, and verification against the curated TCGA Pan-Cancer Clinical Data Resource (CDR). The agent reasons about intermediate results, adapts its approach, and returns clinically contextualized responses with source attribution and auditable traces. We introduce TCGA-Agent-Bench, 440 queries across five difficulty tiers with ground truth from the independently curated TCGA-CDR, evaluated with dual metrics of numerical accuracy and clinical completeness. The system achieves 93.4% overall accuracy (100% single-patient lookups, 99.1% cohort statistics, 92.8% comparative analyses), outperforming a fixed rule-based pipeline (87.1%), a single-pass LLM (81.8%), and retrieval-augmented generation (66.9% on a subset). Most of the benchmark is answerable from the CDR alone, so we locate the extraction layer's value in fields the CDR lacks (drug treatments, TNM components, biomarkers, biospecimen metadata): on 26 queries targeting these, the full system answers 100% versus 3.8% for CDR-only. Ablations show the reasoning loop is most impactful (+9.1% accuracy, +22.0 completeness points). A tool-based agentic architecture enables accurate, auditable analysis of clinical repositories, with value driven by tool design and recovered fields rather than model scale.","rel_num_authors":2,"rel_authors":[{"author_name":"Rajashekar Korutla","author_inst":"Northeastern University"},{"author_name":"Saeed Amal","author_inst":"Northeastern University"}],"rel_date":"2026-07-17","rel_site":"medrxiv"},{"rel_title":"Toward precision rehabilitation in adolescent mild traumatic brain injury: leveraging physiologic data from commercially available smartwatches to identify patient subgroups","rel_doi":"10.64898\/2026.07.16.26358245","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.16.26358245","rel_abs":"Autonomic dysfunction is a common sequela of mild traumatic brain injury (mTBI). Physical activity progression is an integral component of mTBI rehabilitation, particularly in addressing autonomic dysfunction. However, clinicians often rely on point-in-time evaluation of orthostatic and exercise intolerance to guide activity recommendations. Commercially available wearable devices (e.g., Fitbits) provide an opportunity to evaluate heart rate response to activity in a real-world setting. Previous work has used physiologic (heart rate) and activity (step count) data to identify subgroups of adults with stroke that may be used to guide activity recommendations. This method may be useful to subgroup youth post-mTBI to identify those who have abnormal physiologic responses to activity. We aimed to identify subgroups using heart rate and step count data in adolescents presenting for specialty care after diagnosed mTBI. Eighty participants aged 13-18 within six months of mTBI diagnosis were recruited to wear a Fitbit Sense 2. Data from seven days and two nights collected within fourteen days of enrollment were included. A group-based steps per minute (SPM) threshold (25th percentile; 10 SPM) and individualized heart rate threshold (20% heart rate reserve (HRR)) were used to classify each minute of active daytime data into one of four quadrants: SPM>10 & HRR>20% (QI), SPM<10 & HRR>20% (QII), SPM<10 & HRR<20% (QIII), and SPM>10 & HRR<20% (QIV). We used percentage of minutes in each quadrant, mean steps per day, percentage of minutes with zero steps, mean SPM in QI, and resting heart rate in a k-means clustering algorithm to identify subgroups. We evaluated subgroup differences by clustering variables using Kruskal-Wallis tests. Sixty-one participants were included. Three subgroups emerged: Sedentary (n=12), Active (n=23), and Atypically Elevated Heart Rate (AEHR; n=26). Subgroups varied significantly on all clustering variables (p<0.01). The Active subgroup took a high number of steps per day, had lower sedentary time, and had the highest activity intensity (mean SPM in QI). The Sedentary subgroup took fewer steps per day compared to the Active subgroup, had high sedentary time, and showed the highest resting heart rate. The AEHR subgroup took fewer steps per day compared to the Active subgroup and had high sedentary time. The AEHR subgroup also spent a higher percentage of time with an atypically high heart rate response to low levels of activity compared to the other subgroups. Our findings suggest that data from wearable devices can identify subgroups of adolescents with mTBI with distinct physiologic\/physical activity profiles, which may ultimately be used to inform personalized activity prescriptions. Future work should aim to understand how the identified subgroups relate to longitudinal outcomes.","rel_num_authors":6,"rel_authors":[{"author_name":"Sarah A Kettlety","author_inst":"Kennedy Krieger Institute\/Johns Hopkins University School of Medicine"},{"author_name":"Emily R Akrong","author_inst":"Kennedy Krieger Institute"},{"author_name":"Stacy J Suskauer","author_inst":"Kennedy Krieger Institute\/Johns Hopkins University School of Medicine"},{"author_name":"Ryan T Roemmich","author_inst":"Kennedy Krieger Institute\/Johns Hopkins University School of Medicine"},{"author_name":"Beth S Slomine","author_inst":"Kennedy Krieger Institute\/Johns Hopkins University School of Medicine"},{"author_name":"Adrian M Svingos","author_inst":"Kennedy Krieger Institute\/Johns Hopkins University School of Medicine"}],"rel_date":"2026-07-17","rel_site":"medrxiv"},{"rel_title":"Prescribing Trends of Antimicrobials in Obstetric and Gynaecological Inpatients: A Prospective Drug Utilization Study with Concurrent Antimicrobial Stewardship Audit from a Tertiary Care Hospital in Karachi, Pakistan","rel_doi":"10.64898\/2026.07.16.26358229","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.16.26358229","rel_abs":"Background: Antimicrobial resistance (AMR) disproportionately affects low- and middle-income countries (LMICs) such as Pakistan, where obstetric and gynaecological (OBGYN) patients carry high antibiotic exposure. Specialty-specific drug utilization data with concurrent stewardship audit remain scarce. This study evaluated antibiotic prescribing patterns, consumption metrics, and antimicrobial stewardship program (AMS) compliance in OBGYN inpatients at a public sector tertiary care hospital. Methods: A prospective cross-sectional study was conducted in OBGYN wards of Dow University Hospital, Karachi, from 1 September to 31 October 2025. Women receiving [&ge;]1 systemic antibiotic were included. Daily AMS rounds were conducted by an Infectious Diseases physician and pharmacist. Antibiotic consumption was measured as Defined Daily Doses (DDD) and Days of Therapy (DOT) per 1,000 patient-days (total = 821). Antibiotics were classified by WHO AWaRe (2023) framework. Results: Of 812 total admissions, 278 patients (34.2%) received [&ge;]1 antibiotic and were enrolled (205 obstetric, 73 gynaecological), generating 636 prescriptions (mean 2.29\/patient). Surgical prophylaxis was the predominant documented indication (213, 33.5%); 65.1% carried no documented indication. By AWaRe classification, 53.6% were Access-group and 46.1% Watch-group. Ceftriaxone (38.4%) and metronidazole (36.8%) together represented 75.2% of prescriptions. Combined DDD\/1,000 patient-days was 1,758.6 and DOT\/1,000 patient-days was 1,852.7. AMS compliance was 0%. Conclusions: This study documents high antibiotic prescribing burden, near-universal documentation failure, and zero AMS compliance in OBGYN inpatients at a Pakistani public sector hospital. The predominance of Watch-group antibiotics and undocumented surgical prophylaxis highlights structural stewardship gaps. Findings support urgent need for institutional OBGYN antibiotic guidelines and structured pharmacist-led AMS programs.","rel_num_authors":9,"rel_authors":[{"author_name":"Tehreem Ansari","author_inst":"Department of Infectious Diseases, Dow University Hospital, Dow University of Health Sciences, Karachi, Pakistan"},{"author_name":"Ale Zehra","author_inst":"Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Dow College of Pharmacy, Dow University of Health Sciences, Karachi, Pakistan"},{"author_name":"Shazia Jabbar","author_inst":"Department of Obstetrics and Gynaecology, DIMC, Dow University Hospital, Dow University of Health Sciences, Karachi, Pakistan"},{"author_name":"Mehreen Fatima","author_inst":"Department of Infectious Diseases, National Institute of Cardiovascular Diseases, Karachi, Pakistan"},{"author_name":"Beenish Syed","author_inst":"Department of Infectious Diseases, Dow University Hospital, Dow University of Health Sciences, Karachi, Pakistan"},{"author_name":"Syed Shaukat Ali Muttaqi Shah","author_inst":"Department of Clinical Pharmacy, College of Pharmacy, Al-Farahidi University, Baghdad, Iraq."},{"author_name":"Amber Sabeen Ahmed","author_inst":"Department of Internal Medicine and Critical Care Medicine, Aga Khan University Hospital, Karachi, Pakistan."},{"author_name":"Aasma Hamid","author_inst":"Department of Pharmacy Services, Dow University Hospital, Dow University of Health Sciences, Karachi, Pakistan"},{"author_name":"Hafsah Ashafaq","author_inst":"Department of Pharmacy Services, Dow University Hospital, Dow University of Health Sciences, Karachi, Pakistan"}],"rel_date":"2026-07-17","rel_site":"medrxiv"},{"rel_title":"FoodScribe: an open-source semantic framework for nutrient estimation from free-text dietary records","rel_doi":"10.64898\/2026.07.15.26358181","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.15.26358181","rel_abs":"Efficiently summarizing dietary records at scale remains a persistent bottleneck in nutritional epidemiology. We present FoodScribe, which translates free-text meal descriptions into quantitative nutrient profiles by combining ingredient parsing with nutrient retrieval by querying the USDA FoodData Central (FDC) database. Benchmarked using three LLM providers using Nutribench dataset, FoodScribe completed annotation of 3,807 meal descriptions in 2.5 hours, a task otherwise requiring substantial manual effort from trained nutritionists. FoodScribe achieved accuracy across macronutrient estimation (F1=0.79-0.89), with models performing better for protein than fat estimation. Application to a Mediterranean diet intervention cohort indicated dietary shifts consistent with the intervention pattern based on model-derived estimates. Integration with metabolomics data suggested that fiber and vegetable intake were positively associated with a fecal metabolite cluster.","rel_num_authors":11,"rel_authors":[{"author_name":"Harsha Gouda","author_inst":"University of California, San Diego"},{"author_name":"Marta Sala Climent","author_inst":"University of California San Diego"},{"author_name":"Julius Agongo","author_inst":"University of California San Diego"},{"author_name":"Sayli P Gaikwad","author_inst":"University of California San Diego"},{"author_name":"Annie Nattakom","author_inst":"University of California San Diego"},{"author_name":"Haoqi Nina Zhao","author_inst":"University of California San Diego"},{"author_name":"Shipie Xing","author_inst":"University of California San Diego"},{"author_name":"Brigid S Boland","author_inst":"University of California San Diego"},{"author_name":"Tiffany Holt","author_inst":"University of California San Diego"},{"author_name":"Monica Guma","author_inst":"University of California San Diego"},{"author_name":"Pieter C. Dorrestein","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-17","rel_site":"medrxiv"},{"rel_title":"A decision analytic framework for triggering cholera outbreak response based on early-case surveillance","rel_doi":"10.64898\/2026.07.16.26358045","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.16.26358045","rel_abs":"Background: Cholera outbreaks can spread rapidly, which means that the optimal decision-making window for a large, coordinated response is very narrow. Alerts for triggering interventions need to balance tradeoffs between wasting resources on false positives and delaying decisions until they lose effectiveness. A systematic evaluation of such tradeoffs across settings is needed to understand which alerts may have the greatest public health utility and where. Methods: Using weekly suspected cholera surveillance across 4,081 subnational administrative units across 34 countries in Africa from 2010-2023, we evaluated 24 alert definitions (4 alert types with different numeric thresholds) over a 1-year post-alert period on five utility dimensions - potential health impact, potential intervention efficiency, positive predictive value (PPV) for large outbreaks, proportion of missed outbreaks, and timeliness of alert trigger. The dimensions were combined into a utility score, which was used to identify the best alert across the continent and by country. For top-performing alerts, we estimated the reduction in potential health impact for additional delays in response using Bayesian hierarchical models. Results: Fifty suspected cases for three consecutive weeks was the definition with the highest utility score across most contexts. In administrative units with 50,000 to 500,000 people, the year following such an alert experienced a mean of 376 suspected cases (standard deviation: 618.3) and 2 cases per 1000 population (SD: 4.1). Forty percent of such alerts (N alerts: 265) were followed by a 1-year period with over 300 cases, yet the definition missed 40% of outbreaks with over 300 cases (N outbreaks: 278) and was triggered 5.3 weeks (SD: 5) after outbreak start. Each week of delay was estimated to result in an additional 20% reduction (95% CrI: -23 to -17) of potential health impact in the outbreak response. One hundred cases over a three-week period was another definition that had high utility, particularly in administrative units with smaller populations and country-specific evaluations. Conclusion: We present a decision analytic framework that can be deployed in a short decision-making window using case-based surveillance to trigger large-scale cholera response activities with moderately high utility across most African transmission contexts. Future work should consider adaptations based on local data availability and priorities and examine the generalizability of early case-based signals outside Africa.","rel_num_authors":6,"rel_authors":[{"author_name":"Christina Alam","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Qulu Zheng","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Javier Perez-Saez","author_inst":"University of Geneva"},{"author_name":"Andrew S Azman","author_inst":"University of Geneva"},{"author_name":"Jong-Hoon Kim","author_inst":"International Vaccine Institute"},{"author_name":"Elizabeth C Lee","author_inst":"University of Geneva"}],"rel_date":"2026-07-17","rel_site":"medrxiv"},{"rel_title":"Statistical Inference and Power Analysis for Comparative F1 and F\u03b2 Scores under Correlated Classifier Pairs","rel_doi":"10.64898\/2026.07.15.26358166","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.15.26358166","rel_abs":"As machine learning and artificial intelligence systems are increasingly used in healthcare, rigorous evaluation of their classification performance has become critical. The F1 and F{beta} scores are widely adopted metrics for assessing performance in imbalanced biomedical data. Recently, we introduced psF1, a unified statistical framework for inference and study design for single and comparative F1 and F{beta} scores under the assumption of independent classifiers. In practice, however, benchmarking two classifiers on the same dataset creates a correlated paired setting. Ignoring this intrinsic dependency leads to overestimation of the standard error and a substantial loss of statistical power. To address this, we develop psF1pair, an advanced framework for statistical inference and power analysis that explicitly accounts for correlations between classifier pairs. Extensive simulation studies demonstrate the performance of psF1pair, and its utility is further illustrated through application to a real-world imaging classification system. As expected, higher correlation between classifiers yields narrower confidence intervals and enhanced statistical power. A freely available R package is provided to facilitate implementation, supporting accurate evaluation and study design for predictive and classification models in biomedical research.","rel_num_authors":3,"rel_authors":[{"author_name":"Chih-Yuan Hsu","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center"},{"author_name":"Qi Liu","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center"},{"author_name":"Yu Shyr","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center"}],"rel_date":"2026-07-17","rel_site":"medrxiv"},{"rel_title":"Explainable, personalised prediction of emergency readmission and mortality following hospitalisation in patients with heart failure","rel_doi":"10.64898\/2026.07.15.26358201","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.15.26358201","rel_abs":"Background: Unplanned emergency readmissions remain common following hospitalisation for heart failure (HF). Residual congestion, atrial fibrillation, frailty, and other comorbidities contribute to adverse outcomes after discharge. Identifying patients at high risk of readmission or death may help target post-discharge management. Methods: We conducted a retrospective cohort study of patients hospitalised with HF in selected New South Wales hospitals who were discharged alive and not documented as receiving end-of-life care. Clinical, laboratory, medication, and text-derived variables extracted from electronic health records were used to develop predictive models and corresponding risk scores for emergency readmission and all-cause mortality within 180 days of discharge. Feature importance methods were used to identify key predictors and explain individual risk estimates. To illustrate model predictions while preserving patient privacy, we generated representative synthetic patient profiles by summarising the characteristics of groups of patients with similar predicted risk patterns and visualised the major contributors to their predicted risks using Shapley values. Results: The study included 5,202 hospitalisations among 3,933 patients. Within 180 days of discharge, 45.2% of patients experienced at least one emergency readmission and 12.4% died. The most common causes of emergency readmission were recurrent HF, followed by atrial fibrillation, chest pain, and pneumonia. Predictive performance was moderate for emergency readmission (AUC 0.70; calibration slope 1.30) and good for mortality (AUC 0.84; calibration slope 1.01). Emergency readmission risk was primarily associated with greater prior healthcare utilisation, a higher number of active medical problems, high risk of falls, older age, and impaired kidney function. Mortality risk was most strongly associated with abnormal red blood cell distribution width, elevated blood urea, older age, and lower systolic blood pressure. A lower number of discharge medications, particularly cardiovascular therapies, was associated with a higher risk of emergency readmission and a lower risk of mortality. Representative synthetic patient profiles demonstrated heterogeneity in the factors contributing to predicted risks, illustrating the value of patient-level risk visualisation. Conclusions: Predictive models identified clinically meaningful predictors of emergency readmission and mortality following HF hospitalisation. Patient-level visualisation of individual risk drivers may support more personalised post-discharge management.","rel_num_authors":7,"rel_authors":[{"author_name":"Blanca Gallego Luxan","author_inst":"University of New South Wales"},{"author_name":"Leo Huberts","author_inst":"University of Amsterdam"},{"author_name":"Jennifer Yu","author_inst":"Eastern Heart Clinic, Prince of Wales Hospital, Randwick, NSW 2031, Australia; University of New South Wales"},{"author_name":"Victoria Blake","author_inst":"University of New South Wales"},{"author_name":"Leibo Liu","author_inst":"University of New South Wales"},{"author_name":"Louisa Jorm","author_inst":"University of New South Wales"},{"author_name":"Sze-Yuan Ooi","author_inst":"Eastern Heart Clinic, Prince of Wales Hospital, Randwick, NSW 2031, Australia; University of New South Wales"}],"rel_date":"2026-07-17","rel_site":"medrxiv"},{"rel_title":"Scaling ECG Foundation Models and Identifying a Threshold for Effective Representation Learning","rel_doi":"10.64898\/2026.07.15.26358182","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.15.26358182","rel_abs":"We conducted a scaling evaluation of unlabeled pretraining for electrocardiogram foundation model performance. One-dimensional vision transformer masked autoencoders were pretrained across increasing ECG volumes and fine-tuned for rhythm, morphology, diagnostic, and structural heart disease tasks. Models pretrained below 400,000 ECGs failed to consistently exceed controls without self-supervised pre-training, whereas 600,000 to 800,000 ECGs improved AUROC across tasks, suggesting a minimum threshold for effective ECG representation learning.","rel_num_authors":8,"rel_authors":[{"author_name":"Raghav Sriram","author_inst":"University of Michigan"},{"author_name":"Ivan Nenadic","author_inst":"Division of Cardiology, Department of Medicine, Northwestern University, Feinberg School of Medicine Chicago"},{"author_name":"Elan Shahrabani","author_inst":"Department of Internal Medicine, University of California in Los Angeles"},{"author_name":"Sascha Goonewardena","author_inst":"University of Michigan Medical School"},{"author_name":"Shanshan Yao","author_inst":"Department of Internal Medicine, Division of Cardiovascular Medicine"},{"author_name":"Brennen Farrell","author_inst":"Department of Computer Science, North Carolina State University"},{"author_name":"Zak Loring","author_inst":"Duke Heart Center, Duke University Hospital"},{"author_name":"Venkatesh L. Murthy","author_inst":"University of Michigan"}],"rel_date":"2026-07-17","rel_site":"medrxiv"},{"rel_title":"Human GPR174 deficiency drives polyclonal lymphoproliferative disease via defects in T cell function","rel_doi":"10.64898\/2026.07.14.26357774","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26357774","rel_abs":"The X-linked G-protein coupled receptor GPR174 is highly expressed in T and B lymphocytes and has immunoregulatory roles in mice, but its function in humans is unknown. We describe a cohort of six individuals who have function-disrupting variants in GPR174 and a clinical phenotype of lymphadenopathy and autoimmunity. Histological analysis of two patient lymph nodes revealed necrotizing lymphadenitis and lymphoproliferation resembling Kikuchi-Fujimoto disease. In-depth analysis of three patients and related carriers revealed overaccumulation of CD8 terminally differentiated effector memory cells re-expressing CD45RA (TEMRA). Patient cells and GPR174-deficient CD8 T cells generated from controls showed less repression of proliferation by the GPR174 ligand lysophosphatidylserine (lysoPS) and an effector-biased gene expression program. GPR174-deficient CD4 T cells were resistant to lysoPS-mediated suppression of IL2 production. In mice, chronic viral infection led to over-accumulation of GPR174-deficient effector CD8 T cells. We describe an inborn error of immunity associated with dysregulated lymphocyte responses that we propose predisposes to exaggerated lymphoproliferation and autoimmunity following viral infection.","rel_num_authors":34,"rel_authors":[{"author_name":"Yun-Han Huang","author_inst":"University of California, San Francisco"},{"author_name":"Kathya Arana","author_inst":"University of Pennsylvania"},{"author_name":"Suzanna Rachimi","author_inst":"University of Pennsylvania"},{"author_name":"Hanson Tam","author_inst":"University of California, San Francisco"},{"author_name":"Jarmila Stremenova Spegarova","author_inst":"Newcastle University Translational and Clinical Research Institute"},{"author_name":"Karin R Engelhardt","author_inst":"Newcastle University Translational and Clinical Research Institute"},{"author_name":"Helen Griffin","author_inst":"Newcastle University Translational and Clinical Research Institute"},{"author_name":"Molly Mee","author_inst":"Newcastle University Translational and Clinical Research Institute"},{"author_name":"Maurizio Miano","author_inst":"IRCCS Instituto Giannina Gaslini"},{"author_name":"Federica Raggi","author_inst":"IRCCS Instituto Giannina Gaslini"},{"author_name":"Alice Grossi","author_inst":"IRCCS Instituto Giannina Gaslini"},{"author_name":"Marta Rusmini","author_inst":"IRCCS Instituto Giannina Gaslini"},{"author_name":"Isabella Ceccherini","author_inst":"IRCCS Instituto Giannina Gaslini"},{"author_name":"Gianluca Dell'Orso","author_inst":"IRCCS Instituto Giannina Gaslini"},{"author_name":"Jacopo Ferro","author_inst":"IRCCS Instituto Giannina Gaslini"},{"author_name":"Maria Carla Giarratana","author_inst":"IRCCS Instituto Giannina Gaslini"},{"author_name":"Vinodh Pillai","author_inst":"University of Pennsylvania"},{"author_name":"Siddarth Banka","author_inst":"University of Manchester"},{"author_name":"Tomaz Garcez","author_inst":"Manchester University NHS Foundation Trust"},{"author_name":"Tracy A Briggs","author_inst":"Manchester University NHS Foundation Trust"},{"author_name":"Fethi Mellouli","author_inst":"National Bone Marrow Transplant Center of Tunis"},{"author_name":"Sandra von Hardenberg","author_inst":"Hannover Medical School"},{"author_name":"Rita Beier","author_inst":"Hannover Medical School"},{"author_name":"Bernd Auber","author_inst":"Hannover Medical School"},{"author_name":"Ulrich Baumann","author_inst":"Hannover Medical School"},{"author_name":"Hasan Tawamie","author_inst":"Essen University Hospital"},{"author_name":"Edward Behrens","author_inst":"University of Pennsylvania"},{"author_name":"Derek A Oldridge","author_inst":"University of Pennsylvania"},{"author_name":"Emylette Cruz Cabrera","author_inst":"University of Pennsylvania"},{"author_name":"Ying Xu","author_inst":"University of California, San Francisco"},{"author_name":"Shinyi Ouyang","author_inst":"University of California, San Francisco"},{"author_name":"Sophie Hambleton","author_inst":"Newcastle University Translational and Clinical Research Institute"},{"author_name":"Neil Romberg","author_inst":"University of Pennsylvania"},{"author_name":"Jason G Cyster","author_inst":"University of California, San Francisco"}],"rel_date":"2026-07-17","rel_site":"medrxiv"},{"rel_title":"Chart review and genetic validation of electronic medical record dementia diagnoses in VA: The impact of CMS data","rel_doi":"10.64898\/2026.07.14.26358063","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358063","rel_abs":"Background: International Classification of Diseases (ICD) codes are often used in epidemiological studies to track disease rates over time. Objective: This evaluation of ICD-code-based algorithms for electronic medical record (EMR) studies of Alzheimers disease (AD) and related dementias (ADRD) examines the impact of incorporating Centers for Medicare and Medicaid (CMS) data as an additional source of diagnostic and treatment information in Department of Veterans Affairs (VA) EMR studies. Methods: We performed a chart review of 100 VA Million Veteran Program (MVP) participants to evaluate algorithm performance. We also assessed genetic associations across algorithms in a large MVP cohort (n=396k). Results: Adding CMS data increased the number of detected cases, sensitivity, and positive predictive value, but decreased specificity and negative predictive value. Genetic analyses showed that broader (ADRD\/dementia) algorithms with just VA data performed similarly to narrow (AD-focused) algorithms incorporating both VA and CMS ICD codes. Additionally, narrow AD algorithms based solely on VA data yielded the highest ORs, indicating the largest proportion of late-onset AD cases. Conclusions: We recommend using a broad (ADRD) algorithm without CMS or medication data, particularly for epidemiological studies or a strict AD algorithm including CMS and medication cases for genetic discovery of late-onset AD associations in VA EMR, and a strict AD algorithm without CMS data for applications focused solely on AD and sensitive to misspecification. Careful evaluation of algorithm performance is warranted in different EMR systems, as ICD coding practices vary by institution, as demonstrated by this comparison of VA EMR and CMS data.","rel_num_authors":14,"rel_authors":[{"author_name":"Mark Logue","author_inst":"Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Sophia O Lee","author_inst":"National Center for PTSD, Behavioral Sciences Division"},{"author_name":"Margaret Gillis","author_inst":"National Center for PTSD, Behavioral Sciences Division"},{"author_name":"Rui Zhang","author_inst":"National Center for PTSD: Behavioral Sciences Division"},{"author_name":"Monica Lee","author_inst":"Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"David Marra","author_inst":"VA Boston Healthcare System"},{"author_name":"Francesca V Lopez","author_inst":"VA San Diego Healthcare System"},{"author_name":"Julie Lynch","author_inst":"Department of Veterans Affairs"},{"author_name":"Matthew S Panizzon","author_inst":"University of California, San Diego"},{"author_name":"Debby W Tsuang","author_inst":"VA Puget Sound Health Care System"},{"author_name":"Richard L Hauger","author_inst":"VA San Diego Healthcare System"},{"author_name":"- The MVP Cognitive Decline and Dementia During Aging Working Group","author_inst":"-"},{"author_name":"VA Million Veteran Program","author_inst":"VA Boston Healthcare System"},{"author_name":"Victoria C Merritt","author_inst":"VA San Diego Healthcare System"}],"rel_date":"2026-07-17","rel_site":"medrxiv"},{"rel_title":"Photobiomodulation promotes wound healing and functional improvement following lumbar decompression surgery: a double-blinded, placebo-controlled study","rel_doi":"10.64898\/2026.07.15.26357882","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.15.26357882","rel_abs":"Objective: Photobiomodulation therapy has emerged as a promising modality to facilitate scar healing and pain management in dermatology and plastic surgery. However, its role in postoperative care following spine surgeries remains understudied. This double-blinded, placebo-controlled study aimed to investigate the effects of photobiomodulation in patients with chronic lower back pain undergoing lumbar decompression, with postoperative wound healing as the primary outcome and pain reduction and functional recovery as secondary outcomes. Methods: Patients were randomized to receive either active photobiomodulation braces (N=13) or placebo braces (N=12). Follow-up assessments were performed at 2, 4, 6, 8, and 12 weeks postoperatively. Outcomes included wound healing (Stony Brook Scar Evaluation Scale), back and leg pain (Visual Analog Scale), quality of life (EuroQol 5D), and functional status (Oswestry Disability Index). Results: Compared to the placebo group, the photobiomodulation treatment group had a 4.12-fold cumulative improvement in final scar scores, with significant between-group differences at postoperative weeks 6, 8, and 12 (p = 0.0062, 0.010, 0.042). Among patients with severe preoperative disability, treatment resulted in a 1.89-fold faster improvement in back pain (p=0.025) and a 1.80-fold faster improvement in ODI scores (p=0.025); and superior treatment effect on wound healing were again observed at weeks 6, 8, and 12. Among patients with poor initial scars, treatment led to a significantly better scar outcome than placebo at week 6 and a 1.94-fold faster EQ5D improvement (p=0.052), with significant gains observed as early as two weeks after surgery. There were no adverse events associated with photobiomodulation treatment. Conclusions: Photobiomodulation significantly promoted postoperative wound healing following lumbar decompression surgery, with therapeutic benefits preserved even in patients with poor baseline scar scores and functional impairment. This indicates that the efficacy of photobiomodulation is not limited by the initial scar condition or disability, supporting its broad clinical applicability. Additionally, patients with severe preoperative disability experienced greater benefits from photobiomodulation than placebo, including faster reduction in back pain and more rapid improvement in functional capacity, highlighting its role in postoperative pain management and rehabilitation. These therapeutic effects are likely mediated by photobiomodulation-induced reduction of inflammation and enhancement of tissue repair. Together, this study suggests that photobiomodulation can be a promising adjunct therapy to facilitate postoperative recovery in patients undergoing spine surgery.","rel_num_authors":18,"rel_authors":[{"author_name":"Joshua Rivera","author_inst":"UCLA"},{"author_name":"Yan Zhou","author_inst":"University of Colorado School of Medicine"},{"author_name":"Lara Sak","author_inst":"UCLA"},{"author_name":"Fiona Pudewa","author_inst":"California University of Science and Medicine, Los Angeles, CA"},{"author_name":"Jihoon Lee","author_inst":"UCLA"},{"author_name":"Mark T Yamamoto","author_inst":"UCLA"},{"author_name":"Habin Yoo","author_inst":"UCLA"},{"author_name":"Meachelle Lum","author_inst":"UCLA"},{"author_name":"Michelle Zhang","author_inst":"University of Pittsburgh"},{"author_name":"Aakash Patel","author_inst":"UCLA"},{"author_name":"Louise E Vandenberghe","author_inst":"UCLA"},{"author_name":"Sara K Fenn","author_inst":"UCLA"},{"author_name":"Yuanchen Wang","author_inst":"UCLA"},{"author_name":"Brooke Bailey","author_inst":"UCLA"},{"author_name":"Sandra M Holley","author_inst":"UCLA"},{"author_name":"Andrew C Vivas","author_inst":"UCLA"},{"author_name":"Langston T Holly","author_inst":"UCLA"},{"author_name":"Daniel C Lu","author_inst":"UCLA"}],"rel_date":"2026-07-17","rel_site":"medrxiv"},{"rel_title":"Implementation of a standardized Video-based Asynchronous Neurological Examination (VANE) in a multi-center observational study of Alzheimer's disease (AD) and AD related dementias","rel_doi":"10.64898\/2026.07.15.26357456","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.15.26357456","rel_abs":"Introduction: The Diabetes Prevention Program Outcomes Study (DPPOS) is an established cohort of aging persons with pre-diabetes and type 2 diabetes with 25 years of median follow-up. In 2022 DPPOS added Alzheimer's disease (AD), and AD related dementias (ADRD) phenotyping using the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDSv3), which included a standardized neurological examination across 25 clinical sites, administered by clinical staff and interpreted centrally by clinicians. Methods: A DPPOS video-based asynchronous neurological examination (DPPOS-VANE) was developed iteratively through consensus from research clinicians and staff feedback to harmonize with UDSv3 to identify common neurological diagnoses aside from dementia including diabetic cranial neuropathies, stroke and parkinsonism. DPPOS-VANE was designed to be conducted without direct participant contact by the examiner, reproducible, and independent of clinical skills of PCs. An iPad camera recorded the video exam, comprised of assessments of extraocular and facial movements, visual fields, speech, gross motor strength, pronator drift, praxis and parkinsonism. A 10-minute training video demonstrated the examination step-by-step with scripts and instructions in English and Spanish. Site-specific performance review, feedback, and staff certification preceded central reading of video recordings by physicians. After two years of implementation, 1286 DPPOS-VANEs led to 1284 examination reviews. Of these, 1204 (93%) were completed by having the examiner follow the standard script. Overall, 1237 examinations (96%) were delivered as planned, 41 (3%) had minor errors but were still usable, and 6 (0.4%) had major deviations in exam technique; two additional recorded evaluations were not usable as recorded videos were inaccessible due to technical errors. Each examination was completed within 10-15 minutes. Each site on average completed 51.4 examinations (range 14-92). Discussion: Engaging 55 research staff across 25 sites and 3 physician-reviewers, this study is the first to demonstrate feasibility of a VANE as an efficient neurological examination model enabled by commonly used devices. Such a multisite standardized VANE represents a novel paradigm for large epidemiological studies.","rel_num_authors":14,"rel_authors":[{"author_name":"James M Noble","author_inst":"Department of Neurology, Columbia University Irving Medical Center, New York, NY andTaub Institute for Research on Alzheimer Disease and the Aging Brain, and G."},{"author_name":"Neelesh K Nadkarni","author_inst":"Department of Medicine (Division of Geriatric Medicine), and Neurology, University of Pittsburgh, Pittsburgh PA"},{"author_name":"Dianilka Martinez","author_inst":"Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, New York, NY"},{"author_name":"Marinella Temprosa","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute of Public Health, George Washington University, Bethesda, MD"},{"author_name":"Anna Bowers","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute of Public Health, George Washington University, Bethesda, MD"},{"author_name":"Owen Carmichael","author_inst":"Pennington Biomedical Research Center, Baton Rouge, LA"},{"author_name":"Lindsay Doherty","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute of Public Health, George Washington University, Bethesda, MD"},{"author_name":"Gerardo J Febres","author_inst":"Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, New York, NY"},{"author_name":"Danurys L Sanchez","author_inst":"Department of Neurology, Columbia University Irving Medical Center, New York, NY"},{"author_name":"Terry E Goldberg","author_inst":"Department of Psychiatry, Columbia University Irving Medical Center, New York, NY"},{"author_name":"Hanna Sherif","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute of Public Health, George Washington University, Bethesda, MD"},{"author_name":"Vallabh Shah","author_inst":"Department of Internal Medicine, University of New Mexico HSC, Albuquerque, NM"},{"author_name":"Jose A Luchsinger","author_inst":"Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, New York, NY"},{"author_name":"- DPP Research Group","author_inst":"-"}],"rel_date":"2026-07-17","rel_site":"medrxiv"},{"rel_title":"Truncating ASXL1 variants rewire cellular metabolism via mitochondrial pyruvate carrier repression","rel_doi":"10.64898\/2026.07.13.737346","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.737346","rel_abs":"Bohring-Opitz syndrome (BOS, OMIM#605309) is a rare neurodevelopmental disorder caused by heterozygous and truncating variants in ASXL1 (Additional Sex Combs Like 1), a chromatin-associated epigenetic regulator that forms the catalytic PR-DUB complex with BAP1. Truncating ASXL1 variants are also recurrent somatic drivers in myeloid leukemia, yet the metabolic consequences of these mutations remain undefined. Using patient derived dermal fibroblasts, we show that truncating ASXL1 variants drive a Warburg-like metabolic state characterized by increased glycolytic flux, and accumulation of pyruvate and lactate. Truncated ASXL1 and BAP1 show aberrant co-occupancy at an H3K4me3-marked intronic regulatory element within MPC2 intron 1, with broadened ASXL1 occupancy extending beyond BRD4-defined regulatory boundaries while BRD4 positioning remains unchanged, consistent with aberrant PR-DUB complex spreading beyond its normally constrained chromatin territory. This altered occupancy is accompanied by modest but significant reduction in MPC2 transcript abundance and a disproportionately larger reduction in MPC1 and MPC2 protein levels, indicating that transcriptional dysregulation at this intronic element is amplified at the protein level through post-transcriptional mechanisms including impaired MPC1\/MPC2 heterodimer stability. Pharmacologic MPC inhibition recapitulates both the metabolic and Wnt signaling phenotypes of BOS cells, while canonical Wnt activation increases glycolytic flux without reducing MPC abundance, establishing mitochondrial pyruvate restriction as causally upstream of signaling dysregulation. These findings define a previously unrecognized chromatin-to-metabolism axis connecting gain-of-function ASXL1 truncation to mitochondrial pyruvate transport, identifying MPC as a central mediator of epigenetic-metabolic crosstalk in both a rare developmental syndrome and ASXL1-mutant myeloid malignancy.","rel_num_authors":12,"rel_authors":[{"author_name":"Isabella Lin","author_inst":"UCLA"},{"author_name":"Michael Sigfried S. Reyes","author_inst":"UCLA"},{"author_name":"Abigail Krall","author_inst":"UCLA"},{"author_name":"Neerja Vashist","author_inst":"UCLA"},{"author_name":"Suzanna Sarkissian","author_inst":"UCLA"},{"author_name":"Nedas Matulionis","author_inst":"UCLA"},{"author_name":"Aileen Ning","author_inst":"UCLA"},{"author_name":"Linsey Stiles","author_inst":"UCLA"},{"author_name":"Bianca E Russell","author_inst":"UCLA"},{"author_name":"Paul Mark B. Medina","author_inst":"University of the Philippines"},{"author_name":"Heather A Christofk","author_inst":"UCLA"},{"author_name":"Valerie A Arboleda","author_inst":"UNIVERSITY OF CALIFORNIA LOS ANGELES"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Turning an object into a scene: buildings activate scene-selective visual cortex independently of visual features","rel_doi":"10.64898\/2026.07.12.738103","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.738103","rel_abs":"Human visual cortex contains regions that selectively respond to both scenes and large objects, particularly buildings. The cortical overlap between buildings and scenes has been attributed to shared visual features (e.g., cardinal orientations, rectilinearity). Alternative accounts propose that buildings may also activate scene representations indirectly, independently of specific visual features, for example because buildings evoke a sense of space. Here, we tested for such feature-independent activation by comparing EEG and fMRI responses in human participants (both sexes) to buildings and visually-matched boxes, and relating these responses to scene-selective responses. Buildings and boxes were matched, across exemplars, using image-based metrics, deep neural networks, and a perceptual similarity task. Time-resolved EEG decoding showed that buildings and boxes evoked discriminable responses from 360ms post-stimulus onset, incompatible with feedforward visual feature processing. Importantly, the building-box classifier generalized to discriminate scenes from chairs, providing EEG evidence for a representational overlap between buildings and scenes. Temporal generalization analyses further showed that the late building-selective response corresponded to an earlier scene-selective response, with a temporal offset of ~130ms. Finally, ultra-fast fMRI (TR=140ms) revealed that these findings were mirrored in the response of the scene-selective parahippocampal place area (PPA), which similarly showed a feature-independent building-selective response that was delayed and prolonged relative to the scene-selective response. These results clarify the nature of building selectivity in visual cortex by showing that this selectivity can arise independently of visual features, putatively reflecting associative processes between buildings and scenes (or space).","rel_num_authors":3,"rel_authors":[{"author_name":"Yuanfang Zhao","author_inst":"Johns Hopkins University"},{"author_name":"Simen Hagen","author_inst":"KU Leuven"},{"author_name":"Marius V. Peelen","author_inst":"Radboud University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"ITPKB is a conserved regulator of natural killer cell desensitization\/education that constrains antitumor immunity","rel_doi":"10.64898\/2026.07.12.738073","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.738073","rel_abs":"Natural Killer (NK) cell desensitization induced by persistent stimulation limits durable antitumor immunity, yet the molecular mechanisms governing this dysfunctional state remain poorly defined. To identify conserved regulators of NK cell desensitization, we performed comparative transcriptomic analyses across multiple murine models of persistent activation and dysfunction. This approach defined a shared transcriptional program of desensitization and identified Itpkb to be upregulated across multiple distinct contexts. Genetic and pharmacological inhibition of ITPKB enhanced degranulation, cytokine production, and cytotoxicity in both murine and human NK cells under multiple desensitization settings. Mechanistically, ITPKB regulated signaling downstream of persistent activation through the IP3\/IP4 axis, limiting calcium mobilization and NFAT-dependent transcriptional responses in desensitized NK cells. Furthermore, inhibition or deletion of ITPKB enhanced NK-cell mediated tumor control in vivo and improved the efficacy of adoptively transferred CAR-NK cells, underscoring the translational potential of targeting this pathway. Together, these findings identify ITPKB as a cell-intrinsic regulator of NK cell desensitization and support targeting the IP3\/IP4 signaling axis to enhance NK cell-mediated antitumor immunity.","rel_num_authors":17,"rel_authors":[{"author_name":"Yeara Jo","author_inst":"University of California, Berkeley"},{"author_name":"Alexandros Karampatzakis","author_inst":"University of California, Berkeley"},{"author_name":"Seung Won Lee","author_inst":"University of California, Berkeley"},{"author_name":"Alice Peng","author_inst":"University of California, Berkeley"},{"author_name":"Zaina Ghouri","author_inst":"University of California, Berkeley"},{"author_name":"Monsserratt Moya","author_inst":"University of California, Berkeley"},{"author_name":"Elizabeth Andrews","author_inst":"University of California, Berkeley"},{"author_name":"Harrison Sudholz","author_inst":"Walter and Eliza Hall Institute of Medical Research"},{"author_name":"Chenyu Zhang","author_inst":"University of California, Berkeley"},{"author_name":"Berna Bou Tayeh","author_inst":"Ludwig Institute for Cancer Research, University of Oxford"},{"author_name":"Alejandro N Medina","author_inst":"University of California, Berkeley"},{"author_name":"Jiucheng Ding","author_inst":"University of California, Berkeley"},{"author_name":"Robert A Saxton","author_inst":"University of California, Berkeley"},{"author_name":"Ziyang Zhang","author_inst":"University of California, Berkeley"},{"author_name":"Yang Shi","author_inst":"Ludwig Institute for Cancer Research, University of Oxford"},{"author_name":"Hideho Okada","author_inst":"University of California, San Francisco"},{"author_name":"David H Raulet","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"ITPKB is a conserved regulator of natural killer cell desensitization\/education that constrains antitumor immunity","rel_doi":"10.64898\/2026.07.12.738073","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.738073","rel_abs":"Natural Killer (NK) cell desensitization induced by persistent stimulation limits durable antitumor immunity, yet the molecular mechanisms governing this dysfunctional state remain poorly defined. To identify conserved regulators of NK cell desensitization, we performed comparative transcriptomic analyses across multiple murine models of persistent activation and dysfunction. This approach defined a shared transcriptional program of desensitization and identified Itpkb to be upregulated across multiple distinct contexts. Genetic and pharmacological inhibition of ITPKB enhanced degranulation, cytokine production, and cytotoxicity in both murine and human NK cells under multiple desensitization settings. Mechanistically, ITPKB regulated signaling downstream of persistent activation through the IP3\/IP4 axis, limiting calcium mobilization and NFAT-dependent transcriptional responses in desensitized NK cells. Furthermore, inhibition or deletion of ITPKB enhanced NK-cell mediated tumor control in vivo and improved the efficacy of adoptively transferred CAR-NK cells, underscoring the translational potential of targeting this pathway. Together, these findings identify ITPKB as a cell-intrinsic regulator of NK cell desensitization and support targeting the IP3\/IP4 signaling axis to enhance NK cell-mediated antitumor immunity.","rel_num_authors":17,"rel_authors":[{"author_name":"Yeara Jo","author_inst":"University of California, Berkeley"},{"author_name":"Alexandros Karampatzakis","author_inst":"University of California, Berkeley"},{"author_name":"Seung Won Lee","author_inst":"University of California, Berkeley"},{"author_name":"Alice Peng","author_inst":"University of California, Berkeley"},{"author_name":"Zaina Ghouri","author_inst":"University of California, Berkeley"},{"author_name":"Monsserratt Moya","author_inst":"University of California, Berkeley"},{"author_name":"Elizabeth Andrews","author_inst":"University of California, Berkeley"},{"author_name":"Harrison Sudholz","author_inst":"Walter and Eliza Hall Institute of Medical Research"},{"author_name":"Chenyu Zhang","author_inst":"University of California, Berkeley"},{"author_name":"Berna Bou Tayeh","author_inst":"Ludwig Institute for Cancer Research, University of Oxford"},{"author_name":"Alejandro N Medina","author_inst":"University of California, Berkeley"},{"author_name":"Jiucheng Ding","author_inst":"University of California, Berkeley"},{"author_name":"Robert A Saxton","author_inst":"University of California, Berkeley"},{"author_name":"Ziyang Zhang","author_inst":"University of California, Berkeley"},{"author_name":"Yang Shi","author_inst":"Ludwig Institute for Cancer Research, University of Oxford"},{"author_name":"Hideho Okada","author_inst":"University of California, San Francisco"},{"author_name":"David H Raulet","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Integrating activation-induced costimulation and cytokine signals enhance TCR-based cell therapies","rel_doi":"10.64898\/2026.07.12.738084","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.738084","rel_abs":"TCR based cell therapies offer broad targeting of tumor antigens with high sensitivity but often low durability due to insufficient costimulation (signal 2) and cytokine (signal 3) support. To address this, we developed a dual stimulatory receptor (DSR) consisting of the 4 1BBL ectodomain fused to the thrombopoietin receptor (cMPL) endodomain. DSR engages 4-1BB that is transiently upregulated upon TCR stimulation eliciting signal 2 and simultaneously activates cMPL driven STAT3\/5 phosphorylation providing signal 3. DSR increases the expansion of T cells, preserving their effector function and an effector-associated transcriptional profile upon repeated antigen stimulation. DSR arming significantly improves in vivo antitumor activity of T cells redirected to cancer through engineered TCRs or soluble T-cell engagers in diverse xenograft tumor models by enhancing T cell expansion and persistence post-infusion. These results demonstrate broad utility and establish DSR as a modular receptor for the effective and synchronized delivery of signals 2 and 3 to support TCR based immunotherapies.","rel_num_authors":9,"rel_authors":[{"author_name":"MANSI NARULA","author_inst":"Baylor College of Medicine"},{"author_name":"Johannes Englisch","author_inst":"Baylor College of Medicine"},{"author_name":"Cheryl Ou","author_inst":"Baylor College of Medicine"},{"author_name":"Tadahiro Honda","author_inst":"Baylor College of Medicine"},{"author_name":"Ismael de la Iglesia San Sebastian","author_inst":"Baylor College of Medicine"},{"author_name":"Azlann B Arnett","author_inst":"Baylor College of Medicine"},{"author_name":"Feiyan Mo","author_inst":"Baylor College of Medicine"},{"author_name":"Maksim Mamonkin","author_inst":"Baylor College of Medicine"},{"author_name":"Norihiro Watanabe","author_inst":"Baylor College of Medicine"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Multiscale learning and topological analysis across complex postures enable robust nematode size quantification in pharmacological assays","rel_doi":"10.64898\/2026.07.12.738008","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.738008","rel_abs":"Body size is an important trait that reflects animal development and physiology. In nematodes, precise measurement is valuable for linking variation in body dimensions to biological questions such as developmental timing, genetic regulation, and drug responses. However, robust size measurements can be difficult to obtain because nematodes can vary in curvature, have self-intersecting postures, and overlap with neighboring animals. Current image analysis software, such as CellProfiler, can measure isolated animals in straight postures but struggles with curly or overlapping animals. Here, we present NemaSize, an artificial intelligence (AI)-aided pipeline to measure Caenorhabditis nematode body sizes across complex postures using multi-scale learning and topology-aware skeletonization. Using You Only Look Once (YOLO) models trained at different spatial scales, NemaSize first identifies individual animals in a large field of view (FOV; 6.75 x 6.75 mm) and then performs high-resolution body segmentation in the region of interest (ROI). Next, NemaSize converts segmented body masks into topological graph representations, allowing curly and overlapping animals to be classified and skeletonized according to the body topology. NemaSize achieved less than 4% overall error in length and width measurements across all posture classes. Compared to CellProfiler, NemaSize demonstrated higher robustness for complex postures, including a 48% error reduction in length measurements for curly or self-overlapping animals. Application of NemaSize in high-throughput imaging assays further shows that NemaSize provides accurate quantification of Caenorhabditis briggsae larval development in response to the anthelmintic drug ivermectin, a task that was difficult for CellProfiler because of curly animal postures. Together, NemaSize provides a robust approach for automated body size quantification for Caenorhabditis nematodes and will support broad applications in high-throughput pharmacological and genetic screens. Beyond nematodes, NemaSize introduces a multiscale computational framework for analyzing elongated biological objects with complex topologies.","rel_num_authors":15,"rel_authors":[{"author_name":"Zihao (John) Li","author_inst":"Johns Hopkins University"},{"author_name":"Amanda O. Shaver","author_inst":"Johns Hopkins University"},{"author_name":"Michael E.G. Sauria","author_inst":"Johns Hopkins University"},{"author_name":"Jack Weinstein","author_inst":"Johns Hopkins University"},{"author_name":"Maya K. Mastronardo","author_inst":"Johns Hopkins University"},{"author_name":"Nikita S. Jhaveri","author_inst":"Johns Hopkins University"},{"author_name":"Kate Stone","author_inst":"Johns Hopkins University"},{"author_name":"Rachel Choo","author_inst":"Johns Hopkins University"},{"author_name":"Colin Lilley","author_inst":"Johns Hopkins University"},{"author_name":"Esha Sharma","author_inst":"Johns Hopkins University"},{"author_name":"Rohan Shrishrimal","author_inst":"Johns Hopkins University"},{"author_name":"Grayson Benson","author_inst":"Johns Hopkins University"},{"author_name":"Ariel Shi","author_inst":"Johns Hopkins University"},{"author_name":"Cecilia Soko","author_inst":"Johns Hopkins University"},{"author_name":"Erik C. Andersen","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Mapping absolute membrane voltage using dynamic photocycle control","rel_doi":"10.64898\/2026.07.17.739178","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.17.739178","rel_abs":"Fluorescent voltage indicators are widely used to report relative changes in membrane potential, but mapping absolute voltages remains difficult. Here we present Voltage Measurement by Activated Photocycles (VMAP), a simple method for absolute voltage imaging based on a photophysical switch between voltage-insensitive and sensitive indicator states. VMAP requires no specialized hardware or additional labeling, and is applicable across species, sample preparations, and microscope configurations. Using VMAP, we quantified drug-induced shifts in neuronal resting potential, revealed the emergence of bioelectric patterns during multi-day recordings of human iPSC populations, and created 3D membrane-potential maps across whole live zebrafish embryos. By making absolute voltage imaging accessible from cellular to organismal scales and from milliseconds to days, VMAP opens a route to mapping bioelectrical organization in complex living systems.","rel_num_authors":6,"rel_authors":[{"author_name":"Daozheng Gong","author_inst":"Harvard University"},{"author_name":"Jinfan Zhang","author_inst":"Harvard University"},{"author_name":"Madeleine R. Howell","author_inst":"Harvard University"},{"author_name":"Xiang Wu","author_inst":"Harvard University"},{"author_name":"Bill Z. Jia","author_inst":"University of California, San Francisco"},{"author_name":"Adam Ezra Cohen","author_inst":"Harvard University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Computational Counterfactuals Reveal Non-Additive Audiovisual Semantics in Natural Movie Responses","rel_doi":"10.64898\/2026.07.12.738026","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.738026","rel_abs":"Natural audiovisual perception may not be fully captured by decomposing movies into auditory and visual streams. I introduce a computational-counterfactual framework that keeps movie viewing intact while varying only AI-derived descriptions of the same clips. Using 7 Tesla movie fMRI imaging data from 176 participants, I tested whether cortical responses were better predicted by native audiovisual semantics than by a dimension-matched additive reconstruction from audio-only and video-only descriptions. The native model outperformed the matched additive baseline under content-aware purged cross-validation, with strongest gains in auditory, visual, and dorsal attention systems. Representational-similarity, feature-replacement, and content-gating analyses showed that the advantage reflected feature- and network-specific routing linked to coherent audiovisual semantic emergence rather than raw auditory-visual discrepancy. The effect survived stronger temporal purging and repeat-content exclusion, suggesting that intact movie viewing evokes cortical structure aligned with native audiovisual meaning beyond additive unimodal semantics.","rel_num_authors":1,"rel_authors":[{"author_name":"Muwei Li","author_inst":"Vanderbilt University Institute of Imaging Science"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"How specific structural differences of Bcl2 proteins modulate the interaction with BH3 domains and apoptotic function","rel_doi":"10.64898\/2026.07.17.739112","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.17.739112","rel_abs":"Intrinsic apoptosis is mainly regulated through a network of conserved interactions between Bcl-2 proteins involving hydrophobic binding grooves and BH3 domains. Despite these conserved interfaces, family members exhibit distinct binding affinities and play opposing roles in apoptosis. While static structural differences partially account for this divergence, it remains unclear how opposing apoptotic function reflects in BH3 helix engagement of individual members. Here, we investigate how a BidBH3 peptide engages with the hydrophobic groove of full-length membrane-anchored Bcl-xL and Bax to identify shared and unique features of binding that may relate to distinct apoptotic functions. Using state-of-the-art enhanced-sampling simulations, we mapped the complete binding and folding landscapes of these critical cell-death regulators in membranes. Our simulations align with experimental measurements in terms of predicted absolute binding affinities, and also capture the dynamic, atomistic details of the conformational changes induced by BH3 helices. Together, these details highlight the structural principles of BH3 in-groove engagement that determine apoptotic function, paving the way towards the modulation of the interactions among the Bcl-2 family members.","rel_num_authors":5,"rel_authors":[{"author_name":"Anton Hanke","author_inst":"University of Geneva"},{"author_name":"Christina Elsner","author_inst":"University of Geneva"},{"author_name":"Simone Aureli","author_inst":"University of Geneve"},{"author_name":"Enrica Bordignon","author_inst":"University of Geneva"},{"author_name":"Francesco Luigi Gervasio","author_inst":"University of Geneva"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Robean: A Standalone Freeware for Automated Rodent Neurobehavioural Analysis with Integrated Tracking, Visualization, and Reporting","rel_doi":"10.64898\/2026.07.11.737999","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737999","rel_abs":"Quantitative analysis of rodent behaviour is fundamental to neuroscience, preclinical drug discovery and neurotoxicology research. Although several commercial and open-source software packages are available for behavioural assessment, some are expensive, some require programming expertise, and some provide limited flexibility for user-defined experimental configurations. To address these limitations, we developed Robean, a freely available standalone software platform for automated rodent neurobehavioural analysis from both live camera feeds and pre-recorded videos. Robean provides an intuitive graphical user interface that enables users to design experimental arenas, define custom analysis zones, perform spatial calibration, and automatically track rodent movement without requiring programming knowledge. The software currently supports automated analysis of three widely used behavioural paradigms: the Morris Water Maze, Elevated Plus Maze, and Open Field Test. Robean extracts behavioural metrics including escape latency, path efficiency, platform crossings, target quadrant preference, thigmotaxis, locomotor activity, zone occupancy, arm entries, and centre exploration specific to behavioural tests. In addition, the software generates trajectory maps, occupancy heatmaps, comma-separated value (CSV) datasets, comprehensive PDF reports, and batch study summaries for multiple experimental sessions. Developed using open-source software technologies and distributed as a standalone freeware application, Robean provides an accessible and reproducible solution for behavioural neuroscience laboratories. Its modular architecture facilitates future integration of additional behavioural paradigms and analytical modules, making it a flexible platform for automated rodent behavioural assessment.","rel_num_authors":4,"rel_authors":[{"author_name":"Vikas Mishra","author_inst":"Babasaheb Bhimrao Ambedkar University"},{"author_name":"Rajkumar Verma","author_inst":"University of Connecticut School of Medicine, 263 Farmington Ave, Farmington, CT 06032, USA"},{"author_name":"Paruvathanahalli Siddalingam Rajinikanth","author_inst":"Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow-226025, (U.P.), India"},{"author_name":"Ravinder Kumar Kaundal","author_inst":"Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli New Transit Campus, Bijnor - Sisendi Road, Sar"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Quorum sensing underlies the establishment and maintenance of marginal zone B cells","rel_doi":"10.64898\/2026.07.11.737964","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737964","rel_abs":"The marginal zone (MZ) of the spleen harbors B cells that play an indispensable role in immune defense, orchestrating rapid responses to blood-borne pathogens. Under steady-state conditions, MZ B cell numbers are maintained through the balance of de novo generation from precursors, proliferative self-renewal, and loss. The mechanisms governing this homeostatic control remain elusive. Further, the developmental pathways underlying the establishment and continued supplementation of the MZ B cell compartment are not fully elucidated. To address these gaps, we combined multiple fate-mapping tools and mathematical models to study MZ B cell dynamics in mice across the life course. Our analyses find evidence of quorum sensing mechanisms that regulate both the accumulation of mature MZ B cells during early life and their maintenance throughout adulthood. Specifically, we demonstrate that they derive predominantly from transitional B cell precursors with an efficiency that increases with age, reaching stable levels only in adulthood. MZ B cells compensate for this early developmental inefficiency through cell density-dependent proliferation, ensuring the timely establishment of a stable pool. Collectively, these findings unveil critical roles of quorum sensing and immune system maturation in the maintenance of this vital B cell subset.","rel_num_authors":6,"rel_authors":[{"author_name":"Apoorva Singh","author_inst":"Columbia University"},{"author_name":"Melissa Verheijen","author_inst":"University College London"},{"author_name":"Thea Hogan","author_inst":"University College London"},{"author_name":"Andrew  J. Yates","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Benedict Seddon","author_inst":"University College London"},{"author_name":"Sanket Rane","author_inst":"Columbia University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Amplitude-Modulated Kilohertz Stimulation Targeting Beta-Band Activity Disrupts Motor Learning","rel_doi":"10.64898\/2026.07.11.737109","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737109","rel_abs":"Sensorimotor learning is associated with the modulation of neural rhythms in the primary motor cortex (M1). Beta-band activity (\"beta\"; 15-30 Hz) is suppressed during learning, while delta oscillations (1-4 Hz) become increasingly correlated with movement kinematics as skill improves. These observations have been complemented by experimental manipulations designed to perturb oscillatory activity with externally applied electric fields (E-fields). In non-human primates, invasive beta stimulation has been shown to disrupt motor learning whereas delta stimulation enhanced motor recovery in a stroke model. Causal evidence in humans remains limited, partly because established non-invasive methods cannot achieve continuous, narrowband E-fields at sufficient amplitude in the brain. To address this gap, we employed kilohertz transcranial magnetic perturbation (kTMP), a non-invasive magnetic induction technique that delivers continuous narrowband kilohertz E-fields which can be amplitude-modulated (AM) to target cortical rhythms. We applied AM-kTMP to test the functional relevance of beta and delta activity in human motor learning. In a double-blind mixed design, 40 participants performed a force-control task while receiving AM-kTMP at E-field amplitudes of 8 V\/m in M1. We targeted either beta or delta, each paired with a sham condition. AM-kTMP influenced motor performance in a frequency-dependent manner: Beta-kTMP suppressed performance gains relative to both delta-kTMP and sham, whereas delta-kTMP showed no effect. These results suggest that increased beta activity in human M1 can interfere with motor learning. More broadly, kTMP offers a novel approach to probe frequency-specific cortical dynamics.","rel_num_authors":12,"rel_authors":[{"author_name":"Philipp Reber","author_inst":"Department of Psychology, University of California, Berkeley, CA, USA; Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Christina M Merrick","author_inst":"Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Guy Avraham","author_inst":"Department of Psychology, University of California, Berkeley, CA, USA; Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Ida Killebrew","author_inst":"Department of Psychology, University of California, Berkeley, CA, USA"},{"author_name":"Katheryn Thayer-Pham","author_inst":"Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Haajar Ahmad-Ali","author_inst":"Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Angel V Peterchev","author_inst":"Departments of Biomedical Engineering, Neurosurgery, Psychiatry & Behavioral Sciences, and Electrical & Computer Engineering, Duke University, Durham, NC, USA"},{"author_name":"Karunesh Ganguly","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA"},{"author_name":"Cidnee Luu","author_inst":"Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Daniel Sheltraw","author_inst":"Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Ludovica Labruna","author_inst":"Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Richard B Ivry","author_inst":"Department of Psychology, University of California, Berkeley, CA, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Amplitude-Modulated Kilohertz Stimulation Targeting Beta-Band Activity Disrupts Motor Learning","rel_doi":"10.64898\/2026.07.11.737109","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737109","rel_abs":"Sensorimotor learning is associated with the modulation of neural rhythms in the primary motor cortex (M1). Beta-band activity (\"beta\"; 15-30 Hz) is suppressed during learning, while delta oscillations (1-4 Hz) become increasingly correlated with movement kinematics as skill improves. These observations have been complemented by experimental manipulations designed to perturb oscillatory activity with externally applied electric fields (E-fields). In non-human primates, invasive beta stimulation has been shown to disrupt motor learning whereas delta stimulation enhanced motor recovery in a stroke model. Causal evidence in humans remains limited, partly because established non-invasive methods cannot achieve continuous, narrowband E-fields at sufficient amplitude in the brain. To address this gap, we employed kilohertz transcranial magnetic perturbation (kTMP), a non-invasive magnetic induction technique that delivers continuous narrowband kilohertz E-fields which can be amplitude-modulated (AM) to target cortical rhythms. We applied AM-kTMP to test the functional relevance of beta and delta activity in human motor learning. In a double-blind mixed design, 40 participants performed a force-control task while receiving AM-kTMP at E-field amplitudes of 8 V\/m in M1. We targeted either beta or delta, each paired with a sham condition. AM-kTMP influenced motor performance in a frequency-dependent manner: Beta-kTMP suppressed performance gains relative to both delta-kTMP and sham, whereas delta-kTMP showed no effect. These results suggest that increased beta activity in human M1 can interfere with motor learning. More broadly, kTMP offers a novel approach to probe frequency-specific cortical dynamics.","rel_num_authors":12,"rel_authors":[{"author_name":"Philipp Reber","author_inst":"Department of Psychology, University of California, Berkeley, CA, USA; Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Christina M Merrick","author_inst":"Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Guy Avraham","author_inst":"Department of Psychology, University of California, Berkeley, CA, USA; Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Ida Killebrew","author_inst":"Department of Psychology, University of California, Berkeley, CA, USA"},{"author_name":"Katheryn Thayer-Pham","author_inst":"Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Haajar Ahmad-Ali","author_inst":"Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Angel V Peterchev","author_inst":"Departments of Biomedical Engineering, Neurosurgery, Psychiatry & Behavioral Sciences, and Electrical & Computer Engineering, Duke University, Durham, NC, USA"},{"author_name":"Karunesh Ganguly","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA"},{"author_name":"Cidnee Luu","author_inst":"Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Daniel Sheltraw","author_inst":"Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Ludovica Labruna","author_inst":"Magnetic Tides Inc., Berkeley, CA, USA"},{"author_name":"Richard B Ivry","author_inst":"Department of Psychology, University of California, Berkeley, CA, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Age-Related Increases in 40Hz Neural Synchrony Are Specific to Typical Development: A Cross-Sectional Study of Autism Spectrum Disorder","rel_doi":"10.64898\/2026.07.16.738569","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738569","rel_abs":"Background: The 40Hz auditory steady-state response (ASSR) is a measure of gamma-band neural synchrony sensitive to excitation-inhibition (E\/I) balance. Disruptions to E\/I balance have been implicated in autism spectrum disorder (ASD), making ASSR an efficient tool for investigating neural synchrony development in this population. Whether age-related differences in 40Hz ASSR are detectable across development in ASD remains understudied. Phelan-McDermid syndrome (PMS), a rare genetic disorder with a phenotype overlapping with autism, caused by SHANK3 disruption, provides a genetically defined model for further investigating E\/I-related neural synchrony disruptions. Methods: We examined 40Hz inter-trial phase coherence (ITPC) as an index of neural synchrony across a wide age range (2-37 years) in 127 participants from four groups: TD (n=43), ASD without intellectual disability (w\/o ID; n=37), ASD with intellectual disability (w\/ID; n=24), and PMS (n=23). Given the distinct age and cognitive profiles of ASD subgroups in this sample, analyses were conducted in separate models: TD vs. ASD w\/o ID across all ages, and TD vs. ASD w\/ID vs. PMS restricted to participants under 18. Results: For the first time in a cross-sectional sample spanning a large age range, we show that 40Hz ITPC increases significantly with age in TD individuals, while this developmental trajectory is absent in ASD without intellectual disability. Among children and adolescents under 18, 40Hz ITPC did not differ across TD, ASD w\/ID, and PMS, and IQ did not predict ITPC in clinical groups. A post-hoc analysis revealed higher ITPC in TD males than females, with no sex differences in ASD or PMS. Conclusions: We demonstrate that gamma-band ITPC trajectories diverge between TD and ASD, specifically in adulthood, with no such difference detectable in childhood. No significant group differences were found among TD, ASD w\/ID, and PMS individuals under 18. These findings highlight the importance of age as a critical variable when measuring ASSR, and underscore the need for lifespan studies, particularly in genetically defined conditions such as PMS, to determine whether similar divergence emerges in adulthood.","rel_num_authors":11,"rel_authors":[{"author_name":"Abigael Thinakaran","author_inst":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Jennifer Foss-Feig","author_inst":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Serena Cai","author_inst":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Julia Savino","author_inst":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Matthew Suh","author_inst":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Amir Lavi","author_inst":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Paige Siper","author_inst":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Tess Levy","author_inst":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Joseph Buxbaum","author_inst":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Alexander Kolevzon","author_inst":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Shlomit Beker","author_inst":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Molecular organization of the \tChlorella sorokiniana pyrenoid","rel_doi":"10.64898\/2026.07.17.739135","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.17.739135","rel_abs":"To overcome the enzymatic limitations of Rubisco, algae operate CO2-concentrating mechanisms (CCMs) that deliver concentrated CO2 to Rubisco tightly packaged in a specialized microcompartment called a pyrenoid. Pyrenoids are globally important biomolecular condensates, but their convergent evolution means that their molecular composition and emergent architecture cannot be inferred across clades. Here we characterize the pyrenoid of the Trebouxiophyceae alga, Chlorella sorokiniana. Using cryo-electron tomography, we provide an architectural overview of the pyrenoid and visualize pyrenoid-specific protein complexes. Quantitative proteomics and Rubisco co-immunoprecipitation followed by mass spectrometry demonstrate that inorganic carbon delivery machinery is conserved across green algae but the pyrenoid structural components are not. In vitro reconstitution supports the role of two previously undescribed proteins, one in assembly of pyrenoid traversing thylakoids (putative matrix thylakoid tether; PMTT) and another in starch tethering to the Rubisco matrix (putative matrix starch tether; PMST). In Nicotiana benthamiana, PMTT localized to the thylakoid stromal lamellae and PMST to chloroplast starch granules. Our findings provide insights into the molecular logic of pyrenoid assembly; how proteins mediate condensate-membrane and condensate-starch interactions; and expands the pyrenoid plant engineering toolkit, setting the stage for engineering a Chlorella pyrenoid into plants.","rel_num_authors":11,"rel_authors":[{"author_name":"Mihris I.S. Naduthodi","author_inst":"University of York"},{"author_name":"James Barrett","author_inst":"University of York"},{"author_name":"Jessica Pritchard","author_inst":"University of Edinburgh"},{"author_name":"Philippe Van der Stappen","author_inst":"Biozentrum, University of Basel"},{"author_name":"Manon Demulder","author_inst":"Biozentrum, University of Basel"},{"author_name":"Tommaso Garfagnini","author_inst":"University of York"},{"author_name":"Adam Dowle","author_inst":"University of York"},{"author_name":"Maria Hondele","author_inst":"Biozentrum, University of Basel"},{"author_name":"Benjamin D. Engel","author_inst":"Biozentrum, University of Basel"},{"author_name":"Alistair McCormick","author_inst":"University of Edinburgh"},{"author_name":"Luke C.M. Mackinder","author_inst":"University of York"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Genetically interacting mutations and mechanical stress affect the stochasticity of developmental eye defects in yap1 mutants","rel_doi":"10.64898\/2026.07.11.737910","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737910","rel_abs":"Congenital abnormalities of eye formation show remarkably variable penetrance with phenotypes even varying between left and right eyes. Here we explore this phenomenon through analysis of the mechanistic basis of low penetrance retinal coloboma in zebrafish yap1nl13\/nl13 mutants and identification of factors that modify the probability of this phenotype. We find that the low penetrance stochastically occurring coloboma in yap1nl13\/nl13 mutants is due to rupture in the ventral retina at the point of apposition of the lips of the closing choroid fissure and that provision of wild-type Yap in the retinal pigment epithelium suppressed this phenotype. Decreasing actomyosin contractility increased the penetrance of coloboma whereas increasing myosin phosphorylation rescued the phenotype suggesting that altered mechanical properties of the RPE sensitize the eye to stochastic failure of choroid fissure closure. Genetic interaction screening revealed enhanced and synthetic eye phenotypes in yap1nl13\/nl13 mutants upon abrogation of function of genes encoding extracellular matrix and other genes implicated in eye formation. Our data reveal that the variable penetrance of congenital eye abnormalities can be due to genetic and environmental factors impacting the stochastic variability inherent in the developmental processes underlying eye morphogenesis.","rel_num_authors":19,"rel_authors":[{"author_name":"Niccolo Fioritti","author_inst":"University College London"},{"author_name":"Mahum shaikh","author_inst":"University College London"},{"author_name":"Giulia Cazzagon","author_inst":"University College London"},{"author_name":"Gareth Thomas Powell","author_inst":"University College London"},{"author_name":"Kate Turner","author_inst":"University College London"},{"author_name":"Lisa tucker","author_inst":"University College London"},{"author_name":"Anna Mallucci","author_inst":"University College London"},{"author_name":"Evdokia Hadjieconomou","author_inst":"University College London"},{"author_name":"stephen carter","author_inst":"University College London"},{"author_name":"Daniel Wehner","author_inst":"University of Cologne"},{"author_name":"Gilbert Weidinger","author_inst":"Ulm University"},{"author_name":"Richard J Poole","author_inst":"University College London"},{"author_name":"Florencia Cavodeassi","author_inst":"St. George's University"},{"author_name":"Leonardo E Valdivia","author_inst":"Universidad Mayor"},{"author_name":"Rodrigo Young","author_inst":"UCL"},{"author_name":"Masazumi Tada","author_inst":"University College London"},{"author_name":"Alex Nechiporuk","author_inst":"OHSU"},{"author_name":"Stephen W. Wilson","author_inst":"University College London"},{"author_name":"Gaia Gestri","author_inst":"University College London"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Assembling and annotating the Tainung 67 rice genome to trace its japonica and indica ancestries","rel_doi":"10.64898\/2026.07.15.738793","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738793","rel_abs":"Here we reported the 409.0 Mb assembly of the Tainung 67 (TNG67) genome, an early hybrid of japonica and indica cultivars. We used different platforms to sequence the TNG67 genome with a total coverage of 209.8x, from a combination of Illumina paired-end reads, Illumina mate-pair reads, and Oxford Nanopore Technology long reads. The assembly has an N50 of 32.3 Mb with the longest scaffold = 45.2 Mb. We have annotated 38,938 genes where 28,376 (72.9%) finished with the Blast2GO annotation stage. There were 4,821 genes, (98.4%) of the total gene count that have complete BUSCOs. 48.33% (197.5Mb) of the TNG67 genome is composed of repeats. We predicted a total of 527 blast-resistant genes in TNG67. We also analyzed a total of 20 grain size genes and 38 photoperiod-related genes of TNG67, Nipponbare and TN1, and grouped them in terms of whether the TNG67 genes are more similar to Nipponbare, more similar to TN1, hybrid, same, or unique. We also determined whether the sequences of the TNG67 genome were derived from its japonica or indica ancestors. This TNG67 genome may help rice researchers improve yield, develop resistance against biotic and abiotic stress, and understand the evolution of a hybrid cultivar of japonica and indica.","rel_num_authors":6,"rel_authors":[{"author_name":"Jerome Pe\u00f1aflor Panibe","author_inst":"Biodiversity Research Center, Academia Sinica"},{"author_name":"Long Wang","author_inst":"State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University"},{"author_name":"Tzi-Yuan Wang","author_inst":"Biodiversity Research Center, Academia Sinica"},{"author_name":"Chang-Sheng Wang","author_inst":"Department of Agronomy, National Chung-Hsing University"},{"author_name":"Mei-Yeh Jade Lu","author_inst":"Biodiversity Research Center, Academia Sinica"},{"author_name":"Wen-Hsiung Li","author_inst":"Department of Ecology and Evolution, University of Chicago"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Assembling and annotating the Tainung 67 rice genome to trace its japonica and indica ancestries","rel_doi":"10.64898\/2026.07.15.738793","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738793","rel_abs":"Here we reported the 409.0 Mb assembly of the Tainung 67 (TNG67) genome, an early hybrid of japonica and indica cultivars. We used different platforms to sequence the TNG67 genome with a total coverage of 209.8x, from a combination of Illumina paired-end reads, Illumina mate-pair reads, and Oxford Nanopore Technology long reads. The assembly has an N50 of 32.3 Mb with the longest scaffold = 45.2 Mb. We have annotated 38,938 genes where 28,376 (72.9%) finished with the Blast2GO annotation stage. There were 4,821 genes, (98.4%) of the total gene count that have complete BUSCOs. 48.33% (197.5Mb) of the TNG67 genome is composed of repeats. We predicted a total of 527 blast-resistant genes in TNG67. We also analyzed a total of 20 grain size genes and 38 photoperiod-related genes of TNG67, Nipponbare and TN1, and grouped them in terms of whether the TNG67 genes are more similar to Nipponbare, more similar to TN1, hybrid, same, or unique. We also determined whether the sequences of the TNG67 genome were derived from its japonica or indica ancestors. This TNG67 genome may help rice researchers improve yield, develop resistance against biotic and abiotic stress, and understand the evolution of a hybrid cultivar of japonica and indica.","rel_num_authors":6,"rel_authors":[{"author_name":"Jerome Pe\u00f1aflor Panibe","author_inst":"Biodiversity Research Center, Academia Sinica"},{"author_name":"Long Wang","author_inst":"State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University"},{"author_name":"Tzi-Yuan Wang","author_inst":"Biodiversity Research Center, Academia Sinica"},{"author_name":"Chang-Sheng Wang","author_inst":"Department of Agronomy, National Chung-Hsing University"},{"author_name":"Mei-Yeh Jade Lu","author_inst":"Biodiversity Research Center, Academia Sinica"},{"author_name":"Wen-Hsiung Li","author_inst":"Department of Ecology and Evolution, University of Chicago"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"MetaboXcan: A multiomic framework linking genetically predicted metabolites, gene expression, and complex traits","rel_doi":"10.64898\/2026.07.15.738631","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738631","rel_abs":"Genetically regulated molecular phenotypes, such as gene expression and metabolites, are widely thought to mediate the effect of disease-relevant genetic loci identified by genome-wide association studies (GWAS); however, molecular mechanisms connecting genetic variation to disease remain poorly understood. While transcriptome-wide association studies (TWAS) have identified disease-associated genes, strategies that integrate the metabolome remain underexplored. Here, we introduce MetaboXcan, a framework for predicting plasma metabolite levels from genetic data and associating them with complex traits using GWAS summary statistics. We trained lasso regression models on plasma metabolite and genotype data from the Metabolic Syndrome in Men Study (METSIM); these models outperform existing genetic metabolite predictors and generalize well across independent cohorts. MetaboXcan leverages these models to perform four complementary association analyses: (i) gene-to-trait (TWAS), (ii) gene-to-metabolite (M-TWAS), (iii) metabolite-to-trait (MWAS), and (iv) gene-expression-based metabolite-to-trait associations (g-MWAS). The framework further organizes results into metabolic pathways and gene-metabolite interaction networks to facilitate biological interpretation. Applied to chronic kidney disease (CKD), MetaboXcan identified known disease risk genes (PDILT\/UMOD, SPATA5L1\/GATM), as well as multiple CKD-relevant metabolites (e.g., glycine, homoarginine). Our integrated multiomic analysis enables biological interpretation by revealing glycine availability-centered biochemical axes spanning oxidative stress, cellular energetics, and vascular signaling, while nominating candidate mechanisms for downstream investigation. These results validate known disease-related biology with genetic evidence and generate new hypotheses for further investigation. MetaboXcan is publicly available and broadly applicable to any GWAS phenotype.","rel_num_authors":22,"rel_authors":[{"author_name":"Festus Nyasimi","author_inst":"University of Chicago Pritzker School of Medicine"},{"author_name":"Sarah Sumner","author_inst":"University of Chicago Pritzker School of Medicine"},{"author_name":"Yanyu Liang","author_inst":"University of Chicago Medical Center: The University of Chicago Medicine"},{"author_name":"Xianyong Yin","author_inst":"University of Michigan"},{"author_name":"Yoson Park","author_inst":"Eli Lilly and Company"},{"author_name":"Andrew Brown","author_inst":"University of Dundee"},{"author_name":"Sulaiman  A Lawal","author_inst":"University of Newcastle"},{"author_name":"Ana Vinuela","author_inst":"University of Dundee"},{"author_name":"Lilian Fernandez Silva","author_inst":"University of Eastern Finland - Kuopio Campus: Ita-Suomen yliopisto - Kuopion kampus"},{"author_name":"Chunyu Liu","author_inst":"Boston University School of Public Health"},{"author_name":"Sarah  D Slack","author_inst":"University of Colorado School of Medicine: University of Colorado Anschutz Medical Campus School of Medicine"},{"author_name":"Erika Esquinca","author_inst":"University of Colorado School of Medicine: University of Colorado Anschutz Medical Campus School of Medicine"},{"author_name":"Randi  K Johnson","author_inst":"University of Colorado School of Medicine: University of Colorado Anschutz Medical Campus School of Medicine"},{"author_name":"Katerina Kechris","author_inst":"University of Colorado School of Medicine: University of Colorado Anschutz Medical Campus School of Medicine"},{"author_name":"Markku Laasko","author_inst":"University of Eastern Finland - Kuopio Campus: Ita-Suomen yliopisto - Kuopion kampus"},{"author_name":"Michael Boehnke","author_inst":"University of Michigan School of Public Health"},{"author_name":"Eric Fauman","author_inst":"Pfizer Inc"},{"author_name":"Abraham  A Palmer","author_inst":"University of California San Diego"},{"author_name":"Sandra Sanchez-Roige","author_inst":"University of California San Diego"},{"author_name":"Ani Manichaikul","author_inst":"University of Virginia"},{"author_name":"Nicholette  D Palmer","author_inst":"Wake Forest School of Medicine: Wake Forest University School of Medicine"},{"author_name":"Hae Kyung Im","author_inst":"University of Chicago"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"MetaboXcan: A multiomic framework linking genetically predicted metabolites, gene expression, and complex traits","rel_doi":"10.64898\/2026.07.15.738631","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738631","rel_abs":"Genetically regulated molecular phenotypes, such as gene expression and metabolites, are widely thought to mediate the effect of disease-relevant genetic loci identified by genome-wide association studies (GWAS); however, molecular mechanisms connecting genetic variation to disease remain poorly understood. While transcriptome-wide association studies (TWAS) have identified disease-associated genes, strategies that integrate the metabolome remain underexplored. Here, we introduce MetaboXcan, a framework for predicting plasma metabolite levels from genetic data and associating them with complex traits using GWAS summary statistics. We trained lasso regression models on plasma metabolite and genotype data from the Metabolic Syndrome in Men Study (METSIM); these models outperform existing genetic metabolite predictors and generalize well across independent cohorts. MetaboXcan leverages these models to perform four complementary association analyses: (i) gene-to-trait (TWAS), (ii) gene-to-metabolite (M-TWAS), (iii) metabolite-to-trait (MWAS), and (iv) gene-expression-based metabolite-to-trait associations (g-MWAS). The framework further organizes results into metabolic pathways and gene-metabolite interaction networks to facilitate biological interpretation. Applied to chronic kidney disease (CKD), MetaboXcan identified known disease risk genes (PDILT\/UMOD, SPATA5L1\/GATM), as well as multiple CKD-relevant metabolites (e.g., glycine, homoarginine). Our integrated multiomic analysis enables biological interpretation by revealing glycine availability-centered biochemical axes spanning oxidative stress, cellular energetics, and vascular signaling, while nominating candidate mechanisms for downstream investigation. These results validate known disease-related biology with genetic evidence and generate new hypotheses for further investigation. MetaboXcan is publicly available and broadly applicable to any GWAS phenotype.","rel_num_authors":22,"rel_authors":[{"author_name":"Festus Nyasimi","author_inst":"University of Chicago Pritzker School of Medicine"},{"author_name":"Sarah Sumner","author_inst":"University of Chicago Pritzker School of Medicine"},{"author_name":"Yanyu Liang","author_inst":"University of Chicago Medical Center: The University of Chicago Medicine"},{"author_name":"Xianyong Yin","author_inst":"University of Michigan"},{"author_name":"Yoson Park","author_inst":"Eli Lilly and Company"},{"author_name":"Andrew Brown","author_inst":"University of Dundee"},{"author_name":"Sulaiman  A Lawal","author_inst":"University of Newcastle"},{"author_name":"Ana Vinuela","author_inst":"University of Dundee"},{"author_name":"Lilian Fernandez Silva","author_inst":"University of Eastern Finland - Kuopio Campus: Ita-Suomen yliopisto - Kuopion kampus"},{"author_name":"Chunyu Liu","author_inst":"Boston University School of Public Health"},{"author_name":"Sarah  D Slack","author_inst":"University of Colorado School of Medicine: University of Colorado Anschutz Medical Campus School of Medicine"},{"author_name":"Erika Esquinca","author_inst":"University of Colorado School of Medicine: University of Colorado Anschutz Medical Campus School of Medicine"},{"author_name":"Randi  K Johnson","author_inst":"University of Colorado School of Medicine: University of Colorado Anschutz Medical Campus School of Medicine"},{"author_name":"Katerina Kechris","author_inst":"University of Colorado School of Medicine: University of Colorado Anschutz Medical Campus School of Medicine"},{"author_name":"Markku Laasko","author_inst":"University of Eastern Finland - Kuopio Campus: Ita-Suomen yliopisto - Kuopion kampus"},{"author_name":"Michael Boehnke","author_inst":"University of Michigan School of Public Health"},{"author_name":"Eric Fauman","author_inst":"Pfizer Inc"},{"author_name":"Abraham  A Palmer","author_inst":"University of California San Diego"},{"author_name":"Sandra Sanchez-Roige","author_inst":"University of California San Diego"},{"author_name":"Ani Manichaikul","author_inst":"University of Virginia"},{"author_name":"Nicholette  D Palmer","author_inst":"Wake Forest School of Medicine: Wake Forest University School of Medicine"},{"author_name":"Hae Kyung Im","author_inst":"University of Chicago"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"When Music Loses Its Pleasure: Hippocampal Cingulum White Matter as a Structural Mediator of Musical Reward Decline in Aging","rel_doi":"10.64898\/2026.07.16.738989","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738989","rel_abs":"Individuals' ability to obtain pleasure from music, referred to as musical reward sensitivity, declines with age, yet the neural mechanisms underlying this decline remain unclear. In this study, we investigated musical reward sensitivity measured in 58 older adults and 131 young adults. Consistent with prior findings, young adults reported higher musical reward sensitivity than older adults (p < 0.05). To identify neuroanatomical predictors of musical reward sensitivity, we employed the elastic-net model to predict musical reward sensitivity using white matter microstructural properties and gray matter morphometric properties from the whole brain. In older adults, fractional anisotropy (FA) in the bilateral hippocampal cingulum (CGH) and external capsule (EC) reliably predicted individual differences in musical reward sensitivity. Moreover, FA in the right CGH significantly mediated the relationship between age and musical reward sensitivity in older adults. Notably, these associations were specific to musical reward sensitivity in older adults, that is, they did not replicate in young adults, and did not extend to general reward sensitivity. Together, these findings highlight the critical role of white matter integrity, particularly within the hippocampal-limbic pathways, in age-related changes in musical reward processing, and suggest a potential neurobiological target for interventions aimed at enhancing well-being in older adulthood.","rel_num_authors":8,"rel_authors":[{"author_name":"Jinyu Wang","author_inst":"Northeastern University"},{"author_name":"Nicholas Kathios","author_inst":"Northeastern University"},{"author_name":"Benjamin Kubit","author_inst":"Northeastern University"},{"author_name":"Kelsie Lopez","author_inst":"Northeastern University"},{"author_name":"Ji Chul Kim","author_inst":"University of Connecticut"},{"author_name":"Edward Large","author_inst":"University of Connecticut"},{"author_name":"Stephanie Noble","author_inst":"Northeastern University"},{"author_name":"Psyche Loui","author_inst":"Northeastern University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"A Role for Astrocyte Metabolism in Species-Specific Neuronal Development","rel_doi":"10.64898\/2026.07.15.737608","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.737608","rel_abs":"Human neurons develop more slowly than non-human primate neurons. This phenomenon, termed neoteny, is thought to contribute to several human-specific features of the brain, including humans' expanded cortices. However, much of the research on this difference in neuronal development rate has focused on neuron-intrinsic drivers of developmental timing. Because astrocytes serve as critical support cells of neurons and are increasingly implicated in neuronal maturation during development, we hoped to further elucidate any species-specific divergence in function and the astrocytes' role in influencing species-specific development rate. In this study, we began with a transcriptomic characterization of human and non-human primate astrocytes in vitro. We then measured how the metabolic role of astrocytes differs between humans and non-human primates. We then performed a multi-electrode array assay and observed an increase in electrophysiological maturation in human neurons cultured with rhesus macaque astrocyte conditioned media as opposed to human astrocyte conditioned media and a change in the trajectory of neuronal development, as measured by transcriptomics. Curiously, we observed an increase in synaptogenic and axon growth-related proteins in the secretome of human astrocytes, suggesting that human astrocytes play a different, more synaptogenic and dendritic arborization-focused role in neurodevelopment than non-human primate astrocytes. Finally, we demonstrated that these changes in neuronal differentiation are in part mediated by the different metabolic roles that astrocytes play in humans versus non-human primates through chemical inhibition of a key metabolic pathway. Our results collectively suggest a cell-extrinsic role for astrocyte metabolism in shaping the differences in neurodevelopment rate and trajectory in humans versus non-human primates.","rel_num_authors":10,"rel_authors":[{"author_name":"Sheila C Steiner","author_inst":"Salk Institute"},{"author_name":"Kaia Foster","author_inst":"University of California San Diego"},{"author_name":"Rebecca R Chinn","author_inst":"Salk Institute"},{"author_name":"Joshua Pratt","author_inst":"Salk Institute"},{"author_name":"Sarah Fernandes","author_inst":"Salk Institute"},{"author_name":"Amandeep Sharma","author_inst":"Salk Institute"},{"author_name":"Renata Santos","author_inst":"Institute of Psychiatry and Neuroscience of Paris"},{"author_name":"Christian C Metallo","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Maria Carolina Marchetto","author_inst":"University of California, San Diego"},{"author_name":"Fred H. Gage","author_inst":"Salk Institute"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"A Role for Astrocyte Metabolism in Species-Specific Neuronal Development","rel_doi":"10.64898\/2026.07.15.737608","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.737608","rel_abs":"Human neurons develop more slowly than non-human primate neurons. This phenomenon, termed neoteny, is thought to contribute to several human-specific features of the brain, including humans' expanded cortices. However, much of the research on this difference in neuronal development rate has focused on neuron-intrinsic drivers of developmental timing. Because astrocytes serve as critical support cells of neurons and are increasingly implicated in neuronal maturation during development, we hoped to further elucidate any species-specific divergence in function and the astrocytes' role in influencing species-specific development rate. In this study, we began with a transcriptomic characterization of human and non-human primate astrocytes in vitro. We then measured how the metabolic role of astrocytes differs between humans and non-human primates. We then performed a multi-electrode array assay and observed an increase in electrophysiological maturation in human neurons cultured with rhesus macaque astrocyte conditioned media as opposed to human astrocyte conditioned media and a change in the trajectory of neuronal development, as measured by transcriptomics. Curiously, we observed an increase in synaptogenic and axon growth-related proteins in the secretome of human astrocytes, suggesting that human astrocytes play a different, more synaptogenic and dendritic arborization-focused role in neurodevelopment than non-human primate astrocytes. Finally, we demonstrated that these changes in neuronal differentiation are in part mediated by the different metabolic roles that astrocytes play in humans versus non-human primates through chemical inhibition of a key metabolic pathway. Our results collectively suggest a cell-extrinsic role for astrocyte metabolism in shaping the differences in neurodevelopment rate and trajectory in humans versus non-human primates.","rel_num_authors":10,"rel_authors":[{"author_name":"Sheila C Steiner","author_inst":"Salk Institute"},{"author_name":"Kaia Foster","author_inst":"University of California San Diego"},{"author_name":"Rebecca R Chinn","author_inst":"Salk Institute"},{"author_name":"Joshua Pratt","author_inst":"Salk Institute"},{"author_name":"Sarah Fernandes","author_inst":"Salk Institute"},{"author_name":"Amandeep Sharma","author_inst":"Salk Institute"},{"author_name":"Renata Santos","author_inst":"Institute of Psychiatry and Neuroscience of Paris"},{"author_name":"Christian C Metallo","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Maria Carolina Marchetto","author_inst":"University of California, San Diego"},{"author_name":"Fred H. Gage","author_inst":"Salk Institute"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Synthesis of Ultra-Large Fibrous Proteins from Bacteria via a Looped-Translation System","rel_doi":"10.64898\/2026.07.16.738376","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738376","rel_abs":"High molecular weight fibrous proteins such as silk, elastin, and collagens, are fundamental for providing shape to macroscopic biological structures, yet their recombinant production remains challenging because of their extreme size and sequence repetitiveness. Here, we report a circular RNA-based ribosome translation platform that enables iterative ribosome synthesis of fibrous proteins through continuously 'looped' translation. To promote efficient circularization of repetitive fibrous protein-transcripts, we combined a synonymous codon locker sequence strategy with RNA circularization chaperones. Guided by a ribosome traffic model, we further optimized the translation bottlenecks within the circular RNA, substantially improving translation yields. The established looped translation platform is applicable to at least six classes of fibrous proteins and generated products with molecular weight exceeding titin at 3.8 MDa. The synthesized polypeptides were characterized through electron microscopy, bulk material fabrication, and mechanical analysis, demonstrating properties associated with ultra-high molecular weight polypeptides. Finally, we coupled looped translation to secretion through a programmed ribosomal frameshift, enabling export of fibrous protein across cellular membranes in both Escherichia coli and Bacillus subtilis. We envision that the genetic tools presented here could find a range of applications in bioplastics and engineered living materials.","rel_num_authors":6,"rel_authors":[{"author_name":"Qi Xie","author_inst":"Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218 USA"},{"author_name":"Louis J. Papa III","author_inst":"Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 USA"},{"author_name":"Anton M. Barybin","author_inst":"Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 USA"},{"author_name":"Michael Xiong","author_inst":"Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 USA"},{"author_name":"Matthew D. Shoulders","author_inst":"Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 USA"},{"author_name":"Stephen D. Fried","author_inst":"Department of Chemistry, Johns Hopkins University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Synthesis of Ultra-Large Fibrous Proteins from Bacteria via a Looped-Translation System","rel_doi":"10.64898\/2026.07.16.738376","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738376","rel_abs":"High molecular weight fibrous proteins such as silk, elastin, and collagens, are fundamental for providing shape to macroscopic biological structures, yet their recombinant production remains challenging because of their extreme size and sequence repetitiveness. Here, we report a circular RNA-based ribosome translation platform that enables iterative ribosome synthesis of fibrous proteins through continuously 'looped' translation. To promote efficient circularization of repetitive fibrous protein-transcripts, we combined a synonymous codon locker sequence strategy with RNA circularization chaperones. Guided by a ribosome traffic model, we further optimized the translation bottlenecks within the circular RNA, substantially improving translation yields. The established looped translation platform is applicable to at least six classes of fibrous proteins and generated products with molecular weight exceeding titin at 3.8 MDa. The synthesized polypeptides were characterized through electron microscopy, bulk material fabrication, and mechanical analysis, demonstrating properties associated with ultra-high molecular weight polypeptides. Finally, we coupled looped translation to secretion through a programmed ribosomal frameshift, enabling export of fibrous protein across cellular membranes in both Escherichia coli and Bacillus subtilis. We envision that the genetic tools presented here could find a range of applications in bioplastics and engineered living materials.","rel_num_authors":6,"rel_authors":[{"author_name":"Qi Xie","author_inst":"Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218 USA"},{"author_name":"Louis J. Papa III","author_inst":"Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 USA"},{"author_name":"Anton M. Barybin","author_inst":"Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 USA"},{"author_name":"Michael Xiong","author_inst":"Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 USA"},{"author_name":"Matthew D. Shoulders","author_inst":"Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 USA"},{"author_name":"Stephen D. Fried","author_inst":"Department of Chemistry, Johns Hopkins University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Metabolic responses to physiological stressors assessed using continuous glucose monitoring integrated with indirect calorimetry in mice","rel_doi":"10.64898\/2026.07.13.738308","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738308","rel_abs":"Continuous glucose monitoring (CGM) in rodents has provided unprecedented temporal resolution of glycemic dynamics in vivo. Even in the absence of deliberate perturbation, glucose levels in mice are dynamic, fluctuating in response to the timing and duration of feeding events, changes in neurological and hormonal states, physical activity, and photoperiod. To obtain a comprehensive view of metabolic adaptations under common experimental conditions, we monitored freely moving mice simultaneously using CGM and indirect calorimetry to quantify glucose, food intake, physical activity and metabolic rate. We characterized glycemic and metabolic responses to routine laboratory interventions, including short-term and overnight fasting, refeeding, tail blood sampling during glucose tolerance tests, changes in ambient temperature to cold or thermoneutral conditions, and access to running wheels. We found that food removal induced a robust, transient stress response characterized by increased blood glucose, body temperature, energy expenditure, and physical activity. However, prolonged fasting ultimately led to hypoglycemia and torpor. The magnitude and variability of glycemic responses to insulin tolerance tests were strongly influenced by fasting duration, and tail-tip blood collection itself elicited substantial hyperglycemia. In contrast to prolonged fasting, refeeding produced relatively modest and transient effects on glucose and energy expenditure. Cold exposure elicited increased energy expenditure along with a sustained hyperglycemic response. Voluntary wheel running induced transient increases in glucose and metabolic activity and promoted a shift toward increased fatty acid oxidation. Together, these findings demonstrate that common laboratory manipulations exert dynamic, often substantial effects on glycemia and whole-body metabolism that are readily revealed by CGM and indirect calorimetry.","rel_num_authors":8,"rel_authors":[{"author_name":"Evelyn Y Zhou","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Corey Holman","author_inst":"University of Pennsylvania"},{"author_name":"Michelle Lee","author_inst":"University of Pennsylvania"},{"author_name":"William B Rubio","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Ryan Calhoun","author_inst":"University of Pennsylvania"},{"author_name":"Qingwei Chu","author_inst":"University of Pennsylvania"},{"author_name":"Alexander Banks","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Joseph A Baur","author_inst":"University of Pennsylvania"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Perinatal exposure to individual and a metal mixture induces persistent and sex-specific alterations to the cardiac transcriptome of offspring","rel_doi":"10.64898\/2026.07.11.737950","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737950","rel_abs":"Exposure to heavy metals, such as lead, arsenic, cadmium, and chromium, has been individually linked to cardiac dysfunction during development and into adulthood. Although these metals are commonly encountered as a mixture, few studies have investigated the mixture effects of gestational exposure to these metals on the developing postnatal heart. To this end, we investigated the transcriptomic effects of individual heavy metals (arsenic, cadmium, chromium, and lead) and the combined mixture on female C57BI\/6 mice prior to gestation through lactation. RNA was extracted from whole offspring hearts, and total RNA was sent for bulk RNA-sequencing. We found heavy metal exposure altered genes associated with circadian rhythm, cell division and DNA damage repair, and immune signaling. Moreover, we detected changes to the cellular composition of these hearts and an increase in Il2ra expression, indicating an increase in activated natural killer cells. When targeting postnatal heart development and maturation pathways, we found the mixture induced a general upregulation of almost all targeted pathways, which seemed to be driven by co-exposure to all metals instead of one metal driving the mixture phenotype, and revealed a potential functional-energetic mismatch. This study is one of the first to show that perinatal exposure to heavy metals altered circadian rhythm and immune signaling gene expression in a metal- and sex-specific manner, disrupted normal cardiac cellular composition, and upregulated genes associated with postnatal heart maturation.","rel_num_authors":7,"rel_authors":[{"author_name":"Morgan Steiner","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Jason Laird","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Sylvia S. Sanchez","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Susmitha Pagadala","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Shyam Biswal","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Fenna C. M. Sille","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Mark J. Kohr","author_inst":"Johns Hopkins Bloomberg School of Public Health"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Shared QTLs underlie loss of a conserved trait in replicate mapping populations of Arabidopsis thaliana","rel_doi":"10.64898\/2026.07.14.738505","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738505","rel_abs":"The evolutionary mechanisms leading to nonfunctional trait loss are not well understood. Some Arabidopsis thaliana populations display incomplete loss of short stamens, floral organs that do not contribute significantly to seed set in this species. In nature, short stamen number is correlated with ovule number and flowering time, suggesting that pleiotropy with these traits could drive stamen number evolution. To investigate the role of pleiotropy in short stamen number evolution, we performed QTL mapping of stamen number and ovule number and examined previously published QTL analyses of flowering time for two sets of RILs, Belm-12 x Roda-47 and Tsu-1 x Kas-1. Flowering time, ovule number, and short stamen loss were correlated in Belm-12 x Roda-47 RILs, but not Tsu-1 x Kas-1 RILs. For both stamen and ovule number, some QTLs were unique to each RIL set and others were shared. Notably, for Belm-12 x Roda-47 RILs, we mapped QTLs affecting ovule and short stamen number to a region of chromosome 5 that also affects flowering time. For Tsu-1 x Kas-1 RILs, we identified the same chromosome 5 region as a short stamen number QTL, but ovule number and flowering time QTLs map to other genomic regions. While some genetic architectures of short stamen number and traits that are correlated in nature suggest linked or pleiotropic loci on chromosome 5, other architectures allow for recombination between QTLs that affect stamen number, ovule number, and flowering time. The role of pleiotropy in short stamen number evolution is therefore context dependent.","rel_num_authors":5,"rel_authors":[{"author_name":"Madison Plunkert","author_inst":"Michigan State University"},{"author_name":"Ousseini Issaka Salia","author_inst":"Michigan State University"},{"author_name":"Esther Woolcock","author_inst":"Michigan State University"},{"author_name":"Samuel Perez","author_inst":"Michigan State University"},{"author_name":"Jeffrey K Conner","author_inst":"Michigan State University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Massively parallel characterization and predictive modelling of neuronal regulatory variation","rel_doi":"10.64898\/2026.07.16.738760","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738760","rel_abs":"Disease-associated variants reside frequently in noncoding cis-regulatory elements (CREs), yet their functional consequences remain poorly understood. We performed a large-scale lentiMPRA in human excitatory neurons, quantifying the impact of >46,000 naturally occurring variants across >27,000 candidate CREs near 524 disease-associated genes. These data improved regulatory variant effect predictions beyond state-of-the-art models. Significant allelic effects occurred at comparable rates across common, rare, and singleton variants, demonstrating that, within MPRA-measurable effects, population frequency carries limited information about per-variant regulatory impact. Variant effect detectability and magnitude were governed primarily by baseline activity of the enclosing regulatory element and local sequence context. Regulatory effects were distributed across numerous transcription factors rather than concentrated in master regulators, consistent with a combinatorial enhancer architecture. We establish a large-scale functional variant catalog and provide a complementary benchmark and resource for developing and evaluating models of noncoding regulatory variation.","rel_num_authors":16,"rel_authors":[{"author_name":"Kilian Salomon","author_inst":"Berlin Institute of Health at Charite - Universitatsmedizin Berlin, Germany"},{"author_name":"Chengyu Deng","author_inst":"University of California San Francisco, CA"},{"author_name":"Pyaree Mohan Dash","author_inst":"Berlin Institute of Health at Charite - Universitatsmedizin Berlin, Germany"},{"author_name":"Theofilos Chalkiadakis","author_inst":"Berlin Institute of Health at Charite - Universitatsmedizin Berlin, Germany"},{"author_name":"Qunrui Li","author_inst":"University of California San Francisco, CA"},{"author_name":"Ziwei Chen","author_inst":"Stanford University, Stanford, CA"},{"author_name":"Nicholas Francis Page","author_inst":"University of California San Francisco, CA"},{"author_name":"Mustafa Helal","author_inst":"University of Lubeck, Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Lubeck, Germany"},{"author_name":"Sebastian Roener","author_inst":"Berlin Institute of Health at Charite - Universitatsmedizin Berlin, Germany"},{"author_name":"Anshul Kundaje","author_inst":"Stanford University, Stanford, CA"},{"author_name":"Claudia Langenberg","author_inst":"Queen Mary University of London, UK"},{"author_name":"Maik Pietzner","author_inst":"Berlin Institute of Health at Charite - Universitatsmedizin Berlin, Germany"},{"author_name":"Jay Shendure","author_inst":"University of Washington, WA"},{"author_name":"Max Schubach","author_inst":"Berlin Institute of Health at Charite - Universitatsmedizin Berlin, Germany"},{"author_name":"Nadav Ahituv","author_inst":"University of California San Francisco, CA"},{"author_name":"Martin Kircher","author_inst":"University of Lubeck, Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Lubeck, Germany"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"A Promoter Competition Hub Orchestrates Runx1 Alternative Promoter Usage during Skeletal Muscle Stem Cell Activation","rel_doi":"10.64898\/2026.07.13.738242","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738242","rel_abs":"Alternative promoter (AP) usage profoundly expands transcriptomic and proteomic diversity, yet the regulatory principles governing promoter choice remain poorly understood. Here, using the dual-promoter Runx1 locus as a paradigm in skeletal muscle stem cells (MuSCs), we uncover a promoter competition hub that orchestrates AP selection during MuSC fate transition from activation to proliferation. We find antagonistic expression dynamics between the two Runx1 promoters, with the primary promoter (PP) active in the early activating stage and the secondary promoter (SP) induced later in proliferation. Combinatorial genetic perturbations in vitro and in vivo establish the non-redundant roles of PP- and SP-derived isoforms in MuSC lineage progression. Mechanistically, we find that PP and SP engage in reciprocal competition in a multi-connected enhancer-promoter (E-P) loop hub. Further dissection identifies a cohort of key enhancers that dynamically interact with PP\/SP to orchestrate the competition. Moreover, we establish the transcription factor USF1 as a key factor driving the dynamic E-P interactions and PP\/SP competition. Beyond Runx1, high-resolution Micro-C reveals promoter competition as a general mechanism regulating a subset of AP choices in MuSC activation\/proliferation. Collectively, our study uncovers a dynamic promoter competition hub that governs AP selection in MuSC lineage progression, offering fundamental insights into how 3D genome architecture coordinates precise, stage-specific gene expression programs during cell fate transitions.","rel_num_authors":9,"rel_authors":[{"author_name":"Liangqiang HE","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Qiang SUN","author_inst":"Chinese Academy of Sciences"},{"author_name":"Yulong Qiao","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Ziliu Wang","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Qin Zhou","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Lifang Han","author_inst":"the Hong Kong University of Science & Technology"},{"author_name":"Zhenguo Wu","author_inst":"Hong Kong University of Science & Technology"},{"author_name":"Hao Sun","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Huating Wang","author_inst":"The Chinese University of Hong Kong"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Re-invasion of the New World screwworm in Central and North America: comparative analysis of three SIT eradication efforts","rel_doi":"10.64898\/2026.07.16.738939","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738939","rel_abs":"In sharp contrast to biological control that seeks control of pests below economic levels, eradication programs seek total extermination of pest species. However, eradication programs are often undertaken without knowledge of the pest's potential geographic distribution and relative abundance (i.e., geographic risk assessment), often leading to eradication efforts conducted across areas much greater than the potential permanent range of the target species. To demonstrate this, we review eradication efforts against the tropical New World screwworm (Cochliomyia hominivorax) in the SE USA and Mexico, the exotic sub-tropical tephritid Mediterranean fruit fly (Ceratitis capitata, medfly) in California, and the exotic tropical pink bollworm (Pectinophora gossypiella, PBW) in the SW USA. We use mechanistic physiologically based demographic models (PBDMs) that are physiologically based time varying life tables to decompose the systems and to assess risk under extant and climate change scenarios.","rel_num_authors":2,"rel_authors":[{"author_name":"Andrew Paul Gutierrez","author_inst":"Division of Ecosystem Science, College of Natural Resources, University of California, Berkeley, CA 94720-3114, USA"},{"author_name":"Luigi Ponti","author_inst":"Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Centro Ricerche Casaccia, Via Anguillarese 301, 00123 Roma, Ita"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Intranucleolar Invasion of Cajal Body Remnants Suppresses Ribosomal Biogenesis in cis and Telomerase Functions in trans","rel_doi":"10.64898\/2026.07.16.738943","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738943","rel_abs":"Cellular processes are compartmentalized within immiscible heterotypic condensates, yet the functional consequences of losing their physical segregation remain unclear. Here, we show that genetic inactivation of the RNA chaperone SMN forces the aberrant intermixing of the two most prominent nuclear condensates: nucleolus and Cajal Body (CB). Upon SMN depletion, CB components invade the nucleolus and undergo reduced mobility and solubility consistent with a liquid-to-gel-like hardening transition. The CB-scaffold coilin aberrantly enriches at the nucleolar FC\/DFC boundary and occupies rDNA chromatin, thereby locally suppressing rRNA production. Concurrently, this sequestration globally impairs coilin targeting to snRNA\/snoRNA loci and limits telomerase access to telomeres, reducing telomeric synthesis. Crucially, genetic coilin depletion alone alleviates this mistargeting and rescues these functional impairments across condensates. Our findings reveal an inter-condensate rheostat model in which the loss of CB-nucleolar immiscibility is directly sensed, communicated, and executed by CB remnants, thereby proportionally coupling the functional outputs of otherwise distinct RNPs essential for splicing, translation, and genomic integrity.","rel_num_authors":15,"rel_authors":[{"author_name":"Alexander Morris","author_inst":"Fox Chase Cancer Center"},{"author_name":"Julia Hoopman","author_inst":"Fox Chase Cancer Center"},{"author_name":"Vidhyadhar Nandana","author_inst":"Fox Chase Cancer Center"},{"author_name":"Cameron Genxuan Lian","author_inst":"Fox Chase Cancer Center"},{"author_name":"Emily Pochet","author_inst":"Fox Chase Cancer Center"},{"author_name":"Maria Ruiz","author_inst":"Fox Chase Cancer Center"},{"author_name":"Baihao Su","author_inst":"Fox Chase Cancer Center"},{"author_name":"Andrey Efimov","author_inst":"Fox Chase Cancer Center"},{"author_name":"Cynthia Myers","author_inst":"Fox Chase Cancer Center"},{"author_name":"Yingda Tao","author_inst":"Binghamton University"},{"author_name":"Luciano Saieva","author_inst":"Columbia University"},{"author_name":"Guoyu Lu","author_inst":"Binghamton University"},{"author_name":"Erica Golemis","author_inst":"Fox Chase Cancer Center"},{"author_name":"Livio Pellizzoni","author_inst":"Columbia University"},{"author_name":"Lu Chen","author_inst":"Fox Chase Cancer Center"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Selectivity for high-level language processing is highly localized in individual brains","rel_doi":"10.64898\/2026.07.16.738967","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738967","rel_abs":"Some aspects of human behavior and cognition depend on focal and selective cortical areas, such as the frontal eye fields or fusiform face area, while others, like semantic knowledge, are broadly distributed across the cortex. Whether higher-level cognitive functions like language can also be highly localized has been a longstanding matter of debate. Here, we provide multiple lines of evidence that receptive language in the brain is subserved by a network of discrete, focal, and uniquely language-selective areas when examining individual brains. Using precision neuroimaging, we observed highly circumscribed patches of cortex that are distinctly selective for language, uniquely consistent in their response properties during language processing, and highly reliable in their anatomical locations within individuals (though variable in location across individuals). These findings indicate that language regions in the brain are characterized by unique functional profiles and sharp boundaries, consistent with the systems neuroscience definition of true \"cortical areas.\"","rel_num_authors":3,"rel_authors":[{"author_name":"Rebecca M Belisle","author_inst":"Boston University"},{"author_name":"Terri L Scott","author_inst":"Northeastern University"},{"author_name":"Tyler K Perrachione","author_inst":"Boston University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Hilar mossy cells control structural and functional organization in the dentate gyrus","rel_doi":"10.64898\/2026.07.15.738260","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738260","rel_abs":"Hilar mossy cells in the dentate gyrus project widely throughout the hippocampus, broadly contributing to circuit function. Their loss in disease is associated with local functional and structural rearrangements, including retrograde granule cell axon sprouting, aberrant neurogenesis, and disinhibition. To examine how mossy cell loss contributes to these circuit rearrangements, we ablated or silenced hilar mossy cells using viral approaches in transgenic (Crlr-Cre) mice. Both mossy cell ablation and silencing dramatically altered dentate gyrus structure and function, as assessed using immunohistochemical, viral labeling, electrophysiology, and anatomical methods. Both manipulations accelerated the maturation of adult-born neurons, but did not alter neuroblast proliferation or cause granule cell axon sprouting. However, mossy cell ablation, but not silencing, caused collapse of the inner molecular layer accompanied by proximal translocation of middle molecular layer inputs. In both cases, granule cell activity measured by cFos labeling and seizure susceptibility were unchanged after mossy cell loss, indicating functional compensation for the altered network organization. Our results highlight how mossy cells influence dentate gyrus organization and adult neurogenesis but also demonstrate the resilience of the hippocampal circuit to structural or functional perturbations.","rel_num_authors":6,"rel_authors":[{"author_name":"Corwin R Butler","author_inst":"Portland VA Medical Center"},{"author_name":"Connor R Squellati","author_inst":"Oregon Health & Science University"},{"author_name":"Alyssa B Danis","author_inst":"Oregon Health & Science University"},{"author_name":"Arielle Isakharov","author_inst":"Oregon Health & Science University"},{"author_name":"Gary L Westbrook","author_inst":"Oregon Health & Science University"},{"author_name":"Eric Schnell","author_inst":"Oregon Health and Science University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"DNA-Programmed Condensate-Membrane Wetting and Cellular Internalization","rel_doi":"10.64898\/2026.07.15.738578","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738578","rel_abs":"Deformable condensates offer dynamic interfaces for biomolecule delivery, yet membrane adhesion does not necessarily lead to cellular internalization. The physical transition that determines whether a membrane-bound soft material remains surface-anchored or proceeds through wetting towards productive uptake remains poorly understood, particularly at active living-cell membranes. Here, we engineer sequence-defined DNA condensates through liquid-liquid phase separation (LLPS) and program their interfacial behavior by tuning sticky-end valency and cholesterol organization. These molecular designs precisely regulate condensate fluidity, fusion dynamics and internal organization, generating distinct states of weak contact, persistent anchoring and rapid wetting. Increasing cholesterol-mediated affinity does not enhance uptake. Instead, productive internalization emerges from a balance between membrane adhesion and condensate fluidity and deformability. Native membrane composition further modulates condensate interfacial fate across mammalian cells and plant protoplasts. DNA condensates enrich and deliver CpG ODNs, mRNA (~2000 nt) and proteins, while cargo loading experiments reveal that preserving condensate architecture is essential for functional delivery. Our findings identify wetting competence as a design parameter for controlling soft material engagement and cellular entry.","rel_num_authors":8,"rel_authors":[{"author_name":"Zeyu Chen","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Weifen Chen","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Jingyi Ye","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Dan Lu","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Markita P Landry","author_inst":"University of California Berkeley"},{"author_name":"Honglu Zhang","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Chunhai Fan","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Huan Zhang","author_inst":"Shanghai Jiao Tong University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Structure-affinity correlations and separable optical activity in carbon nanotube protein coronas","rel_doi":"10.64898\/2026.07.16.739030","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.739030","rel_abs":"Biomolecular corona on nanoparticle surfaces enriches low-abundance proteins and compresses the dynamic range of the plasma proteome. Single-walled carbon nanotubes are particularly attractive because their surface chemistry is highly tunable, and their near-infrared fluorescence directly reports corona modulation. However, how surface chemistry shapes the corona and how the corona relates to the fluorescence response remain unclear. We profiled protein enrichment patterns and the resulting fluorescence in a library of 25 chemically modified carbon nanotubes by quantitative proteomics and near-infrared fluorescence spectroscopy. We found that polymer and quantum-defect chemistry orthogonally modulate corona composition and dispersion forces are the dominant, universal driver of protein-nanotube binding. Proteomics and fluorescence correlation analyses indicate that enrichment and fluorescence response are partially decoupled. A subset of corona proteins stays optically silent, but where responses occur, enriched proteins respond at lower, physiologically relevant ranges than depleted ones. Our findings inform design principles for carbon nanomaterial-based sensors and biomarker discovery platforms.","rel_num_authors":4,"rel_authors":[{"author_name":"Jacob Miller","author_inst":"Georgia Institute of Technology"},{"author_name":"Alexis Coscia","author_inst":"Georgia Institute of Technology"},{"author_name":"Aceer Nadeem","author_inst":"Georgia Institute of Technology"},{"author_name":"Mijin Kim","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Assessing the Role of Marker Density and Minor Allele Frequency on Machine Learning Driven Genomic Selection Accuracy in Grapevine","rel_doi":"10.64898\/2026.07.11.737951","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737951","rel_abs":"Although grapevine (Vitis spp.) is among the oldest and most economically significant fruit species globally, its genetic improvement faces major bottlenecks due to long juvenile periods and extended cycles for phenotypic evaluation. In this context, genomic selection (GS) has emerged as an effective alternative to traditional selection, offering a robust framework to optimize breeding programs by significantly reducing generation intervals while enhancing predictive accuracy (PA) in early generations and expected genetic gains (EGGs). Nevertheless, factors such as minor allele frequency (MAF) and population size can significantly affect predictive models, even to the point of making their use unfeasible in breeding programs. In this context, this study evaluated the effect of data dimensionality reduction on GS accuracy by selecting single-nucleotide polymorphisms (SNPs) based on MAF thresholds. The experimental design tested the predictive capacities of four machine learning (ML) algorithms (ElasticNet, K-Neighbors, Support Vector Machine Regression, and XGBoost) alongside the conventional Genomic Best Linear Unbiased Prediction (gBLUP) model. These were validated using three SNP datasets (11,115, 9,494, and 6,100 markers) filtered by MAF levels of 0.05, 0.1, and 0.2 across six genetic traits, and EGGs were compared between conventional breeding and GS via the breeders` equation. The results revealed that the ML models exhibited remarkable stability, with no significant differences in PA across the different MAF-based SNP densities, except for berry length, which showed a substantial difference with XGBoost at an MAF of 0.2. Conversely, gBLUP demonstrated high sensitivity to dimensionality reduction, with its performance significantly impacted by MAF filtering across all the traits. These results suggest that compared with traditional GS models that rely on a genomic kinship matrix, ML-based approaches offer greater flexibility in feature reduction. Additionally, compared with chemical traits, morphological traits generally had greater predictive ability. Furthermore, every GS model provided estimated genetic gains superior to traditional breeding, with improvements ranging from an 8.90-fold increase in berry length to a 2.86-fold increase in total soluble solids, confirming that GS integration is promising for enhancing breeding efficiency in grapevines.","rel_num_authors":6,"rel_authors":[{"author_name":"Felipe Roberto Francisco","author_inst":"Advanced Fruit Research Division, Instituto Agronomico (IAC)"},{"author_name":"Geovani Luciano de Oliveira","author_inst":"Molecular Biology and Genetic Engineering Center (CBMEG)"},{"author_name":"Guilherme Francio Niederauer","author_inst":"Molecular Biology and Genetic Engineering Center (CBMEG)"},{"author_name":"Roberto Fritsche-Neto","author_inst":"Horticulture Sciences, College of Agriculture and Life Sciences, North Carolina State University"},{"author_name":"Anete Pereira de Souza","author_inst":"Molecular Biology and Genetic Engineering Center (CBMEG)"},{"author_name":"Mara Fernandes Moura Furlan","author_inst":"Advanced Fruit Research Division, Instituto Agronomico (IAC)"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Parental care enhances reproductive success without remodeling the carcass microbiome in a wild burying beetle","rel_doi":"10.64898\/2026.07.16.739041","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.739041","rel_abs":"Nutrient cycling depends on interactions between insect decomposers and the microbial communities that colonize ephemeral resources such as animal carcasses. Burying beetles (Nicrophorus spp.) are thought to manipulate carcass microbiomes to facilitate reproduction, yet most experimental work relies on a few standardized laboratory carcasses that obscure the ecological heterogeneity beetles face in the wild. Using 76 carcasses from 27 vertebrate species of birds, mammals, and reptiles, we manipulated Nicrophorus nepalensis parental care and characterized carcass, adult-gut, and larval-gut microbiomes by 16S rRNA sequencing. Parental care strongly increased breeding success and brood mass, and buffered reproductive success against variation in carcass identity. By contrast, carcass type and decomposition stage, not care, primarily structured the carcass microbiome; a modest care signature emerged only late in decomposition, was strongest in the adult gut, and was absent from the larval gut. Parental care thus acts principally as a direct driver of reproductive success rather than by remodeling the carcass or larval microbiomes.","rel_num_authors":3,"rel_authors":[{"author_name":"Wei-Jiun Lin","author_inst":"National Taiwan University"},{"author_name":"Chi-Heng Hsieh","author_inst":"National Taiwan University"},{"author_name":"Syuan-Jyun Sun","author_inst":"National Taiwan University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Whole human organ clearing and multimodal mapping","rel_doi":"10.64898\/2026.07.16.738626","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738626","rel_abs":"Human anatomy has traditionally been studied using low-resolution approaches such as cadaveric dissection and conventional medical imaging, limiting our understanding of macroscopic structures. Tissue clearing has emerged as a transformative approach, enabling three-dimensional mapping of organs at microscopic resolution, and offering the opportunity to interrogate anatomy across scales. However, its application to human organs remains challenging due to their size, density and optical properties. Here, we establish multiorgan CleLight (mCleLight) as a generalizable method for clearing, labeling and imaging whole human tissues. mCleLight is broadly applicable across major organ systems and enables the analysis of particularly challenging specimens, including highly heterogeneous samples, dense bones, pigmented tissues and decades-old formalin-fixed archival material. We demonstrate that controlled photoclearing is critical across human tissues both for efficient clearing and for quenching endogenous fluorescence, thereby substantially improving imaging depth as compared to previous methods. mCleLight allows specific labeling and quantitative analysis of complex extended structures such as collagen fibers, vasculature, and innervation, while preserving anatomical relationships, which cannot be easily done with classical histology. We integrated mCleLight into a pipeline with clinical imaging to achieve a comprehensive, multiscale understanding of organ architecture. We demonstrate the voxel-by-voxel alignment between MRI and microscopy datasets, merging cellular-scale detail and protein-specific labeling with macroscopic medical imaging. By bridging the gap between imaging scales and modalities, mCleLight provides a versatile method for integrated three-dimensional histological mapping and macroscopic anatomy of human organs in health and disease.","rel_num_authors":10,"rel_authors":[{"author_name":"H\u00e9lo\u00efse Policet-B\u00e9tend","author_inst":"Unit of Anatomy, Faculty of Medicine, University of Geneva"},{"author_name":"Tom\u00e0s Jord\u00e0-Siquier","author_inst":"Unit of Anatomy, Faculty of Medicine, University of Geneva"},{"author_name":"Geraldine Cuenu","author_inst":"Department of Basic Neuroscience, Faculty of Medicine, University of Geneva, Geneva, Switzerland"},{"author_name":"Maeva Badr\u00e9","author_inst":"Unit of Anatomy, Faculty of Medicine, University of Geneva"},{"author_name":"Sami Schranz","author_inst":"University Centre of Legal Medicine Lausanne-Geneva, University of Geneva"},{"author_name":"Julien Da Costa","author_inst":"Unit of Anatomy, Faculty of Medicine, University of Geneva"},{"author_name":"C\u00e9line Brockmann","author_inst":"Faculty of Medicine, University of Geneva"},{"author_name":"Pascal Senn","author_inst":"Department of Otorhinolaryngology-Head and Neck Surgery, Geneva University Hospitals"},{"author_name":"Daniel Huber","author_inst":"Department of Basic Neuroscience, Faculty of Medicine, University of Geneva, Geneva, Switzerland"},{"author_name":"Christophe M Lamy","author_inst":"Unit of Anatomy, Faculty of Medicine, University of Geneva and Department of Psychiatry, Geneva University Hospitals"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Protein-based, live-cell PAINT microscopy with fluorogenic exchangeable HaloTag ligands","rel_doi":"10.64898\/2026.07.16.738981","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738981","rel_abs":"We report a generalizable method for single-molecule localization super-resolution microscopy in living cells. Live-cell protein-based PAINT (points accumulation for imaging in nanoscale topography) is achieved by pairing exceptionally fluorogenic bis-trifluoromethyl rhodamine (BF) dyes with reversible HaloTag ligands. This far-red small molecule update to protein-based PAINT is readily incorporated into existing super-resolution microscopy workflows: pairing with photoactivatable fluorescent proteins further enables simultaneous two-color live-cell super-resolution microscopy and single-molecule diffusivity mapping (SMdM).","rel_num_authors":8,"rel_authors":[{"author_name":"Tong Zhan","author_inst":"University of California, Berkeley"},{"author_name":"Nels C Gerstner","author_inst":"University of California, Berkeley"},{"author_name":"Julia G Martin","author_inst":"University of California, Berkeley"},{"author_name":"Jack T McCann","author_inst":"University of California, Berkeley"},{"author_name":"Marissa C Lynch","author_inst":"University of California, Berkeley"},{"author_name":"Hsin-Jung Wu","author_inst":"University of California, Berkeley"},{"author_name":"Ke Xu","author_inst":"University of California, Berkeley"},{"author_name":"Evan W Miller","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Protein-based, live-cell PAINT microscopy with fluorogenic exchangeable HaloTag ligands","rel_doi":"10.64898\/2026.07.16.738981","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738981","rel_abs":"We report a generalizable method for single-molecule localization super-resolution microscopy in living cells. Live-cell protein-based PAINT (points accumulation for imaging in nanoscale topography) is achieved by pairing exceptionally fluorogenic bis-trifluoromethyl rhodamine (BF) dyes with reversible HaloTag ligands. This far-red small molecule update to protein-based PAINT is readily incorporated into existing super-resolution microscopy workflows: pairing with photoactivatable fluorescent proteins further enables simultaneous two-color live-cell super-resolution microscopy and single-molecule diffusivity mapping (SMdM).","rel_num_authors":8,"rel_authors":[{"author_name":"Tong Zhan","author_inst":"University of California, Berkeley"},{"author_name":"Nels C Gerstner","author_inst":"University of California, Berkeley"},{"author_name":"Julia G Martin","author_inst":"University of California, Berkeley"},{"author_name":"Jack T McCann","author_inst":"University of California, Berkeley"},{"author_name":"Marissa C Lynch","author_inst":"University of California, Berkeley"},{"author_name":"Hsin-Jung Wu","author_inst":"University of California, Berkeley"},{"author_name":"Ke Xu","author_inst":"University of California, Berkeley"},{"author_name":"Evan W Miller","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Protein-based, live-cell PAINT microscopy with fluorogenic exchangeable HaloTag ligands","rel_doi":"10.64898\/2026.07.16.738981","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738981","rel_abs":"We report a generalizable method for single-molecule localization super-resolution microscopy in living cells. Live-cell protein-based PAINT (points accumulation for imaging in nanoscale topography) is achieved by pairing exceptionally fluorogenic bis-trifluoromethyl rhodamine (BF) dyes with reversible HaloTag ligands. This far-red small molecule update to protein-based PAINT is readily incorporated into existing super-resolution microscopy workflows: pairing with photoactivatable fluorescent proteins further enables simultaneous two-color live-cell super-resolution microscopy and single-molecule diffusivity mapping (SMdM).","rel_num_authors":8,"rel_authors":[{"author_name":"Tong Zhan","author_inst":"University of California, Berkeley"},{"author_name":"Nels C Gerstner","author_inst":"University of California, Berkeley"},{"author_name":"Julia G Martin","author_inst":"University of California, Berkeley"},{"author_name":"Jack T McCann","author_inst":"University of California, Berkeley"},{"author_name":"Marissa C Lynch","author_inst":"University of California, Berkeley"},{"author_name":"Hsin-Jung Wu","author_inst":"University of California, Berkeley"},{"author_name":"Ke Xu","author_inst":"University of California, Berkeley"},{"author_name":"Evan W Miller","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Fungal microbial enrichment method enables fungal metagenomics directly from human clinical samples","rel_doi":"10.64898\/2026.07.16.738568","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738568","rel_abs":"Fungi play important roles in health and disease, but current methods such as culture, PCR, and amplicon sequencing cannot provide genome-level characterization directly from clinical samples. Although metagenomic sequencing could overcome these limitations, it remains impractical in clinical samples where fungal DNA is present at low abundance relative to human DNA. Here, we extend a recently described microbial enrichment method (MEM) to fungi (fungal Microbial Enrichment Method; fMEM) and test the method in bronchoalveolar lavage (BAL) samples to demonstrate direct-from-sample fungal metagenomic analysis and metagenome-assembled genome (MAG) recovery. In BAL samples, fMEM depleted human DNA by more than 1000-fold while preserving fungal DNA within 10-fold, enabling shotgun sequencing from samples with fungal biomass as low as 10 picograms fungal DNA per 200 microliters BAL. fMEM enabled de novo recovery of fungal MAGs from three of four sequenced BAL samples, including two near-complete MAGs (>90% BUSCO completeness) and one 82.1% complete MAG, with low BUSCO-estimated contamination ([&le;]1.5%). Fungal MAGs recovered by fMEM also resolved potentially clinically-relevant genes, not fully predictable from taxonomy alone and revealed genomic content absent from currently-available same-species reference genomes. fMEM is compatible with a whole-genome amplification (including long-read sequencing workflows). Long reads from fMEM-processed samples provided high coverage (>10X) over fungal assemblies. fMEM compatibility with long-read sequencing enables recovery of genes that would be difficult to assemble with short reads alone. fMEM may enable new insights into the role of human-associated fungi, impacting public health, clinical management, and research into complex diseases with suspected fungal roles.","rel_num_authors":12,"rel_authors":[{"author_name":"Michael K. Porter","author_inst":"California Institute of Technology"},{"author_name":"Reid T. Akana","author_inst":"California Institute of Technology"},{"author_name":"Anna E. Romano","author_inst":"California Institute of Technology"},{"author_name":"Xinyue (Penny) Pei","author_inst":"California Institute of Technology"},{"author_name":"Bishoy Kamel","author_inst":"U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory"},{"author_name":"Sajeet F. Haridas","author_inst":"U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory"},{"author_name":"Kurt LaButti","author_inst":"U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory"},{"author_name":"Igor V. Grigoriev","author_inst":"U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory"},{"author_name":"Natalie J. Wu-Woods","author_inst":"California Institute of Technology"},{"author_name":"Omai Garner","author_inst":"University of California Los Angeles"},{"author_name":"David Underhill","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Rustem F. Ismagilov","author_inst":"California Institute of Technology"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Integrated Interactomics Reveals Novel Protein Associations: The FOXA1-PBX1 Complex as a Case Study","rel_doi":"10.64898\/2026.07.16.738938","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738938","rel_abs":"Protein-protein interactions (PPIs) are fundamental to cellular signaling networks, yet many remain undetected due to technical limitations of individual affinity purification approaches. To address this, we systematically mapped the interaction landscapes of six regulatory proteins involved in cell proliferation, immunity, and inflammation, including three transcription factors (TFs) and three kinases. We implemented an integrated proteomics workflow that combined four complementary affinity purification strategies: native immunoprecipitation, two crosslinking-assisted capture methods, and proximity labeling. Combining these approaches revealed distinct yet overlapping interaction profiles, uncovered numerous previously unreported interactors not reliably detected by individual methods, and robustly recovered known interactions while substantially extending PPI networks. Despite method-specific differences at the protein level, functional enrichment analyses showed strong convergence on coherent biological pathways. Biochemical approaches validated most of the previously unreported interactions, including putative weak and transient complexes stabilized by crosslinking. Functional assays revealed a previously unrecognized physical interaction between FOXA1 and PBX1 TFs and demonstrated their cooperative regulation of transcriptional programs and cell fitness in estrogen receptor (ER) positive breast cells. We propose that the FOXA1-PBX1 complex could represent a higher-order regulatory node integrating chromatin accessibility and ER-driven transcriptional output.","rel_num_authors":16,"rel_authors":[{"author_name":"Zhi Chen","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Istvan Szepesi-Nagy","author_inst":"HUN-REN Research Centre for Natural Sciences"},{"author_name":"Qingyue Zhang","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Srushti Kittane","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Yangzhenyu Gao","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Juliana Ortiz-Pacheco","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Ethan Lane","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Justin Hatcher","author_inst":"University of Washington Department of Pharmacology"},{"author_name":"Jeffrey Estrada","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Manor Askenazi","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Lan Huang","author_inst":"University of California Irvine Department of Physiology and Biophysics"},{"author_name":"Beatrix Ueberheide","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Ning Zheng","author_inst":"University of Washington Department of Pharmacology"},{"author_name":"Eneda Toska","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Gergely Rona","author_inst":"HUN-REN Research Centre for Natural Sciences"},{"author_name":"Michele Pagano","author_inst":"NYU Grossman School of Medicine"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Shifting resource limitation explains multiphasic patterns of density dependence","rel_doi":"10.64898\/2026.07.16.738797","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738797","rel_abs":"Several recent studies have presented sublinear density dependence as a universal phenomenon across species, driven by factors unrelated to resource limitation (e.g. predation or non-resource based inhibition). Through a combination of bacterial growth experiments and mathematical modelling, we instead show that regimes of sublinear density dependence readily emerge under sequential shifts in resource limitation, without the need to invoke other processes. We nevertheless predict that superlinear density dependence, driven by standard resource limitation, will still predominate at both high and low densities.","rel_num_authors":7,"rel_authors":[{"author_name":"Andrew David Letten","author_inst":"University of Queensland"},{"author_name":"James A Orr","author_inst":"University of Queensland"},{"author_name":"Jan Engelstaedter","author_inst":"The University of Queensland"},{"author_name":"Noelle A Held","author_inst":"University of Southern California"},{"author_name":"Christopher A Klausmeier","author_inst":"Michigan State University"},{"author_name":"Michael Manhart","author_inst":"Rutgers University"},{"author_name":"Daniel B Stouffer","author_inst":"Leibniz Institute of Freshwater Ecology and Inland Fisheries (IGB)"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Shifting resource limitation explains multiphasic patterns of density dependence","rel_doi":"10.64898\/2026.07.16.738797","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738797","rel_abs":"Several recent studies have presented sublinear density dependence as a universal phenomenon across species, driven by factors unrelated to resource limitation (e.g. predation or non-resource based inhibition). Through a combination of bacterial growth experiments and mathematical modelling, we instead show that regimes of sublinear density dependence readily emerge under sequential shifts in resource limitation, without the need to invoke other processes. We nevertheless predict that superlinear density dependence, driven by standard resource limitation, will still predominate at both high and low densities.","rel_num_authors":7,"rel_authors":[{"author_name":"Andrew David Letten","author_inst":"University of Queensland"},{"author_name":"James A Orr","author_inst":"University of Queensland"},{"author_name":"Jan Engelstaedter","author_inst":"The University of Queensland"},{"author_name":"Noelle A Held","author_inst":"University of Southern California"},{"author_name":"Christopher A Klausmeier","author_inst":"Michigan State University"},{"author_name":"Michael Manhart","author_inst":"Rutgers University"},{"author_name":"Daniel B Stouffer","author_inst":"Leibniz Institute of Freshwater Ecology and Inland Fisheries (IGB)"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Targeting cellular senescence alleviates bone marrow aging","rel_doi":"10.64898\/2026.07.16.736849","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.736849","rel_abs":"Aging of the hematopoietic system impairs hematopoietic stem cell (HSC) function and alters bone marrow niche behavior, increasing susceptibility to anemia, infections, and hematologic malignancies. Here, pharmacologic clearance of senescent cells with the PROTAC compound 753b simultaneously targeting BCL-xL and BCL-2 reverses key secretory, transcriptional, and functional hallmarks of hematopoietic aging with low toxicity, restoring balanced lineage output. Single-cell RNA sequencing further demonstrates that 753b treatment attenuates aging-associated transcriptional signatures in HSCs, while selectively eliminating senescent, pro-survival niche cells without grossly perturbing niche composition. Functionally, 753b suppresses pro-inflammatory cues from both niche and hematopoietic cells including those emanating from neutrophil progenitors, rebalancing global bone marrow secretory ecosystem across stromal and hematopoietic compartments. Collectively, we identify 753b-induced senescent cell clearance as a powerful strategy to rejuvenate aged hematopoiesis and re-establish homeostatic communication between HSCs and their microenvironment, with implications for mitigating age-related hematologic dysfunction and improving hematologic health in older individuals.","rel_num_authors":17,"rel_authors":[{"author_name":"Bowen Yan","author_inst":"Department of Pharmacology & Therapeutics, University of Florida College of Medicine, University of Florida Health Cancer Center, Gainesville, FL"},{"author_name":"Jin Han","author_inst":"Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21231, USA."},{"author_name":"Yang Yang","author_inst":"Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Peiyi Zhang","author_inst":"Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA"},{"author_name":"Jason O Brant","author_inst":"Department of Biostatistics, University of Florida College of Medicine, University of Florida Health Cancer Center, Gainesville, FL"},{"author_name":"Jianhui Chang","author_inst":"Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA"},{"author_name":"Ha-Neui Kim","author_inst":"Division of Endocrinology, Department of Internal Medicine, Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases,"},{"author_name":"Maria Almeida","author_inst":"Division of Endocrinology, Department of Internal Medicine, Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases,"},{"author_name":"Prabhjot Kaur","author_inst":"University of Florida College of Medicine, Gainesville, FL"},{"author_name":"Qingchen Yuan","author_inst":"University of Florida College of Medicine, Gainesville, FL"},{"author_name":"Marco Demaria","author_inst":"University of Groningen (RUG), European Research Institute for the Biology of Aging (ERIBA), University Medical Center Groningen (UMCG), Groningen, the Netherla"},{"author_name":"Kalyanee Shirlekar","author_inst":"University of Florida Health Cancer Institute, Gainesville, FL, USA"},{"author_name":"Jennifer Elisseeff","author_inst":"Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21231, USA."},{"author_name":"Guangrong Zheng","author_inst":"Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA"},{"author_name":"Ying Liang","author_inst":"Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA."},{"author_name":"Daohong Zhou","author_inst":"Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Olga A Guryanova","author_inst":"Department of Pharmacology & Therapeutics, University of Florida College of Medicine, University of Florida Health Cancer Center, Gainesville, FL"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"The Disease Gene THAP12 is a Transcriptional Regulator of Mitochondrial ETC Complex I","rel_doi":"10.64898\/2026.07.16.738975","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738975","rel_abs":"Complex I (CI) is the largest and most disease-associated component of the mitochondrial electron transport chain. While many diseases are linked to defects in specific CI subunits, the extent to which non-mitochondrial proteins contribute to CI function or disease is less clear. Here, we perform genome-wide CRISPR screens to identify regulators of CI abundance across its N, Q, and P modules, which mediate NADH oxidation, quinone reduction, and proton pumping, respectively. These screens identify THAP12 as a previously unrecognized transcriptional regulator of CI biogenesis. THAP12 loss selectively destabilizes CI and impairs oxidative ATP production. Mechanistically, THAP12 functions in the nucleus as a DNA-binding factor that directly activates genes required for CI assembly and iron-sulfur cluster maintenance, including NDUFAF3, NDUFAF4 and BOLA3. Patient-derived fibroblasts carrying THAP12 mutations exhibit conserved transcriptional defects and profound CI deficiency, establishing THAP12-associated neurodevelopmental disorder as a secondary mitochondrial CI disease. Finally, hypoxia rescues growth defects in THAP12-deficient cells, nominating low-oxygen therapy as a potential treatment strategy. Together, these findings identify THAP12 as a dedicated regulator of CI assembly and expand the genetic landscape of CI disease.","rel_num_authors":4,"rel_authors":[{"author_name":"Brandon R Desousa","author_inst":"University of California, San Francisco (UCSF)"},{"author_name":"Yohei Abe","author_inst":"Arc Institute"},{"author_name":"Martin Kampmann","author_inst":"University of California, San Francisco"},{"author_name":"Isha H Jain","author_inst":"Gladstone Institutes"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Chromatic contrasts predict human target detection in a natural search task","rel_doi":"10.64898\/2026.07.11.737926","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737926","rel_abs":"Natural scenes are visually complex, with dynamic variation in colour and luminance presenting challenges for detecting salient objects. However, the cues guiding human detection under such natural conditions remain largely untested. We placed custom-built coloured targets in a forest-like setting and quantified their contrasts against natural backgrounds using human visual models. Across human observers (n = 51) detection performance rose sharply with hue and saturation contrast, whereas luminance contrast, long considered a primary driver of visual search, contributed little explanatory power. Strikingly, even large changes in ambient light chromaticity barely altered detection, despite the patchy illumination of the habitat. Under these naturalistic conditions, hue and saturation contrasts were stronger predictors of detection than luminance contrast, providing a rare, field-based test of visual models widely applied across human and animal vision research.","rel_num_authors":4,"rel_authors":[{"author_name":"Thomas E White","author_inst":"The University of Sydney"},{"author_name":"Bibiana Rojas","author_inst":"University of Veterinary Medicine Vienna"},{"author_name":"Johanna Mappes","author_inst":"University of Helsinki"},{"author_name":"Darrell J Kemp","author_inst":"Macquarie University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Rocking Without a Tune: Ex vivo and in vivo Responses to Sound in the Basilar Papilla of the Tokay Gecko","rel_doi":"10.64898\/2026.07.16.738899","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738899","rel_abs":"Like mammals, some reptiles possess sensitive and frequency-selective hearing at high frequencies. Both groups employ a place-frequency map within the inner ear to encode sound stimuli, but the mechanisms by which they achieve tuned nerve activation along the cochlea are believed to be distinct. To investigate the mechanical origins of auditory sensation in the reptiles, we measured sound-evoked displacement responses in the hearing organ of the tokay gecko (Gekko gecko), known as the basilar papilla. Using optical coherence tomography, we were able to resolve sub-nanometer-scale vibrations throughout the organ both in vivo and ex vivo. We found that tuning was not present in the tissue-scale mechanics at any position within the organ; it instead exhibits an untuned rotational motion. We developed a mathematical model which predicted that this motion induces hair-bundle-stimulating fluid velocity, and is due to an anatomical asymmetry seen in many reptile and bird species. These results suggest that hair-bundle-level mechanics are primarily responsible for tuning in the tokay gecko cochlea, and we argue that our proposed mechanisms generalize to many other species across the Reptilia class.","rel_num_authors":5,"rel_authors":[{"author_name":"Brian L. Frost","author_inst":"Columbia University"},{"author_name":"Yuriria V\u00e1zquez","author_inst":"Rockefeller University"},{"author_name":"Kazuhiro Horii","author_inst":"Gifu University, Rockefeller University"},{"author_name":"Brian A. Fabella","author_inst":"Rockefeller University"},{"author_name":"A. J. Hudspeth","author_inst":"Rockefeller University"}],"rel_date":"2026-07-17","rel_site":"biorxiv"},{"rel_title":"Multimodal gene prioritization reveals nonlinear regulatory architecture in childhood-onset asthma","rel_doi":"10.64898\/2026.07.14.26357983","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26357983","rel_abs":"Asthma is a heritable complex disease that disproportionately burdens minority and admixed populations in the US. However, the causal genes and regulatory mechanisms governing inherited risk remain largely unresolved. We performed a European-ancestry meta-analysis of 141,894 cases and 1,361,846 controls drawn from the Trans-national Asthma Genetic Consortium (TAGC) and Global Biobank Meta-analysis Initiative (GBMI), yielding an estimated h2SNP of 0.056 (SE = 0.0038) and 275 independently associated loci. To enhance mechanistic inference beyond variant-level associations, we developed a multimodal framework to predict asthma risk integrating GWAS summary statistics, bulk tissue expression quantitative trait loci (eQTL) data from the Genotype-Tissue Expression (GTEx) project, and single-cell gene eQTL data from the OneK1K Project. We performed transcriptome-wide association studies (TWAS) and subsequently applied probabilistic fine-mapping with FOCUS to prioritize putative causal genes expressed in bulk tissues and higher resolution immune cell populations. Fine-mapping asthma-associated genes implicated barrier-immune and metabolic-endocrine tissues alongside adaptive T-cell subsets as the primary mediators of asthma genetic risk, resolving canonical CD4+ Th2 effector genes including IL1RL1, TSLP, STAT6, and GATA3. Using these prioritized genes, we constructed a polygenic transcriptome risk score (PTRS) using random forest to integrate gene-level effects across critical tissues and cell types. Evaluated in two ancestrally distinct pediatric asthma cohorts, the Childhood Asthma Management Program (CAMP) and the Genetics of Asthma in Costa Rica Study (GACRS), our PTRS demonstrated improved transferability over the standard variant-level and gene-level baseline models. While modest common variant heritability limits the discriminative power of our models, we estimated a theoretical maximum achievable area under the receiver operating characteristic (AUROC) curve of 0.64. Our integrative nonlinear model of PRS-CSx and cross-modal (bulk tissue and single cell) FOCUS PTRS resulted in the best cross-cohort performance (CAMP AUC = 0.632, sd = 0.04, 3.55 case\/control odds ratio in top vs. bottom quartiles), representing an increase of +0.118 AUC over PRS-CSx, +0.067 AUC over tissue-specific TWAS pruning and thresholding, and +0.041 AUC over cell-type-specific FOCUS PTRS. Our results demonstrate that modeling nonlinear interactions between variant- and gene-level effects across both bulk tissue and single cell eQTL data improves our ability to determine high-risk individuals and to explain the likely mechanisms driving genetic susceptibility of childhood-onset asthma.\n\nHighlightsO_LIMultimodal putative causal gene prioritization integrates GWAS summary statistics, bulk tissue, and single-cell expression data to resolve effector genes underlying childhood-onset asthma.\nC_LIO_LIGene-level fine-mapping of underlying asthma GWAS loci reveals CD4+ Th2 effector genes, which are known drivers of eosinophilic airway inflammation, across multiple tissue and cell types including CD4+ cytotoxic T cells, naive CD4+ T cells, and natural killer cells.\nC_LIO_LIWe constructed and evaluated variant-level multi-ancestry asthma PRS and gene-level PTRS for genes in fine-mapped credible sets.\nC_LIO_LIWe identified tissues and cell types that consistently helped discriminate asthma cases from controls, namely esophagus mucosa and CD4+ naive T cells.\nC_LIO_LIWe found that nonlinear modeling of both variant-level and gene-level effects across top tissues and cell types, tested across various integration strategies, substantially outperformed linear models in the distinction of asthma cases from controls.\nC_LIO_LIThe model that most effectively distinguished cases from controls was a cross-modal model of PRS-CSx combined with the esophagus mucosa and CD4+ naive T cell PTRS models, resulting in an AUC = 0.632 {+\/-} 0.040 and case\/control enrichment odds ratio of 3.55 in top\/bottom quartiles.\nC_LIO_LIOverall modest discrimination between cases and controls with genetic predictors supports asthma as a complex disease with a substantial non-genetic component.\nC_LI\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC=\"FIGDIR\/small\/26357983v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@1869929org.highwire.dtl.DTLVardef@1b15387org.highwire.dtl.DTLVardef@e2da7aorg.highwire.dtl.DTLVardef@175831e_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":5,"rel_authors":[{"author_name":"Nan Huang","author_inst":"UC San Diego"},{"author_name":"Michelle F Ragsac","author_inst":"UC San Diego"},{"author_name":"Xiaoyu Gui","author_inst":"UC San Diego"},{"author_name":"Kelan  G. Tantisira","author_inst":"University of San Diego"},{"author_name":"Tiffany Amariuta","author_inst":"University of California San Diego"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Consecutive day effects between sleep quality and affective symptoms among youth in the Brazilian High-Risk Cohort study","rel_doi":"10.64898\/2026.07.14.26358099","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358099","rel_abs":"Background: Bidirectional next-day associations between sleep disturbances and affective symptoms have been shown in previous research, yet the consecutive day effects between these factors remains poorly understood. Methods: We analysed longitudinal ecological momentary assessment (EMA) data obtained from a subsample of young persons in the Brazilian High-Risk Cohort (BHRC) study collected in 2020-2021. Participants reported sleep quality each morning and rated affective symptoms relating to mood, anxiety, and energy four times daily for 28 days. We selected 88 individuals (17.83{+\/-}1.74 years, 56 [63.6%] female gender) with at least one instance where individuals were observed three-days in a row. Within-person bidirectional next-day effects between sleep quality and affective symptoms were estimated using mixed-effects regression analysis adjusting. We then applied g-estimation approaches to estimate the effect that lagged sleep quality and consecutive improvements in sleep quality had on affective symptoms. Results: Sleep quality and affective symptoms had bidirectional next-day effects, with sleep quality tending to have greater influence on affective symptoms than the reverse. Improved lagged sleep quality had positive effects on affective symptoms incrementally above the prior night's sleep quality. Also, improvement of sleep quality across consecutive days had incremental and approximately equal effects on affective symptoms. Conclusions: Sleep quality and affective symptoms exhibit a feedback loop, whereby poor sleep quality influences affective symptoms over consecutive days. Breaking these feedback loops, by improving sleep quality across several consecutive nights should improve affective symptoms. This supports interventions that target sustained improvement in sleep and possibly circadian regulation to improve affective symptoms.","rel_num_authors":12,"rel_authors":[{"author_name":"Mathew R Varidel","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Luke Borgnolo","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Victor An","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Joanne S Carpenter","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Ian B Hickie","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Pedro M Pan","author_inst":"National Institute of Developmental Psychiatry, Sao Paulo, Brazil"},{"author_name":"Francisco da Silva Jr.","author_inst":"National Institute of Developmental Psychiatry, Sao Paulo, Brazil"},{"author_name":"Jacob J Crouse","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Euripedes C Miguel","author_inst":"National Institute of Developmental Psychiatry, Sao Paulo, Brazil"},{"author_name":"Luis A Rohde","author_inst":"National Institute of Developmental Psychiatry, Sao Paulo, Brazil"},{"author_name":"Giovanni A Salum Jr.","author_inst":"National Institute of Developmental Psychiatry, Sao Paulo, Brazil"},{"author_name":"Frank Iorfino","author_inst":"Brain and Mind Centre, The University of Sydney"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Hospital and operator procedural volumes and one-year outcomes for TAVR in the United States: A STS\/ACC TVT Registry Analysis","rel_doi":"10.64898\/2026.07.13.26358001","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26358001","rel_abs":"BackgroundPrior analyses have demonstrated an inverse association between transcatheter aortic valve replacement (TAVR) procedural volume and short-term outcomes. However, less is known regarding the relationship between procedural volume and 1-year outcomes in the contemporary TAVR era.\n\nObjectivesTo evaluate the association between annual hospital and operator TAVR procedural volumes and 1-year clinical outcomes in a contemporary national cohort.\n\nMethodsClinical records from the Society of Thoracic Surgeons (STS)\/American College of Cardiology (ACC) Transcatheter Valve Therapies (TVT) Registry for patients undergoing commercial TAVR between January 2020 and December 2022 were linked to Centers for Medicare & Medicaid Services administrative claims. Annualized hospital and operator TAVR volumes were modeled continuously and categorized into tertiles. Primary outcomes included 1-year all-cause mortality, stroke, the composite of mortality or stroke, and all-cause readmissions. Hierarchical risk-adjusted models accounting for patient clustering within sites were used to evaluate associations between procedural volume and outcomes.\n\nResultsAmong 215,335 patients undergoing TAVR at 788 hospitals by 3,444 operators between 2020 and 2022, median annual hospital and operator volumes were 74 (IQR: 43-115) and 16 (IQR: 10-32), respectively. Volume was then categorized into tertiles (low, medium and high). Compared with high-volume hospitals ([&ge;]102\/year), low-volume hospitals ([&le;]52\/year) had higher adjusted rates of 1-year all-cause mortality (Odds Ratio (OR): 1.10 [95% CI: 1.05-1.16]), stroke (OR: 1.10 [95% CI: 1.01-1.19]), mortality or stroke (OR: 1.10 [95% CI: 1.05-1.15]), and all-cause readmissions (OR: 1.05 [95% CI: 1.00-1.09]). Compared with high-volume operators ([&ge;]25\/year), low-volume operators ([&le;]11\/year) had higher adjusted rates of stroke (OR: 1.16 [95% CI: 1.05-1.28]) and mortality or stroke (OR: 1.09 [95% CI: 1.03-1.15]) but not other endpoints.\n\nConclusionsIn a large, contemporary national TAVR registry, lower annual hospital ([&le;] 52\/year) and operator ([&le;] 11\/year) procedural volumes were independently associated with worse 1-year clinical outcomes. These findings suggest that procedural experience continues to influence outcomes despite maturation of contemporary TAVR practice.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC=\"FIGDIR\/small\/26358001v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (59K):\norg.highwire.dtl.DTLVardef@1ca01f0org.highwire.dtl.DTLVardef@14563aaorg.highwire.dtl.DTLVardef@926c19org.highwire.dtl.DTLVardef@f6fb59_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOCentral illustration:C_FLOATNO Central illustration\n\nC_FIG","rel_num_authors":21,"rel_authors":[{"author_name":"Dharam J. Kumbhani","author_inst":"UT Southwestern"},{"author_name":"wayne batchelor","author_inst":"Inova Health"},{"author_name":"Joseph C Cleveland","author_inst":"University of Colorado"},{"author_name":"Pratik Manandhar","author_inst":"Duke Clinical Research Institute, Duke University Medical Center"},{"author_name":"Andrzej Kosinski","author_inst":"Duke University"},{"author_name":"Samir R. Kapadia","author_inst":"Cleveland Clinic"},{"author_name":"Gorav Ailawadi","author_inst":"University of Michigan"},{"author_name":"Gregory Fontana","author_inst":"HCA Healthcare Research Institute"},{"author_name":"Andrei M. Pop","author_inst":"Ascencion Health, Elk Grove, IL"},{"author_name":"Saket Girotra","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"James A de Lemos","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"John D. Carroll","author_inst":"University of Colorado"},{"author_name":"Ralph Brindis","author_inst":"Philip R. Lee Institute for Health Policy Studies and the Department of Medicine, University of California-San Francisco, San Francisco, CA"},{"author_name":"Tsuyoshi Kaneko","author_inst":"Washington University St. Louis"},{"author_name":"Vinod Thourani","author_inst":"Piedmont Heart Institute, Atlanta, GA"},{"author_name":"Robert W Yeh","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Amit N Vora","author_inst":"Yale University School of Medicine"},{"author_name":"Michael J. Mack","author_inst":"The Heart Hospital Baylor Plano"},{"author_name":"Vinay Badhwar","author_inst":"West Virginia University"},{"author_name":"Roxana Mehran","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sreekanth Vemulapalli","author_inst":"Duke Clinical Research Institute"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Hospital and operator procedural volumes and one-year outcomes for TAVR in the United States: A STS\/ACC TVT Registry Analysis","rel_doi":"10.64898\/2026.07.13.26358001","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26358001","rel_abs":"BackgroundPrior analyses have demonstrated an inverse association between transcatheter aortic valve replacement (TAVR) procedural volume and short-term outcomes. However, less is known regarding the relationship between procedural volume and 1-year outcomes in the contemporary TAVR era.\n\nObjectivesTo evaluate the association between annual hospital and operator TAVR procedural volumes and 1-year clinical outcomes in a contemporary national cohort.\n\nMethodsClinical records from the Society of Thoracic Surgeons (STS)\/American College of Cardiology (ACC) Transcatheter Valve Therapies (TVT) Registry for patients undergoing commercial TAVR between January 2020 and December 2022 were linked to Centers for Medicare & Medicaid Services administrative claims. Annualized hospital and operator TAVR volumes were modeled continuously and categorized into tertiles. Primary outcomes included 1-year all-cause mortality, stroke, the composite of mortality or stroke, and all-cause readmissions. Hierarchical risk-adjusted models accounting for patient clustering within sites were used to evaluate associations between procedural volume and outcomes.\n\nResultsAmong 215,335 patients undergoing TAVR at 788 hospitals by 3,444 operators between 2020 and 2022, median annual hospital and operator volumes were 74 (IQR: 43-115) and 16 (IQR: 10-32), respectively. Volume was then categorized into tertiles (low, medium and high). Compared with high-volume hospitals ([&ge;]102\/year), low-volume hospitals ([&le;]52\/year) had higher adjusted rates of 1-year all-cause mortality (Odds Ratio (OR): 1.10 [95% CI: 1.05-1.16]), stroke (OR: 1.10 [95% CI: 1.01-1.19]), mortality or stroke (OR: 1.10 [95% CI: 1.05-1.15]), and all-cause readmissions (OR: 1.05 [95% CI: 1.00-1.09]). Compared with high-volume operators ([&ge;]25\/year), low-volume operators ([&le;]11\/year) had higher adjusted rates of stroke (OR: 1.16 [95% CI: 1.05-1.28]) and mortality or stroke (OR: 1.09 [95% CI: 1.03-1.15]) but not other endpoints.\n\nConclusionsIn a large, contemporary national TAVR registry, lower annual hospital ([&le;] 52\/year) and operator ([&le;] 11\/year) procedural volumes were independently associated with worse 1-year clinical outcomes. These findings suggest that procedural experience continues to influence outcomes despite maturation of contemporary TAVR practice.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC=\"FIGDIR\/small\/26358001v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (59K):\norg.highwire.dtl.DTLVardef@1ca01f0org.highwire.dtl.DTLVardef@14563aaorg.highwire.dtl.DTLVardef@926c19org.highwire.dtl.DTLVardef@f6fb59_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOCentral illustration:C_FLOATNO Central illustration\n\nC_FIG","rel_num_authors":21,"rel_authors":[{"author_name":"Dharam J. Kumbhani","author_inst":"UT Southwestern"},{"author_name":"wayne batchelor","author_inst":"Inova Health"},{"author_name":"Joseph C Cleveland","author_inst":"University of Colorado"},{"author_name":"Pratik Manandhar","author_inst":"Duke Clinical Research Institute, Duke University Medical Center"},{"author_name":"Andrzej Kosinski","author_inst":"Duke University"},{"author_name":"Samir R. Kapadia","author_inst":"Cleveland Clinic"},{"author_name":"Gorav Ailawadi","author_inst":"University of Michigan"},{"author_name":"Gregory Fontana","author_inst":"HCA Healthcare Research Institute"},{"author_name":"Andrei M. Pop","author_inst":"Ascencion Health, Elk Grove, IL"},{"author_name":"Saket Girotra","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"James A de Lemos","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"John D. Carroll","author_inst":"University of Colorado"},{"author_name":"Ralph Brindis","author_inst":"Philip R. Lee Institute for Health Policy Studies and the Department of Medicine, University of California-San Francisco, San Francisco, CA"},{"author_name":"Tsuyoshi Kaneko","author_inst":"Washington University St. Louis"},{"author_name":"Vinod Thourani","author_inst":"Piedmont Heart Institute, Atlanta, GA"},{"author_name":"Robert W Yeh","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Amit N Vora","author_inst":"Yale University School of Medicine"},{"author_name":"Michael J. Mack","author_inst":"The Heart Hospital Baylor Plano"},{"author_name":"Vinay Badhwar","author_inst":"West Virginia University"},{"author_name":"Roxana Mehran","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sreekanth Vemulapalli","author_inst":"Duke Clinical Research Institute"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Comparative Effectiveness of Recommended and Delayed Dosing Schedules for Rotavirus Vaccine: Target Trial Emulation","rel_doi":"10.64898\/2026.07.13.26357904","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357904","rel_abs":"Background: Live oral rotavirus vaccines were found to be less effective in low-income countries compared to high-income countries when using the same product and dosing schedule. We investigated whether altering dose timing may improve immune protection using a target trial emulation approach. Methods: We emulated a target trial with clone-censor weighting to compare the effectiveness of the recommended 2-dose rotavirus vaccine schedule with a delayed schedule among children under two years of age in Peru and Brazil. Secondary data from the Malnutrition and Enteric Disease Study (MAL-ED) birth cohort (2009-2014) were analyzed. Children were followed from the date of birth until the earliest occurrence of a rotavirus outcome (infection confirmed by PCR or enzyme immunoassay (EIA) or diarrhea confirmed by EIA), protocol nonadherence, loss to follow-up, or their second birthday. Results: We included 154 children in Brazil and 192 in Peru. At two years of follow-up, the risk ratio (RR) for PCR-confirmed infection, using the recommended schedule as the reference, was 1.00 (95% confidence interval [CI]: 0.73-1.37) in Peru and 0.85 (95% CI: 0.31-1.66) in Brazil. In Peru, the delayed schedule was associated with a higher cumulative risk of EIA-confirmed rotavirus diarrhea (RR at two years: 1.73; 95% CI: 1.02-2.77). Conclusions: Delaying the two-dose rotavirus vaccine schedule did not change the cumulative risk of rotavirus infection, but the delayed schedule was associated with a higher risk of rotavirus diarrhea in Peru, where rotavirus incidence was higher.","rel_num_authors":4,"rel_authors":[{"author_name":"Shae Gantt","author_inst":"Boston University School of Public Health"},{"author_name":"Toshiaki Komura","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Elizabeth  Rogawski McQuade","author_inst":"Emory University"},{"author_name":"Kayoko Shioda","author_inst":"Boston University School of Public Health"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Strategies to Reach Employees Nurturing Guidance and Trust in Healthcare (STRENGTH): Understanding Employee Drivers for Employer-Based Influenza Vaccination Programs","rel_doi":"10.64898\/2026.07.13.26357995","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357995","rel_abs":"Background: Vaccine hesitancy and logistical barriers continue to limit influenza vaccination uptake among healthcare personnel. The STRENGTH initiative evaluated employee drivers of influenza vaccine acceptance in healthcare workgroups with lower vaccination compliance. Methods: This mixed-methods program evaluation used a custom Epic electronic medical record dashboard to identify workgroups with lower influenza vaccination rates, followed by focus groups, targeted worksite vaccination clinics, and an anonymous survey. Survey data from 73 respondents were analyzed using descriptive statistics, Mann-Whitney U tests, Kruskal-Wallis tests, chi-square or Fisher exact tests, and Spearman rank correlations. Results: Respondents had a mean age of 44.8 years (SD 11.3); 36 of 70 respondents reporting binary gender were male. Convenience of worksite vaccination received the highest importance ratings (mean 4.72\/5), followed by protection from influenza (mean 4.38\/5). Both were rated significantly above the neutral midpoint of 3 (Wilcoxon p<0.001). The strongest observed Spearman correlations were between peer pressure and leadership participation (rho=0.47) and between protection from influenza and willingness to receive a future combined influenza\/COVID-19 vaccine (rho=0.42). Conclusions: Convenience and perceived protection were the most important vaccination drivers. Employer-sponsored workplace vaccination programs can reduce logistical barriers while providing opportunities for targeted education and trust-building. Keywords: influenza vaccination; healthcare workers; vaccine hesitancy; occupational health; workplace vaccination; employer-sponsored vaccination","rel_num_authors":5,"rel_authors":[{"author_name":"Arthur P Sanchez","author_inst":"University of California San Diego Health"},{"author_name":"Kent Isakari","author_inst":"The Bishops School"},{"author_name":"Morgan Keefe","author_inst":"University of California San Diego Health"},{"author_name":"Marcia Isakari","author_inst":"University of California Davis"},{"author_name":"Amy Sitapati","author_inst":"University of California San Diego Health"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Genome-wide association study of susceptibility to pneumococcal carriage amongst children","rel_doi":"10.64898\/2026.07.13.26356474","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26356474","rel_abs":"Background Pneumococcal disease is a leading cause of paediatric pneumonia and meningitis. Pneumococcal colonisation is the fundamental step to pneumococcal disease causation. We aimed to identify genetic loci associated with pneumococcal colonisation amongst children. Methods We conducted a genome-wide association study on 2111 Nepalese children, comprising 1346 cases carrying pneumococcus and 765 controls. We tested 8.1 million imputed variants using logistic regression and ten principal components as covariates. Fine mapping and functional evidence were used to identify suspected causal variants and related genes of interest. Findings A cluster of 22 variants of genome-wide significance (p<5x10-8) were identified on chromosome 12q21.31, eight of which were within PPFIA2. Fine mapping of this region identified 5 variants within 0.1 Mb of the 5-prime region of PPFIA2 all of which are significant eQTLs for PPFIA2. We further describe three loci (10q23.31, 12q23.1, and 20p11.21) which had variants with highly suggestive associations (p<5x10-7)with pneumococcal carriage. Interpretation Our study demonstrate human susceptibility to pneumococcal carriage to be polygenic with genetic variations which regulate PPFIA2 expression playing a key role in the ability for pneumococcus to colonise children. Targeting these genetic factors and the associated pathways are a means for preventing pneumococcal disease. Funding This study was supported by funding from Gavi - the vaccine alliance, the European Unions Horizon 2020 research and innovation program under grant agreement number 668303 (PERFORM), and a Robert Austrian Research Award.","rel_num_authors":12,"rel_authors":[{"author_name":"Rama Kandasamy","author_inst":"Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Australia"},{"author_name":"Meeru Gurung","author_inst":"Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal"},{"author_name":"Sonu Shrestha","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom"},{"author_name":"Sagida Bibi","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom"},{"author_name":"Stephen Thorson","author_inst":"Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal"},{"author_name":"Michael Carter","author_inst":"Centre for Human Genetics, University of Oxford, Oxford, United Kingdom"},{"author_name":"Daniel O'Connor","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom"},{"author_name":"David R Murdoch","author_inst":"Department of Pathology, University of Otago, Christchurch, New Zealand"},{"author_name":"Dominic F Kelly","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom"},{"author_name":"Shrijana Shrestha","author_inst":"Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal"},{"author_name":"Michael Levin","author_inst":"Department of Infectious Disease, Faculty of Medicine, Imperial College London, United Kingdom"},{"author_name":"Andrew J Pollard","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Clonal hematopoiesis is enriched in melanoma and associated with genotype-specific differences in tumor growth and survival","rel_doi":"10.64898\/2026.07.13.26357981","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357981","rel_abs":"BackgroundThe clinical significance of clonal hematopoiesis of indeterminate potential (CHIP) in melanoma remains incompletely defined, particularly with respect to CHIP genotype, clone size, and somatic mutations (e.g BRAF mutations). We integrated human cohort data and a syngeneic melanoma mouse model to evaluate whether CHIP is associated with melanoma risk, tumor growth, and differential clinical outcomes.\n\nMethodsWe analyzed CHIP prevalence and survival in a large treatment-unselected melanoma cohort (n=2,480), evaluated tumor growth in a syngeneic BRAF-mutant (BRAFmut) melanoma murine model of TET2-CHIP and DNMT3A-CHIP, and assessed survival outcomes in an immune checkpoint inhibitor (ICI)-treated advanced melanoma cohort (n=361). Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier analyses and multivariable Cox proportional hazards models.\n\nResultsCHIP was enriched among patients with treatment-unselected melanoma compared with age\/sex-matched healthy controls, and larger CHIP clone size showed an age-adjusted association with inferior OS. In a syngeneic BRAFmut melanoma murine model, TET2-CHIP, but not DNMT3A-CHIP, was associated with significantly increased primary melanoma tumor growth. Among patients with ICI-treated advanced melanoma, CHIP was associated with worse OS compared with patients without CHIP. TET2-CHIP had the strongest adverse association with survival, whereas DNMT3A-CHIP was not significantly associated with PFS or OS.\n\nConclusionsCHIP is enriched in melanoma and exploratory analyses demonstrate genotype-specific differences in melanoma tumor growth and clinical outcomes. These findings support further investigation of genotype-specific CHIP profiling as a potential biomarker for melanoma risk stratification and immunotherapy outcomes.\n\nWhat is already known on this topicClonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition linked to inflammation, cardiovascular disease, hematologic malignancy, and adverse outcomes across several cancer settings. Prior studies have suggested that CHIP may influence immune function and response to immune checkpoint inhibitors, but the clinical relevance of CHIP in melanoma, particularly by CHIP genotype, clone size, and tumor BRAF genotype, remains incompletely defined.\n\nWhat this study addsThis study shows that CHIP is enriched among patients with melanoma and that larger CHIP clone size is associated with inferior overall survival in age-adjusted analyses. In complementary murine and clinical cohorts, TET2-CHIP, but not DNMT3A-CHIP, was associated with increased melanoma tumor growth and worse survival outcomes among patients with ICI-treated advanced melanoma, with exploratory evidence that CHIP-associated risk may be most pronounced in BRAF-mutant melanoma.\n\nHow this study might affect research, practice or policyThese findings support further investigation of CHIP as a genotype-specific biomarker of melanoma biology that has the potential to refine risk stratification for patients with advanced melanoma. They further motivate mechanistic studies of how hematopoietic mutations shape antitumor immunity in specific tumor genomic contexts.","rel_num_authors":13,"rel_authors":[{"author_name":"Mason N Alford-Holloway","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sarah C Reed","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Yash Pershad","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Joseph C Van Amburg","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Chad Potts","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sanjay R Mohan","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Leo Y Luo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"P. Brent Ferrell","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Michael R Savona","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ben H Park","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Douglas B Johnson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alexander G Bick","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ashwin Kishtagari","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Curation of Mini Mental State Examination (MMSE) Scores in the VA Million Veteran Program (MVP): Applications for Cognitive Aging Research","rel_doi":"10.64898\/2026.07.14.26358064","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358064","rel_abs":"BackgroundElectronic health record (EHR)-linked biorepositories provide opportunities to advance epidemiological research in Alzheimers disease (AD) and related dementias.\n\nObjectiveEvaluate the extraction, curation, and associative validity of Mini Mental State Examination (MMSE) scores from the VA EHR for participants in the VA Million Veteran Program (MVP).\n\nMethodsThe sample (N = 49,555; 7.4% women) included a multiethnic cohort (European [68.3%], African [20.4%], Hispanic [9.0%]) with EHR-extracted MMSE scores; 30.7% were apolipoprotein E (APOE) {varepsilon}4 carriers, and 25.8% had multiple scores. Linear regressions examined cross-sectional associations between {varepsilon}4 dosage (0, 1, 2) and first and lowest MMSE scores. MMSE scores were also evaluated against MVP dementia diagnostic algorithms in participants aged [&ge;]65 years.\n\nResultsAmong participants of European ancestry, there was a significant {varepsilon}4 dose-response relationship (ps < .001) with MMSE scores. Homozygote carriers scored lower than heterozygote carriers (Mdiff: first = -0.5; lowest = -0.9), who scored lower than non-carriers (Mdiff: first = -0.4; lowest = -0.6). Among Veterans of African and Hispanic ancestry, no dose-response relationship was observed, although {varepsilon}4 carriers had lower scores than non-carriers (ps [&le;] .04). MMSE scores corresponded strongly with dementia case\/control status across phenotypes: mild impairment on the MMSE was strongly associated with AD (odds ratio [OR] = 11.48), with more severe MMSE impairment showing stronger associations (moderate OR = 17.95; severe OR = 27.83).\n\nConclusionThis study demonstrated MMSE scores can be systematically extracted and curated from the VA EHR. Findings offer a scalable framework for future studies on risk stratification, highlighting the potential for harnessing MVP to explore genetic and clinical factors contributing to cognitive and dementia outcomes in diverse samples.","rel_num_authors":9,"rel_authors":[{"author_name":"Francesca V Lopez","author_inst":"VA San Diego Healthcare System, UC San Diego"},{"author_name":"Margaret Gillis","author_inst":"VA Boston Healthcare System"},{"author_name":"Sophia Lee","author_inst":"VA Boston Healthcare System"},{"author_name":"McKenna S Sakamoto","author_inst":"Penn State University"},{"author_name":"Rui Zhang","author_inst":"VA Boston Healthcare System"},{"author_name":"- VA Million Veteran Program","author_inst":""},{"author_name":"Richard Sherva","author_inst":"VA Boston Healthcare System; Boston University School of Medicine"},{"author_name":"Mark Logue","author_inst":"National Center for PTSD, VA Boston Healthcare System"},{"author_name":"Victoria C Merritt","author_inst":"VA San Diego Healthcare System\/UC San Diego"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"From Genes to Neurochemistry: Excitation and Inhibition Mechanisms of Sensory Differences in Autism","rel_doi":"10.64898\/2026.07.14.26358047","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358047","rel_abs":"Sensory processing differences are a core feature of autism, affecting 60-95% of individuals, yet the associated neural mechanisms remain unclear. An excitation-inhibition (E\/I) imbalance in brain circuits has been proposed, but in vivo evidence linking genetic variation in E\/I pathways, regional neurochemistry, neural circuit function, and sensory behaviour has been lacking. Here we performed a multimodal investigation in 206 individuals (130 autistic), integrating gene-set polygenic scores for excitatory glutamatergic and inhibitory gamma-aminobutyric acid (GABA)-ergic pathways, magnetic resonance spectroscopy (MRS) measures of regional GABA and Glx (glutamate + glutamine) levels, vibrotactile psychophysical measures of tactile perception, and questionnaire measures of behavioural sensory reactivity. We found that glutamatergic polygenic scores predicted thalamic glutamate levels in neurotypical but not autistic individuals, suggesting altered genotype-neurochemistry coupling in autism. Thalamic Glx:GABA levels associated with tactile perception in both groups, but with opposing directions of effect, indicating that autistic and neurotypical individuals achieve similar perceptual outcomes with potentially differing thalamocortical circuit mechanisms. Within autistic individuals, tactile perceptual differences further related to behavioural sensory reactivity. Together, these findings suggest that autistic sensory processing potentially relies on distinct circuit mechanisms linking genetic variation, neurochemistry and perception. This work thus has important implications for how sensory differences are conceptualised, studied, and interpreted, and ultimately for how interventions and support are developed.","rel_num_authors":22,"rel_authors":[{"author_name":"Alice Rose Thomson","author_inst":"King's College London"},{"author_name":"Viola Hollestein","author_inst":"King's College London"},{"author_name":"Martina Arenella","author_inst":"King's College London"},{"author_name":"Helen Powell","author_inst":"King's College London"},{"author_name":"Jason He","author_inst":"King's College London"},{"author_name":"Beth Oakley","author_inst":"King's College London"},{"author_name":"Eva Loth","author_inst":"King's College London"},{"author_name":"Rosemary Holt","author_inst":"University of Cambridge"},{"author_name":"Jan K Buitelaar","author_inst":"Donders Institute for Brain, Cognition and Behaviour"},{"author_name":"Laura Colomar","author_inst":"King's College London"},{"author_name":"Natalie J Forde","author_inst":"Donders Institute for Brain, Cognition and Behaviour"},{"author_name":"Thomas Bourgeron","author_inst":"University de Paris"},{"author_name":"Terje Falck-Ytter","author_inst":"Uppsala University"},{"author_name":"Giorgia Bussu","author_inst":"Uppsala University"},{"author_name":"Tobia Banaschweski","author_inst":"German Center for Mental Health (DZPG)"},{"author_name":"Pascal M Aggensteiner","author_inst":"German Center for Mental Health (DZPG)"},{"author_name":"Richard Edden","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Tony Charman","author_inst":"King's College London"},{"author_name":"Charlotte Pretzsch","author_inst":"King's College London"},{"author_name":"Declan Murphy","author_inst":"King's College London"},{"author_name":"Tomoki Arichi","author_inst":"King's College London"},{"author_name":"Nicolaas Puts","author_inst":"King's College London"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Associations of Trajectories of Loneliness and Neighborhood Stability with Depression, Alcohol and Substance Use, and Quality of Life among Women Living with HIV","rel_doi":"10.64898\/2026.07.14.26358061","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358061","rel_abs":"Social relationships are an important social determinant of health. Loneliness, the perceived gap between one's actual and desired relationships, has emerged as an important mechanism through which social relationships impact health. Like other intrapersonal-level factors associated with health, loneliness is influenced by broader social and structural factors, including characteristics of one's neighborhood social environment. Although neighborhood-level protective and risk factors for loneliness and for mental health have been identified, prior studies have often focused solely on self-reported perceptions of the neighborhood environment. Further, few have considered aspects of the neighborhood social environments, such as neighborhood stability (i.e., stability of the community with long or short-term residents), independent of neighborhood socioeconomic conditions. In the current analysis, we explored longitudinal patterns of loneliness in conjunction with neighborhood stability among women with HIV (WWH) enrolled into the MACS\/WIHS Combined Cohort Study (MWCCS) from 2014-2019 (N2019=1,394) to examine whether trajectories of loneliness and neighborhood stability were associated with depressive symptoms, non-prescription substance use, past-year cannabis use, number of alcoholic drinks per week, and several domains of quality of life. Loneliness at baseline (Betas = 0.24 - 0.54) and changes in loneliness over time (Betas = 0.11 - 0.26) were associated with each outcome, except for the association between changes in loneliness over time and drinks per week (Beta=0.13, p = 4.14x10-2), which did not persist after correcting for multiple comparisons. Neighborhood stability at baseline was associated with past year cannabis use (Beta=0.26, p = 1.00x10-2), depressive symptoms (Beta=-0.12, p = 1.54x10-3), and overall self-reported health (Beta=-0.08, p = 2.05x10-2). Changes in neighborhood stability across time were not associated with any outcome. Neighborhood stability moderated the association between changes in loneliness and general health perceptions. Our results demonstrate both overall loneliness and changes in loneliness over time have implications for current mental health in WWH, while changes in neighborhood stability did not.","rel_num_authors":21,"rel_authors":[{"author_name":"Peter B. Barr","author_inst":"VA New York Harbor Healthcare System, Brooklyn, NY Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Ins"},{"author_name":"Andrew Edmonds","author_inst":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC"},{"author_name":"Bradley Aouizerat","author_inst":"Department of Oral and Maxillofacial Surgery, College of Dentistry, New York University, New York, NY Translational Research Center, College of Dentistry, New Y"},{"author_name":"Mardge Cohen","author_inst":"Department of Medicine, Stroger Hospital of Cook County Health and Hospitals System, Chicago, IL"},{"author_name":"Judith A Cook","author_inst":"Center on Mental Health Services Research and Policy, University of Illinois, Chicago, Chicago, IL"},{"author_name":"M. Reuel Friedman","author_inst":"Department of Urban-Global Public Health, Rutgers School of Public Health, Newark, NJ"},{"author_name":"Sabina Haberlen","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD"},{"author_name":"Susan Holman","author_inst":"Department of Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Mirjam-Colette Kempf","author_inst":"Schools of Nursing, Public Health and Medicine, University of Alabama at Birmingham, Birmingham, AL"},{"author_name":"Deborah Konkle-Parker","author_inst":"Schools of Nursing, Medicine and Population Health, University of Mississippi Medical Center, Jackson, MS"},{"author_name":"Jennafer L. Kwait","author_inst":"Whitman-Walker Institute, Washington, DC"},{"author_name":"David B. Hanna","author_inst":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY"},{"author_name":"Gayathri Pandey","author_inst":"Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Michael Plankey","author_inst":"Department of Medicine, Division of General Internal Medicine, Georgetown University, Washington, DC"},{"author_name":"Leah H. Rubin","author_inst":"Departments of Neurology and Psychiatry and Behavioral Sciences, and Molecular and Cellular Pathobiology, Johns Hopkins University School of Medicine, Baltimore"},{"author_name":"Anna A. Rubtsova","author_inst":"Department of Behavioral, Social, and Health Education Sciences, Rollins School of Public Health, Emory University, Atlanta, GA"},{"author_name":"Rebecca M. Schwartz","author_inst":"Northwell Health, New Hyde Park, NY"},{"author_name":"Azure B. Thompson","author_inst":"Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Deborah L. Jones","author_inst":"Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL"},{"author_name":"Jacquelyn L. Meyers","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Institute for Genomics in Health (IGH), SUNY Downstate"},{"author_name":"Tracey Wilson","author_inst":"Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Associations of Trajectories of Loneliness and Neighborhood Stability with Depression, Alcohol and Substance Use, and Quality of Life among Women Living with HIV","rel_doi":"10.64898\/2026.07.14.26358061","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358061","rel_abs":"Social relationships are an important social determinant of health. Loneliness, the perceived gap between one's actual and desired relationships, has emerged as an important mechanism through which social relationships impact health. Like other intrapersonal-level factors associated with health, loneliness is influenced by broader social and structural factors, including characteristics of one's neighborhood social environment. Although neighborhood-level protective and risk factors for loneliness and for mental health have been identified, prior studies have often focused solely on self-reported perceptions of the neighborhood environment. Further, few have considered aspects of the neighborhood social environments, such as neighborhood stability (i.e., stability of the community with long or short-term residents), independent of neighborhood socioeconomic conditions. In the current analysis, we explored longitudinal patterns of loneliness in conjunction with neighborhood stability among women with HIV (WWH) enrolled into the MACS\/WIHS Combined Cohort Study (MWCCS) from 2014-2019 (N2019=1,394) to examine whether trajectories of loneliness and neighborhood stability were associated with depressive symptoms, non-prescription substance use, past-year cannabis use, number of alcoholic drinks per week, and several domains of quality of life. Loneliness at baseline (Betas = 0.24 - 0.54) and changes in loneliness over time (Betas = 0.11 - 0.26) were associated with each outcome, except for the association between changes in loneliness over time and drinks per week (Beta=0.13, p = 4.14x10-2), which did not persist after correcting for multiple comparisons. Neighborhood stability at baseline was associated with past year cannabis use (Beta=0.26, p = 1.00x10-2), depressive symptoms (Beta=-0.12, p = 1.54x10-3), and overall self-reported health (Beta=-0.08, p = 2.05x10-2). Changes in neighborhood stability across time were not associated with any outcome. Neighborhood stability moderated the association between changes in loneliness and general health perceptions. Our results demonstrate both overall loneliness and changes in loneliness over time have implications for current mental health in WWH, while changes in neighborhood stability did not.","rel_num_authors":21,"rel_authors":[{"author_name":"Peter B. Barr","author_inst":"VA New York Harbor Healthcare System, Brooklyn, NY Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Ins"},{"author_name":"Andrew Edmonds","author_inst":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC"},{"author_name":"Bradley Aouizerat","author_inst":"Department of Oral and Maxillofacial Surgery, College of Dentistry, New York University, New York, NY Translational Research Center, College of Dentistry, New Y"},{"author_name":"Mardge Cohen","author_inst":"Department of Medicine, Stroger Hospital of Cook County Health and Hospitals System, Chicago, IL"},{"author_name":"Judith A Cook","author_inst":"Center on Mental Health Services Research and Policy, University of Illinois, Chicago, Chicago, IL"},{"author_name":"M. Reuel Friedman","author_inst":"Department of Urban-Global Public Health, Rutgers School of Public Health, Newark, NJ"},{"author_name":"Sabina Haberlen","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD"},{"author_name":"Susan Holman","author_inst":"Department of Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Mirjam-Colette Kempf","author_inst":"Schools of Nursing, Public Health and Medicine, University of Alabama at Birmingham, Birmingham, AL"},{"author_name":"Deborah Konkle-Parker","author_inst":"Schools of Nursing, Medicine and Population Health, University of Mississippi Medical Center, Jackson, MS"},{"author_name":"Jennafer L. Kwait","author_inst":"Whitman-Walker Institute, Washington, DC"},{"author_name":"David B. Hanna","author_inst":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY"},{"author_name":"Gayathri Pandey","author_inst":"Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Michael Plankey","author_inst":"Department of Medicine, Division of General Internal Medicine, Georgetown University, Washington, DC"},{"author_name":"Leah H. Rubin","author_inst":"Departments of Neurology and Psychiatry and Behavioral Sciences, and Molecular and Cellular Pathobiology, Johns Hopkins University School of Medicine, Baltimore"},{"author_name":"Anna A. Rubtsova","author_inst":"Department of Behavioral, Social, and Health Education Sciences, Rollins School of Public Health, Emory University, Atlanta, GA"},{"author_name":"Rebecca M. Schwartz","author_inst":"Northwell Health, New Hyde Park, NY"},{"author_name":"Azure B. Thompson","author_inst":"Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Deborah L. Jones","author_inst":"Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL"},{"author_name":"Jacquelyn L. Meyers","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Institute for Genomics in Health (IGH), SUNY Downstate"},{"author_name":"Tracey Wilson","author_inst":"Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Early Feasibility of NIVA Score Decongestion Responsiveness: A Pilot Clinical and Preclinical Study","rel_doi":"10.64898\/2026.07.13.26357910","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357910","rel_abs":"Residual congestion is the principal driver of heart failure readmission, and reliable serial assessment of volume status remains an unmet clinical need. This study asked whether a wrist-worn, machine-learning-based device for non-invasive venous waveform analysis in heart failure (the NIVAHF device), which produces an integer-scaled estimate of pulmonary capillary wedge pressure termed the NIVA Score, responds to acute changes in volume status.\n\nAgreement between the NIVA Score and invasively measured pulmonary capillary wedge pressure at single time points has been established in a separate prospective, multi-site study; however, such static agreement does not establish whether the measure tracks dynamic decongestion. We therefore evaluated the directional responsiveness of the locked NIVA Score in two prespecified cohorts: hospitalized adults with acute decompensated heart failure undergoing routine intravenous diuresis, and a controlled porcine model of volume overload followed by diuresis. In eleven patients contributing thirteen paired measurements (mean net fluid balance -2.1 {+\/-} 1.0 L), NIVA Scores decreased significantly after diuresis (paired t-test, P = 0.04). In five pigs contributing twenty-four paired measurements, NIVA Scores decreased significantly after intravenous furosemide following crystalloid loading (P <0.01), and the direction of change was concordant with measured urine output in every animal. Statistical significance was reached in both cohorts despite modest sample sizes, indicating a measurable NIVA Score reduction with volume removal. In an exploratory analysis, the discharge NIVA Score yielded an area under the receiver-operating-characteristic curve of 0.85 (95% confidence interval 0.575-1.00; P = 0.04) for thirty-day readmission. Together, the significant, directionally concordant NIVA Score reductions across independent clinical and preclinical cohorts demonstrate that the device tracks acute decongestion and support its use for serial, non-invasive congestion monitoring; an adequately powered prospective study is the planned next step.","rel_num_authors":21,"rel_authors":[{"author_name":"Bret D. Alvis","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jeffrey Schmeckpeper","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Aniket  S Rali","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jessica Huston","author_inst":"University of Pittsburgh Medical Center"},{"author_name":"Stacy Tsai","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kaushik Amancherla","author_inst":"Vanderbilt University Medical Center"},{"author_name":"David Armstrong","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Richa Gupta","author_inst":"MedStar Health"},{"author_name":"Jonathan  S. Whitfield","author_inst":"VoluMetrix, Inc."},{"author_name":"Rene Harder","author_inst":"VoluMetrix, Inc."},{"author_name":"Katharine Miller","author_inst":"VoluMetrix, Inc."},{"author_name":"Mackenzie Horne","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Dawson Wervey","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Romy Pein","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Tara Isanaka","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Marisa Case","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Eric Wise","author_inst":"University of Minnesota Medical Center Fairview: M Health Fairview University of Minnesota Medical Center East Bank"},{"author_name":"Bryce Perrien","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Colleen Brophy","author_inst":"Vanderbilt University Medical Center"},{"author_name":"JoAnn Lindenfeld","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kyle Hocking","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"West Nile virus in Italy: history and evolving transmission patterns","rel_doi":"10.64898\/2026.07.12.26357540","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.12.26357540","rel_abs":"BACKGROUNDWest Nile virus (WNV) has become an important public health concern in Europe. Italy is one of the most affected countries, yet our understanding of WNV epidemiology, genomics, and dispersal across hosts and geographic regions is incomplete.\n\nAIMTo reveal the history of WNV in Italy by integrating epidemiological, genomic, and environmental data into descriptive and quantitative assessments of its past spatio-temporal surveillance and expansion.\n\nMETHODSWe collated vertebrate and mosquito WNV records from national surveillance and the scientific literature spanning multiple decades. Historical serological and molecular data were summarized by host and region, climatic associations with case trends were assessed using regression models, and phylodynamic and phylogeographic analyses reconstructed viral introductions and dispersal within Italy.\n\nRESULTSWNV circulation in Italy has changed markedly over time, with increasing human case reporting and expansion beyond historically affected northern regions. Climate-informed regression models explained recent reporting trends, supporting an environmental contribution to transmission. Phylodynamic analyses identified multiple independent introductions and sustained local transmission with increasing regional connectivity. Wavefront analyses revealed lineage-specific dispersal patterns associated with seasonal climatic gradients. Discrepancies between epidemiological records and genomic sampling highlighted uneven surveillance across regions and host species.\n\nCONCLUSIONWNV emergence in Italy reflects repeated viral introductions, local persistence, heterogeneous surveillance, and environmentally associated dispersal dynamics. Strengthening integrated surveillance combining epidemiological, environmental, and genomic data will improve early detection, the monitoring of transmission dynamics, and public health preparedness under ongoing environmental change.","rel_num_authors":25,"rel_authors":[{"author_name":"Marta Giovanetti","author_inst":"Fundacao Oswaldo Cruz"},{"author_name":"Eleonora Cella","author_inst":"University of Central Florida"},{"author_name":"Vagner Fonseca","author_inst":"Departamento de Ciencias Exatas e da Terra, Campis I, Universidade do Estado da Bahia (UNEB), Salvador, Brasil; Centre for Epidemic Response and Innovation (CER"},{"author_name":"Monika Moir","author_inst":"Stellenbosch University"},{"author_name":"Bas Oude Munnink","author_inst":"ErasmusMC"},{"author_name":"Claudio de Martinis","author_inst":"Department of Animal Health, Istituto Zooprofilattico Sperimentale del Mezzogiorno, Via Salute, 2, Portici, Naples, 80055, Italy"},{"author_name":"Ana Moreno","author_inst":"Istituto Zooprofilattico Sperimentale della Lombardia e dell Emilia-Romagna Bruno Ubertini"},{"author_name":"Alberto Rizzo","author_inst":"Laboratory of Clinical Microbiology, Virology and Bioemergencies, Luigi Sacco Hospital, Regional Center for Infectious Diseases (CEREMI), Lombardy Region, Milan"},{"author_name":"Davide Mileto","author_inst":"Laboratory of Clinical Microbiology, Virology and Bioemergencies, Luigi Sacco Hospital, Regional Center for Infectious Diseases (CEREMI), Lombardy Region, Milan"},{"author_name":"Francesca Caccuri","author_inst":"University of Brescia: Universita degli Studi di Brescia"},{"author_name":"Arnaldo Caruso","author_inst":"Universita degli Studi di Brescia"},{"author_name":"Enzo Tramontano Prof.","author_inst":"University of Cagliari"},{"author_name":"Svetoslav Nanev Slavov","author_inst":"Butantan Institute, Sao Paulo, Brazil"},{"author_name":"Ana Maria Bispo de Filippis","author_inst":"Laboratorio de Arbovirus e Virus Hemorragicos, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil."},{"author_name":"Tulio de Oliveira","author_inst":"University of KwaZulu-Natal"},{"author_name":"Luiz  C. J. Alcantara","author_inst":"FIOCRUZ"},{"author_name":"Alessandro Marcello","author_inst":"International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy"},{"author_name":"Vittorio Colizzi","author_inst":"Faculty of Medicine, University Hospital Complex Le Bon Samaritain, NDjamena, Chad"},{"author_name":"Giovanni Rezza","author_inst":"Faculty of Medicine, Vita-Salute San Raffaele University, Milan, Italy"},{"author_name":"Massimo Ciccozzi","author_inst":"University Campus Bio-Medico of Rome"},{"author_name":"Concetta Castilletti","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Italy"},{"author_name":"Edward C Holmes","author_inst":"University of Sydney"},{"author_name":"Fabrizio Maggi","author_inst":"Laboratory ofVirology and Laboratories of Biosafety, National Institute for infectious Diseases Lazzaro Spallanzani, IRCCS, Rome, Italy"},{"author_name":"Luisa Barzon","author_inst":"Department of Molecular Medicine, University of Padova, Padova, Italy"},{"author_name":"Jose Lourenco","author_inst":"Universidade Catolica Portuguesa"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Data-driven calibration of low-cost wearable motion trackers for gait and dynamic stability measurement","rel_doi":"10.64898\/2026.07.13.26357919","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357919","rel_abs":"Low-cost inside-out wearable trackers can be deployed at scale to measure body motion, but errors in estimated sensor position propagate through coordinate transformations into derived gait and dynamic-stability metrics. Healthy adults walked on a treadmill at 0.5-2.0 m\/s while VIVE Ultimate Tracker (VUT) and Vicon data were recorded. Data-driven calibration models were developed to correct tracker coordinates and to estimate full-body centre of mass (CoM) from a sacrum-only configuration. Agreement with Vicon was assessed using RMSE, mixed-effects Bland-Altman limits of agreement, MAE, and intraclass correlation coefficients. Calibration improved coordinate-level agreement. For gait parameters, model-corrected VUT showed small errors against Vicon (MAE: 0.24-0.71 mm step height, 1.73-4.63 mm step length, 0.15-0.95 mm step width, 0.26-0.88 mm foot clearance). Proxy CoM-derived margin of stability (MoS) agreed excellently with Vicon. For the sacrum-only pipeline, calibration reduced CoM RMSE from 103.65-104.04 mm to 7.55-8.95 mm, and markedly reduced systematic error in stability outcomes, with extrapolated CoM bias decreasing from 172.92 to 0.29 mm and MoS bias from -75.09 to -3.54 mm. Data-driven calibration improved the measurement utility of low-cost VUTs, enabling inexpensive, relatively simple gait and stability measurement from a sacrum-only setup in controlled settings.","rel_num_authors":6,"rel_authors":[{"author_name":"Yixuan He","author_inst":"Neuroscience Research Australia"},{"author_name":"Yuxin Dong","author_inst":"University of New South Wales"},{"author_name":"Matthew Andrew Brodie","author_inst":"University of New South Wales"},{"author_name":"Juno Kim","author_inst":"University of New South Wales"},{"author_name":"Stephen R. Lord","author_inst":"Neuroscience Research Australia"},{"author_name":"Yoshiro Okubo","author_inst":"Neuroscience Research Australia"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"A Multimodal Benchmark for Evaluating Cause-of-Death Inference Using Child Health and Mortality Data","rel_doi":"10.64898\/2026.07.13.26357980","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357980","rel_abs":"AO_SCPLOWBSC_SCPLOWtO_SCPLOWRC_SCPLOWactAccurately attributing causes of death is vital for global health, yet fewer than 5% of deaths in resource-constrained regions are medically certified. To assign causes to these unlabeled deaths at scale, practitioners traditionally rely on verbal autopsy, using supervised statistical models to classify based on structured survey data. However, modern mortality surveillance increasingly collects rich, unstructured multimodal data, such as free-text caregiver narratives and postmortem diagnostics, which traditional supervised statistical models struggle to seamlessly integrate. In this paper, we present a comprehensive, multimodal benchmark for cause-of-death classification using data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network, a unique surveillance platform spanning nine countries across South Asia and Sub-Saharan Africa. Using this dataset, we introduce an evaluation framework designed to rigorously assess diagnostic reasoning, moving beyond traditional metrics that fail to capture complex clinical realities. We demonstrate the utility of this benchmark by evaluating zero-shot large language models against supervised baselines across various data modalities. Our results reveal distinct differences in how these modeling approaches synthesize unstructured medical evidence. This benchmark provide a rigorously defined resource for assessing clinical reasoning in next-generation mortality surveillance.","rel_num_authors":21,"rel_authors":[{"author_name":"Junhe Yang","author_inst":"University of Washington"},{"author_name":"Soumyakanti Pan","author_inst":"University of Washington"},{"author_name":"Hyun Seung Lim","author_inst":"Northeastern University"},{"author_name":"Yue Chu","author_inst":"Ohio State University"},{"author_name":"Yuting Guo","author_inst":"Emory University School of Medicine"},{"author_name":"Nishtha Agarwal","author_inst":"University of Washington"},{"author_name":"Varun Babbar","author_inst":"Duke University"},{"author_name":"Gaurav Rajesh Parikh","author_inst":"Duke University"},{"author_name":"Yiqun T. Chen","author_inst":"Johns Hopkins University"},{"author_name":"Chris  A Rees","author_inst":"Emory University School of Medicine"},{"author_name":"Ziyaad Dangor","author_inst":"University of the Witwatersrand"},{"author_name":"Sanjay G. Lala","author_inst":"University of the Witwatersrand"},{"author_name":"Zehang Richard Li","author_inst":"University of California, Santa Cruz"},{"author_name":"Samuel J. Clark","author_inst":"Ohio State University"},{"author_name":"Zhenke Wu","author_inst":"University of Michigan"},{"author_name":"Abhirup Datta","author_inst":"Johns Hopkins University"},{"author_name":"Li Liu","author_inst":"Johns Hopkins University"},{"author_name":"Cynthia Rudin","author_inst":"Duke University"},{"author_name":"Samuel V. Scarpino","author_inst":"Northeastern University"},{"author_name":"Benjamin M. Gyori","author_inst":"Northeastern University"},{"author_name":"Tyler H. McCormick","author_inst":"University of Washington"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"A Multimodal Benchmark for Evaluating Cause-of-Death Inference Using Child Health and Mortality Data","rel_doi":"10.64898\/2026.07.13.26357980","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357980","rel_abs":"AO_SCPLOWBSC_SCPLOWtO_SCPLOWRC_SCPLOWactAccurately attributing causes of death is vital for global health, yet fewer than 5% of deaths in resource-constrained regions are medically certified. To assign causes to these unlabeled deaths at scale, practitioners traditionally rely on verbal autopsy, using supervised statistical models to classify based on structured survey data. However, modern mortality surveillance increasingly collects rich, unstructured multimodal data, such as free-text caregiver narratives and postmortem diagnostics, which traditional supervised statistical models struggle to seamlessly integrate. In this paper, we present a comprehensive, multimodal benchmark for cause-of-death classification using data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network, a unique surveillance platform spanning nine countries across South Asia and Sub-Saharan Africa. Using this dataset, we introduce an evaluation framework designed to rigorously assess diagnostic reasoning, moving beyond traditional metrics that fail to capture complex clinical realities. We demonstrate the utility of this benchmark by evaluating zero-shot large language models against supervised baselines across various data modalities. Our results reveal distinct differences in how these modeling approaches synthesize unstructured medical evidence. This benchmark provide a rigorously defined resource for assessing clinical reasoning in next-generation mortality surveillance.","rel_num_authors":21,"rel_authors":[{"author_name":"Junhe Yang","author_inst":"University of Washington"},{"author_name":"Soumyakanti Pan","author_inst":"University of Washington"},{"author_name":"Hyun Seung Lim","author_inst":"Northeastern University"},{"author_name":"Yue Chu","author_inst":"Ohio State University"},{"author_name":"Yuting Guo","author_inst":"Emory University School of Medicine"},{"author_name":"Nishtha Agarwal","author_inst":"University of Washington"},{"author_name":"Varun Babbar","author_inst":"Duke University"},{"author_name":"Gaurav Rajesh Parikh","author_inst":"Duke University"},{"author_name":"Yiqun T. Chen","author_inst":"Johns Hopkins University"},{"author_name":"Chris  A Rees","author_inst":"Emory University School of Medicine"},{"author_name":"Ziyaad Dangor","author_inst":"University of the Witwatersrand"},{"author_name":"Sanjay G. Lala","author_inst":"University of the Witwatersrand"},{"author_name":"Zehang Richard Li","author_inst":"University of California, Santa Cruz"},{"author_name":"Samuel J. Clark","author_inst":"Ohio State University"},{"author_name":"Zhenke Wu","author_inst":"University of Michigan"},{"author_name":"Abhirup Datta","author_inst":"Johns Hopkins University"},{"author_name":"Li Liu","author_inst":"Johns Hopkins University"},{"author_name":"Cynthia Rudin","author_inst":"Duke University"},{"author_name":"Samuel V. Scarpino","author_inst":"Northeastern University"},{"author_name":"Benjamin M. Gyori","author_inst":"Northeastern University"},{"author_name":"Tyler H. McCormick","author_inst":"University of Washington"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"The topology of adolescent mental health","rel_doi":"10.64898\/2026.07.13.26357465","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357465","rel_abs":"The increased vulnerability to mental health problems in adolescence is frequently reported but poorly understood, hampered by a rigid diagnostic system which fails to capture intertwining symptoms and only loosely aligns with biological axes of variability. Here, we reconceptualised the mental health symptoms of young adolescents in the ABCD cohort (N=11862) as a latent topology of overlapping symptom dimensions, using an unsupervised machine learning algorithm to establish how transdiagnostic dimensions co-occur and overlap within individuals. Combining this with a novel classification approach, we delineated zones within this landscape, within which specific profiles of symptoms were robustly represented. These data-driven profiles were leveraged to establish associated resting-state functional connectivity and genetic characteristics. In doing so we recaptured the commonly reported p- factor axis as well as further symptom-subtype dimensions. Gene ontology analysis revealed that shared neurobiological and cellular mechanisms embedded in both the genome and transcriptome may confer risk for psychopathology.","rel_num_authors":11,"rel_authors":[{"author_name":"Maria Barbara Jelen","author_inst":"University of Cambridge"},{"author_name":"Alexa Mousley","author_inst":"University of Cambridge"},{"author_name":"Kayson Fakhar","author_inst":"University of Cambridge"},{"author_name":"Estherina Trachtenberg","author_inst":"University of Cambridge"},{"author_name":"Yuankai He","author_inst":"University of Cambridge"},{"author_name":"Robert Kohler","author_inst":"Yale University"},{"author_name":"Shambhavi Aggarwal","author_inst":"McGill University"},{"author_name":"Varun Warrier","author_inst":"University of Cambridge"},{"author_name":"Danilo Bzdok","author_inst":"McGill University"},{"author_name":"Sarah W. Yip","author_inst":"Yale University"},{"author_name":"Duncan E. Astle","author_inst":"University of Cambridge"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Serious Illness Conversations in Older Patients at High Risk of Mortality in Primary Care During the COVID-19 Pandemic: A Quasi-Experimental Study","rel_doi":"10.64898\/2026.07.12.26357462","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.12.26357462","rel_abs":"PurposeSerious Illness Conversations (SICs) are essential to delivering person-centered care for older adults with chronic conditions, but are rarely integrated into routine primary care. To address this gap, we compared the effectiveness of a structured training strategy versus passive dissemination of educational materials on SIC documentation rates during the COVID-19 pandemic.\n\nMethodsA quasi-experimental study across 13 primary care clinics in Quebec, Canada. Five clinics received structured team-based Serious Illness Care Program training (intervention group) with a provincially disseminated SIC toolkit and eight received the toolkit only (control group). The primary outcome was the proportion of patients with a documented SIC across three time periods (Period 1, pre pandemic; Period 2, pandemic initial wave; and Period 3, post dissemination of SIC toolkit). We used generalized estimating equations (GEE).\n\nResultsAcross 13 clinics, 2,368 eligible patients (mean age 75.8 years (SD = 7.5), 54% female, with a mean Charlson Comorbidity Index of 4.88 (SD = 2)) accounted for 19,134 clinical visits, 49.5% in person and 49.6% virtually. SIC documentation rates were 3.3% (control) and 3.4% (intervention) in Period 1, 9.3% and 4.3% in Period 2, and 6.4% and 4.8% in Period 3, respectively. There was no statistically significant improvement to SIC documentation in the intervention group at Period 2 nor Period 3.\n\nConclusionStructured training was not more effective than passive dissemination for SIC documentation. Educational interventions must be supported by structural changes, workflow integration, and organizational leadership. Multi-level implementation strategies are needed to embed SICs sustainably into primary care.","rel_num_authors":11,"rel_authors":[{"author_name":"Gabrielle Chicoine","author_inst":"Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada"},{"author_name":"Nathalie Germain","author_inst":"Centre de recherche du CISSS de Chaudi\u00e8re-Appalaches, L\u00e9vis, QC, Canada"},{"author_name":"St\u00e9phane Turcotte","author_inst":"Centre de recherche du CISSS de Chaudi\u00e8re-Appalaches, L\u00e9vis, QC, Canada"},{"author_name":"\u00c9milie C\u00f4t\u00e9","author_inst":"Centre de recherche du CISSS de Chaudi\u00e8re-Appalaches, L\u00e9vis, QC, Canada"},{"author_name":"V\u00e9ronique G\u00e9linas","author_inst":"Centre de recherche du CISSS de Chaudi\u00e8re-Appalaches, L\u00e9vis, QC, Canada"},{"author_name":"France L\u00e9gar\u00e9","author_inst":"VITAM - Centre de recherche en sant\u00e9 durable; CIUSSS de la Capitale-Nationale, Quebec City, QC, Canada; Department of Family and Emergency Medicine, Universit\u00e9 "},{"author_name":"Jean-S\u00e9bastien Paquette","author_inst":"CSSS du Nord de Lanaudi\u00e8re, Saint-Charles-Borrom\u00e9e, QC, Canada; Department of Family and Emergency Medicine, Universit\u00e9 Laval, Quebec City, QC, Canada; VITAM - "},{"author_name":"Annette M Totten","author_inst":"Department of Medical Informatics and Clinical Epidemiology, School of Medicine, Oregon Health and Science University, Portland, OR, USA"},{"author_name":"Mich\u00e8le Morin","author_inst":"Centre de recherche du CISSS de Chaudi\u00e8re-Appalaches, L\u00e9vis, QC, Canada"},{"author_name":"Sharon E Straus","author_inst":"Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada"},{"author_name":"Patrick M Archambault","author_inst":"Centre de recherche du CISSS de Chaudi\u00e8re-Appalaches, L\u00e9vis, QC, Canada; Department of Family and Emergency Medicine, Universit\u00e9 Laval, VITAM - Centre de recher"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Description of the Intervention for Virological Suppression in Youth with HIV (iVY): A telehealth behavioral intervention focused on mental health, substance use, and HIV care engagement among youth living with HIV","rel_doi":"10.64898\/2026.07.13.26357907","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357907","rel_abs":"ObjectiveYouth with HIV experience persistent disparities across the HIV care continuum, including low rates of engagement in care and viral suppression. In a recent national survey, youth and young adults, defined by the CDC as ages 13-34, accounted for approximately 20- 40% of new HIV diagnoses in the United States. We describe the Intervention for Virological Suppression in Youth with HIV (iVY), a youth-friendly, tailored approach that integrates mental health and substance use support with HIV treatment engagement.\n\nTrial DesignThis paper describes the development of the intervention used in iVY, which is currently being evaluated in a randomized clinical trial (RCT) using an adaptive treatment strategy. HIV virological suppression is measured via dried blood spot at 16 weeks.\n\nMethodsThe intervention is delivered fully remotely across California and Florida. YWH aged 18-29 who are not durably virally suppressed are enrolled and randomized to the intervention or usual care. The RCT will enroll and randomize 200 participants to the intervention (n = 100) versus usual care (n = 100). iVY includes: (1) tailored brief, weekly video-counseling sessions focused on HIV treatment adherence and engagement, mental health, substance use, and related barriers; and (2) a mobile health application designed to support adherence, resource access, and peer connection. Participants who are not virally suppressed receive an additional 16 weeks of intensified intervention, while responders continue with app-based support.\n\nResultsN\/A\n\nConclusionThis paper provides a detailed description of a telehealth-based behavioral intervention tailored to the needs of youth with HIV. The intervention offers a scalable model for integrating behavioral health and HIV care to address barriers to treatment engagement in this priority population.","rel_num_authors":6,"rel_authors":[{"author_name":"Celeste Balaban","author_inst":"University of California San Francisco"},{"author_name":"Caravella McCuistian","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Hiromi Ortega Roque","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Valerie  A. Gruber","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Mallory  O. Johnson","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Parya Saberi","author_inst":"UCSF: University of California San Francisco"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Multi-tissue analyses of allele-specific chromatin accessibility nominate likely functional variants for type 2 diabetes","rel_doi":"10.64898\/2026.07.14.26358094","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358094","rel_abs":"Genome-wide association studies (GWAS) have identified >1,200 signals associated with type 2 diabetes (T2D), yet identifying functional variants remains challenging because the majority of them lie in noncoding regions of the genome and are in areas of high linkage disequilibrium (LD). While chromatin accessibility QTL (caQTL) and expression QTL (eQTL) analyses are useful for nominating regulatory mechanisms underlying GWAS signals, limitations still exist in pinpointing functional variants within regions of high LD. A complementary approach that has been less frequently applied is to focus on the allele-specific effect on chromatin accessibility at heterozygous single-nucleotide polymorphisms (SNPs), hereafter referred to as \"allelic imbalance\". We analyzed the allelic imbalance of reads generated from an assay for transposase-accessible chromatin with sequencing (ATAC-seq) across genotyped samples from 490 donors in T2D-relevant tissues: skeletal muscle, liver, pancreatic islets, adipose tissue, and relevant cell types. We identified 119,949 allelically imbalanced SNPs (FDR<0.05) across the genome. The allelic imbalance was often most prominent in one tissue and showed an enrichment overlapping with tissue-specific transcription factor (TF) binding footprints. Focusing on the 8,581 SNPs in previously published 99% credible sets from 338 T2D GWAS signals, we identified 256 imbalanced SNPs across 123 (36.4% of) signals, each showing allelic imbalance in at least one tissue or cell type. Of these, 71 signals contained only a single imbalanced SNP, representing excellent candidate causative variants. As a proof-of-concept, we showed that 23 of the 256 imbalanced SNPs were supported by allelic assays from previous studies. Further, we experimentally validated two imbalanced SNPs as likely functional variants: rs34584161 among a seven-SNP T2D credible set at the RNF6 signal in islets and rs849134 among a 13-SNP credible set at the JAZF1 signal in liver. This study demonstrates the power of integrating ATAC-seq allelic imbalance (ASAI) with GWAS statistical fine-mapping to identify candidate functional regulatory variants from among tightly linked GWAS variants in disease-relevant tissues. While applied here in T2D, this approach represents a widely applicable high-throughput framework for refining the genetic architecture of complex traits.","rel_num_authors":35,"rel_authors":[{"author_name":"Narisu Narisu","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Hannah X Li","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Caleb J M Rathbun","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Arushi Varshney","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA"},{"author_name":"Amy J Swift","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Tingfen Yan","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Neelam Sinha","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Kevin W Currin","author_inst":"Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA"},{"author_name":"Dongxiang Xue","author_inst":"Department of Surgery, Center for Genomic Health, Weill Cornell Medicine, New York, NY 10065, USA"},{"author_name":"Catherine C Robertson","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA"},{"author_name":"D Leland Taylor","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Henry J Taylor","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Aimee Beck","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Brian N Lee","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Li Wang","author_inst":"Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA"},{"author_name":"K Alaine Broadaway","author_inst":"Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA"},{"author_name":"Emma P Wilson","author_inst":"Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA"},{"author_name":"Heather Stringham","author_inst":"Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Jouko Saramies","author_inst":"South Karelia Social and Health Care District, Wellbeing Services County of South Karelia, Finland"},{"author_name":"Timo A Lakka","author_inst":"Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland"},{"author_name":"Cassandra N Spracklen","author_inst":"Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, MA 01003, USA"},{"author_name":"Laura J Scott","author_inst":"Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Michael L Stitzel","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA"},{"author_name":"Jaakko Tuomilehto","author_inst":"Finnish Institute for Health and Welfare, Helsinki, Finland"},{"author_name":"Markku Laakso","author_inst":"Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland"},{"author_name":"Heikki A Koistinen","author_inst":"Finnish Institute for Health and Welfare, Helsinki, Finland"},{"author_name":"Michael Boehnke","author_inst":"Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"H Efsun Arda","author_inst":"Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, US"},{"author_name":"Shuibing Chen","author_inst":"Department of Surgery, Center for Genomic Health, Weill Cornell Medicine, New York, NY 10065, USA"},{"author_name":"Leslie G Biesecker","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Lori L Bonnycastle","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Michael R Erdos","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Karen L Mohlke","author_inst":"Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA"},{"author_name":"Stephen C J Parker","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA"},{"author_name":"Francis S Collins","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Quantifying the contribution of genetic variation to healthcare expenditure across diverse healthcare systems","rel_doi":"10.64898\/2026.07.14.26358031","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358031","rel_abs":"Healthcare systems must balance rising costs with the delivery of effective care, yet the factors underlying large inter-individual differences in healthcare expenditure remain incompletely understood. Here we examine how genome-wide genetic variation contributes to healthcare costs, analysing inpatient, outpatient, primary care and prescription drug expenditure in up to 1,429,889 individuals from 11 studies across 7 countries.\n\nWe identify hundreds of common genetic variants robustly associated with healthcare costs, revealing a reproducible polygenic architecture shared across healthcare systems. Individual common variants have modest effects, typically altering annual costs by [~]1-2% per allele, with the strongest signals arising from the HLA region, consistent with pleiotropic effects across autoimmune and inflammatory diseases. In contrast, putative loss-of-function (pLOF) variants (ClinVar\/ENIGMA pathogenic variants or LOFTEE high-confidence pLOF) in clinically actionable genes, studied in UK Biobank, have large individual-level consequences: carriers of such variants in BRCA1, BRCA2, MSH2 and APC experience more than a two-fold increase in annual inpatient costs.\n\nCost-associated signals colocalize extensively with autoimmune disorders, cardiometabolic risk factors, pain sensitivity, and depression amongst others. Polygenic scores derived for healthcare costs can predict up to 1.4% of drug-related healthcare expenditure in independent cohorts and retain their effects in within-family analyses, indicating largely direct genetic influences. By linking genetic risk to healthcare expenditure, this work provides a foundation for integrating human genetics into health economics, preventive strategies and population-level screening.","rel_num_authors":57,"rel_authors":[{"author_name":"Sebastian May-Wilson","author_inst":"University of Helsinki"},{"author_name":"Jiwoo Lee","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Tomoko Nakanishi","author_inst":"University of Helsinki"},{"author_name":"Camiel M van der Laan","author_inst":"Vrije Universiteit Amsterdam"},{"author_name":"Ioannis Louloudis","author_inst":"Novo Nordisk Foundation Center for Protein Research"},{"author_name":"Kuang Lin","author_inst":"University of Oxford"},{"author_name":"Stavroula Kanoni","author_inst":"Queen Mary University London"},{"author_name":"Patrick Fahr","author_inst":"University of Oxford"},{"author_name":"Anne Richmond","author_inst":"The University of Edinburgh"},{"author_name":"Chadi Saad","author_inst":"Qatar Precision Health Institute"},{"author_name":"Penelope Lind","author_inst":"QIMR Berghofer"},{"author_name":"Zaina Al-Kanaani","author_inst":"Hamad Medical Corporation"},{"author_name":"Mykyta Artomov","author_inst":"Nationwide Children's Hospital"},{"author_name":"Karina Banasik","author_inst":"Copenhagen University Hospital"},{"author_name":"Enda M Byrne","author_inst":"University of Queensland"},{"author_name":"Zhengming Chen","author_inst":"Oxford University"},{"author_name":"Christian Erikstrup","author_inst":"Aarhus University Hospital"},{"author_name":"Erik Sorensen","author_inst":"Rigshospitalet"},{"author_name":"Jakob German","author_inst":"Institute for Molecular Medicine Finland \/ Broad Institute of MIT and Harvard"},{"author_name":"Giulia Brunelli","author_inst":"University of Helsinki"},{"author_name":"Daniel F. Gudbjartsson","author_inst":"deCODE Genetics\/Amgen"},{"author_name":"Unnur Thorsteinsdottir","author_inst":"deCODE Genetics\/Amgen"},{"author_name":"Ian B. Hickie","author_inst":"University of Sydney"},{"author_name":"Nikita Kolosov","author_inst":"University of Helsinki"},{"author_name":"Satoshi Koyama","author_inst":"The Broad Institute of MIT And Harvard"},{"author_name":"Arne Kukkonen","author_inst":"University of Tartu"},{"author_name":"Liming Li","author_inst":"Peking University Health Science Center"},{"author_name":"Daniel L. McCartney","author_inst":"University of Edinburgh"},{"author_name":"Laust Hvas Mortensen","author_inst":"University of Copenhagen"},{"author_name":"Sisse R. Ostrowski","author_inst":"Rigshospitalet"},{"author_name":"Ole Birger Pedersen","author_inst":"Naestved Hospital"},{"author_name":"Henning Bundgaard","author_inst":"Copenhagen University Hospital (Rigshospitalet)"},{"author_name":"Dan J. Siskind","author_inst":"The University of Queensland"},{"author_name":"Doug Speed","author_inst":"Aarhus University"},{"author_name":"Patrick Sulem","author_inst":"deCODE Genetics\/Amgen"},{"author_name":"Andres Vork","author_inst":"University of Tartu"},{"author_name":"Sarah Wordsworth","author_inst":"Broad Institute of Harvard and MIT"},{"author_name":"Zhiyu Yang","author_inst":"University of Helsinki"},{"author_name":"Kristina Zguro","author_inst":"University of Helsinki"},{"author_name":"- Genes & Health Research Team","author_inst":"-"},{"author_name":"- FinnGen","author_inst":"-"},{"author_name":"Sarah Medland","author_inst":"QIMR"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Hamdi Mbarek","author_inst":"Qatar Genome"},{"author_name":"Dorret I. Boomsma","author_inst":"Vrije Universiteit Amsterdam"},{"author_name":"Riccardo Marioni","author_inst":"University of Edinburgh"},{"author_name":"James Buchanan","author_inst":"Wolfson Institute of Population Health"},{"author_name":"Pradeep Natarajan","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Sarah Finer","author_inst":"Queen Mary University of London"},{"author_name":"David A van Heel","author_inst":"Queen Mary University of London"},{"author_name":"Robin Walters","author_inst":"Oxford University"},{"author_name":"Erik Abner","author_inst":"Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia"},{"author_name":"Soren Brunak","author_inst":"Novo Nordisk Foundation Center for Protein Research"},{"author_name":"Neil Martin Davies","author_inst":"University College London"},{"author_name":"Tatiana Cajuso Pons","author_inst":"University of Helsinki"},{"author_name":"Padraig Dixon","author_inst":"University of Oxford"},{"author_name":"Andrea Ganna","author_inst":"University of Helsinki"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Local ancestry-informed rare variant burden testing improves gene discovery in admixed populations","rel_doi":"10.64898\/2026.07.13.26357993","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357993","rel_abs":"Rare-variant association studies enable the discovery of high-impact genetic contributors often missed by conventional genome-wide association studies focused on common variation. However, standard burden tests aggregate variants without accounting for local ancestry in admixed genomes, reducing power when rare variant frequencies or genetic effects differ across ancestral backgrounds. Here, we introduce Tractor-Burden, an ancestry-aware gene-based association method that partitions rare-variant burden by inferred local ancestry and estimates ancestry-specific effects within a unified regression. In simulations, Tractor-Burden is well calibrated and improves power over standard burden tests under effect heterogeneity. Applied to whole-genome sequencing data from 47,152 admixed African-European individuals in the All of Us Research Program, Tractor-Burden recapitulates known associations, including ancestry-enriched effects at LDLR, and identifies additional suggestive genes and pathways for type 2 diabetes. Tractor-Burden extends rare-variant association testing to admixed genomes and provides a scalable framework for detecting and interpreting gene-level effects across local ancestry backgrounds.","rel_num_authors":9,"rel_authors":[{"author_name":"Pragati Kore","author_inst":"Baylor College of Medicine"},{"author_name":"Taotao Tan","author_inst":"Baylor College of Medicine"},{"author_name":"Wenxuan Lu","author_inst":"Johns Hopkins University"},{"author_name":"Astrid Manuel-Friedman","author_inst":"Baylor College of Medicine"},{"author_name":"Linfeng Hu","author_inst":"The Broad Institute of MIT and Harvard"},{"author_name":"Nilanjan Chatterjee","author_inst":"Johns Hopkins University"},{"author_name":"Wei Zhou","author_inst":"The Broad Institute of MIT and Harvard"},{"author_name":"Ryan S. Dhindsa","author_inst":"Baylor College of Medicine"},{"author_name":"Elizabeth G. Atkinson","author_inst":"Baylor College of Medicine"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Concerns, Priorities, and Pathways: Healthcare Provider Perspectives on Implementing Tuberculosis Preventive Treatment for People with HIV in Indonesia and the Philippines","rel_doi":"10.64898\/2026.07.13.26357999","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357999","rel_abs":"BackgroundTuberculosis preventive therapy (TPT) is a cornerstone intervention for reducing TB incidence among people living with HIV, yet its integration into routine care remains inconsistent in high-burden settings. While policy frameworks are well established, less is known about how frontline healthcare workers (HCWs) operationalize TPT within constraint health systems. Thisstudy explores healthcare workers (HCWs) perspectives on TPT implementation in Indonesia and the Philippines using normalization process theory (NPT), to understand how TPT is (or fails to be) embedded in everyday clinical practice.\n\nMethodsWeconducted ten focus group discussions and four in-depth interviews with HCWs across major TB\/HIV treatment centers in Manila, Philippines and Jakarta, Indonesiabetween June to December 2023. Data were analyzed using reflexive thematic analysis, followed by interpretative mappingontofour NPT constructs: coherence, cognitive participation, collective action and reflexive monitoring.\n\nResultsTPT implementation was characterized by a persistent gap between policy intent and routine practice. Under coherence, HCWsdescribed fragmented knowledge and limited exposure to standardized protocols, undermining confidence in TPT delivery. Cognitive participation was constrained by a doctor-centric model and high staff turnover, weakening shared ownership of TPT. In collective action, operational fragilities, including weak documentation systems, supply interruptions, and poor inter-level coordination, resulted in inconsistent delivery. Through reflexive monitoring, HCWs identified patient concerns around side effects and pill burden, alongside provider concerns regarding diagnostic uncertainty and fears of missing active TB. Across settings, HCWs actively proposed system-oriented solutions, including SOP standardization, team-based training, digital reminders, and strengthened care continuity mechanisms.\n\nConclusionsTPT implementation is not limited by awareness alone but by the absence of routinized systems that support consistent practice. Strengthening implementation requires shifting from individual-dependent delivery toward system-enabled integration, through standardized protocols, distributed workforce engagement, embedded monitoring mechanisms, and uninterrupted drug supply systems. Interventions that align with everyday clinical workflows and reinforce collective responsibility across cadres are critical to closing policy and practice gap.","rel_num_authors":17,"rel_authors":[{"author_name":"Prashant Kulkarni","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Laura Steiner","author_inst":"Johns Hopkins School of Medicine: The Johns Hopkins University School of Medicine"},{"author_name":"Alieen Gianan-Gascon","author_inst":"RITM: Research Institute for Tropical Medicine"},{"author_name":"Candice  Eula Lamigo","author_inst":"RITM: Research Institute for Tropical Medicine"},{"author_name":"Bianca  Joyce Sornillo","author_inst":"RITM: Research Institute for Tropical Medicine"},{"author_name":"Ruth  Anne Hechanova-Cruz","author_inst":"RITM: Research Institute for Tropical Medicine"},{"author_name":"Anna  Maureen Dungca-Lorilla","author_inst":"RITM: Research Institute for Tropical Medicine"},{"author_name":"Aljira  Fitya Hapsari","author_inst":"Universitas Indonesia"},{"author_name":"Retnosari Hardaningsih","author_inst":"Hospital Dr Cipto Mangunkusumo: Rumah Sakit Dr Cipto Mangunkusumo"},{"author_name":"Mira Yulianti","author_inst":"Hospital Dr Cipto Mangunkusumo: Rumah Sakit Dr Cipto Mangunkusumo"},{"author_name":"Anshari  Saifuddin Hasibuan","author_inst":"Hospital Dr Cipto Mangunkusumo: Rumah Sakit Dr Cipto Mangunkusumo"},{"author_name":"Evy Yunihastuti","author_inst":"Hospital Dr Cipto Mangunkusumo: Rumah Sakit Dr Cipto Mangunkusumo"},{"author_name":"Priyanka Raichur","author_inst":"Johns Hopkins University"},{"author_name":"Rossana Ditangco","author_inst":"RITM: Research Institute for Tropical Medicine"},{"author_name":"Jonathan  E Golub","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Christopher  J Hoffmann","author_inst":"Johns Hopkins University"},{"author_name":"Mark  Donald C. Re\u00f1osa","author_inst":"RITM: Research Institute for Tropical Medicine"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Mortality in Eastern Democratic Republic of the Congo: A Population-Based Survey Following the 2025 M23 Offensive and Humanitarian Funding Withdrawal","rel_doi":"10.64898\/2026.07.10.26357778","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357778","rel_abs":"IntroductionIn early 2025, North and South Kivu Provinces in the Democratic Republic of the Congo (DRC) underwent a major geopolitical shift marked by the concurrent abrupt withdrawal of humanitarian support and large-scale military takeover by the M23 armed group. This study sought to quantify mortality before and after the humanitarian and security collapse.\n\nMethodsWe conducted a retrospective, two-stage cluster household survey comparing mortality in the pre- and post-crisis periods. Difference-in-differences were analyzed using survey-weighted Poisson regression with a log-link and person-time offset to estimate adjusted incident rate ratios for crude, under-five, and sex-specific mortality. We interviewed community leaders and health facility staff as key informants to provide qualitative data.\n\nResultsThe adjusted risk of death was 2.02 times higher in the post-crisis than the pre-crisis period (95% CI 1.07, 3.80; p=0.03). Crude mortality rose from a pre-crisis adjusted marginal mean of 0.38 (95% CI 0.22, 0.53) to 0.74 (95% CI 0.56, 0.92) deaths\/10,000\/day. The increase in mortality was consistent across DRC-Government and M23 controlled areas. Results indicate that 165,391 (95%CI: 63,557, 267,225) excess deaths occurred in the post-crisis period, equating to 245,397 annual excess deaths.\n\nConclusionThe crisis in DRC is driven by the convergence of humanitarian funding withdrawals and escalating conflict. Averting further preventable deaths requires large-scale restoration of humanitarian assistance. The resources needed to do so represent a small fraction of global economic capacity.\n\nWhat is already known on this topicElevated population mortality has been widely documented in periods of conflict. Eastern DRC is currently experiencing an escalation of conflict and simultaneous withdrawal of humanitarian aid, indicating increased risk of preventable death.\n\nWhat this study addsThis study will provide the first published mortality estimates based on primary data collection for eastern DRC since the fall of Goma in January 2025.\n\nHow this study might affect research, practice or policyThis study measured a doubling of population mortality over a 7-month period, meeting the emergency threshold of a humanitarian crisis. Declaration of a crisis should trigger urgent response from humanitarian actors to avert further preventable death.","rel_num_authors":3,"rel_authors":[{"author_name":"Jennifer OKeeffe","author_inst":"Rebuild Hope for Africa"},{"author_name":"Augustin Gang Baderha Karume","author_inst":"Rebuild Hope for Africa"},{"author_name":"Les Roberts","author_inst":"Rebuild Hope for Africa"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Intermittent theta burst stimulation modulates working memory-related theta-gamma coupling in adolescents with ADHD","rel_doi":"10.64898\/2026.07.13.26357958","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357958","rel_abs":"ObjectiveWorking memory (WM) deficits are a co-occurring feature to numerous neuropsychiatric disorders, particularly attention- deficit\/hyperactivity disorder (ADHD), and there remain no treatments that directly target WM. The coupling between the phase of theta band activity and amplitude of gamma band activity (i.e., TGC) is an established neural correlate of WM. However, no studies have examined WM-related TGC in ADHD or whether neuromodulation can modulate these oscillatory dynamics in youth. This set of studies examined the effects of intermittent theta burst stimulation (iTBS) to the left dorsolateral prefrontal cortex (DLPFC) and left posterior parietal cortex (PPC) on TGC in youth with ADHD.\n\nMethodsIn two randomized, double-blind, sham-controlled crossover trials, adolescents with ADHD and clinically significant parent-reported WM symptoms first completed a single-session study comparing DLPFC versus PPC iTBS targeting (n = 47) and then a multi-session clinical trial comparing 10 sessions of active versus sham left DLPFC iTBS (n = 29). Participants completed a computerized visuospatial Sternberg WM task with concurrent electroencephalography (EEG) before and after the single sessions, as well as at baseline, midway through treatment, and approximately 24 hours after the final session within the multi-session trial. Phase-amplitude coupling between theta phase and gamma amplitude was quantified using the Kullback-Leibler modulation index at frontoparietal electrodes. Linear mixed-effects models examined treatment effects and associations between change in TGC and WM status (including accuracy, reaction time, and clinical symptoms).\n\nResultsAcross participants, lower TGC was associated with lower symptoms and better WM performance, including higher accuracy, faster and more consistent RT. Active iTBS increased frontoparietal TGC relative to sham stimulation, with effects observed both acutely after a single session and [~]24 hours after multiple sessions. DLPFC-targeted iTBS increased TGC, whereas PPC-iTBS had no measurable effect. Change in TGC was associated with change in WM, such that a decrease in TGC was associated with faster RT and decreased RT variability. Higher baseline TGC was associated with greater improvement in WM. Active iTBS decoupled the TGC-WM association observed during sham iTBS, and greater electric field intensity of iTBS was associated with greater improvement in WM accuracy and greater decrease in TGC.\n\nConclusionsActive iTBS to the left DLPFC modulated WM-related TGC in youth with ADHD. These findings provide preliminary evidence that neuromodulation may improve WW by modifying oscillatory dynamics within frontoparietal networks. Larger clinical trials with higher stimulation doses are needed to determine whether targeting oscillatory coupling represents a potential therapeutic strategy for WM deficits.\n\nTrial Registrations: NCT05102864; NCT05662280","rel_num_authors":14,"rel_authors":[{"author_name":"Brian Kavanaugh","author_inst":"Brown University Health\/Bradley Hospital"},{"author_name":"Megan Vigne","author_inst":"Butler Hospital"},{"author_name":"Christopher Legere","author_inst":"Bradley Hospital"},{"author_name":"Zachary Borden","author_inst":"Butler Hospital"},{"author_name":"Elena Lynott","author_inst":"Brown University"},{"author_name":"Daniel Cheong","author_inst":"Brown University"},{"author_name":"Alexa Warren","author_inst":"Connecticut College"},{"author_name":"W Luke Acuff","author_inst":"Butler Hospital"},{"author_name":"Eric Tirrell","author_inst":"Butler Hospital"},{"author_name":"Elena Festa","author_inst":"Brown University"},{"author_name":"Stephanie Jones","author_inst":"Brown University"},{"author_name":"Richard Jones","author_inst":"Brown University"},{"author_name":"Anthony Spirito","author_inst":"Brown University"},{"author_name":"Linda Carpenter","author_inst":"Butler Hospital"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Platform-Specific Safety of Pulsed Field Ablation for Atrial Fibrillation: A MAUDE Analysis","rel_doi":"10.64898\/2026.07.13.26358008","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26358008","rel_abs":"BackgroundThree pulsed-field ablation (PFA) systems are FDA-approved for atrial fibrillation (AF), yet whether their safety profiles differ from each other and from radiofrequency (RF) ablation has not been systematically characterized using real-world adverse event data. We compared platform-specific complication profiles across three FDA-approved PFA systems and contemporary RF catheters in MAUDE.\n\nMethodsWe analyzed 2,262 manually adjudicated MAUDE adverse event reports (760 PFA, 1,502 RF) through July 2025. Neurologic events underwent independent adjudication into five tiers by three auditors. Disproportionality was assessed using Reporting Odds Ratios (ROR) with Benjamini-Hochberg (BH) correction.\n\nResultsPooled PFA had significantly lower BH-adjusted ROR for tamponade (0.52, 95% CI 0.41-0.67) and esophageal injury (0.09, 0.01-0.66), consistent with a tissue-selective reporting profile across platforms. Platform-level analysis, however, revealed substantial heterogeneity: the stroke signal was driven by Varipulse (ROR 16.41, 8.61-31.28) and was not observed with Farapulse (ROR 1.26, NS). Pooled PFA had higher ROR for imaging-confirmed stroke (3.84, 2.27-6.49) and arrhythmia (2.57, 1.91-3.45). Coronary vasospasm (24 vs. 0 events) and hemolysis (15 vs. 1 events) were PFA-specific. Composite serious adverse events were similar. In a pre-specified extension period analysis (August-December 2025), the pooled PFA stroke signal attenuated to non-significance (ROR 1.60, 0.89-2.85), consistent with notoriety bias following the FDA Safety Communication.\n\nConclusionsPFA adverse-event reporting shows substantial platform heterogeneity across approved systems. Varipulse was associated with a disproportionate neurologic reporting signal, while all PFA platforms show tissue-selective reporting patterns relative to RF. These findings support platform-aware clinical decision-making and post-market surveillance.","rel_num_authors":4,"rel_authors":[{"author_name":"Ahsan Ullah","author_inst":"Rutgers New Jersey Medical School Division of Cardiology"},{"author_name":"Jose Fossas-Espinosa","author_inst":"Rutgers New Jersey Medical School Division of Cardiology"},{"author_name":"Luka Petrovic","author_inst":"Rutgers New Jersey Medical School Division of Cardiology"},{"author_name":"Emad Aziz","author_inst":"Rutgers University, New Jersey Medical School"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Orthogonal Contributions of Genetic, Clinical, and Social Determinants of Health Risk Burdens on Alzheimer's Disease Pathophysiology","rel_doi":"10.64898\/2026.07.07.26357509","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357509","rel_abs":"ImportanceAlzheimers disease (AD) arises from complex interactions among genetic, clinical, and social determinants of health (SDoH) risk factors, yet their independent contributions to underlying AD pathophysiology remain elusive.\n\nObjectiveTo quantify the effects of risk factors across amyloid (A{beta})\/tau, neurodegeneration, and cognition.\n\nDesignCross-sectional analysis using structural equation modeling (SEM).\n\nSettingHealth and Aging Brain Study-Health Disparities (HABS-HD), a community-based cohort study.\n\nParticipantsA total of 2,276 participants with demographics, genetic, clinical, and biomarker data from the baseline visit.\n\nExposuresAPOE {varepsilon}4 carrier status, AD polygenic risk score (AD-PRS), clinical risk score (CogDRisk), and a social determinants of health (SDoH) latent score derived using factor analysis.\n\nMain Outcomes and MeasuresLatent variables representing A{beta}\/tau pathology (plasma pTau181, plasma pTau217\/A{beta}42, amyloid PET positivity, and global standardized uptake value ratio), neurodegeneration (plasma neurofilament light, cortical thickness, hippocampal volume), and cognition (memory, executive, and language tests) were modeled and regressed on AD latent variables using SEM adjusted for age, sex, genetic principal components, and spoken language.\n\nResultsThe total analytic sample included 2,276 participants (mean age: 65.3 {+\/-} 8.7; non-Hispanic White: 43.0%, non-Hispanic Black: 16.2%, and Latinx\/Hispanic adults: 40.8%). APOE {varepsilon}4 was strongly associated with worse A{beta}\/tau latent variable ({beta}=0.31; p<0.001), with smaller but significant associations with neurodegeneration ({beta}=0.085; p<0.001) and cognition ({beta}=0.083; p<0.001). Higher AD-PRS was modestly associated with worse A{beta}\/tau ({beta}=0.075; p<0.01) but was not associated with neurodegeneration or cognition. A higher clinical risk score was significantly associated with worse neurodegeneration ({beta}=0.16; p<0.001) but not with A{beta}\/tau or cognition. Adverse SDoH was associated with worse neurodegeneration ({beta}=0.071; p<0.05) and strongly associated with worse cognition ({beta}=0.22; p<0.001), with no associations with A{beta}\/tau.\n\nConclusion and RelevanceGenetic risks were primarily associated with A{beta} and tau pathology, clinical risks with neurodegeneration, and SDoH risks with cognition, suggesting that risk factors exert differential effects on AD pathophysiology. Future studies investigating additional risk factors and their longitudinal associations with AD pathophysiological changes are warranted.\n\nKey PointsO_ST_ABSQuestionsC_ST_ABSDo Alzheimers disease (AD) risk factors differentially influence underlying AD pathophysiological processes, and do these associations vary across demographic subgroups?\n\nFindingsGenetic and genomic risk burdens demonstrated the strongest associations with amyloid and tau pathology; clinical risk burden with neurodegeneration; and adverse social determinants of health with cognition.\n\nMeaningBecause of the differential effects of risk factors on the underlying AD pathophysiology, a one-size-fits-all approach to AD risk prediction and prevention is insufficient. AD risk assessment should leverage multidomain frameworks incorporating genomic, clinical, and social determinants of health information to better inform disease development and progression.","rel_num_authors":8,"rel_authors":[{"author_name":"Meri S. Okorie","author_inst":"University of California, San Francisco"},{"author_name":"Xiaqing Jiang","author_inst":"University of California, San Francisco"},{"author_name":"Paulina Tolosa-Tort","author_inst":"University of California, San Francisco"},{"author_name":"Rakshya U Sharma","author_inst":"University of California, San Francisco"},{"author_name":"Alexandra L. Clark","author_inst":"University of Texas at Austin"},{"author_name":"Kristine Yaffe","author_inst":"University of California San Francisco"},{"author_name":"Jennifer S. Yokoyama","author_inst":"University of California, San Francisco"},{"author_name":"Shea J Andrews","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"PRANA: A Deep Learning Method for Adapting Polygenic Risk Scores to Diverse Ethnic Groups","rel_doi":"10.64898\/2026.07.12.26357860","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.12.26357860","rel_abs":"Polygenic risk scores (PRSs), which quantify inherited susceptibility to complex traits and diseases, have emerged as valuable tools for risk stratification and precision medicine. Despite their promise, PRS developed on European cohorts often demonstrate substantially reduced predictive accuracy in non-European populations, due to differences in genetic architecture. The disproportionate representation of European ancestry cohorts in genome-wide association studies (GWAS) leads to inequitable deployment of PRS technologies across diverse populations. Here, we introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework that adapts an existing PRS developed on one population to other ancestries. Unlike methods that require large-scale GWAS in the target population, PRANA leverages pre-trained PRS models derived from European cohorts and adapts them using modestly sized cohorts from the target population.\n\nWe evaluated PRANA on seven complex traits in South Asian, East Asian and Ashkenazi Jewish populations, as well as in selected smaller East Asian subpopulations where the scarcity of training data poses a particular challenge. PRANA mostly improved predictive performance of the baseline PRS models by 5%-20% in terms of effect size ({beta}) and Nagelkerkes R{superscript 2}, and, in most cases, outperformed existing cross-ancestry multi-PRS approaches. These results highlight PRANA as a scalable and practical strategy to reduce disparities in genomic risk prediction and advance the equitable application of PRS in diverse populations.","rel_num_authors":5,"rel_authors":[{"author_name":"Hagai Levi","author_inst":"Tel Aviv University"},{"author_name":"- The Breast Cancer Association Consortium","author_inst":""},{"author_name":"Kyriaki Michailidou","author_inst":"The Cyprus Institute of Neurology and Genetics"},{"author_name":"Ran Elkon","author_inst":"Tel Aviv University"},{"author_name":"Ron Shamir","author_inst":"Tel Aviv University"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Two-Year Evolution of a Prospective Audit and Feedback of an Antimicrobial Stewardship Program in a quaternary Intensive Care Unit in Ghana","rel_doi":"10.64898\/2026.07.11.26357812","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.11.26357812","rel_abs":"ObjectivesTo evaluate two-year, side-by-side outcomes of a prospective audit and feedback (PAF)-based antimicrobial stewardship program (ASP) in a quaternary ICU in Ghana, comparing diagnostic stewardship, antimicrobial prescribing patterns, and clinician adherence to stewardship recommendations between 2024 and 2025. Longitudinal PAF data from low- and middle-income countries (LMIC) quaternary ICUs are scarce; this study addresses that evidence gap.\n\nMethodsA retrospective comparative analysis of routine Antimicrobial Stewardship (AMS) surveillance data was conducted at the University of Ghana Medical Centre ICU: 102 visits in 2024 and 63 in 2025. Proportions were compared by chi-square or Fishers exact test; continuous variables by Mann-Whitney U. Wilson score 95% confidence intervals (CIs) were computed for primary proportions.\n\nResultsBiomarker-guided prescribing rose from 86.3% to 100% of visits (p=0.005) and culture and sensitivity testing from 74.5% to 90.5% (p=0.02). Targeted (culture-guided) therapy increased significantly from 23.5% to 41.7% of antibiotic recipients (p=0.03), while empiric prescribing declined correspondingly. Overall antibiotic utilization remained high in both years (96.1% vs 95.2%; p=1.00), and meropenem use rose from 42.9% to 56.7% (p=0.13). AMS interventions were recommended in 67.6% and 63.5% of visits, respectively. Clinician acceptance improved markedly from 40.6% (95% CI: 29.8-52.4%) to 67.5% (95% CI: 52.0-79.9%) (p=0.01).\n\nConclusionsTwo years of PAF in a Ghanaian quaternary ICU demonstrated progressive program maturation: universal biomarker adoption, a significant shift toward targeted prescribing, and markedly enhanced clinician acceptance. Persistently high antibiotic utilization and rising carbapenem dependence underscore the need for sustained surveillance and carbapenem-sparing strategies in LMIC critical care.","rel_num_authors":9,"rel_authors":[{"author_name":"Peter  Kwamina McCarthy","author_inst":"University of Ghana Medical Centre"},{"author_name":"Nana  Ama Buadiba Osei","author_inst":"University of Ghana Medical Centre"},{"author_name":"Daniel  Freeman Owusu Ansah","author_inst":"University of Ghana Medical Centre"},{"author_name":"Josephine Mensah","author_inst":"University of Ghana Medical Centre"},{"author_name":"Salomey  Asaah Denkyira","author_inst":"University of Ghana Medical Centre"},{"author_name":"Fareeda  Serwaa Brobbey","author_inst":"University of Ghana Medical Centre"},{"author_name":"Glennsa  Nana Abena Ohene","author_inst":"University of Ghana Medical Centre"},{"author_name":"Blessing  Boakye Yiadom","author_inst":"Greater Accra Regional Hospital"},{"author_name":"George  Boateng Kyei","author_inst":"Washington University In St Louis: Washington University in St Louis"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Comparing a trial of labour with planned caesarean after one previous caesarean delivery: a protocol for a population-based cohort study","rel_doi":"10.64898\/2026.07.12.26357849","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.12.26357849","rel_abs":"The caesarean section rate has risen. An increasing number of women who have had one previous caesarean section need to consider mode of delivery in a subsequent pregnancy. Both trial of labour after caesarean (TOLAC) and planned repeat caesarean section are associated with maternal and perinatal risks. We will undertake a retrospective cohort study of recorded livebirths for women who have had one previous caesarean section in the United States from 2011 to 2024. Using multivariable logistic regression, we will examine the relationship between the intended mode of delivery at 39 weeks gestational age (TOLAC at 39 weeks or any mode of delivery at 39 to 43 weeks versus caesarean section without trial of labour at 39 weeks) and important maternal and neonatal outcomes. We will also examine the relationship between TOLAC and caesarean section without a trial of labour for maternal outcomes at 20 to 43 weeks and for perinatal outcomes at 37 to 43 weeks. Due to the large data size, this study will be able to report on rare maternal and perinatal outcomes and contribute to evidence that influences important decisions about mode of delivery after one caesarean section.","rel_num_authors":9,"rel_authors":[{"author_name":"Romy Ehrlich","author_inst":"Royal Prince Alfred Hospital"},{"author_name":"Pejman Adily","author_inst":"Sydney Institute for Women, Children and their Families"},{"author_name":"Mark Lauer","author_inst":"Sydney Institute for Women, Children and their Families"},{"author_name":"Rajit Narayan","author_inst":"Royal Prince Alfred Hospital"},{"author_name":"Hala Phipps","author_inst":"Sydney Institute for Women, Children and their Families"},{"author_name":"Adam Mackie","author_inst":"Royal Prince Alfred Hospital"},{"author_name":"Vincenzo Berghella","author_inst":"Sydney Kimmel Medical College of Thomas Jefferson University"},{"author_name":"Adrienne Gordon","author_inst":"Reproduction and Perinatal Centre, Faculty of Medicine and Health, University of Sydney"},{"author_name":"Bradley de Vries","author_inst":"Royal Prince Alfred Hospital"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Statistical Analysis Plan (SAP) - DREAM: an adaptive, randomised, placebo-controlled trial of duloxetine for reducing leg pain in people with chronic sciatica","rel_doi":"10.64898\/2026.07.12.26357883","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.12.26357883","rel_abs":"2DREAM is a randomised, superiority, parallel-group, placebo-controlled, participant, clinician, and assessor blinded trial with an adaptive group sequential design that allows early stopping for efficacy or futility. The purpose is to investigate whether taking 60 mg of duloxetine daily for 12 weeks in addition to guideline-recommended advice, compared with placebo in addition to guideline-recommended advice, can reduce leg pain intensity in individuals with chronic sciatica.\n\nThe primary outcome is leg pain intensity measured on a 0-10 numerical pain rating scale. It will be analysed using a repeated-measures linear mixed model. This statistical analysis plan pre-specifies the methods of analysis to be used in the interim analysis and the final analysis for the outcomes and key variables collected in the trial. It includes planned sensitivity analyses for the final analysis, including covariate adjustments and subgroup analyses, as well as the health economics analysis plan.","rel_num_authors":18,"rel_authors":[{"author_name":"Xiaoqiu Liu","author_inst":"The George Institute for Global Health"},{"author_name":"Laurent Billot","author_inst":"The George Institute for Global Health"},{"author_name":"Anthony Devaux","author_inst":"The George Institute for Global Health"},{"author_name":"Christopher Maher","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney"},{"author_name":"Christine Lin","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney"},{"author_name":"Richard Day","author_inst":"St Vincent's Clinical School, Faculty of Medicine, University of New South Wales"},{"author_name":"Rowena Ivers","author_inst":"Graduate School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong"},{"author_name":"Martin Underwood","author_inst":"Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick"},{"author_name":"Andrew McLachlan","author_inst":"Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney"},{"author_name":"Bethan Richards","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney"},{"author_name":"Nanna Finnerup","author_inst":"Danish Pain Research Centre, Department of Clinical Medicine, Aarhus University"},{"author_name":"Cecilia Taing","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Kate Tong","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Masoud Jamshidi","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Maliha Hassan","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Melanie Hamilton","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Emily Atkins","author_inst":"The George Institute for Global Health"},{"author_name":"Giovanni Ferreira","author_inst":"The University of Sydney"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Statistical Analysis Plan (SAP) - DREAM: an adaptive, randomised, placebo-controlled trial of duloxetine for reducing leg pain in people with chronic sciatica","rel_doi":"10.64898\/2026.07.12.26357883","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.12.26357883","rel_abs":"2DREAM is a randomised, superiority, parallel-group, placebo-controlled, participant, clinician, and assessor blinded trial with an adaptive group sequential design that allows early stopping for efficacy or futility. The purpose is to investigate whether taking 60 mg of duloxetine daily for 12 weeks in addition to guideline-recommended advice, compared with placebo in addition to guideline-recommended advice, can reduce leg pain intensity in individuals with chronic sciatica.\n\nThe primary outcome is leg pain intensity measured on a 0-10 numerical pain rating scale. It will be analysed using a repeated-measures linear mixed model. This statistical analysis plan pre-specifies the methods of analysis to be used in the interim analysis and the final analysis for the outcomes and key variables collected in the trial. It includes planned sensitivity analyses for the final analysis, including covariate adjustments and subgroup analyses, as well as the health economics analysis plan.","rel_num_authors":18,"rel_authors":[{"author_name":"Xiaoqiu Liu","author_inst":"The George Institute for Global Health"},{"author_name":"Laurent Billot","author_inst":"The George Institute for Global Health"},{"author_name":"Anthony Devaux","author_inst":"The George Institute for Global Health"},{"author_name":"Christopher Maher","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney"},{"author_name":"Christine Lin","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney"},{"author_name":"Richard Day","author_inst":"St Vincent's Clinical School, Faculty of Medicine, University of New South Wales"},{"author_name":"Rowena Ivers","author_inst":"Graduate School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong"},{"author_name":"Martin Underwood","author_inst":"Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick"},{"author_name":"Andrew McLachlan","author_inst":"Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney"},{"author_name":"Bethan Richards","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney"},{"author_name":"Nanna Finnerup","author_inst":"Danish Pain Research Centre, Department of Clinical Medicine, Aarhus University"},{"author_name":"Cecilia Taing","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Kate Tong","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Masoud Jamshidi","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Maliha Hassan","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Melanie Hamilton","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Emily Atkins","author_inst":"The George Institute for Global Health"},{"author_name":"Giovanni Ferreira","author_inst":"The University of Sydney"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Multi-omic Profiling of Recurrence Risk Across Breast Cancer Subtypes","rel_doi":"10.64898\/2026.07.10.26357777","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357777","rel_abs":"Recurrence risk greatly varies across intrinsic subtypes in breast cancer, yet the molecular and immune programs within primary tumors that go on to develop recurrence remains poorly understood. We performed multi-omic analysis of 340 breast cancer tumors across Basal-like, Luminal A, and Luminal B subtypes to identify tumor-intrinsic and microenvironmental features associated with recurrence. Within each intrinsic subtype, we compared recurrent and non-recurrent tumors across RNA, copy-number, and pathway-level mutational features. Basal-like tumors in patients who developed recurrence were characterized by reduced lymphocytes and pro-inflammatory M1 macrophages, enrichment of TGF-{beta}\/EMT activity, copy number gains within 5p\/7p\/7q, 4q losses, and increased pathway tumor mutational burden (pTMB) in growth-factor, inflammatory, and motility-associated signaling pathways, each of which was associated with increased recurrence risk. In Luminal A tumors, recurrent cases showed higher lymphocytes and pro-inflammatory M1 macrophages, enrichment of metabolic, stress-response, and stemness\/plasticity associated pathways, and higher pTMB in growth-factor, inflammatory, motility-associated, DNA repair and apoptosis signaling pathways all associated with recurrence risk. Among Luminal B tumors, recurrent cases were enriched for proliferation, genomic instability, DNA repair, and stress-response pathways, showed a prominent 1q copy number amplification, and exhibited increased pTMB in Hedgehog signaling which increased recurrence risk. Subtype-specific prediction models were developed to generate recurrence-risk scores and validated using an external cohort (METABRIC; 1,170 total cases). The performance of our recurrence risk scores in METABRIC were associated with recurrence free survival (RFS) across subtypes (Basal: HR=1.27, 95% CI [1.07-1.50], p=0.006, Luminal A: HR=1.18, 95% CI [1.06-1.31], p=0.002, Luminal B: HR=1.41, 95% CI [1.03-1.93], p=0.03). Together, these findings demonstrate that primary tumors in patients who develop recurrence harbor distinct subtype-specific biological programs detectable at diagnosis and support a subtype-informed multi-omic modeling as a framework for recurrence-risk stratification.","rel_num_authors":4,"rel_authors":[{"author_name":"A. Eden Cruikshank","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Pooja Chandra","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Chistopher I Li","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Gavin Ha","author_inst":"Fred Hutchinson Cancer Research Center"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Comorbidity Exposure-Window Definitions and Multidimensional Disparities in Long COVID Risk: Evidence from a U.S. National Cohort (2020-2024)","rel_doi":"10.64898\/2026.07.11.26357794","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.11.26357794","rel_abs":"Long COVID (LC) affects millions of individuals worldwide, particularly those with preexisting comorbidities. However, whether these comorbidities should be defined before SARS-CoV-2 infection or before LC diagnosis remains unresolved, and this methodological choice may substantially bias estimates of comorbidity-associated LC risk. In addition, most previous studies were conducted during earlier phases of the pandemic and relied on relatively small or geographically restricted cohorts, limiting understanding of temporal trends and population disparities in LC risk. Leveraging Electronic Health Records (EHR) from 6,130,413 adults with documented COVID-19 across 49 U.S. states in the National COVID Cohort Collaborative (N3C) from 2020 to 2024, we evaluated the impact of different comorbidity exposure-window definitions on LC risk estimation. We utilized ensemble cross-fitted double\/debiased machine learning to adjust for complex individual- and county-level confounders. Across the 16 major comorbidities evaluated, defining conditions before SARS-CoV-2 infection, rather than before LC diagnosis, yielded 23%-115% higher adjusted attributable risks and 6%-37% higher adjusted relative risks. Additionally, comorbidity-associated risks generally declined from 2020 to 2024, with substantial demographic, socioeconomic, geographic, and multimorbidity-related disparities persisting throughout the study period. These findings identify temporal exposure-window specification as a major source of bias in LC epidemiology. Failure to distinguish preexisting comorbidities from conditions identified during postinfection follow-up can substantially alter estimates of disease burden, the identification of high-risk populations, and the interpretation of temporal and geographic disparities. More broadly, our results highlight how temporal misclassification of exposures in longitudinal EHR studies can distort risk attribution and population-level inference.","rel_num_authors":12,"rel_authors":[{"author_name":"Yewen Chen PhD","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Zhetao Chen MS","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Ge Yang PhD","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Bingnan Li MS","author_inst":"Department of Statistics, Franklin College of Arts and Science, University of Georgia, Athens, GA, USA"},{"author_name":"Kehinde Olawale Ogunyemi MD","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Jialing Liu MS","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Fangzhi Luo MS","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Yuan Ke PhD","author_inst":"Department of Statistics, Franklin College of Arts and Science, University of Georgia, Athens, GA, USA"},{"author_name":"Leonardo Martinez PhD","author_inst":"Division of Epidemiology, School of Public Health, University of California, Berkeley, USA"},{"author_name":"Xianyan Chen PhD","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Janani Rajbhandari PhD","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Ye Shen PhD","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"PAUSE-Agents: A Clinician-in-the-Loop Multi-Agent AI Pipeline for ICU-to-Ward Handoff Briefs","rel_doi":"10.64898\/2026.07.10.26357759","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357759","rel_abs":"ICU-to-ward transfers are high-risk transitions marked by information loss and burdensome handoff preparation. We developed PAUSE-Agents, a clinician-in-the-loop multi-agent LLM pipeline that drafts source-attributed handoff briefs from structured ICU data and clinical notes using the clinician-developed ICU-PAUSE template. Mirroring ICU team structure, PAUSE-Agents routes each record through a scribe extractor, 6 role-specialized agents, explicit conflict surfacing, and deterministic safety checks before synthesis, producing an editable first draft rather than an autonomous note. In a single-center medical ICU cohort, 5 physicians completed 100 reviews of 84 agent-drafted briefs. Among adjudicable claims, 98.8% were verified and 1.2% were incorrect; 88% of briefs had no pertinent omission, and mean PDSQI-9 quality was 4.20\/5. PAUSE-Agents surfaced 118 conflict warnings and 421 safety flags, making documentation inconsistencies visible before handoff. An o4-mini PDSQI-9 judge showed limited case-level discrimination but supported aggregate monitoring. We release PAUSE-Agents and its clinician evaluation application.","rel_num_authors":15,"rel_authors":[{"author_name":"Saki Amagai","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Wan-Ting Liao","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Caleb Murphy","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Courtney Reamer","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Yupeng Liu","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Bhavana Ambil","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Glenn Fernandes","author_inst":"Northwestern University"},{"author_name":"Lekshmi Santhosh","author_inst":"University of California, San Francisco"},{"author_name":"Patrick Lyons","author_inst":"Oregon Health & Science University School of Medicine"},{"author_name":"Neil Jordan","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"David Liebovitz","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Adrienne Kline","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Juan C Rojas","author_inst":"Rush University"},{"author_name":"Yuan Luo","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Catherine Gao","author_inst":"Northwestern University Feinberg School of Medicine"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"PAUSE-Agents: A Clinician-in-the-Loop Multi-Agent AI Pipeline for ICU-to-Ward Handoff Briefs","rel_doi":"10.64898\/2026.07.10.26357759","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357759","rel_abs":"ICU-to-ward transfers are high-risk transitions marked by information loss and burdensome handoff preparation. We developed PAUSE-Agents, a clinician-in-the-loop multi-agent LLM pipeline that drafts source-attributed handoff briefs from structured ICU data and clinical notes using the clinician-developed ICU-PAUSE template. Mirroring ICU team structure, PAUSE-Agents routes each record through a scribe extractor, 6 role-specialized agents, explicit conflict surfacing, and deterministic safety checks before synthesis, producing an editable first draft rather than an autonomous note. In a single-center medical ICU cohort, 5 physicians completed 100 reviews of 84 agent-drafted briefs. Among adjudicable claims, 98.8% were verified and 1.2% were incorrect; 88% of briefs had no pertinent omission, and mean PDSQI-9 quality was 4.20\/5. PAUSE-Agents surfaced 118 conflict warnings and 421 safety flags, making documentation inconsistencies visible before handoff. An o4-mini PDSQI-9 judge showed limited case-level discrimination but supported aggregate monitoring. We release PAUSE-Agents and its clinician evaluation application.","rel_num_authors":15,"rel_authors":[{"author_name":"Saki Amagai","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Wan-Ting Liao","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Caleb Murphy","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Courtney Reamer","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Yupeng Liu","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Bhavana Ambil","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Glenn Fernandes","author_inst":"Northwestern University"},{"author_name":"Lekshmi Santhosh","author_inst":"University of California, San Francisco"},{"author_name":"Patrick Lyons","author_inst":"Oregon Health & Science University School of Medicine"},{"author_name":"Neil Jordan","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"David Liebovitz","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Adrienne Kline","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Juan C Rojas","author_inst":"Rush University"},{"author_name":"Yuan Luo","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Catherine Gao","author_inst":"Northwestern University Feinberg School of Medicine"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Autonomous Agents for Auditable Cardiovascular Artificial Intelligence Development","rel_doi":"10.64898\/2026.07.10.26357656","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357656","rel_abs":"Clinical artificial intelligence (AI) models are usually reported as finished artifacts, but each model reflects a limited human search across a much larger space of architectures, inputs, losses, optimizers, and training recipes. We tested whether autonomous code-writing agents could perform a controlled model-development experiment: proposing and evaluating code changes, and seeking performance gains without new data or human-guided edits. We built two such agents: an Iteration Agent that searches sequentially, keeping the best variant at each step, and an Evolution Agent that searches for variations in parallel using multiple large language models and prioritizes high-performing lineages across generations. In two architecturally distinct AI-enhanced electrocardiography (AI-ECG) models for structural heart disease, agent-optimized variants improved rank discrimination across held-out, external, and cross-institution evaluations, with area under the receiver operating characteristic curve gains of +0.006 to +0.039 (paired p < 0.05). At a fixed 90% sensitivity, specificity rose by up to 7.1 percentage points and positive predictive value by up to 4.8 percentage points. The selected code changes were substantive, spanning architecture, representation, and training recipe variations. These findings position autonomous agents as an auditable layer for clinical AI model improvement, provided that candidate selection, external validation, and post-update governance are explicit. We release these agents as an open, reusable toolkit.","rel_num_authors":6,"rel_authors":[{"author_name":"Lovedeep Singh Dhingra","author_inst":"Yale School of Medicine"},{"author_name":"Bruno Batinica","author_inst":"Yale University"},{"author_name":"Ryan B Choi","author_inst":"Yale School of Medicine"},{"author_name":"Philip M Croon","author_inst":"Yale School of Medicine"},{"author_name":"Evangelos K Oikonomou","author_inst":"Yale School of Medicine"},{"author_name":"Rohan Khera","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-14","rel_site":"medrxiv"}]}