{"gname":"University of Geneva","grp_id":"26","rels":[{"rel_title":"Access Consequences of Restricting Mohs Micrographic Surgery to Fellowship-Trained Surgeons: A National Workforce, Board-Certification, and Drive-Time Simulation Study","rel_doi":"10.64898\/2026.09.12.26362922","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.12.26362922","rel_abs":"Background: Policies restricting Mohs micrographic surgery (MMS) to only fellowship-trained (FT) surgeons -- through privileging standards, laboratory-director qualifications, or payer credentialing -- would bar residency\/practice-trained (R\/P-trained) surgeons from MMS. The access consequences have not been quantified. Objective: To quantify the workforce, board-certification, geographic, and patient-access consequences of restricting MMS to only fellowship-trained surgeons. Methods: Cross-sectional analysis of all Medicare MMS billers (2020-2024; n=3,451), classified FT versus R\/P-trained by complete ACMS directory linkage (the definition of prior national analyses; audited); linkage to American Board of Dermatology Micrographic Dermatologic Surgery (MDS) certification records; county\/market access classes; road-network drive-time simulation of R\/P-trained exclusion against CMS network-adequacy standards; fellowship-pipeline replacement modeling. Results: R\/P-trained surgeons were 45.3% of the 2024 workforce, 55.6% held MDS certification, and they supplied 52.1% of nonmetropolitan MMS volume. In 223 counties (23.4 million residents) they were the only Mohs surgeons. Simulated exclusion pushed 15.6 million more people beyond 60 minutes' drive and 23.1 million out of CMS dermatology time-and-distance standards, disproportionately rural (3.2x). Pipeline replacement of rural capacity would require approximately 21 years. Absorbing the displaced volume (353,736 Medicare cases\/year, 88% metropolitan) would require surviving surgeons to raise volume by 45.5%; even if every surviving surgeon took on 20% more cases, 211,848 cases\/year would have no slot, and at 50% more, when national capacity would suffice, 94,982 would still remain beyond the reach of any surgeon with room because of the workforce's geographic distribution -- implying longer waits and stranded patients in metropolitan and rural areas alike. All findings were robust to the audited misclassification error of the training-pathway definition. Limitations: Medicare fee-for-service claims; directory-based training-pathway classification, audited and adjusted. Conclusion: A fellowship-only restriction -- for example, a fellowship-gated qualification for directing the laboratories in which Mohs frozen sections are examined -- would bar R\/P-trained surgeons from directing the Mohs laboratories where they operate and would produce large, geographically concentrated access losses, borne disproportionately by rural America, without demonstrated quality benefit. Workforce policy should instead expand every route into Mohs surgery -- more fellowship positions, stronger Mohs training within dermatology residency, practice-based training that certifying boards and payers continue to recognize, and a reopened practice pathway to MDS certification -- while keeping regulatory eligibility keyed to primary dermatology board certification, which both pathways share.","rel_num_authors":4,"rel_authors":[{"author_name":"Henry Jeon","author_inst":"Corewell Trenton Dermatology Residency, Trenton, Michigan"},{"author_name":"Mary E. Logue","author_inst":"Department of Dermatology, University of New Mexico, Albuquerque, New Mexico; Monument Health Dermatology, Spearfish, South Dakota"},{"author_name":"George Murakawa","author_inst":"Somerset Skin Centre and Derm Center, Troy, Michigan; Department of Internal Medicine, Michigan State University, East Lansing, Michigan"},{"author_name":"Kenneth K. Yu","author_inst":"Plymouth Dermatology Associates, Plymouth, Massachusetts; Division of Dermatology, Department of Medicine, Cambridge Health Alliance, Cambridge, Massachusetts; "}],"rel_date":"2026-09-14","rel_site":"medrxiv"},{"rel_title":"Career Intentions and Research-Environment Factors Across the Physician-Scientist Pipeline","rel_doi":"10.64898\/2026.09.12.26362877","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.12.26362877","rel_abs":"Importance: Physician-scientist careers depend on sustained research funding, protected time, and institutional resources. However, data on career-retention attitudes across career stages are limited. Objective: To characterize career intentions and associated research-environment factors among MD-PhD students and early-career physician-scientists. Design: Two independent, national cross-sectional surveys were conducted during nonoverlapping periods in 2025; MD-PhD applicant and matriculant trends were also examined. Setting: Medical schools and academic health centers in the United States. Participants: MD-PhD students and early-career physician-scientists (ECPS). Exposures: MD-PhD exposures included perceived institutional support, training-related mental health impact, and research disruption. ECPS exposures included institutional support, adverse funding-related wellbeing, and direct National Institutes of Health funding-process disruption. Main Outcome and Measures: Primary outcomes were consideration of leaving the physician-scientist pathway among MD-PhD students and consideration of leaving academic medicine or research among ECPS. Secondary outcomes included likelihood of staying in academic medicine, research-intensive career preference, and consideration for leaving the US to continue research. Results: Among MD-PhD programs confirmed to have distributed the survey, 838 student responses were received (estimated response rate of 19.3%); 175 ECPS responses were received, with no calculable individual-level response rate. Among MD-PhD students, 423 of 835 (50.7%) reported considering leaving the physician-scientist pathway; 712 of 837 (85.1%) reported a high likelihood of remaining in academic medicine, and 664 of 836 (79.4%) preferred a research-intensive career. Adequate institutional support was associated with lower odds of considering leaving (adjusted odds ratio [aOR], 0.28; 95% CI, 0.14-0.54) and higher odds of staying in academic medicine (aOR, 5.65; 95% CI, 2.91-10.98). Training-related mental health impact (aOR, 2.34; 95% CI, 1.72-3.19) and research disruption (aOR, 1.83; 95% CI, 1.35-2.48) were associated with greater odds of considering leaving. Among ECPS, 57.7% considered leaving, 52.6% reported a high likelihood of staying, and 42.9% considered leaving the United States to continue research. Adverse funding-related well-being was associated with considering leaving academic medicine (aOR, 3.13; 95% CI, 1.52-6.63) and leaving the United States to continue research (aOR, 5.29; 95% CI, 2.35-13.12). Conclusions and Relevance: Consideration of leaving was common despite continued interest in academic and research-intensive careers. Institutional support, adverse well-being, and research disruptions were associated with career intentions.","rel_num_authors":18,"rel_authors":[{"author_name":"Sanaea Z Bhagwagar","author_inst":"MD-PhD Program, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Abdelrahman Abushouk","author_inst":"Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"John Dempsey","author_inst":"Norton College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Daniel C Brock","author_inst":"Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Aleksandar Obradovic","author_inst":"Department of Medicine, Columbia University, New York, NY, USA"},{"author_name":"Alisha Faraz","author_inst":"Khan Lab school, Mountain View, CA, USA"},{"author_name":"James L Cross","author_inst":"Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Aisha Siebert","author_inst":"Department of Pediatric Urology and Medical Genetics & Genomics, Boston Children's Hospital, Boston, MA, USA"},{"author_name":"Han Naung Tun","author_inst":"Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, USA"},{"author_name":"Kevin M Lin","author_inst":"MD-PhD Program, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Elena M Wilson","author_inst":"Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, USA"},{"author_name":"Cynthia Y Tang","author_inst":"Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA"},{"author_name":"Auyon Ghosh","author_inst":"Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Mytien Nguyen","author_inst":"Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, USA"},{"author_name":"Alokkumar Jha","author_inst":"Weill Cornell Medicine, New York, NY USA"},{"author_name":"Daniel Shalev","author_inst":"Division of Geriatrics and Palliative Medicine, Weill Cornell Medicine, New York, New York, USA"},{"author_name":"Evan Noch","author_inst":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Jennifer M Kwan","author_inst":"Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT, USA"}],"rel_date":"2026-09-14","rel_site":"medrxiv"},{"rel_title":"Career Intentions and Research-Environment Factors Across the Physician-Scientist Pipeline","rel_doi":"10.64898\/2026.09.12.26362877","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.12.26362877","rel_abs":"Importance: Physician-scientist careers depend on sustained research funding, protected time, and institutional resources. However, data on career-retention attitudes across career stages are limited. Objective: To characterize career intentions and associated research-environment factors among MD-PhD students and early-career physician-scientists. Design: Two independent, national cross-sectional surveys were conducted during nonoverlapping periods in 2025; MD-PhD applicant and matriculant trends were also examined. Setting: Medical schools and academic health centers in the United States. Participants: MD-PhD students and early-career physician-scientists (ECPS). Exposures: MD-PhD exposures included perceived institutional support, training-related mental health impact, and research disruption. ECPS exposures included institutional support, adverse funding-related wellbeing, and direct National Institutes of Health funding-process disruption. Main Outcome and Measures: Primary outcomes were consideration of leaving the physician-scientist pathway among MD-PhD students and consideration of leaving academic medicine or research among ECPS. Secondary outcomes included likelihood of staying in academic medicine, research-intensive career preference, and consideration for leaving the US to continue research. Results: Among MD-PhD programs confirmed to have distributed the survey, 838 student responses were received (estimated response rate of 19.3%); 175 ECPS responses were received, with no calculable individual-level response rate. Among MD-PhD students, 423 of 835 (50.7%) reported considering leaving the physician-scientist pathway; 712 of 837 (85.1%) reported a high likelihood of remaining in academic medicine, and 664 of 836 (79.4%) preferred a research-intensive career. Adequate institutional support was associated with lower odds of considering leaving (adjusted odds ratio [aOR], 0.28; 95% CI, 0.14-0.54) and higher odds of staying in academic medicine (aOR, 5.65; 95% CI, 2.91-10.98). Training-related mental health impact (aOR, 2.34; 95% CI, 1.72-3.19) and research disruption (aOR, 1.83; 95% CI, 1.35-2.48) were associated with greater odds of considering leaving. Among ECPS, 57.7% considered leaving, 52.6% reported a high likelihood of staying, and 42.9% considered leaving the United States to continue research. Adverse funding-related well-being was associated with considering leaving academic medicine (aOR, 3.13; 95% CI, 1.52-6.63) and leaving the United States to continue research (aOR, 5.29; 95% CI, 2.35-13.12). Conclusions and Relevance: Consideration of leaving was common despite continued interest in academic and research-intensive careers. Institutional support, adverse well-being, and research disruptions were associated with career intentions.","rel_num_authors":18,"rel_authors":[{"author_name":"Sanaea Z Bhagwagar","author_inst":"MD-PhD Program, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Abdelrahman Abushouk","author_inst":"Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"John Dempsey","author_inst":"Norton College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Daniel C Brock","author_inst":"Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Aleksandar Obradovic","author_inst":"Department of Medicine, Columbia University, New York, NY, USA"},{"author_name":"Alisha Faraz","author_inst":"Khan Lab school, Mountain View, CA, USA"},{"author_name":"James L Cross","author_inst":"Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Aisha Siebert","author_inst":"Department of Pediatric Urology and Medical Genetics & Genomics, Boston Children's Hospital, Boston, MA, USA"},{"author_name":"Han Naung Tun","author_inst":"Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, USA"},{"author_name":"Kevin M Lin","author_inst":"MD-PhD Program, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Elena M Wilson","author_inst":"Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, USA"},{"author_name":"Cynthia Y Tang","author_inst":"Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA"},{"author_name":"Auyon Ghosh","author_inst":"Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Mytien Nguyen","author_inst":"Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, USA"},{"author_name":"Alokkumar Jha","author_inst":"Weill Cornell Medicine, New York, NY USA"},{"author_name":"Daniel Shalev","author_inst":"Division of Geriatrics and Palliative Medicine, Weill Cornell Medicine, New York, New York, USA"},{"author_name":"Evan Noch","author_inst":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Jennifer M Kwan","author_inst":"Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT, USA"}],"rel_date":"2026-09-14","rel_site":"medrxiv"},{"rel_title":"Dosimetric Impact of Residual Intrafraction Motion in Gated MR-Guided Prostate SBRT With Focal Dose Intensification","rel_doi":"10.64898\/2026.09.11.26362864","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362864","rel_abs":"Purpose: To quantify the dosimetric effect of residual intrafraction motion during gated MR-guided prostate stereotactic body radiotherapy with simultaneous integrated boost to the dominant intraprostatic lesion, and to derive and evaluate target-specific, population-based margins designed to mitigate motion-induced coverage loss. Materials and Methods: Thirty patients were treated on a 1.5-T MR-Linac with 36.25, 40, and 45 Gy prescribed to the planning target volume, clinical target volume (CTV), and gross tumor volume (GTV), in 5 fractions. Across 150 fractions, segment-level dose matrices synchronized with time-resolved target displacements were combined to reconstruct per-fraction and cumulative dose. Directional prescription-isodose deviations were used to derive internal target volume margins, which were evaluated through offline replanning, gating-envelope analysis, and dose reconstruction. Results: Median 95th-percentile motion ranges were 0.5, 1.4, and 2.9 mm in the left-right, anterior-posterior, and superior-inferior directions; these exceeded 3 mm in 0.7%, 13.2%, and 47.7% of fractions, respectively. The median treatment time was 13.2 min (IQR, 12.0-15.1 min) with a median gating duty cycle of 93.2% (80.6%-97.8%). Per-fraction median GTV deviations were -1.2% (-2.4% to -0.1%) for D95 and -5.6% (-15.3% to -0.2%) for V45Gy; corresponding CTV deviations were -0.5% (-1.1% to -0.1%) and -2.1% (-4.1% to -0.4%). Cohort-derived margins of 2\/2\/1\/2\/1\/2 mm for the GTV and 1\/1\/1\/2\/1\/2 mm for the CTV in the left\/right\/anterior\/posterior\/superior\/inferior directions achieved sufficient coverage in approximately 94% of fractions in each direction. Gated delivery using the proposed margins improved coverage but may reduce duty cycle by an average of 6.9 +\/- 4.7 %. Conclusion: Residual intrafraction motion produced directionally asymmetric coverage loss, with the largest effect on the boosted GTV. Motion-inclusive dose reconstruction enabled derivation of practical asymmetric margins that improved robustness while identifying the tradeoff between target coverage and delivery efficiency.","rel_num_authors":20,"rel_authors":[{"author_name":"Ka Ho Tam","author_inst":"MD Anderson Cancer Center, University of Texas"},{"author_name":"Sandeep Jogi","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Angela Sobremonte","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Jared D. Ohrt","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Dong Joo Rhee","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Jinzhong Yang","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Yao Ding","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Kristy K. Brock","author_inst":"Departments of Radiation Physics and Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Peter A. Balter","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Comron J. Hassanzadeh","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Michael Kevin Rooney","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Seungtaek Choi","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Ryan Jin-hyung Park","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Chad Tang","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Krishnan R. Patel","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Steven Jay Frank","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Phuoc T. Tran","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Daniel E. Hyer","author_inst":"Department of Radiation Oncology, University of Iowa Health Care, Iowa City, IA, USA"},{"author_name":"Neelam Tyagi","author_inst":"Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Ergys D. Subashi","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"rel_date":"2026-09-14","rel_site":"medrxiv"},{"rel_title":"P5 promoter-mediated incorporation explains REP\/CAP manufacturing contaminants in patient liver after rAAV gene therapy","rel_doi":"10.64898\/2026.09.10.26362787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362787","rel_abs":"Sequencing of liver tissue from a patient treated with the rAAV gene therapy Zolgensma for spinal muscular atrophy recently revealed contaminating plasmid sequences derived from rAAV manufacturing within the patient's hepatocytes. In particular, REP\/CAP-derived sequences were remarkably abundant, corresponding to 0.5-1% of the therapeutic transgene. We hypothesized that these contaminants originated through Rep-mediated incorporation initiated at the AAV P5 promoter. Through reanalysis of the sequencing data, we inferred that an intact P5 promoter had been placed directly downstream of the rAAV capsid gene in the manufacturing plasmid. De novo assembly revealed a contiguous contaminant sequence spanning the rAAV REP and CAP genes and terminating within P5 at the Rep nicking site, immediately downstream of the Rep-binding element (RBE). This analysis also revealed a distinct vector-plasmid backbone contig consistent with reverse packaging. Among partially aligned REP\/CAP reads, nearly 17% were linked to rAAV ITR-derived sequence at heterogeneous junctions. Long-read data independently identified the P5 promoter as the most frequent recombination breakpoint region. Together, these findings identify a defined, avoidable mechanism by which REP\/CAP manufacturing contaminants arise. Positioning of the P5 promoter within the manufacturing plasmid is therefore a modifiable determinant of rAAV product purity and the transfer of rAAV DNA contaminants to recipient patients.","rel_num_authors":6,"rel_authors":[{"author_name":"Mark A. Brimble","author_inst":"Washington University School of Medicine"},{"author_name":"Shaoyuan Tan","author_inst":"St. Jude Children's Research Hospital"},{"author_name":"Sarah Buddle","author_inst":"Great Ormond Street Hospital for Children NHS Foundation Trust"},{"author_name":"Li-An K. Brown","author_inst":"University College London"},{"author_name":"Judith Breuer","author_inst":"University College London"},{"author_name":"Jeremy Chase Crawford","author_inst":"St. Jude Children's Research Hospital"}],"rel_date":"2026-09-14","rel_site":"medrxiv"},{"rel_title":"Multistate Enzyme Design Enables Efficient and Stereoselective Multistep Catalysis","rel_doi":"10.64898\/2026.09.11.750617","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.750617","rel_abs":"Enzymes catalyze multistep reactions by stabilizing successive transition states within well organized, yet dynamic active sites. However, computational enzyme design typically targets a single transition state using rigid active-site models. Here, we introduce multistate enzyme design, which uses conformational ensembles to optimize active sites across an entire reaction coordinate. Applied to a de novo Morita--Baylis--Hillmanase, multistate enzyme design outperformed conventional single-state design, with the most active variant achieving >100-fold higher bi-substrate catalytic efficiency and surpassing an extensively optimized enzyme from directed evolution in both efficiency and enantioselectivity. Structural and kinetic analyses revealed that multistate design preserved catalytic preorganization and conformational plasticity, distributed stabilization across the reaction coordinate and avoided kinetic bottlenecks created by single-state optimization. By contrast, single-state design compromised preorganization, destabilized upstream states and shifted rate limitation away from the targeted transition state. Multistate enzyme design provides a framework for designing catalytic landscapes rather than static active sites, opening a route to efficient de novo enzymes for complex multistep chemistry.","rel_num_authors":13,"rel_authors":[{"author_name":"N. T. Hang Pham","author_inst":"University of Ottawa"},{"author_name":"Rui Guo","author_inst":"University of Ottawa"},{"author_name":"Rosalinda P Garcia Jimenez","author_inst":"University of California, Merced"},{"author_name":"Amy E Hutton","author_inst":"University of Manchester"},{"author_name":"Linus O Johannissen","author_inst":"University of Manchester"},{"author_name":"Johann A Wehrstedt","author_inst":"University of Ottawa"},{"author_name":"Behnoush Seifinoferest","author_inst":"University of California, Merced"},{"author_name":"Zachary Birch-Price","author_inst":"University of Manchester"},{"author_name":"Jordan Berreur","author_inst":"University of Manchester"},{"author_name":"Sam Hay","author_inst":"University of Manchester"},{"author_name":"Michael C Thompson","author_inst":"University of California, Merced"},{"author_name":"Anthony P Green","author_inst":"University of Manchester"},{"author_name":"Roberto A Chica","author_inst":"University of Ottawa"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Multistate Enzyme Design Enables Efficient and Stereoselective Multistep Catalysis","rel_doi":"10.64898\/2026.09.11.750617","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.750617","rel_abs":"Enzymes catalyze multistep reactions by stabilizing successive transition states within well organized, yet dynamic active sites. However, computational enzyme design typically targets a single transition state using rigid active-site models. Here, we introduce multistate enzyme design, which uses conformational ensembles to optimize active sites across an entire reaction coordinate. Applied to a de novo Morita--Baylis--Hillmanase, multistate enzyme design outperformed conventional single-state design, with the most active variant achieving >100-fold higher bi-substrate catalytic efficiency and surpassing an extensively optimized enzyme from directed evolution in both efficiency and enantioselectivity. Structural and kinetic analyses revealed that multistate design preserved catalytic preorganization and conformational plasticity, distributed stabilization across the reaction coordinate and avoided kinetic bottlenecks created by single-state optimization. By contrast, single-state design compromised preorganization, destabilized upstream states and shifted rate limitation away from the targeted transition state. Multistate enzyme design provides a framework for designing catalytic landscapes rather than static active sites, opening a route to efficient de novo enzymes for complex multistep chemistry.","rel_num_authors":13,"rel_authors":[{"author_name":"N. T. Hang Pham","author_inst":"University of Ottawa"},{"author_name":"Rui Guo","author_inst":"University of Ottawa"},{"author_name":"Rosalinda P Garcia Jimenez","author_inst":"University of California, Merced"},{"author_name":"Amy E Hutton","author_inst":"University of Manchester"},{"author_name":"Linus O Johannissen","author_inst":"University of Manchester"},{"author_name":"Johann A Wehrstedt","author_inst":"University of Ottawa"},{"author_name":"Behnoush Seifinoferest","author_inst":"University of California, Merced"},{"author_name":"Zachary Birch-Price","author_inst":"University of Manchester"},{"author_name":"Jordan Berreur","author_inst":"University of Manchester"},{"author_name":"Sam Hay","author_inst":"University of Manchester"},{"author_name":"Michael C Thompson","author_inst":"University of California, Merced"},{"author_name":"Anthony P Green","author_inst":"University of Manchester"},{"author_name":"Roberto A Chica","author_inst":"University of Ottawa"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Antibody evasion and receptor binding of SARS-CoV-2 RW.1.1","rel_doi":"10.64898\/2026.09.10.750645","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.10.750645","rel_abs":"The continued evolution of SARS-CoV-2 is shaped by changes in antibody evasion and receptor engagement that influence viral fitness. RW.1.1, an emerging descendant of XFJ carrying five additional spike substitutions, has recently increased in frequency in North America. Here, we characterized the serum antibody evasion, monoclonal antibody sensitivity, and ACE2 receptor engagement of RW.1.1. Pseudovirus neutralization assays using sera from adults showed that RW.1.1 was not more resistant to serum neutralization than currently circulating variants, with neutralizing titers comparable to XFG, BA.3.2.2, and NB.1.8.1 in the tested cohort. Neutralization of RW.1.1 also did not differ significantly among adults, children, and infants and toddlers. Despite the absence of increased overall serum antibody resistance, monoclonal antibody neutralization assays revealed substantial resistance to several RBD class 1 antibodies and increased resistance to a subset of class 1\/4 antibodies. Moreover, RW.1.1 exhibited reduced ACE2 receptor engagement compared with XFG, which itself has reduced receptor engagement relative to earlier JN.1 subvariants. Thus, RW.1.1 has continued to expand despite a further reduction in receptor engagement and without a substantial increase in overall serum antibody evasion. These findings suggest that the fitness of emerging SARS-CoV-2 variants may depend not only on the magnitude of antibody evasion but also on the specific components of the polyclonal antibody response that are evaded, highlighting the increasingly complex interplay between population immunity and receptor engagement in shaping SARS-CoV-2 evolution.","rel_num_authors":7,"rel_authors":[{"author_name":"Kristin Daniel","author_inst":"Columbia University"},{"author_name":"Hsiang Hong","author_inst":"Columbia University"},{"author_name":"Chien-Yu Huang","author_inst":"Columbia University"},{"author_name":"Aubree Gordon","author_inst":"University of Michigan"},{"author_name":"Yicheng Guo","author_inst":"Columbia University"},{"author_name":"David D Ho","author_inst":"Columbia University"},{"author_name":"Ian A Mellis","author_inst":"Columbia University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Reinforcement learning discovers new mechanisms of reentry in excitable media","rel_doi":"10.64898\/2026.09.08.750287","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750287","rel_abs":"The transition from transient excitation to sustained reentry is a fundamental problem in the physics of excitable media. In cardiac tissue, reentry underlies many life-threatening cardiac arrhythmias, yet the pathway to initiation of reentry remains incompletely understood. Here, we formulate reentry initiation as a reinforcement-learning problem in which an agent applies sequences of spatial stimulation patterns while being rewarded for sustained activity and penalized according to the number of stimuli applied. Using cellular automata in one-, two-, and three-dimensional geometries, the agent discovered several mechanisms for generating unidirectional propagation and reentry. These included a previously described mechanism combining superthreshold and subthreshold stimulation, as well as two new mechanisms based entirely on subthreshold stimuli: a sequential mechanism involving stimuli delivered at different locations and times, and a spatial mechanism in which several individually subthreshold sites collectively initiated reentry. In geometries containing boundaries and branches, the learned protocols additionally exploited structural source-sink asymmetries. Optogenetic experiments in cardiac monolayers further demonstrated reproducible induction of unidirectional propagation using the learned spatial subthreshold patterns, while whole-heart experiments provided preliminary evidence that such patterns can shape early propagation in intact tissue. More broadly, we show that reinforcement learning provides a general framework for discovering mechanisms of reentry in arbitrary geometries and generating testable hypotheses about reentry initiation in excitable systems.","rel_num_authors":8,"rel_authors":[{"author_name":"Thomas M Bury","author_inst":"University of California, Riverside"},{"author_name":"Glisant Plasa","author_inst":"McGill University"},{"author_name":"Jose Miguel Romero Sepulveda","author_inst":"McGill University"},{"author_name":"Nicolas Masse","author_inst":"The University of Chicago"},{"author_name":"Valentina Romanelli","author_inst":"University of Florence"},{"author_name":"Leonardo Sacconi","author_inst":"IFC-CNR"},{"author_name":"Emilia Entcheva","author_inst":"George Washington University"},{"author_name":"Gil Bub","author_inst":"McGill University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"LucaCell: a sequence-centric foundation model for cross-species single-cell analysis","rel_doi":"10.64898\/2026.09.08.750024","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750024","rel_abs":"Single-cell foundation models have transformed transcriptomic analysis, yet most rely on fixed gene identifiers that limit transfer across species and data types. Here we present LucaCell, a sequence-centric foundation model that represents genes through pre-trained mRNA sequence embeddings rather than static gene annotations. Gene expression is discretized into bins and modeled with a Transformer encoder, enabling sequence-informed cell representation without a fixed gene-ID vocabulary. Pre-training on 85 million human and mouse single cells, LucaCell is evaluated on human, mouse and lemur gene expression profiles, human chromatin accessibility data, unaligned reads from more than 50 prokaryotic taxa, and five influenza A virus genomes. LucaCell enables manual-mapping-free cross-species cell type annotation and an alignment-free microbial embedding framework that simultaneously distinguishes bacterial species identity and intra-species physiological states. It also improves gene expression reconstruction by incorporating donor-specific exonic SNP information into mRNA sequence embeddings, and predicts cellular viral load across influenza A virus strains while highlighting infection-like transcriptional states in mock-infected cells. These results show that sequence-informed gene representation can improve the generalization of single-cell foundation models across species, data types, and predictive tasks.","rel_num_authors":11,"rel_authors":[{"author_name":"Yan Sun","author_inst":"College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China"},{"author_name":"Yong He","author_inst":"Token Foundry, Alibaba Token Hub, Alibaba Group, Hangzhou, China"},{"author_name":"Minsi Ren","author_inst":"Department of Artificial Intelligence, School of Engineering, Westlake University, Hangzhou, China"},{"author_name":"Yanhui Wang","author_inst":"College of Ocean and Earth Sciences and State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, China"},{"author_name":"Penghao Xu","author_inst":"ZJU-Veminsyn Bio-AI joint Research & Development Center, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China"},{"author_name":"Yong Hou","author_inst":"College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China"},{"author_name":"Yu Kang","author_inst":"College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China"},{"author_name":"Tingjun Hou","author_inst":"College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China"},{"author_name":"Jieping Ye","author_inst":"Token Foundry, Alibaba Token Hub, Alibaba Group, Hangzhou, China"},{"author_name":"Huanming Yang","author_inst":"BGI Research, Shenzhen, China"},{"author_name":"Zheng Wang","author_inst":"Token Foundry, Alibaba Token Hub, Alibaba Group, Hangzhou, China"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"3D-Printable and Cytocompatible Hydrogel from Acinetobacter baylyi ADP1 Extracellular Matrix","rel_doi":"10.64898\/2026.09.11.750904","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.750904","rel_abs":"Tissue engineering has advanced significantly, yet multicomponent hydrogels inspired by the compositional complexity of natural extracellular matrices (ECMs) are still underexplored. Most current hydrogels are based on single-component formulations, which can limit their biochemical and mechanical versatility. Developing synthetic multicomponent hydrogels remains challenging because it requires the controlled integration of multiple functional groups within a single material platform. Here, a biologically driven strategy is introduced by leveraging Acinetobacter baylyi ADP1, a bacterium that naturally produces extracellular polymeric substances (EPS) composed of a multicomponent matrix of polysaccharides and proteins. Through three-day cultivation and a simple extraction method, a hydrogel is obtained that can be methacrylated and photocrosslinked using red or blue light. This hydrogel is porous, cytocompatible, 3D-bioprintable, injectable, and undergoes rapid gelation for in situ crosslinking. This work highlights the potential of using bacterial-derived multicomponent hydrogels for biofabrication.","rel_num_authors":14,"rel_authors":[{"author_name":"Shahla Radmehr","author_inst":"Tampere University, Tampere, Finland"},{"author_name":"Petra Cassiani Ingoni","author_inst":"Tampere University, Tampere, Finland"},{"author_name":"Ali Eftekhari","author_inst":"Tampere University, Tampere, Finland"},{"author_name":"Laura Yl\u00e4-Outinen","author_inst":"Tampere University, Tampere, Finland"},{"author_name":"Vijay Singh Parihar","author_inst":"Tampere University, Tampere, Finland"},{"author_name":"Mohammad Khavani","author_inst":"University of California, Berkeley, Berkeley, CA, USA"},{"author_name":"Noora Perho","author_inst":"Tampere University, Tampere, Finland"},{"author_name":"Jack Morikka","author_inst":"Tampere University, Tampere, Finland"},{"author_name":"Dario Greco","author_inst":"Tampere University, Tampere, Finland"},{"author_name":"Timo Laaksonen","author_inst":"University of Helsinki, Helsinki, Finland"},{"author_name":"Minna Kellom\u00e4ki","author_inst":"Tampere University, Tampere, Finland"},{"author_name":"Heli Skottman","author_inst":"Tampere University, Tampere, Finland"},{"author_name":"Suvi Santala","author_inst":"Tampere University, Tampere, Finland"},{"author_name":"Ville Santala","author_inst":"Tampere University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"A novel class of conserved sucrose-phosphate phosphatases highlights the diversity of cyanobacterial sucrose metabolism","rel_doi":"10.64898\/2026.09.11.751015","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.751015","rel_abs":"Sucrose metabolism is an important feature of the physiology of the green lineage of photosynthetic organisms and has therefore been the subject of considerable research on plants, algae, and cyanobacteria. Canonical sucrose biosynthesis pathways often involve the condensation of NDP-glucose and fructose-6-phosphate through the action of sucrose-phosphate synthase, then the dephosphorylation of sucrose 6-phosphate into sucrose via sucrose-phosphate phosphatase (SPP). However, many cyanobacterial genomes encode multiple homologs of SPP proteins (SPP-like), including variants that appear to lack key residues reported to be important for sucrose 6-phosphate binding. Herein, we examine these SPP-like proteins, focusing on the biochemical and physiological characterization of the SPP-like protein encoded by the cyanobacterial model, Synechococcus elongatus PCC 7942. Bioinformatic analysis suggests that the SPP-like family of proteins is highly conserved across cyanobacterial species and forms distinct phylogenetic clades that are more widely distributed than the canonical SPP proteins themselves. Biochemical analysis of the purified S. elongatus PCC 7942 SPP-like protein reveals that it not only retains the capacity to dephosphorylate sucrose 6-phosphate, but it also may have physiologically relevant phosphatase activity on 3-phosphoglycerate (3-PGA). We provide evidence that the SPP-like family of proteins represents a well-conserved group of phosphatases across cyanobacteria and suggest some enzymes in this family may have evolved a broader substrate specificity relative to the well-characterized SPP family. Our results have broader implications for cyanobacterial regulation of sucrose biosynthesis and other key steps of central carbon metabolism.","rel_num_authors":6,"rel_authors":[{"author_name":"Maria Santos-Merino","author_inst":"Michigan State University"},{"author_name":"Sreeahila Retnadhas","author_inst":"Michigan State University"},{"author_name":"Sigal Lechno-Yossef","author_inst":"Michigan State University"},{"author_name":"Matthew E. Dwyer","author_inst":"Michigan State University"},{"author_name":"Mariana Aubele-Gonzalez","author_inst":"Michigan State University"},{"author_name":"Daniel C. Ducat","author_inst":"Michigan State University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Single-cell proteomics reveals cell-type-specific functional coordination in PBMCs","rel_doi":"10.64898\/2026.09.11.751068","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.751068","rel_abs":"The coordination of molecular networks defines cellular functions. This is reflected in molecular covariation within a cell type, which is more subtle than the differences separating cell types and has therefore been difficult to quantify. To achieve the depth, consistency and accuracy required to resolve such covariation, we leveraged single-cell proteomics (plexDIA) and transcriptomics (Smart-seq3xpress) to analyze the proteomes and transcriptomes of thousands of single peripheral blood mononuclear cells (PBMCs). plexDIA quantified more protein-coding gene products per cell with higher data completeness while Smart-seq3xpress quantified more gene products across all cells. The protein measurements revealed cell-type-specific proteome architecture -- shaped in part by protein stability, and complex coordination -- that was undetectable in our mRNA data. Specifically, protein covariation within a cell type suggests cell-type-specific protein-protein interactions and functional rewiring of biological pathways independent of previously characterized abundance differences. Covariation analysis within cell types resolves a B cell-specific axis of translational states inversely covarying with GDF6 cytokine abundance. Our framework captures cell-type-specific functional coordination representing a distinct information layer accessible via single-cell proteomics.","rel_num_authors":7,"rel_authors":[{"author_name":"Luke Koury","author_inst":"Northeastern University"},{"author_name":"Andrew Leduc","author_inst":"Northeastern University"},{"author_name":"Saad Khan","author_inst":"Northeastern University"},{"author_name":"Michael Hagemann-Jensen","author_inst":"Karolinska Institutet"},{"author_name":"Jakob Michaelsson","author_inst":"Karolinska Institutet"},{"author_name":"Jeffrey E Mold","author_inst":"Karolinska Institutet"},{"author_name":"Nikolai Slavov","author_inst":"Northeastern University and Parallel Squared Technology Institute"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"PHACTn enables training-free, context-independent inference of nucleotide variant tolerance across the genome","rel_doi":"10.64898\/2026.09.08.750126","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750126","rel_abs":"Accurate prediction of single-nucleotide variant (SNV) tolerability across the entire human genome remains a fundamental challenge in computational genomics, particularly for non-coding regions where the regulatory landscape is vast and poorly understood. Machine learning classifiers suffer from data circularity and demographic bias, while genomic language models demand massive computational resources and offer little biological interpretability. Here, we present PHACTn (Phylogeny-Aware Computing of Tolerance for nucleotide variants), a training-free, parameter-minimal method that infers nucleotide variant tolerability by traversing the mammalian phylogenetic tree and explicitly modeling the evolutionary independence of observed substitutions and their distance from the query species. With only 4 interpretable parameters, no training and no GPU requirement, PHACTn outperforms all evaluated tools on non-coding variants curated from both the ClinVar, and on non-coding variants potentially responsible for selected Mendelian diseases curated from OMIM. Additionally, it achieves state-of-the-art performance on variants within the informative range of alignment-based inference. These results establish that principled probabilistic phylogenetic modeling captures evolutionary constraint signals that large-scale sequence models fail to recover, offering a powerful, accessible, and mechanistically transparent alternative for genome-wide variant effect prediction.","rel_num_authors":3,"rel_authors":[{"author_name":"Ceren Yildirim","author_inst":"Sabanci University"},{"author_name":"Nurdan Kuru","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Ogun Adebali","author_inst":"Sabanci University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Cell type-specific histone acetylation landscape in Alzheimer's disease reveals a putative role of MITF in microglia","rel_doi":"10.64898\/2026.09.09.750356","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750356","rel_abs":"Alzheimer's disease (AD) is characterised by aberrant amyloid beta and tau aggregation, neuroinflammation, demyelination and neurodegeneration, which have been linked to changes in cell-specific gene expression signatures. Among the mechanisms driving cell-type-specific transcriptional changes, histone acetylation plays a central role in regulating gene activity. While global alterations in histone acetylation have been implicated in AD, the contribution of individual cell types to these epigenetic changes remains poorly understood. To decode cell-type-specific changes in gene regulation in AD pathogenesis, we profiled histone H3 lysine 27 acetylation (H3K27ac) in microglia, oligodendrocytes and neurons from the prefrontal cortex of individuals with late-stage AD and non-dementia controls. Oligodendrocytes had the highest number of differential H3K27ac regions in AD, followed by microglia. Genes nearest to differential H3K27ac in purified microglia were enriched for phagocytosis, lipid processing, inflammatory and disease-associated cell state signature genes. Gene network analysis revealed downregulation of homeostatic genes in AD microglia and upregulation of immune activation, including signatures of lipid-handling and monocyte-derived macrophages. Oligodendrocyte co-regulated regions were indicative of increased MHC class I antigen presentation and altered neuron-oligodendrocyte interactions in AD. We identified H3K27ac allele-specific variants (ASVs) enriched near endolysosomal and ubiquitin-proteasome-associated genes in microglia and neurons. ASVs coincided with AD genome-wide association study (GWAS) risk loci, including CLU in oligodendrocytes and HLA-DRB1 in microglia. DNA motif analysis identified putative transcription factor drivers of AD glial dysregulation, including the lysosomal-associated MITF, Cap'n'collar (CNC) family (BACH1 and NFE2) and AP-1 activation in microglia. DNA binding of the MITF protein in human microglia was localised to lysosomal-associated genes and enriched in H3K27ac regions upregulated in AD and near disease-associated microglia (DAM) genes. Collectively, these findings implicate lysosomal dysfunction and upstream transcriptional regulation via MITF as key processes in AD microglia.","rel_num_authors":18,"rel_authors":[{"author_name":"Charbel Gergian","author_inst":"Imperial College London"},{"author_name":"Paulina Urbanaviciute","author_inst":"King's College London"},{"author_name":"Philippa M Wells","author_inst":"Imperial College London"},{"author_name":"Janis L Transfeld","author_inst":"Imperial College London"},{"author_name":"Aydan Askarova","author_inst":"Imperial College London"},{"author_name":"Reuben M Yaa","author_inst":"Imperial College London"},{"author_name":"Yukyee Wu","author_inst":"Imperial College London"},{"author_name":"Kevin Chris Ziegler","author_inst":"Imperial College London"},{"author_name":"Christian K Nickl","author_inst":"Univeristy of California San Diego"},{"author_name":"Martina P Pasillas","author_inst":"University of California San Diego"},{"author_name":"Johannes C. M Schlachetzki","author_inst":"University of California San Diego"},{"author_name":"Inge R Holtman","author_inst":"University Medical Center Groningen"},{"author_name":"Peter T Nelson","author_inst":"University of Kentucky"},{"author_name":"Robert A Rissman","author_inst":"University of California San Diego"},{"author_name":"James B Brewer","author_inst":"University of California San Diego"},{"author_name":"Sarah J Marzi","author_inst":"King's College London"},{"author_name":"Christopher K Glass","author_inst":"University of California San Diego"},{"author_name":"Alexi Nott","author_inst":"Imperial College London"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage","rel_doi":"10.64898\/2026.09.13.750663","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.13.750663","rel_abs":"Proliferating cells must acquire nucleotides to support DNA replication, yet how cells meet these nucleotide demands for proliferation under physiological conditions remains understudied. Here, we investigated how physiological nutrient availability shapes nucleotide acquisition strategies in a mouse model of B-cell acute lymphoblastic leukemia (B-ALL). To assess how environmental nutrients impact nucleotide metabolism, we formulated a mouse plasma-like medium (MPM) that reproduces the circulating metabolite composition of plasma from mice with B-ALL and assessed how this influenced nucleotide metabolism relative to standard culture conditions, where nucleotide acquisition has historically been studied. We find that leukemia cells cultured in MPM acquire nucleotides through salvage pathways, and that select nucleotide salvage pathways are required for proliferation under physiological conditions. Of note, this dependency on nucleotide salvage in plasma-like conditions was not caused by precursor metabolite limitation for de novo synthesis. Instead, we found that physiological folate levels are insufficient to support deoxynucleotide triphosphate (dNTP) synthesis for genome replication, leading to DNA replication stress and impaired proliferation when nucleotide salvage is disrupted. Consistently, dietary folate restriction exacerbates the impaired leukemia progression phenotype of nucleotide salvage-deficient B-ALL cells. Together, these findings demonstrate that access to folates is an endogenous limitation for nucleotide synthesis in plasma-like nutrient conditions, increasing the relevance of nucleotide salvage pathways for leukemia progression. More broadly, this work highlights how micronutrient abundance can influence metabolic dependencies and reveals that folate levels shape nucleotide metabolism under physiological conditions.","rel_num_authors":18,"rel_authors":[{"author_name":"Ryan Elbashir","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Keene L. Abbott","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Diya L. Ramesh","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Ahmed Ali","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Anna Shevzov-Zebrun","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Anna M. Barbeau","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Michelle Wu","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Abigail P. Ward","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Yetis Gultekin","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Brian T. Do","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Sharanya L Sivanand","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Azucena Ramos","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Tenzin Kunchok","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Millenia Waite","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Edrees H. Rashan","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Muhammad Bin Munim","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Michael Hemann","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Matthew G. Vander Heiden","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Mechanisms of mucosal immunity to oral Shigella infection in a physiological mouse model","rel_doi":"10.64898\/2026.09.08.750193","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750193","rel_abs":"Shigella flexneri causes bacillary dysentery, a diarrheal disease responsible for significant global morbidity and mortality. Despite extensive efforts, there is no licensed Shigella vaccine, and due to the lack of tractable and physiological models, mechanisms of adaptive immunity to Shigella are poorly understood. Here, we establish a mouse model that permits mechanistic dissection of adaptive immunity to a physiological oral challenge with Shigella. We find primary Shigella infection confers robust cross-serotype protection against secondary challenge, in a manner strictly dependent on the adaptive immune compartment. Shigella infection induces Shigella-specific CD4+ and CD8+ T cells, but only CD4+ T cells are required for protection. CD4+ T cells produce IFN{gamma} upon secondary challenge, and help B cells produce Shigella-specific IgA. Neither anti-Shigella antibodies nor IFN{gamma} are individually required for immunity to Shigella, but loss of both eliminates protective immunity. Collectively, our results demonstrate that CD4+ T cells orchestrate antibody and cytokine defense against shigellosis.","rel_num_authors":10,"rel_authors":[{"author_name":"Janet Peace Babirye","author_inst":"University of California, Berkeley"},{"author_name":"Emma F. Lackner","author_inst":"University of California, Berkeley"},{"author_name":"Sudyut Yuvaraj","author_inst":"University of California, Berkeley"},{"author_name":"Roberto A. Chavez","author_inst":"University of California, Berkeley"},{"author_name":"Charlotte A. Nichols","author_inst":"University of California, Berkeley"},{"author_name":"Kevin D. Eislmayr","author_inst":"University of California, Berkeley"},{"author_name":"Stefan A. Fattinger","author_inst":"University of California, Berkeley"},{"author_name":"Dmitri I Kotov","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"cammie lesser","author_inst":"Tufts University"},{"author_name":"Russell Vance","author_inst":"University of California, Berkeley"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Mechanisms of mucosal immunity to oral Shigella infection in a physiological mouse model","rel_doi":"10.64898\/2026.09.08.750193","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750193","rel_abs":"Shigella flexneri causes bacillary dysentery, a diarrheal disease responsible for significant global morbidity and mortality. Despite extensive efforts, there is no licensed Shigella vaccine, and due to the lack of tractable and physiological models, mechanisms of adaptive immunity to Shigella are poorly understood. Here, we establish a mouse model that permits mechanistic dissection of adaptive immunity to a physiological oral challenge with Shigella. We find primary Shigella infection confers robust cross-serotype protection against secondary challenge, in a manner strictly dependent on the adaptive immune compartment. Shigella infection induces Shigella-specific CD4+ and CD8+ T cells, but only CD4+ T cells are required for protection. CD4+ T cells produce IFN{gamma} upon secondary challenge, and help B cells produce Shigella-specific IgA. Neither anti-Shigella antibodies nor IFN{gamma} are individually required for immunity to Shigella, but loss of both eliminates protective immunity. Collectively, our results demonstrate that CD4+ T cells orchestrate antibody and cytokine defense against shigellosis.","rel_num_authors":10,"rel_authors":[{"author_name":"Janet Peace Babirye","author_inst":"University of California, Berkeley"},{"author_name":"Emma F. Lackner","author_inst":"University of California, Berkeley"},{"author_name":"Sudyut Yuvaraj","author_inst":"University of California, Berkeley"},{"author_name":"Roberto A. Chavez","author_inst":"University of California, Berkeley"},{"author_name":"Charlotte A. Nichols","author_inst":"University of California, Berkeley"},{"author_name":"Kevin D. Eislmayr","author_inst":"University of California, Berkeley"},{"author_name":"Stefan A. Fattinger","author_inst":"University of California, Berkeley"},{"author_name":"Dmitri I Kotov","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"cammie lesser","author_inst":"Tufts University"},{"author_name":"Russell Vance","author_inst":"University of California, Berkeley"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Paired RNA profiling of circulating small extracellular vesicles links survival in ALS to reactive glial - vascular programs","rel_doi":"10.64898\/2026.09.08.749915","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.749915","rel_abs":"Circulating RNA can capture molecular variation associated with amyotrophic lateral sclerosis (ALS) progression, but biofluid heterogeneity makes biologically organized signals difficult to recover. Here, we paired microRNA (miRNA) and messenger RNA (mRNA) profiles from glutamate-aspartate transporter (GLAST)-positive small extracellular-vesicles (sEVs) to estimate survival time and identify survival-associated programs. In 45 participants with ALS and 15 controls, biologically constrained multi-omic factor analysis identified a program in which reciprocal miRNA-mRNA states among target-supported pairs tracked survival. The miRNA arm was then evaluated in an independent total-plasma cohort of 248 participants with ALS, refining a five-miRNA panel that added prognostic information beyond functional decline and neurofilament light chain, particularly over longer survival horizons. The mRNA arm was evaluated across 586 cortical profiles from 308 donors and 527,261 nuclei from 69 donors, identifying a five-gene core associated with glial reactivity, vascular programs and reduced myelinating identity. Together, these findings establish a framework for integrating regulatory RNA layers in circulation to identify clinically relevant programs and relate them to disease-relevant cellular states.","rel_num_authors":4,"rel_authors":[{"author_name":"Jonathan S. Weerakkody","author_inst":"Yale School of Medicine"},{"author_name":"Finja Bokstaller","author_inst":"Yale School of Medicine"},{"author_name":"Uma Sthanu","author_inst":"Yale School of Medicine"},{"author_name":"David S. Pitt","author_inst":"Yale School of Medicine"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Transcranial Random Aperiodic Stimulation Improves Working Memory Precision","rel_doi":"10.64898\/2026.09.08.750163","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750163","rel_abs":"Aperiodic neural activity, historically dismissed as noise, is independently modulated from neural oscillations during visual working memory maintenance. In the context of aging, flatter trait aperiodic activity is associated with poorer visual working memory performance. Here, we causally test the role of aperiodic neural activity in visual working memory in younger adults. We introduce a novel noninvasive neurostimulation method, transcranial random aperiodic stimulation (tRAS), to causally manipulate aperiodic activity to be either steeper or flatter. In a randomized, double-blind, placebo-controlled, crossover neurostimulation design (n = 30), we show that online noninvasive tRAS improves visual working memory precision when aperiodic activity is causally steepened. Our novel stimulation method paves the way for causal studies of non-oscillatory, aperiodic activity in human cognition, aging, and disease.","rel_num_authors":3,"rel_authors":[{"author_name":"Quirine van Engen","author_inst":"University of California San Diego"},{"author_name":"Justin Riddle","author_inst":"Florida State university"},{"author_name":"Bradley Voytek","author_inst":"University of California, San Diego"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"A Wireless Wearable Platform for Intravenous Drug Self-Administration in Freely Behaving Rats","rel_doi":"10.64898\/2026.09.08.750146","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750146","rel_abs":"Studying how drugs act on neuronal circuits requires delivering them with temporal precision while behavior proceeds undisturbed, a combination that tethered infusion systems cannot provide. We developed WEARIT (Wireless Equipment for Autonomous Rat Infusion Tasks), a wearable, tetherless infusion platform that gives freely moving rats intravenous access under either remote or closed-loop operant control. The device houses a reservoir, miniaturized pump, rechargeable battery and Bluetooth circuitry in a 3D-printed enclosure worn on the back. By measuring spontaneous locomotion, amphetamine-induced hyperlocomotion and food-reinforced operant responding, we show that WEARIT leaves these behaviors unchanged. Remotely triggered fentanyl infusions yielded reliable delivery with physiological responses confirmed by pulse oximetry, and self-administration acquisition and dose-response functions were comparable to conventional tethered systems. WEARIT removes a longstanding constraint on intravenous pharmacology, opening self-administration paradigms to naturalistic and enriched environments and to concurrent imaging or optogenetic manipulation of the circuits engaged by drug reinforcement.","rel_num_authors":15,"rel_authors":[{"author_name":"Eun Young Jeong","author_inst":"Korea Advanced Institute of Science and Technology"},{"author_name":"Collin D. Teague","author_inst":"University of California, Los Angeles"},{"author_name":"Anisha Reimert","author_inst":"University of California, Los Angeles"},{"author_name":"Sungwoo Cho","author_inst":"Korea Advanced Institute of Science and Technology"},{"author_name":"Juhyun Lee","author_inst":"Korea Advanced Institute of Science and Technology"},{"author_name":"Thorsten Althoff","author_inst":"University of California, Los Angeles"},{"author_name":"Kenneth Lin","author_inst":"University of California, Los Angeles"},{"author_name":"Meenakshi Nair","author_inst":"University of California, Los Angeles"},{"author_name":"Tess Leong","author_inst":"University of California, Los Angeles"},{"author_name":"Emily Silva","author_inst":"University of California, Los Angeles"},{"author_name":"Kyle E. Parker","author_inst":"Washington University in St. Louis"},{"author_name":"Catherine M. Cahill","author_inst":"University of California, Los Angeles"},{"author_name":"Jordan G. McCall","author_inst":"Washington University in St. Louis"},{"author_name":"Jae-Woong Jeong","author_inst":"Korea Advanced Institute of Science and Technology"},{"author_name":"Nicolas Massaly","author_inst":"University of California, Los Angeles"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"An adaptive noradrenergic-prefrontal circuit for innate avoidance of heights","rel_doi":"10.64898\/2026.09.14.751402","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.14.751402","rel_abs":"Innate preferences determine how animals interact with the environment, but how experience refines the neural processes underlying those intrinsic motivations is not well understood. Here we develop a virtual pole descent task which permitted in which mice can repeat many trials without habituation of height-dependent avoidance. Mice adjusted their choices based on recent trial outcomes without externally imposed behavioral reinforcement or punishment. Using this paradigm, we found that noradrenergic signaling enhances height avoidance while experience refines the prefrontal cortex population representation of the task. Inhibiting locus coeruleus norepinephrine neurons reduced safe choices in apparently tall visual height stimuli, while stimulating their projections to prelimbic cortex enhanced safe decision-making. Anticipatory norepinephrine in prelimbic cortex correlated with height avoidance across animals and reflected trial outcome history. Miniscope calcium imaging revealed prelimbic neurons tracked progress in the task. At the population level, experience induced improvements in the decoding of position which correlated strongly with behavioral improvements. With experience, neural trajectories became less variable during the task and reliability of representations correlated with behavioral improvement. Together these results reveal that innate threat experience can induce prefrontal cortical refinement without externally imposed reinforcement. Innate behavioral preference is thus maintained while the neural processes underlying it evolve, suggesting flexibility in neural circuits for interacting with hardwired environmental motivations.","rel_num_authors":9,"rel_authors":[{"author_name":"Stephanie M Staszko","author_inst":"Yale University"},{"author_name":"Emi Krishnamurthy","author_inst":"Yale University"},{"author_name":"Rohan Lokanadham","author_inst":"Yale University"},{"author_name":"Jessica P He","author_inst":"Yale University"},{"author_name":"Aakash Basu","author_inst":"Yale University"},{"author_name":"Jocelyne Rondeau","author_inst":"Yale University"},{"author_name":"Abigail L Yu","author_inst":"Yale University"},{"author_name":"John H Krystal","author_inst":"Yale University"},{"author_name":"Alfred P Kaye","author_inst":"Yale University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Spared corticospinal neurons activate an endogenous plasticity program after partial CNS injury","rel_doi":"10.64898\/2026.09.08.750239","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750239","rel_abs":"Functional recovery after incomplete spinal cord injury depends substantially on the capacity of anatomically spared neurons to remodel their connections, yet the molecular programs underlying this endogenous plasticity remain poorly understood. To identify and validate these mechanisms, we combined retrograde labeling, unilateral corticospinal tract injury, spatial transcriptomics, and human stem cell-derived neurons. Injured corticospinal neurons exhibited widespread downregulation with remaining activated pathways dominated by stress, cell death, and degenerative programs. In contrast, spared corticospinal neurons activated a coordinated pro-plasticity program characterized by metabolic, immune, and cytoskeletal remodeling together with selective suppression of growth-inhibitory signaling. Network and drug perturbation analyses identified ARHGEF12 suppression and vorinostat treatment as complementary target- and state-based strategies to enhance neurite regeneration in human neurons. Together, these findings define key components of endogenous plasticity and provide a framework for discovering therapeutic targets for neural repair.","rel_num_authors":6,"rel_authors":[{"author_name":"Matias Murillo","author_inst":"Yale University School of Medicine"},{"author_name":"Ciara F O'Brien","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Noa Golan","author_inst":"Yale University"},{"author_name":"Emma X Yin","author_inst":"Yale University"},{"author_name":"Kristen Brennand","author_inst":"Yale University"},{"author_name":"William B Cafferty","author_inst":"Yale University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Spared corticospinal neurons activate an endogenous plasticity program after partial CNS injury","rel_doi":"10.64898\/2026.09.08.750239","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750239","rel_abs":"Functional recovery after incomplete spinal cord injury depends substantially on the capacity of anatomically spared neurons to remodel their connections, yet the molecular programs underlying this endogenous plasticity remain poorly understood. To identify and validate these mechanisms, we combined retrograde labeling, unilateral corticospinal tract injury, spatial transcriptomics, and human stem cell-derived neurons. Injured corticospinal neurons exhibited widespread downregulation with remaining activated pathways dominated by stress, cell death, and degenerative programs. In contrast, spared corticospinal neurons activated a coordinated pro-plasticity program characterized by metabolic, immune, and cytoskeletal remodeling together with selective suppression of growth-inhibitory signaling. Network and drug perturbation analyses identified ARHGEF12 suppression and vorinostat treatment as complementary target- and state-based strategies to enhance neurite regeneration in human neurons. Together, these findings define key components of endogenous plasticity and provide a framework for discovering therapeutic targets for neural repair.","rel_num_authors":6,"rel_authors":[{"author_name":"Matias Murillo","author_inst":"Yale University School of Medicine"},{"author_name":"Ciara F O'Brien","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Noa Golan","author_inst":"Yale University"},{"author_name":"Emma X Yin","author_inst":"Yale University"},{"author_name":"Kristen Brennand","author_inst":"Yale University"},{"author_name":"William B Cafferty","author_inst":"Yale University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Intrasegmental and propriospinal pre-phrenic interneuron circuitry in intact CNS and following cervical spinal cord injury","rel_doi":"10.64898\/2026.09.08.749894","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.749894","rel_abs":"Cervical spinal cord injury (SCI) disrupts descending respiratory circuitry, resulting in debilitating and often persistent ventilatory deficits. Respiratory drive emerges within medulla from the rostral ventral respiratory group (rVRG), whose neurons project to C3-C6 phrenic motor neurons (PhMNs), which then innervate diaphragm, the primary muscle of inspiration. Though rVRG neurons make extensive monosynaptic connection with PhMNs, rVRG input to PhMNs can also be relayed through pre-phrenic interneurons (PP-INs) via polysynaptic pathways. However, the neuroanatomical connectivity between PP-INs and PhMNs remains incompletely understood. In both uninjured rats and the C2 hemisection (C2HS) model of cervical SCI, we performed tracing of PP-INs that were synaptically connected to PhMNs located in rostral (C3-C4) or caudal (C5-C6) portions of the phrenic nucleus by unilaterally injecting retrograde trans-synaptic tracer, pseudorabies (PRV), selectively into ventral or dorsal regions of hemi-diaphragm. We quantified numbers of PRV-labeled PP-INs individually at segments across cervical spinal cord, including separately in dorsal horn, intermediate gray, and ventral horn. We found that PP-INs are widespread throughout C1-C7 spinal cord in the uninjured condition. These PP-INs have a predominant intrasegmental connectivity pattern with PhMNs, though significant numbers of longer distance projecting propriospinal PP-INs also exist both rostral and caudal to the PhMN pool. Furthermore, while PP-INs connect both ipsilaterally and contralaterally with PhMNs, there is a strong bias to ipsilateral projection. C2HS induced major disconnection between PhMNs and ipsilesional propriospinal PP-INs located rostral to the SCI, but conversely induced limited plasticity in connectivity of intrasegmental PP-INs located within C3-C6 spinal cord. These findings greatly improve our knowledge about PP-IN circuitry and also provide important information to aid in developing approaches to target PP-IN plasticity for promoting spinal cord repair.","rel_num_authors":12,"rel_authors":[{"author_name":"Pauline Michel-Flutot","author_inst":"Sidney Kimmel Medical College at Thomas Jefferson University"},{"author_name":"Angela Harbeck","author_inst":"Sidney Kimmel Medical College at Thomas Jefferson University"},{"author_name":"Lan Cheng","author_inst":"Sidney Kimmel Medical College at Thomas Jefferson University"},{"author_name":"Khalil Rust","author_inst":"Sidney Kimmel Medical College at Thomas Jefferson University"},{"author_name":"Megan A. Lyttle","author_inst":"Sidney Kimmel Medical College at Thomas Jefferson University"},{"author_name":"Samantha J. Thomas","author_inst":"Sidney Kimmel Medical College at Thomas Jefferson University"},{"author_name":"David A. Jaffe","author_inst":"Sidney Kimmel Medical College at Thomas Jefferson University"},{"author_name":"Kallon Crowther","author_inst":"Sidney Kimmel Medical College at Thomas Jefferson University"},{"author_name":"Gabriela Daszewska-Smith","author_inst":"Sidney Kimmel Medical College at Thomas Jefferson University"},{"author_name":"George M. Smith","author_inst":"Temple University School of Medicine"},{"author_name":"Shuxin Li","author_inst":"Temple University School of Medicine"},{"author_name":"Angelo C. Lepore","author_inst":"Sidney Kimmel Medical College at Thomas Jefferson University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Closed, Automated CAR-T Cell Manufacturing: from Research to Point of Care production.","rel_doi":"10.64898\/2026.09.08.748871","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.748871","rel_abs":"Background: Point-of-care manufacturing of CAR-T cells could reduce cost and improve patient access, but few closed, automated systems support both flexible process development and GMP production. Methods and results: We describe LimCORE, a single-use consumable for cell incubation and processing, implemented in LimGROW (manual system) and LimONE (closed and automated system). In LimGROW, T cells expanded 246 +\/-18 fold over 10 days at optimized seeding density, versus 89 +\/-9 fold in a G-Rex control, with similar viability (>90%) and phenotype. Process parameters directly transferred to LimONE, where automated, closed buoyancy-based CD3+ selection achieved 90.3 +\/-3.5% purity and 59.2 +\/-17.0% recovery in under two hours. Using this workflow, we manufactured CD19 CAR-T cells in a fully closed, automated 7-day LimONE process requiring 155 minutes of operator intervention. LimONE manufactured CAR-T cells reached 42.6 +\/-2.4 fold expansion (532 +\/-29x10e6; cells at harvest), with 43.6 +\/-6.0% transduction efficiency and viability similar to G-Rex controls. CD4+\/CD8+ ratios, CD8+ differentiation subsets, and cytotoxicity were comparable between platforms, while LimONE-manufactured cells showed increased spare respiratory capacity and oxygen consumption. Across four manufacturing runs on the LimONE, no hardware or software failures occurred, and automated liquid transfers and volume concentration stayed within +\/-5% accuracy. Conclusions: These data show that LimCORE supports T cell expansion, selection, and complete CD19 CAR-T manufacturing with performance similar to existing platforms while reducing operator time, across R&D and GMP scale closed-system formats.","rel_num_authors":15,"rel_authors":[{"author_name":"Caroline Boudousquie","author_inst":"Limula"},{"author_name":"Denis Migliorini","author_inst":"Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland."},{"author_name":"Jonathan Esensten","author_inst":"Advanced Biotherapy Center, Sheba Medical Center, Tel HaShomer, Israel."},{"author_name":"Melita Irving","author_inst":"University of Lausanne"},{"author_name":"Jimmy Maillard","author_inst":"University of Lausanne"},{"author_name":"Romain Vuillefroy de Silly","author_inst":"University of Lausanne"},{"author_name":"Yann Pierson","author_inst":"Limula"},{"author_name":"Valerie Widmer","author_inst":"University of Geneva"},{"author_name":"Martin Pedard","author_inst":"University of Geneva"},{"author_name":"Maria Morbidelli","author_inst":"University of Fribourg"},{"author_name":"Nicola Vannini","author_inst":"University of Fribourg"},{"author_name":"Emilie Nallet","author_inst":"Limula"},{"author_name":"Luca Bellosta","author_inst":"Limula"},{"author_name":"Laeticia Dutoit","author_inst":"Limula"},{"author_name":"Fabien Jammes","author_inst":"Limula"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Reduced inhibition of hippocampal adult-born granule cells by parvalbumin interneurons after TBI","rel_doi":"10.64898\/2026.09.08.750063","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750063","rel_abs":"Traumatic brain injury (TBI) is one of the leading causes of acquired temporal lobe epilepsy. TBI drives hippocampal circuit rearrangements that may contribute to increased seizure risk, such as altered inhibitory circuit function and aberrant post-traumatic neurogenesis. In the hippocampal dentate gyrus, adult-born dentate granule cells (DGCs) acquire inhibitory synaptic inputs from parvalbumin-expressing (PV) interneurons early in their maturation. These inputs are important for circuit integration and feedforward inhibition of these neurons. To test whether DGCs born after TBI have functionally altered PV-mediated innervation, we used genetically modified mice, retroviral vectors, and optogenetics to study adult-born and mature DGCs after TBI. Although DGCs born after TBI acquired inhibitory synaptic inputs during their maturation, PV-mediated inhibition of adult-born DGCs was persistently reduced following TBI. This was not observed in mature granule cells and was not due to TBI-induced changes in PV cell density. This deficit in PV-mediated functional innervation was associated with a transient reduction in release probability at these synapses, which normalized as DGCs matured despite ongoing reduction of functional PV input. Surprisingly, although spontaneous inhibitory postsynaptic currents were reduced for mature granule cells after TBI, these were unchanged in adult-born DGCs. Taken together, these data demonstrate distinct differences in the de novo development and maintenance of PV+ synapses in the dentate gyrus after TBI. The addition of neurons with reduced PV+ interneuron-mediated feed-forward inhibition to the dentate gyrus could contribute to hippocampal hyperexcitability after severe brain injury.","rel_num_authors":3,"rel_authors":[{"author_name":"Corwin R Butler","author_inst":"Oregon Health & Science University"},{"author_name":"Connor R Squellati","author_inst":"Oregon Health & Science University"},{"author_name":"Eric Schnell","author_inst":"Portland VA HCS"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"A single cooperative experience increases corticolimbic synaptic density and prosocial behavior","rel_doi":"10.64898\/2026.09.07.749944","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.07.749944","rel_abs":"Cooperation is typically studied as an output of the social brain, as opposed to an experience that shapes it. Here, we developed a task in rats that permits interaction while requiring joint action for reward. Cooperation depended on dyad familiarity and visual access. Anterior cingulate cortex (ACC) to basolateral amygdala (BLA) projections were activated during cooperation with a familiar partner, whereas ACC to anterior insula (AI) projections were simultaneously suppressed regardless of familiarity. A single 90 min cooperative experience increased presynaptic marker SV2A, detected by positron emission tomography (PET), in the amygdala and insula one day later. Concurrently, rodents demonstrated heightened attention toward a distressed conspecific. Cooperation is thus an experience that recruits dissociable corticolimbic pathways and changes brain and behavior beyond the encounter itself.","rel_num_authors":10,"rel_authors":[{"author_name":"Henry W. Kietzman","author_inst":"Department of Psychiatry, Yale University"},{"author_name":"R. Allie Cauchon","author_inst":"Department of Psychiatry, Yale University"},{"author_name":"Amelia Johnson","author_inst":"Department of Biomedical Engineering, Yale University"},{"author_name":"David R. Backer Peral","author_inst":"Department of Electrical and Computer Engineering, Yale University"},{"author_name":"Robin Bonomi","author_inst":"Department of Psychiatry, Yale University"},{"author_name":"Yiyun Huang","author_inst":"Department of Radiology and Biomedical Imaging, Yale School of Medicine"},{"author_name":"Hayde Sanchez","author_inst":"Department of Psychiatry, Yale University"},{"author_name":"Shreya Saxena","author_inst":"Department of Biomedical Engineering, Yale University"},{"author_name":"S. William Li","author_inst":"Department of Psychiatry, Yale University"},{"author_name":"Jane R. Taylor","author_inst":"Department of Psychiatry, Yale University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Intrinsic Organization of Contrast Sensitivity in Human Vision","rel_doi":"10.64898\/2026.09.07.749815","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.07.749815","rel_abs":"Natural vision operates over an enormous range of luminance while preserving sensitivity to both fine and coarse spatial structure. As luminance increases, the peak of the contrast sensitivity function shifts toward higher spatial frequencies. Existing accounts explain how luminance rescales the amplitude of neural responses through gain control, but not why preferred spatial frequency should reorganize systematically with luminance. Here we propose that recurrent excitatory-inhibitory interactions generate an intrinsic spatial frequency, set by the coupling structure of the circuit, that shapes the network's resonance and thereby predicts changes in preferred spatial frequency. Changes in mean luminance shift this intrinsic spatial frequency by altering the effective balance between excitation and inhibition, thereby moving the network between dynamical regimes rather than simply rescaling its responses. To test this framework, we measured human contrast sensitivity across a finely sampled range of luminance. Preferred spatial frequency followed the predicted course: approximately constant at low luminance, then rising sharply over a narrow range in an S-shaped transition. These results support a circuit-based account in which changes in cortical state reorganize spatial selectivity, linking luminance-dependent perception to the dynamics of cortical computation.","rel_num_authors":4,"rel_authors":[{"author_name":"Sergei Gepshtein","author_inst":"University of California San Diego"},{"author_name":"Sergey Savel'ev","author_inst":"Loughborough University"},{"author_name":"Alexander Alan Minns","author_inst":"Loughborough University"},{"author_name":"Natalia Janson","author_inst":"Loughborough University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Quantitative Modelling of Amyloid-\u03b2 Dynamics in Brain, CSF, and Plasma During Sleep and Wakefulness","rel_doi":"10.64898\/2026.09.07.749991","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.07.749991","rel_abs":"Amyloid-beta (A{beta}) accumulation in the brain is linked to Alzheimer's disease. In healthy individuals, A{beta} rises during wakefulness and is cleared during sleep, yet the effects of sleep disturbances on the A{beta} dynamics are unclear. We developed a model, incorporating brain, cerebrospinal fluid (CSF), and plasma, to investigate the A{beta} dynamics along the sleep-wake cycles. The model reproduces the experimentally observed 24-hour A{beta}42 oscillations in CSF (660-760 pg\/mL) and plasma (15-19 pg\/mL) and predicts brain A{beta} dynamics. Indwelling lumbar catheter data show elevated CSF A{beta}42 levels on the second morning after a full night of sleep compared to first morning. The model predicts this increased level is due to repeated CSF sampling, which affects A{beta} levels through pressure-mediated changes in CSF, impaired sleep associated clearance, or their synergistic effect. These findings provide a framework for understanding A{beta} regulation, highlighting sleep's protective role and the need for non-invasive measurement approaches.","rel_num_authors":6,"rel_authors":[{"author_name":"Satyam Sangeet","author_inst":"School of Physics, The University of Sydney, Camperdown, Australia"},{"author_name":"Craig L Phillips","author_inst":"Center for Sleep and Chronobiology, Woolcock Institute of Medical Research, Macquarie University, Sydney, Australia"},{"author_name":"Camilla M Hoyos","author_inst":"School of Health Sciences and Nursing, Macquarie University, Sydney, Australia"},{"author_name":"Angela L D'Rozario","author_inst":"School of Psychological Sciences, Macquarie University, Sydney, Australia"},{"author_name":"Brendan P Lucey","author_inst":"Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA"},{"author_name":"Svetlana Postnova","author_inst":"School of Physics, The University of Sydney, Camperdown, Australia"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Sex differences in pediatric EEG inter-subject correlation during naturalistic movie watching: a large-scale characterization of the Healthy Brain Network EEG dataset","rel_doi":"10.64898\/2026.09.07.749616","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.07.749616","rel_abs":"Inter-subject correlation (ISC) of EEG during naturalistic viewing is increasingly used as a candidate pediatric biomarker, yet its behavior at cohort scale remains uncharacterized. We characterize ISC in 1143 children and adolescents (765 male, 378 female, ages 5 to 21) from the Healthy Brain Network EEG dataset viewing four naturalistic film clips. Three results follow. First, ISC separates narrative from abstract stimuli by 1.7 to 2.4 fold and exceeds a resting-state baseline by 42 to 99 fold, and the previously reported developmental decline replicates throughout. Second, ISC is sex-dependent: males exceed females in every movie (t = 9.7 to 13.5; Cohen's d = 0.61 to 0.85), concentrated in delta and theta, peaking at a frontocentral cluster and at ages 11 to 14. The direction matches an earlier report where the effect was marginal, and we resolve structure that sample could not. It survives three demographic and clinical robustness analyses, same-sex and size-matched templates, ocular component removal, and exclusion of the releases overlapping that report, and is attenuated, by approximately 10 percent adjusting for interpolation count and by 23 percent in recordings free of cluster interpolation, but not explained by differential channel interpolation. Evoked response magnitude, previously proposed as an alternative account, does differ by sex here (d = 0.55 to 0.60) but mediates only 8.6 to 18.1 percent of the effect. Third, ISC predicts none of four CBCL bifactor dimensions after FDR correction at any feature resolution: zero of 16 grand-mean, 2064 per-channel and 16 cluster tests, with confidence intervals excluding standardized associations beyond |{beta}| = 0.106.","rel_num_authors":5,"rel_authors":[{"author_name":"Eklavya Tomar","author_inst":"Dubai College"},{"author_name":"Aimar Silvan","author_inst":"City College of New York"},{"author_name":"Eugene Yujun Fu","author_inst":"The Education University of Hong Kong, Hong Kong"},{"author_name":"Yong Xiong","author_inst":"Wuhan University of Technology"},{"author_name":"Chi Wai Do","author_inst":"The Hong Kong Polytechnic University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Intravital microscopy and statistical image analysis of early engraftment of haematopoietic stem cells reveal dynamic and evolving cellular behaviours linked to progressive differentiation.","rel_doi":"10.64898\/2026.09.11.750961","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.750961","rel_abs":"Haematopoietic stem cells (HSCs) have long been used in the clinic for bone marrow transplantation applications, critical for the survival of an increasingly wide range of patients with haematological, oncological and immunological pathologies. Despite this, little is known about the mechanisms through which relatively few stem cells are able to regenerate the entire haematopoietic tissue of transplant recipients. To gain insights on this biological process, we used intravital microscopy of calvarium bone marrow, collecting tissue-wide images and a total of 850 hours of tracks of engrafting haematopoietic stem and progenitor cells from 24 hours to 8 days following injection in lethally irradiated recipients. Analysis of the data revealed that regenerating HSCs and their immediate progeny are highly dynamic, migrating through the parenchyma at both the microscopic and near-macroscopic scales, i.e. within and in-and-out of fields of view. HSC-derived cell clusters, expanded locally between day 2 and day 4 post-transplant, leading to patches of densely populated bone marrow by day 8. Single cell level analysis highlighted increasingly heterogenous cellular behaviours over time. Track clustering based on migration and niche interaction parameters combined with post-tracking whole mount immunostaining revealed that persistence in the vicinity of nestin-GFP perivascular cells and relatively slow movement correlated with stemness, while more heterogeneous niche interactions coupled with slowest or faster migration correlated with differentiation, validated through flow cytometry analysis and functional studies. The findings presented here shed light on the fundamental principles driving haematopoietic regeneration in transplantation settings.","rel_num_authors":12,"rel_authors":[{"author_name":"Sara Gonzalez Anton","author_inst":"Imperial College London"},{"author_name":"Chang Liu","author_inst":"Maynooth University"},{"author_name":"Reema A. Khorshed","author_inst":"Imperial College London"},{"author_name":"Mari Carmen Romero-Mulero","author_inst":"Swiss Federal Institute of Technology (ETH Zurich)"},{"author_name":"George Adams","author_inst":"Imperial College London"},{"author_name":"Benjamin Partridge","author_inst":"Imperial College London"},{"author_name":"Ziqi Alvin Lu","author_inst":"Imperial College London"},{"author_name":"Nina Cabezas-Wallscheid","author_inst":"Swiss Federal Institute of Technology (ETH Zurich)"},{"author_name":"Constandina Pospori","author_inst":"Francis Crick Institute"},{"author_name":"Chiu Fan Lee","author_inst":"Imperial College London"},{"author_name":"Ken R. Duffy","author_inst":"Northeastern University"},{"author_name":"Cristina Lo Celso","author_inst":"Imperial College London"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"A protective hybrid protein vaccine informed by mapping major histocompatibility class II epitopes in Cryptococcus neoformans chitin deacetylases that stimulate CD4+ T cell responses","rel_doi":"10.64898\/2026.09.07.749995","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.07.749995","rel_abs":"Infections due to Cryptococcus species are estimated to cause over 100,000 deaths a year. No cryptococcal vaccines are approved for human use. We have shown that vaccine formulations consisting of C. neoformans chitin deacetylase (Cda)2 and Cda1 adjuvanted with Cationic Adjuvant Formulation 01 (CAF01) protect mice against experimental cryptococcosis by a mechanism dependent upon CD4+ T cells. Here, using overlapping peptide libraries, we mapped epitopes in Cda2 and Cda1 that stimulated interferon-gamma (IFN{gamma}) release from splenocytes of C57BL\/6 and DR4 mice immunized with these proteins. DR4 mice lack mouse major histocompatibility class II (MHC-II) proteins and express chimeric MHC-II proteins with the specificity of the human HLA-DR allele, HLA-DRB1*04:01. Experimental results were then compared with MHC-II binding predictions using the Immune Epitope Database (IEDB) NetMHCIIpan 4.1 BA MHC-II epitope prediction tool. Unique epitopes in Cda2 and Cda1 were discovered for each mouse strain, some of which were not predicted to bind well to MHC-II. CD4+ T cells were responsible for cytokine release as IFN{gamma} production was lost if CD4+ T cells were depleted from the splenocyte population. Finally, we tested a hybrid recombinant protein that consisted of portions of Cda2 and Cda1 containing the MHC-II\/CD4+ T cell epitopes which induce CD4+ T cells in DR4 mice. When administered as a CAF01-adjuvanted vaccine, the hybrid protein protected DR4 mice from an otherwise lethal C. neoformans pulmonary challenge. These results provide a proof of principle regarding the utility of MHC-II\/CD4+ T cell epitope mapping in cryptococcal vaccine development.","rel_num_authors":7,"rel_authors":[{"author_name":"Charles Specht","author_inst":"UMass Medical School"},{"author_name":"Lorena V. N. Oliveira","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Diana Carlson","author_inst":"University of Massachusetts Chan Medical School Department of Medicine"},{"author_name":"Maureen M Hester","author_inst":"University of Massachusetts Medical School"},{"author_name":"Satya Ranjan Sahu","author_inst":"University of Massachusetts Chan Medical School Department of Medicine"},{"author_name":"Gabriel Kristian Pedersen","author_inst":"Statens Serum Institut"},{"author_name":"Stuart M Levitz","author_inst":"University of Massachusetts Chan Medical School"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Single-cell transcriptomic and epigenomic analysis reveals X-linked sex differences in aging mouse hypothalamus","rel_doi":"10.64898\/2026.09.08.750001","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750001","rel_abs":"Sex differences contribute to brain aging, neurodegenerative diseases, and more broadly in determining rates of aging across species. The hypothalamus plays a central role in physiological homeostasis and healthy aging, yet how its cellular and molecular landscape diverges between males and females over the lifespan remains poorly understood. Here, we present a single-nucleus multi-omics analysis of the hypothalamus in young, middle aged, and aged male and female mice. We identified major hypothalamic cell types and characterized their sex- and age-dependent transcriptional and chromatin accessibility profiles. Notably, female-specific changes on the X chromosome (chrX) emerged as a prominent feature of aging, including changes to the X inactivation center and an overall increase in chrX gene expression and accessibility in immune cells and neurons. Pseudotime analysis of immune cells revealed an aging trajectory with sex-specific multi-omic programs, featuring increased inflammation in females compared to males. Delving deeper into the epigenetic signatures associated with these sex differences, we found that H3K27me3 - the repressive histone mark enriched on the inactive X in females - increased in abundance and underwent substantial genome-wide redistribution with age in both sexes, particularly on the inactive chrX in females. Collectively, these findings highlight distinct cell-type-specific aging trajectories in the male and female hypothalamus, identify female aging signatures associated with X-linked epigenetic regulatory programs, and provide a comprehensive resource for understanding the molecular basis of sex differences in brain aging.","rel_num_authors":7,"rel_authors":[{"author_name":"Doudou Yu","author_inst":"University of Washington"},{"author_name":"Ilya Osipov","author_inst":"The Buck Institute for Research on Aging"},{"author_name":"Lexi-Amber Hassell","author_inst":"Brown University"},{"author_name":"Neta A Shwartz","author_inst":"The Buck Institute for Research on Aging"},{"author_name":"Kaitlyn H Hajdarovic","author_inst":"NIH"},{"author_name":"Harold Marin","author_inst":"The Buck Institute for Research on Aging"},{"author_name":"Ashley E Webb","author_inst":"The Buck Institute for Research on Aging"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Noise-induced hearing loss delays auditory learning and reduces the influence of acoustic evidence on choice","rel_doi":"10.64898\/2026.09.10.750711","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.10.750711","rel_abs":"Noise-induced hearing loss (NIHL) degrades auditory sensitivity, but how it affects the learning of sound-guided decisions remains unclear. We trained adult Mongolian gerbils with normal-hearing (NH) or permanent NIHL, induced by a 2-hour exposure to 120 dB SPL broadband noise, to discriminate 4- versus 12-Hz amplitude-modulated (AM) broadband noise presented in a two-alternative forced-choice task. Stimuli were presented at comparable sensation levels across groups. Relative to NH animals, NIHL animals required approximately 2.5 times more sessions and 2.9 times more trials to reach task acquisition criterion. This learning delay was not explained by reduced task engagement, response latency, or auditory brainstem response threshold shift. Video tracking showed that spatial occupancy refined with training in both groups, whereas trial-by-trial movement path trajectories became less variable in NH animals. Per-session and dynamic trial-by-trial logistic regression models revealed that the influence of the task-relevant acoustic stimulus increased with training in both groups but remained consistently lower in NIHL animals, whereas sound-independent choice tendencies were largely unchanged. Together, these results suggest that NIHL delays auditory learning by reducing the influence of acoustic evidence on choice, indicating that hearing loss can alter how sensory experience is used to acquire new behaviors.","rel_num_authors":7,"rel_authors":[{"author_name":"Marissa Calvano","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Mia Mohr","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Willems Mortimer","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Samira Alom","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Kamala Prerna Annaji Rao Nookala","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Todd M Mowery","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Justin D Yao","author_inst":"Rutgers, The State University of New Jersey"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Plant ABCC1 orthologs from agronomically relevant species reveal conserved principles of detoxification transport","rel_doi":"10.64898\/2026.09.10.750620","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.10.750620","rel_abs":"Cytosolic detoxification through vacuolar sequestration is essential for plant growth and stress tolerance. A key driver of this process is the vacuolar ABC transporter, ABCC1, which sequesters diverse amphiphilic anions including glutathione (GS)-conjugates, glucuronic acid-conjugates, and thiol-coordinated metal complexes. However, mechanistic studies of plant ABCC1 have largely relied on Arabidopsis genetics and crude membrane transport assays. Here, phylogenetic and sequence-guided analysis of ABCC1 orthologs from multiple plant species was combined with in vitro functional assays with purified protein to investigate plant ABCC1 transporter activity. Compared to mammalian ABCC1, all plant ABCC1 orthologs contain a conserved bipartite binding pocket with a cationic pocket for anion recognition and a hydrophobic pocket. Key differences between mammalian and plant ABCC1 include a substitution in the cation coordinating histidine residue that is compensated by a peripheral arginine mutation to preserve the cationic electrostatic environment. Furthermore, the plant ABCC1 hydrophobic pocket is enlarged relative to its mammalian counterpart due to several substitutions with smaller side-chain residues. To investigate the in vitro activity of plant ABCC1, several orthologs were screened for expression, and those from maize, date palm, and rice exhibited high biochemical stability and comparable substrate-stimulated ATPase activity. ZmABCC1 was further characterized through a series of assay optimization experiments, which found that its ATPase activity is strongly stimulated by E217{beta}G and GS-conjugates, and inhibited by orthovanadate. This study verifies that ABCC1 is widely conserved across plant species with a consistent substrate binding pocket and activity, supporting its role in cytosolic detoxification in plants.","rel_num_authors":2,"rel_authors":[{"author_name":"Madushani RA Wathukoralage","author_inst":"Iowa State University"},{"author_name":"Alan T Culbertson","author_inst":"Iowa State University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"IKK\u03b1 and IKK\u03b2 serve as kinase-independent scaffolds that prevent proteasomal degradation of NEMO","rel_doi":"10.64898\/2026.09.10.750631","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.10.750631","rel_abs":"NF-{kappa}B essential modulator (NEMO) is the critical scaffold protein of the canonical I kappa B kinase (IKK) complex. Whilst studying the contribution of IKK and IKK{beta} to NF-{kappa}B signalling we noted that NEMO protein levels were reduced in IKK knockout (KO) HCT116 cells. Loss of NEMO was more pronounced in IKK KO cells than IKK{beta} KO, whilst IKK+IKK{beta} double knockout (DKO) cells exhibited a 90% reduction in NEMO abundance. In contrast, the abundance of IKKs was unaffected by NEMO KO, although this abolished canonical NF-{kappa}B activation. Loss of IKKs had no effect on NEMO mRNA levels but IKK DKO cells exhibited accelerated NEMO protein turnover that was reversed by the proteasome inhibitor, MG132, but not the NEDDylation inhibitor, MLN4924. TAK-243, a selective inhibitor of UBA1, the E1 ubiquitin-activating enzyme, increased basal NEMO levels in DKO cells but did not prevent NEMO turnover suggesting both ubiquitylation-dependent and independent pathways for degradation. Bioinformatic analysis identified substantial regions of intrinsic disorder within the N- and C-termini of NEMO. NEMO was rapidly degraded by isolated 20S proteasomes in vitro and this was inhibited by interaction with IKK or IKK{beta}. Finally, re-expression of IKK increased NEMO expression in IKK DKO cells and this required the C-terminal NEMO binding domain (NBD) but not a functional kinase domain. Thus the IKKs act as critical kinase-independent scaffolds that stabilise NEMO; loss of these interactions results in NEMO degradation via the proteasome. These results may be relevant to strategies for inhibiting NF-{kappa}B signalling by disrupting NEMO:IKK interactions.","rel_num_authors":6,"rel_authors":[{"author_name":"Simon J Cook","author_inst":"The Babraham Institute"},{"author_name":"Kathryn Balmanno","author_inst":"The Babraham Institute"},{"author_name":"Jack A Prescott","author_inst":"The Babraham Institute"},{"author_name":"Nadav Myers","author_inst":"Weizmann Institute of Science"},{"author_name":"Eleanor J Griffiths","author_inst":"The Babraham Institute"},{"author_name":"Yosef Shaul","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Pathogen-associated odor experience induces inherited olfactory avoidance in a parasitoid wasp","rel_doi":"10.64898\/2026.09.11.751080","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.751080","rel_abs":"Odors allow animals to evaluate resources and risks, but the neural and inherited consequences of experience with ecologically meaningful odors remain poorly understood. Since both parasitoids and entomopathogenic fungi are widely used as agents in integrated biocontrol, we asked whether exposure to pathogen-associated volatiles can reassign odor value in a parasitoid wasp and whether the acquired bias is transmitted to descendants. Adult female Scleroderma guani were exposed, without host contact, to volatiles from Beauveria bassiana-infected hosts or to methyl cinnamate (MC), a representative component of the infected-host odor. Twelve-hour exposure shifted subsequent choices away from infected-host odor and MC, whereas shorter exposure produced different effects, indicating duration-dependent olfactory plasticity. The shift occurred without an explicit reward or punishment and is therefore consistent with non-associative learning. Unexposed F1 and F2 descendants of MC-exposed females expressed the same avoidance bias. MC stimulation elicited stronger calcium responses in mushroom-body regions of trained females and their descendants. Head transcriptomes identified reduced expression of the crustacean cardioactive peptide receptor (CCAPR) as a shared molecular signature, and CCAPR RNA interference phenocopied the odor-avoidance behavior. Finally, maternal treatment with sinefungin, a broad S-adenosylmethionine-dependent methyltransferase inhibitor, left maternal behavioral shift intact but abolished the F1 bias, implicating a methylation-sensitive process in transmission. Together, these results reveal that a pathogen-associated odor can induce durable, cross-generational reweighting of olfactory value in a non-model insect and identify candidate neural and neuropeptidergic mechanisms linking sensory experience to inherited behavior, and providing a new perspective on utilizing training in integrated biocontrol as well.","rel_num_authors":3,"rel_authors":[{"author_name":"Shiyao Liu","author_inst":"Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Jin Ge","author_inst":"Institute of Plant Protection, Shandong Academy of Agricultural Sciences"},{"author_name":"Jianghua Sun","author_inst":"Hebei University"}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Microenvironmental and transcriptional determinants of the robustness of spinal cord regeneration in zebrafish","rel_doi":"10.64898\/2026.09.07.749713","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.07.749713","rel_abs":"Unlike mammals, adult zebrafish can regenerate spinal cord tissue after complete transection. We report here that a substantial proportion of zebrafish receiving this injury fail to regain locomotor function, and we analyzed this critically. After stratifying large cohorts of injured animals according to functional recovery, we directly compared recovered and non-recovered individuals at matched post-injury stages. We find that permanently paralyzed animals form a tissue bridge across the lesion yet exhibit impaired axonal invasion and regrowth to downstream targets. Integrative single-nucleus profiling, spatial transcriptomics, and regulatory network analyses revealed that regenerative success is characterized by the coordinated establishment of a permissive multicellular regenerative state rather than major differences in cellular composition. Furthermore, we find that regenerative failure involves persistent non-permissive regulatory programs, including extracellular matrix remodeling, impaired adaptive T-cell activation, and reduced axon growth-associated signaling. Gene regulatory network and cellular trajectory analyses identified candidate transcriptional regulators that could not be resolved through differential expression analysis alone. Functional CRISPR F0 screening of several of these candidates identified hoxb5a as a critical determinant of regenerative outcome. Stable hoxb5a mutants exhibited impaired swimming recovery, disrupted bridge formation, and limited axon bridging after spinal cord injury. Together, our findings reveal key differences between success and failure in a model of elevated regenerative capacity, with hoxb5a acting as a regulator linking multicellular tissue remodeling to axonal regeneration and functional recovery.","rel_num_authors":7,"rel_authors":[{"author_name":"Pierre Gillotay","author_inst":"Morgridge Institute for Research, Madison, WI, United States; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, United "},{"author_name":"Sushant Brangru","author_inst":"Morgridge Institute for Research, Madison, WI, United States; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, United "},{"author_name":"Jingwen Shen","author_inst":"Morgridge Institute for Research, Madison, WI, United States; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, United "},{"author_name":"Bethany Moore","author_inst":"Morgridge Institute for Research, Madison, WI, United States"},{"author_name":"Jianhong OU","author_inst":"Morgridge Institute for Research, Madison, WI, United States; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, United "},{"author_name":"Ron Stewart","author_inst":"Morgridge Institute for Research, Madison, WI, United States"},{"author_name":"Kenneth D Poss","author_inst":"Morgridge Institute for Research, Madison, WI, United States; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, United "}],"rel_date":"2026-09-14","rel_site":"biorxiv"},{"rel_title":"Integrative Genetic and Single-Cell Analysis Reveals Macrophages as Key Mediators Linking Aging and Osteoporosis","rel_doi":"10.64898\/2026.09.09.26362574","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26362574","rel_abs":"Osteoporosis is a highly prevalent age-related disorder, and accumulating evidence suggests that it does not arise in isolation but is intrinsically linked to the aging process. Here, we employed integrative methods to systematically identify the relationship between aging and osteoporosis, and uncover the critical cell types and molecular regulators that mediate this association. Observational analysis of phenotypic data from UK Biobank and Mendelian Randomization analysis of summary-level statistics revealed that aging and osteoporosis are interrelated, acting as both causes and effects of each other. We identified macrophages as the key cell types mediating this association by integration of GWAS data with a comprehensively assembled single-cell transcriptomic atlas of bone remodeling. And the percentage of macrophages from bone marrow decreases with age. Additionally, shared genetic tools and weight co-expression network analysis were employed to uncover novel molecular regulators underlying this crosstalk. We identified TGFB1 and a novel gene, HNRNPUL1, as key regulators that influence macrophages differentiation and function. In conclusion, our study provides observational and genetic evidence for a bidirectional relationship between aging and osteoporosis and unveils a macrophage-centric mechanism regulated by TGFB1 and HNRNPUL1, offering new insights for age-related bone loss.","rel_num_authors":17,"rel_authors":[{"author_name":"Xin Li","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Meng-Yuan Yang","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Si-Rui Gai","author_inst":"Institute of Basic Medical Sciences, Westlake Institute for Advanced Study and Westlake University, Hangzhou 310030, China"},{"author_name":"Peng Wei","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Zeng-Hui Gu","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Ming-Yu Han","author_inst":"Institute for immunity, Transplantation and Infection, Stanford Medicine, Stanford University, 1215 Welch Road, Modular B Stanford, CA 94305, USA"},{"author_name":"Yue-Zhou Wu","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Jia-Sheng Yu","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Wang-Jun Chen","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Zhen-Rui Liao","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Jia-Xuan Gu","author_inst":"Institute of Basic Medical Sciences, Westlake Institute for Advanced Study and Westlake University, Hangzhou 310030, China"},{"author_name":"Jia-Dong Zhong","author_inst":"Institute of Basic Medical Sciences, Westlake Institute for Advanced Study and Westlake University, Hangzhou 310030, China"},{"author_name":"Pian-Pian Zhao","author_inst":"School of Basic Medical Sciences, Suzhou Medical College of Soochow University Suzhou, Jiangsu, China"},{"author_name":"Ke Zhu","author_inst":"School of Basic Medical Sciences, Suzhou Medical College of Soochow University Suzhou, Jiangsu, China"},{"author_name":"Ching-Lung Cheung","author_inst":"The University of Hong Kong"},{"author_name":"David Karasik","author_inst":"Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel"},{"author_name":"Hou-Feng Zheng","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"}],"rel_date":"2026-09-13","rel_site":"medrxiv"},{"rel_title":"Resolving the Genomic Context of Clinically Relevant Antibiotic Resistance Genes in Wastewater with Ligation-Mediated PCR","rel_doi":"10.64898\/2026.09.09.26361541","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26361541","rel_abs":"Abstract Antimicrobial resistance (AMR) is a pressing global public health challenge. AMR is driven in part by the spread of antibiotic resistance genes (ARGs) through bacterial communities via mobile genetic elements. Influent wastewater is a promising sample type for monitoring AMR because it pools biological inputs shed by individuals across a population. However, untargeted sequencing approaches, such as metagenomic sequencing, often miss low-abundance targets such as clinically important ARGs. In this work, we develop a ligation-mediated PCR (LM-PCR) enrichment strategy that can directionally capture the genomic context surrounding an ARG using long-read sequencing. We applied this method to study the natural genomic context diversity of four clinically relevant ARGs (blaCTX-M, blaKPC, and blaOXA-48-like, and qnrS) across 13 wastewater treatment plants in Washington state, each sampled at two timepoints. Across all timepoints, LM-PCR identified distinct genomic context cluster families associated with each ARG, including seven for blaKPC, 11 for blaCTX-M, 24 for qnrS, and one for blaOXA-48-like. Notably, 11 of the 24 qnrS containing clusters were putatively novel, with no matches to existing sequences in public databases. Genomic contexts associated with blaCTX-M and blaKPC were comparatively conserved across clusters, whereas qnrS was associated with a more diverse set of genetic sequences. Together, these results demonstrate that LM-PCR can resolve low-abundance, ARG-associated genomic variation in complex wastewater samples and provide a scalable framework for tracking the dissemination of clinically relevant AMR determinants.","rel_num_authors":15,"rel_authors":[{"author_name":"Megan E O'Brien","author_inst":"University of Washington"},{"author_name":"Bradie Ahern","author_inst":"Washington State Department of Health"},{"author_name":"Piper Brase","author_inst":"Washington State Department of Health"},{"author_name":"Sooyeol Kim","author_inst":"The University of Sydney"},{"author_name":"Caroline E.M. McCormack","author_inst":"University of California, Berkeley"},{"author_name":"Denise Garcia","author_inst":"University of California, Berkeley"},{"author_name":"Erika Keim","author_inst":"Washington State Department of Health"},{"author_name":"Erin Dahl","author_inst":"Washington State Department of Health"},{"author_name":"Matthew Feck","author_inst":"Washington State Department of Health"},{"author_name":"Kelly Kauber","author_inst":"Washington State Department of Health"},{"author_name":"Jorge A Marchand","author_inst":"University of Washington"},{"author_name":"Rose S Kantor","author_inst":"Lawerence Livermore National Lab"},{"author_name":"Amy J Pickering","author_inst":"University of California, Berkeley"},{"author_name":"Breanna McArdle","author_inst":"Washington State Department of Health"},{"author_name":"Erica R Fuhrmeister","author_inst":"University of Washington"}],"rel_date":"2026-09-13","rel_site":"medrxiv"},{"rel_title":"Resolving the Genomic Context of Clinically Relevant Antibiotic Resistance Genes in Wastewater with Ligation-Mediated PCR","rel_doi":"10.64898\/2026.09.09.26361541","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26361541","rel_abs":"Abstract Antimicrobial resistance (AMR) is a pressing global public health challenge. AMR is driven in part by the spread of antibiotic resistance genes (ARGs) through bacterial communities via mobile genetic elements. Influent wastewater is a promising sample type for monitoring AMR because it pools biological inputs shed by individuals across a population. However, untargeted sequencing approaches, such as metagenomic sequencing, often miss low-abundance targets such as clinically important ARGs. In this work, we develop a ligation-mediated PCR (LM-PCR) enrichment strategy that can directionally capture the genomic context surrounding an ARG using long-read sequencing. We applied this method to study the natural genomic context diversity of four clinically relevant ARGs (blaCTX-M, blaKPC, and blaOXA-48-like, and qnrS) across 13 wastewater treatment plants in Washington state, each sampled at two timepoints. Across all timepoints, LM-PCR identified distinct genomic context cluster families associated with each ARG, including seven for blaKPC, 11 for blaCTX-M, 24 for qnrS, and one for blaOXA-48-like. Notably, 11 of the 24 qnrS containing clusters were putatively novel, with no matches to existing sequences in public databases. Genomic contexts associated with blaCTX-M and blaKPC were comparatively conserved across clusters, whereas qnrS was associated with a more diverse set of genetic sequences. Together, these results demonstrate that LM-PCR can resolve low-abundance, ARG-associated genomic variation in complex wastewater samples and provide a scalable framework for tracking the dissemination of clinically relevant AMR determinants.","rel_num_authors":15,"rel_authors":[{"author_name":"Megan E O'Brien","author_inst":"University of Washington"},{"author_name":"Bradie Ahern","author_inst":"Washington State Department of Health"},{"author_name":"Piper Brase","author_inst":"Washington State Department of Health"},{"author_name":"Sooyeol Kim","author_inst":"The University of Sydney"},{"author_name":"Caroline E.M. McCormack","author_inst":"University of California, Berkeley"},{"author_name":"Denise Garcia","author_inst":"University of California, Berkeley"},{"author_name":"Erika Keim","author_inst":"Washington State Department of Health"},{"author_name":"Erin Dahl","author_inst":"Washington State Department of Health"},{"author_name":"Matthew Feck","author_inst":"Washington State Department of Health"},{"author_name":"Kelly Kauber","author_inst":"Washington State Department of Health"},{"author_name":"Jorge A Marchand","author_inst":"University of Washington"},{"author_name":"Rose S Kantor","author_inst":"Lawerence Livermore National Lab"},{"author_name":"Amy J Pickering","author_inst":"University of California, Berkeley"},{"author_name":"Breanna McArdle","author_inst":"Washington State Department of Health"},{"author_name":"Erica R Fuhrmeister","author_inst":"University of Washington"}],"rel_date":"2026-09-13","rel_site":"medrxiv"},{"rel_title":"Assessing and refining a metabolite-based distress score for use in different populations within three US cohorts","rel_doi":"10.64898\/2026.09.10.26362734","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362734","rel_abs":"Introduction: Psychological distress is associated with metabolic alterations that contribute to adverse cardiometabolic outcomes across diverse populations. We previously developed a metabolite-based distress score (MDS) in predominantly White women. Because men and Black individuals suffer high rates of cardiometabolic disease, we evaluated whether the MDS is similarly associated with depression in these populations, and derived a multi-ethnic MDS (MDS-ME) among Black individuals with replications in independent samples. Methods: Data were from three U.S. cohorts, the Multi-Ethnic Study of Atherosclerosis (MESA), Women's Health Initiative (WHI), and Nurses' Health Study (NHS), evaluated in 4 stages. Stages 1-3 included 2,477 White and 1,625 Black MESA participants with depression status data and plasma metabolomics assessed at baseline. Stage 1: We calculated the MDS and examined its association with depression status. Stage 2: We conducted an agnostic analysis among a 70% random subset of Black participants to identify additional relevant metabolites. Stage 3: We derived an MDS-ME in Black participants. Stage 4: We evaluated the MDS-ME using independent samples from all three cohorts. Results: The previously validated 20-metabolite MDS showed stronger associations with prevalent depression in White (OR: 1.93, 95% CI: 1.71, 2.19) versus Black (OR: 1.13, 95% CI: 0.97, 1.33) MESA participants. Associations were generally similar in men and women. The MDS-ME comprised 33 metabolites, and relative to the MDS was more strongly associated with depression in Black participants (OR: 1.45; 95% CI: 1.04, 2.03), with associations also evident in White participants (OR: 1.81; 95% CI: 1.60, 2.04). The MDS-ME was similarly associated with depression in Black women in WHI and NHS. Conclusion: Results suggest that incorporating metabolites identified in Black participants enhances the utility and generalizability of the MDS across more diverse populations.","rel_num_authors":21,"rel_authors":[{"author_name":"Tianyi Huang","author_inst":"Intramural Research Program, National Institute on Aging"},{"author_name":"Yiwen Zhu","author_inst":"Harvard University"},{"author_name":"Raji Balasubramanian","author_inst":"University of Massachusetts Amherst"},{"author_name":"Andrea Roberts","author_inst":"Harvard University"},{"author_name":"Clary B Clish","author_inst":"Broad Institute"},{"author_name":"Julian Avila Pacheco","author_inst":"The Broad Institute of MIT and Harvard"},{"author_name":"Jerome Rotter","author_inst":"The Lundquist Institute"},{"author_name":"Xiuqing Guo","author_inst":"The Lundquist Institute"},{"author_name":"Jie Yao","author_inst":"The Lundquist Institute for Biomedical Innovation"},{"author_name":"Yii-Der Ida Chen","author_inst":"The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center"},{"author_name":"Steve Rich","author_inst":"Virginia"},{"author_name":"Kent Taylor","author_inst":"The Lundquist Institute"},{"author_name":"Alexis Wood","author_inst":"Baylor College of Medicine"},{"author_name":"W. Craig Johnson","author_inst":"University of Washington"},{"author_name":"Katherine H. Shutta","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Kathryn Rexrode","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Aladdin H Shadyab","author_inst":"University of California, San Diego"},{"author_name":"Su Yon Jung","author_inst":"University of California Los Angeles"},{"author_name":"JoAnn E Manson","author_inst":"Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;"},{"author_name":"Susan E. Hankinson","author_inst":"University of Massachusetts Amherst"},{"author_name":"Laura D. Kubzansky","author_inst":"Harvard TH Chan School of Public Health"}],"rel_date":"2026-09-13","rel_site":"medrxiv"},{"rel_title":"Digital readiness for cardiovascular care in high-burden US communities with cardiology workforce constraints","rel_doi":"10.64898\/2026.09.11.26362838","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362838","rel_abs":"Digital health may extend cardiovascular care in communities with limited specialist access, but its effectiveness depends on whether communities have the infrastructure, devices, affordability, and capacity needed to use digital services. We linked national data on cardiometabolic burden, cardiology workforce, and digital readiness across 82,999 US census tracts to identify communities where digital cardiovascular care could be deployed and those where enabling investment may be needed first. Among 49,948 tracts in 2,582 counties with no cardiologist or declining per-capita cardiologist supply, 26,517 had above-average cardiometabolic burden. Of these, 4,765 had digital readiness at or above the national median and were classified as deployment-priority tracts, whereas 21,752 had lower readiness and were classified as investment-priority tracts. Investment-priority tracts clustered in the rural Southwest, Deep South, Mississippi Delta, and Gulf and Florida metropolitan areas, whereas deployment-priority tracts were dispersed across urban counties nationwide. Contrasting classifications frequently occurred among neighboring census tracts within the same metropolitan area, highlighting geographic variation not captured by county-level targeting. Findings were broadly consistent across eight additional analyses varying measures of readiness, workforce access, and classification thresholds. We also developed public interactive dashboards that allow users to examine local patterns and modify classification thresholds. These findings provide a national framework for distinguishing communities where digital cardiovascular care may be deployed from those where infrastructure and adoption support may be needed to enable equitable implementation.","rel_num_authors":5,"rel_authors":[{"author_name":"Sudheesha Perera","author_inst":"Yale School of Medicine"},{"author_name":"Lovedeep Singh Dhingra","author_inst":"Yale School of Medicine"},{"author_name":"Bruno Batinica","author_inst":"Yale School of Medicine"},{"author_name":"Aline Pedroso","author_inst":"Yale School of Medicine"},{"author_name":"Rohan Khera","author_inst":"Yale School of Medicine"}],"rel_date":"2026-09-13","rel_site":"medrxiv"},{"rel_title":"Epigenetic Effects of HIV and Childhood Maltreatment in Women","rel_doi":"10.64898\/2026.09.11.26362833","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362833","rel_abs":"Introduction: People with HIV have disproportionately higher rates of adverse childhood experiences compared to the general population. This, in turn, is linked to long-term physical and mental health consequences. DNA methylation - a heritable, reasonably stable and quantifiable epigenetic mechanism implicated in gene silencing - may offer a useful lens that helps understand how HIV and childhood trauma become biologically embedded and affect disease risk profiles. Methods: This study aimed to identify regional and network level methylomic signatures associated with HIV and childhood maltreatment scores in South African women who bear the highest dual burden. DNA methylation profiling using the Illumina Infinium EPIC V2 kit was performed on DNA extracted from blood samples of 238 women with or without HIV with varying levels of childhood maltreatment. Regional DNA methylation analyses, composed of correlation tests on specific CpG sites and on genetic regions, were conducted for each of HIV and childhood maltreatment scores. Thereafter, a weighted gene Co-Expression Network Analysis (WGCNA) was conducted on HIV and childhood maltreatment scores to determine co-expression modules associated with the variable of interest. Finally, causal mediation analysis of the most significant network module was conducted to clarify the direction of association. Results: Neither HIV status nor childhood maltreatment was associated with DNA methylation at site-specific or regional levels. Network methylation effects were, however, observed, with three out of four network modules that were differentially methylated in HIV, implicating genes involved in immune pathways. One network module, composed of an abundance of genes relating to neurotransmitter functioning, was associated with childhood maltreatment. Both causal analyses implied that HIV and childhood maltreatment preceded the epigenetic effects. Conclusions: The findings suggest that DNA methylation in immune pathways may partially explain the immune and neurologic effects of HIV. The link between childhood maltreatment and neuronal processes warrants further investigation.","rel_num_authors":6,"rel_authors":[{"author_name":"Aqeedah Abbas Roomaney","author_inst":"Stellenbosch University"},{"author_name":"Sian Megan Joanna Hemmings","author_inst":"Stellenbosch University"},{"author_name":"Georgina Spies","author_inst":"University of Cape Town"},{"author_name":"Scott Lee Letendre","author_inst":"University of California San Diego"},{"author_name":"Soraya Seedat","author_inst":"Stellenbosch University"},{"author_name":"Jacqueline Samantha Womersley","author_inst":"University of Cape Town"}],"rel_date":"2026-09-13","rel_site":"medrxiv"},{"rel_title":"Decision Analysis Modeling Favors Optimal Influenza Vaccination in Late November or Early December","rel_doi":"10.64898\/2026.09.11.26362843","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362843","rel_abs":"Background: Waning vaccine protection and variable epidemic timing create a tradeoff between vaccinating before influenza circulation and preserving protection when disease burden is greatest. Existing guidance does not quantify the week that best balances this tradeoff. Objective: To estimate the optimal week for influenza vaccination while accounting for uncertainty in epidemic timing and vaccine protection. Design: Simulation-based probabilistic decision analysis. Setting: United States outpatient influenza surveillance from the 50 states and District of Columbia during the 2010\/11 through 2018\/19 and 2023\/24 through 2025\/26 seasons. Participants: People in the United States who would receive 1 influenza vaccine dose. Interventions: Vaccination during Morbidity and Mortality Weekly Report (MMWR) weeks 36 through 12. Measurements: We combined influenza-like illness (ILI) syndromic surveillance and influenza-specific data with uncertainty in epidemic timing, initial vaccine effectiveness, waning, and immune-response lag. For each candidate week, the model estimated direct protection against outpatient surveillance burden. Results: The primary model identified the optimal time to vaccinate as week 47, with weeks 47-48 being of similar utility. Our influenza-weighted outpatient analysis (ILI+) selected week 48. Compared with week 44, near the end of the current September-October guidance window, week 48 reduced modeled influenza-weighted outpatient burden by 50 visit equivalents per 10,000 weekly encounters. Limitations: The model assumed vaccination would occur, used outpatient surveillance burden rather than severe outcomes, and did not incorporate transmission effects. Conclusion: Under the primary waning model, these findings favor vaccinating during weeks 47-48, approximately late November through early December, for most one-dose recipients.","rel_num_authors":4,"rel_authors":[{"author_name":"Austin G Meyer","author_inst":"Baylor College of Medicine"},{"author_name":"Brittany N Rosales","author_inst":"University of Texas at Austin"},{"author_name":"Shihao Yang","author_inst":"Georgia Institute of Technology"},{"author_name":"Mauricio Santillana","author_inst":"Northeastern University"}],"rel_date":"2026-09-13","rel_site":"medrxiv"},{"rel_title":"Decision Analysis Modeling Favors Optimal Influenza Vaccination in Late November or Early December","rel_doi":"10.64898\/2026.09.11.26362843","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362843","rel_abs":"Background: Waning vaccine protection and variable epidemic timing create a tradeoff between vaccinating before influenza circulation and preserving protection when disease burden is greatest. Existing guidance does not quantify the week that best balances this tradeoff. Objective: To estimate the optimal week for influenza vaccination while accounting for uncertainty in epidemic timing and vaccine protection. Design: Simulation-based probabilistic decision analysis. Setting: United States outpatient influenza surveillance from the 50 states and District of Columbia during the 2010\/11 through 2018\/19 and 2023\/24 through 2025\/26 seasons. Participants: People in the United States who would receive 1 influenza vaccine dose. Interventions: Vaccination during Morbidity and Mortality Weekly Report (MMWR) weeks 36 through 12. Measurements: We combined influenza-like illness (ILI) syndromic surveillance and influenza-specific data with uncertainty in epidemic timing, initial vaccine effectiveness, waning, and immune-response lag. For each candidate week, the model estimated direct protection against outpatient surveillance burden. Results: The primary model identified the optimal time to vaccinate as week 47, with weeks 47-48 being of similar utility. Our influenza-weighted outpatient analysis (ILI+) selected week 48. Compared with week 44, near the end of the current September-October guidance window, week 48 reduced modeled influenza-weighted outpatient burden by 50 visit equivalents per 10,000 weekly encounters. Limitations: The model assumed vaccination would occur, used outpatient surveillance burden rather than severe outcomes, and did not incorporate transmission effects. Conclusion: Under the primary waning model, these findings favor vaccinating during weeks 47-48, approximately late November through early December, for most one-dose recipients.","rel_num_authors":4,"rel_authors":[{"author_name":"Austin G Meyer","author_inst":"Baylor College of Medicine"},{"author_name":"Brittany N Rosales","author_inst":"University of Texas at Austin"},{"author_name":"Shihao Yang","author_inst":"Georgia Institute of Technology"},{"author_name":"Mauricio Santillana","author_inst":"Northeastern University"}],"rel_date":"2026-09-13","rel_site":"medrxiv"},{"rel_title":"Trajectory of Hyper IgE complications","rel_doi":"10.64898\/2026.09.11.26362846","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362846","rel_abs":"Abstract Objective Our objective was to define the natural history of hyper IgE syndrome. Well, there have been a number of large cross-sectional studies. It has been difficult to provide anticipatory care for the growing adult population. Methods The USIDNET registry was used to identify patients with hyper IgE syndrome. We evaluated all patients regardless of genetic etiology. Complications were extracted as text from the problem list or ICD codes, and each complication was date stamped, which allowed us to estimate the age at which the complication arose. Results Many of the complications previously identified were seen in this cohort. The most feared complications were uncommon, however, developmental delay and psychosis affected nearly a fifth of the cohort which has not been previously reported. Conclusions As the number of adults with hyper IgE syndrome increases our awareness of late onset complications is important. Aspergillus and pneumatoceles were less common than seen in some other cohorts. However, the significant rate of psychosis will represent a significant challenge for clinicians.","rel_num_authors":11,"rel_authors":[{"author_name":"Asteria Mao","author_inst":"Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Rui Xiao","author_inst":"Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Kathleen E Sullivan","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Ramsay Fuleihan","author_inst":"Northwestern University School of Medicine, Chicago, IL"},{"author_name":"Charlotte Cunningham-Rundles","author_inst":"Icahn School of Medicine at Mount Sinai New York, NY, USA"},{"author_name":"Jennifer Puck","author_inst":"UCSF Benihoff Children's Hospital, University of California San Francisco"},{"author_name":"Rebecca Marsh","author_inst":"University of Cincinnati College of Medicine"},{"author_name":"Roshini Abraham","author_inst":"Nationwide Children's Hospital"},{"author_name":"Luigi Daniele Notarangelo","author_inst":"National Institute of Allergy and Infectious Diseases, NIH"},{"author_name":"Vaibhavi Vichare","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"- USIDNET Network members","author_inst":""}],"rel_date":"2026-09-13","rel_site":"medrxiv"},{"rel_title":"Longitudinal changes in control energy of brain networks in older adults at familial risk for Alzheimers disease","rel_doi":"10.64898\/2026.09.06.749740","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.06.749740","rel_abs":"The ability of structural brain networks to control neural dynamics is affected by healthy and pathological aging, including Alzheimers disease (AD). According to network control theory, transitions between functional brain states incur energetic costs. How these costs change longitudinally with aging remains unknown. Here, in 279 older adults at familial risk for AD, control energy increased longitudinally for state maintenance and transitions between sensorimotor and attentional networks, while decreasing for another sensorimotor--attentional transition. Changes in transition costs between higher-order networks were associated with cognitive performance: greater DorsAttn--Executive cost was associated with poorer immediate memory, while lower Executive--Def+Lim cost was associated with poorer attention. Higher plasma p-tau181 was associated with lower DorsAttn--Def+Lim transition cost. These findings reveal transition-specific alterations in the energetic landscape of aging and distinct relationships with cognition and AD pathology. Together, they highlight energetic constraints on brain network reconfiguration as a complementary perspective on neurocognitive aging.","rel_num_authors":11,"rel_authors":[{"author_name":"Paulina Skolasinska","author_inst":"McGill University"},{"author_name":"Alfie Wearn","author_inst":"McGill University"},{"author_name":"Daniel O'Sullivan","author_inst":"University of Ottawa"},{"author_name":"Isabella Stallworthy","author_inst":"University of Pennsylvania"},{"author_name":"Julia K Brynildsen","author_inst":"University of Pennsylvania"},{"author_name":"Ilana R Leppert","author_inst":"McGill University"},{"author_name":"Christine L Tardif","author_inst":"McGill University"},{"author_name":"Gary R Turner","author_inst":"York University"},{"author_name":"Dani S Bassett","author_inst":"University of Pennsylvania"},{"author_name":"R. Nathan Spreng","author_inst":"McGill University"},{"author_name":"- for the PREVENT-AD Research Group","author_inst":""}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"Longitudinal changes in control energy of brain networks in older adults at familial risk for Alzheimers disease","rel_doi":"10.64898\/2026.09.06.749740","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.06.749740","rel_abs":"The ability of structural brain networks to control neural dynamics is affected by healthy and pathological aging, including Alzheimers disease (AD). According to network control theory, transitions between functional brain states incur energetic costs. How these costs change longitudinally with aging remains unknown. Here, in 279 older adults at familial risk for AD, control energy increased longitudinally for state maintenance and transitions between sensorimotor and attentional networks, while decreasing for another sensorimotor--attentional transition. Changes in transition costs between higher-order networks were associated with cognitive performance: greater DorsAttn--Executive cost was associated with poorer immediate memory, while lower Executive--Def+Lim cost was associated with poorer attention. Higher plasma p-tau181 was associated with lower DorsAttn--Def+Lim transition cost. These findings reveal transition-specific alterations in the energetic landscape of aging and distinct relationships with cognition and AD pathology. Together, they highlight energetic constraints on brain network reconfiguration as a complementary perspective on neurocognitive aging.","rel_num_authors":11,"rel_authors":[{"author_name":"Paulina Skolasinska","author_inst":"McGill University"},{"author_name":"Alfie Wearn","author_inst":"McGill University"},{"author_name":"Daniel O'Sullivan","author_inst":"University of Ottawa"},{"author_name":"Isabella Stallworthy","author_inst":"University of Pennsylvania"},{"author_name":"Julia K Brynildsen","author_inst":"University of Pennsylvania"},{"author_name":"Ilana R Leppert","author_inst":"McGill University"},{"author_name":"Christine L Tardif","author_inst":"McGill University"},{"author_name":"Gary R Turner","author_inst":"York University"},{"author_name":"Dani S Bassett","author_inst":"University of Pennsylvania"},{"author_name":"R. Nathan Spreng","author_inst":"McGill University"},{"author_name":"- for the PREVENT-AD Research Group","author_inst":""}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"Clustering without clusters: the meta-criterion and centroid reliability mistake continuous dynamics for discrete states","rel_doi":"10.64898\/2026.09.06.749668","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.06.749668","rel_abs":"Microstate analysis starts with clustering and the meta-criterion is a heuristic to find an optimum cluster number. We address the following questions: (i) what number is found for non-cluster-forming dynamical systems, (ii) do centroids fall in random attractor regions, (iii) do EEG topographies form clusters or a single connected structure in sensor space? We find that (i) the meta-criterion suggests spurious optimal cluster numbers (4-8) with high confidence on different attractor geometries, (ii) cluster centroids reliably fall in the same attractor regions, (iii) topological analysis of dynamical systems and resting-state EEG suggests that all form a single connected structure in their respective phase space, not clusters. We conclude that the meta-criterion should be used with caution and its results should not be taken as representing a ground truth. Cluster numbers deviating from the meta-criterion should not be discarded. A more far-reaching implication is that evidence for the existence of clusters in resting-state EEG data is still lacking. Microstate clustering may correspond to the partitioning of a single connected structure.","rel_num_authors":2,"rel_authors":[{"author_name":"Frederic von Wegner","author_inst":"University of New South Wales"},{"author_name":"Gesine Hermann","author_inst":"Department of Neurology, Christian-Albrechts University, Arnold-Heller-Strasse 3, Kiel, 24105, Germany"}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"Large Language Models Predict Human Social Behavior via Interpretable Mechanisms","rel_doi":"10.64898\/2026.09.06.749667","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.06.749667","rel_abs":"The development of large language models (LLMs) offers promising opportunities for predicting human behavior across diverse contexts. However, most prior work has emphasized behavioral imitation, with limited attention to transparent or interpretable models of the cognitive mechanisms underlying human decisions. In this study, we introduce MindEvolve, an autonomous workflow designed to predict behavior in social interactions by generating interpretable symbolic models of cognition. We systematically evaluate the modeling capabilities of multiple LLMs across a battery of socioeconomic games covering four core domains of social cognition: economic preferences, social preferences, social reasoning (theory of mind), and recursive planning. The symbolic models proposed by the LLMs are assessed by expert human evaluators for interpretability and theoretical coherence. Our results show that while most LLMs robustly capture economic and social preferences in relatively simple strategic settings, and in some cases generate novel models that integrate broader knowledge than those proposed by human experts, their capacity to model more complex psychological processes remains limited. However, a subset of state-of-the-art models demonstrates promising performance in capturing higher-order reasoning processes such as theory of mind and recursive planning. Together, these findings highlight the emerging potential of LLMs not only to imitate behavior, but to generate interpretable, mechanistic accounts of human social decision-making. Our results provide a roadmap for advancing LLM-based cognitive modeling toward human-expert-level theory construction.","rel_num_authors":8,"rel_authors":[{"author_name":"Yingying Ye","author_inst":"East China Normal University"},{"author_name":"Youle Fang","author_inst":"Peking University"},{"author_name":"Xiaoxue Gao","author_inst":"East China Normal University"},{"author_name":"Vered Kurtz-David","author_inst":"Hebrew University of Jerusalem"},{"author_name":"Andreas Hula","author_inst":"Austrian Institute of Technology"},{"author_name":"Chun Fan","author_inst":"Peking University"},{"author_name":"Tingting Long","author_inst":"Peking University"},{"author_name":"Bo Shen","author_inst":"State Key Laboratory of Cognitive Science and Mental Health, Institute of Psychology, Chinese Academy of Sciences"}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"Structural Determinants of Synaptic Vesicle Protein 2C Ligand Selectivity and Their Impact on Dopamine Release","rel_doi":"10.64898\/2026.09.10.750697","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.10.750697","rel_abs":"The synaptic vesicle protein 2 (SV2) family is a highly conserved group of transmembrane glycoproteins sharing approximately 70% sequence identity. SV2A and SV2B are broadly distributed throughout the brain, while SV2C, the evolutionarily oldest member of the family, is primarily found in dopaminergic brain regions in the basal ganglia. Genome-wide association studies have linked SV2C to Parkinson's disease, and SV2C appears to enhance dopamine storage in synaptic vesicles, but the basis for this effect is unknown. SV2s are the target of the racetam class of antiseizure medications, and SV2A-specific ligands are widely used to treat seizures. Recently several SV2C-specific ligands have been developed, but the structural basis for ligand specificity is unclear. A better understanding of SV2C structure, function, and pharmacology could lead to better targeted therapies for epilepsy, Parkinson's disease, and other dopamine-related conditions. Here we present cryo-EM structures of apo SV2C, SV2C bound to the high affinity non-selective SV2 ligand padsevonil, SV2C bound to the SV2C-selective ligand UCB-F, and SV2A bound to the SV2A-selective ligand plosaracetam (also known as ABBV-552\/SDI-118). We find that SV2C has a wider luminal opening than SV2A and SV2B, which allows for UCB-F to bind to the primary site and form favorable interactions that are not possible in the narrower primary binding site of SV2A and SV2B. We also demonstrate that UCB-F and padsevonil, but not plosaracetam, reduce dopamine release in striatal sections of mouse brain. Our biochemical experiments and structures provide insights into SV2 ligand specificity and offer a template for the rational development of therapeutics targeting SV2C.","rel_num_authors":13,"rel_authors":[{"author_name":"Matthew F Martin","author_inst":"University of Pittsburgh"},{"author_name":"Meghan L Bucher","author_inst":"Columbia University"},{"author_name":"Seejon Choi","author_inst":"Columbia University"},{"author_name":"Anshumali Mittal","author_inst":"University of Pittsburgh"},{"author_name":"Eugene Mosharov","author_inst":"Columbia University"},{"author_name":"Adrian Hall","author_inst":"UCB"},{"author_name":"Christian Wolff","author_inst":"UCB"},{"author_name":"Michel Gillard","author_inst":"UCB"},{"author_name":"Laurent Provins","author_inst":"UCB"},{"author_name":"Peter S Horanyi","author_inst":"UCB"},{"author_name":"David Sulzer","author_inst":"Columbia University"},{"author_name":"Gary W Miller","author_inst":"Columbia University"},{"author_name":"Jonathan Coleman","author_inst":"University of Pittsburgh"}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"DDRKOL: A Focused CRISPR Library for Systematic Identification of DNA Damage Response Dependencies in Glioblastoma","rel_doi":"10.64898\/2026.09.11.750882","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.750882","rel_abs":"Background: DNA damage response (DDR) pathways are central regulators of genome maintenance and major determinants of cancer cell survival. The extensive genomic instability and high replicative stress that characterize glioblastoma render tumor cells highly dependent on DDR pathways to preserve genome integrity and sustain proliferation. This reliance creates potential therapeutic vulnerabilities, making the systematic identification of essential DDR genes a promising strategy for uncovering novel therapeutic targets. Methods: We developed DNA Damage Response KnockOut Library (DDRKOL), a custom CRISPR\/Cas9 sgRNA library targeting 819 DDR genes with approximately 10 sgRNAs per gene, together with positive (essential), negative (non-essential) and non-targeting controls. Parallel depletion screens were performed in Cas9-expressing U87-MG and A172 cells cultured for 15 population doublings. Hits were prioritized utilizing TCGA and DepMap databases and validated by viability, clonogenic, apoptosis and GFP competition assays. Clinically relevant patient-derived glioblastoma spheroids and an orthotopic xenograft model was employed to characterize the effects of hit genes. Results: Sequencing confirmed near-complete recovery of the designed sgRNAs from the plasmid pool, with uniform representation across the library and complexity preserved through transduction and selection. Essential-gene controls depleted strongly while non-targeting controls remained neutral, confirming screen performance in both cell lines. The screens identified DDR dependencies in each line and defined a shared core composed of 20 genes belonging to homologous recombination, nucleotide excision repair and ATM\/DSB signaling pathways. This shared dependency landscape highlighted four high-confidence candidate genes (TOP2A, CDK1, XRCC6, and RAD21), which were successfully validated across multiple orthogonal assays. These genes displayed grade-associated expression and their expressions were positively correlated with proliferation markers in TCGA. Individual knockouts reduced viability, colony formation and competitive fitness, induced apoptosis, and impaired growth of patient-derived glioblastoma spheroids. Both genetic depletion and pharmacological inhibition of TOP2A induced S\/G2-M cell cycle arrest. In orthotopic xenografts, TOP2A depletion prevented tumor progression, and led to significantly prolonged survival. Conclusion: DDRKOL represents a robust and versatile focused CRISPR platform for systematic functional interrogation of the DDR associated genes. Using glioblastoma, we demonstrate that the library reliably identifies biologically significant and clinically relevant genetic dependencies through multiple orthogonal validation approaches. As a reusable platform rather than a disease-specific tool, DDRKOL can be broadly applied across diverse biological contexts to discover context-dependent DDR vulnerabilities, therapeutic targets, and mechanisms of treatment resistance.","rel_num_authors":9,"rel_authors":[{"author_name":"Canan Bayraktar-Odabas","author_inst":"Koc University"},{"author_name":"Ipek Kok","author_inst":"Koc University"},{"author_name":"Altar Ozbiyik","author_inst":"Koc University"},{"author_name":"Alisan Kayabolen","author_inst":"Koc University"},{"author_name":"Ali Cenk Aksu","author_inst":"Koc University"},{"author_name":"Ayse Humeyra Dur Karasayar","author_inst":"Koc University"},{"author_name":"Ilknur Sur Erdem","author_inst":"Koc University"},{"author_name":"Ibrahim Kulac","author_inst":"Koc University"},{"author_name":"Tugba Bagci-Onder","author_inst":"Koc University"}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"Nonviral, ultrasound-triggered gene delivery platform via gas-core cationic nanobubbles","rel_doi":"10.64898\/2026.09.11.749060","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.749060","rel_abs":"Despite their promise, lipid nanoparticle gene delivery systems have repeatedly failed clinical trials and struggle to achieve efficient, localized transfection in target tissues. The majority of endocytosed nanoparticles are degraded before nucleic acid release, and an inability to track particle distribution in vivo prevents validation of successful delivery. Alternatively, nanobubbles (NBs) are lipid-shelled, gas-core preclinical ultrasound contrast agents and stimuli-responsive drug delivery vehicles. Under varying acoustic pressures, NBs expand, contract, and burst, releasing cargo in an externally controlled, site-specific manner while scattering unique echoes for simultaneous ultrasound visualization. Here, we introduce a cationic nanobubble (CNB) formulation with a +42.3 mV zeta potential, 265 nm diameter, and 2.43x1011 NBs\/mL concentration. CNBs produce stable ultrasound contrast, electrostatically load plasmid DNA onto their surface, and internalize into >99% of human prostate cancer cells within 15 minutes in vitro. CNBs remain brightly echogenic intracellularly and induce sonication-dependent expression of green fluorescent protein (GFP). In vivo, CNBs generate contrast in mouse livers for 50 minutes after intravenous administration. Therapeutic ultrasound stimulation over the liver causes a sharp reduction in ultrasound contrast, visualizing localized cavitation in the target organ and inducing a 2.5-fold increase in anti-GFP mean fluorescence intensity relative to the untransfected control. Importantly, no GFP expression is observed without ultrasound stimulation, supporting a mechanism for selective and site-specific gene delivery. This study presents a highly stable CNB capable of efficient DNA loading and ultrasound-dependent gene expression. These results provide a foundation for the future development of CNB platforms to advance image-guided, ultrasound-triggered gene therapy.","rel_num_authors":18,"rel_authors":[{"author_name":"Laura E. Chen","author_inst":"Case Western Reserve University"},{"author_name":"Pinunta Nittayacharn","author_inst":"Mahidol University"},{"author_name":"Aayushi Laliwala","author_inst":"Case Western Reserve University"},{"author_name":"Marcus Vincent Bella Jaro","author_inst":"Case Western Reserve University"},{"author_name":"Salima El Yakhlifi","author_inst":"Case Western Reserve University"},{"author_name":"Jean F. Eastman","author_inst":"Case Western Reserve University"},{"author_name":"Xu Han","author_inst":"Case Western Reserve University"},{"author_name":"Aaqib H. Khan","author_inst":"Case Western Reserve University"},{"author_name":"Kathryn HartMoore","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Fatma Dogan","author_inst":"Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School"},{"author_name":"Valentina F. Giai","author_inst":"Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School"},{"author_name":"Timothy Brauns","author_inst":"Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School"},{"author_name":"Mark C. Poznansky","author_inst":"Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School"},{"author_name":"Richard K.P. Benninger","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Marvin T. Nieman","author_inst":"Case Western Reserve University"},{"author_name":"Ilya Bederman","author_inst":"Case Western Reserve University"},{"author_name":"Mitchell L. Drumm","author_inst":"Case Western Reserve University"},{"author_name":"Agata A. Exner","author_inst":"Case Western Reserve University"}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"A genetically encoded redox bottleneck constrains human developmental rate","rel_doi":"10.64898\/2026.09.10.750701","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.10.750701","rel_abs":"The intrinsically slow pace of human development poses challenges for regenerative medicine and disease modeling. This trait is attributed to low metabolic rates, yet the endogenous mechanisms determining species-specific metabolic flux remain unknown. Here, we identify coupling between glycolytic NADH production and mitochondrial oxidation through the glycerol-3-phosphate (G3P) shuttle as a genetic bottleneck constraining human developmental tempo. Using stem cell-derived models of the segmentation clock, an oscillator whose period reflects developmental rate, we show that low expression of the G3P shuttle enzyme GPD1L limits NADH oxidation in human progenitors compared to mouse. Overexpressing GPD1L boosts metabolic flux, accelerating the segmentation clock, cell cycle, and differentiation across germ layers. G3P-mediated redox coupling is thus a genetically encoded, rate-limiting mechanism that sets the tempo of human development.","rel_num_authors":15,"rel_authors":[{"author_name":"Gabriel E. Valdebenito","author_inst":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA"},{"author_name":"Jack P. Madden","author_inst":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA"},{"author_name":"Carolina Mendez","author_inst":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA"},{"author_name":"Leslie M. Azurdia","author_inst":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA"},{"author_name":"Xintao Zhu","author_inst":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; D"},{"author_name":"Siyu Chen","author_inst":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA"},{"author_name":"Diana Atlas","author_inst":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA"},{"author_name":"Katherine Introcaso","author_inst":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA"},{"author_name":"Hao Zhang","author_inst":"Center of Mass Spectrometry & Metabolic Tracing, Washington University in St. Louis, St. Louis, MO, USA; Department of Chemistry, Washington University in St. L"},{"author_name":"Yahui Wang","author_inst":"Center of Mass Spectrometry & Metabolic Tracing, Washington University in St. Louis, St. Louis, MO, USA; Department of Chemistry, Washington University in St. L"},{"author_name":"Fangcong Dong","author_inst":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Howard Hughes Medical Institute, Boston, MA, USA; Department of Systems "},{"author_name":"Rohit Sharma","author_inst":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Howard Hughes Medical Institute, Boston, MA, USA; Department of Systems "},{"author_name":"Vamsi K. Mootha","author_inst":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Howard Hughes Medical Institute, Boston, MA, USA; Department of Systems "},{"author_name":"Gary J. Patti","author_inst":"Center of Mass Spectrometry & Metabolic Tracing, Washington University in St. Louis, St. Louis, MO, USA; Department of Chemistry, Washington University in St. L"},{"author_name":"Margarete Diaz-Cuadros","author_inst":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA"}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"A transitional senescence program drives inflammatory monocyte state expansion in aging humans","rel_doi":"10.64898\/2026.09.09.750459","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750459","rel_abs":"Dysfunctional monocyte states contribute to age-related pathologies and systemic inflammation. However, the gene regulatory networks governing the transition to these states remain unknown. Here we used bulk and single-cell multidimensional integrative profiling to reveal previously uncharacterized monocyte state transitions during human aging. We show that a transient senescent-like population arising from classical CD14++ CD16- monocytes drives the accumulation of an inflammatory monocyte state in aging humans. This senescence-associated transition is orchestrated by the master senescence regulator AP-1, which acts on a pre-established chromatin landscape to rewire the monocyte transcription factor (TF) network and activate both senescence- and age-associated inflammatory transcriptional programs. Through integration with clinical transcriptomic datasets, we demonstrate that senescent-like and aged monocytes are transcriptionally primed toward sepsis-associated states. Overall, our study provides the core gene-regulatory principles underlying a senescent-like transitional state in monocytes and identifies AP-1 as an attractive target to modulate systemic inflammation in age and disease.","rel_num_authors":8,"rel_authors":[{"author_name":"Themistoklis Vasilopoulos","author_inst":"Department of Pharmacology, Rutgers-Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ, USA."},{"author_name":"Paolo S Turano","author_inst":"Rutgers-New Jersey Medical School, Center for Cell Signaling, Department of Microbiology, Biochemistry and Molecular Genetics, 205 South Orange Avenue, Newark, "},{"author_name":"Luis Garza-Martinez","author_inst":"Rutgers-New Jersey Medical School, Department of Pathology, Immunology, and Laboratory Medicine, 185 South Orange Avenue, Newark, NJ, USA"},{"author_name":"Elizabeth Akbulut","author_inst":"Rutgers-New Jersey Medical School, Department of Pathology, Immunology, and Laboratory Medicine, 185 South Orange Avenue, Newark, NJ, USA"},{"author_name":"Mounika Konda","author_inst":"Department of Pharmacology, Rutgers-Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ, USA."},{"author_name":"Utz Herbig","author_inst":"Rutgers-New Jersey Medical School, Center for Cell Signaling, Department of Microbiology, Biochemistry and Molecular Genetics, 205 South Orange Avenue, Newark, "},{"author_name":"Patricia Fitzgerald-Bocarsly","author_inst":"Rutgers-New Jersey Medical School, Department of Pathology, Immunology, and Laboratory Medicine, 185 South Orange Avenue, Newark, NJ, USA"},{"author_name":"Ricardo Ivan Martinez Zamudio","author_inst":"Department of Pharmacology, Rutgers-Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ, USA."}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"Demography and selection shape gene loss in freshwater sticklebacks - A pangenomic perspective","rel_doi":"10.64898\/2026.09.08.750278","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750278","rel_abs":"The extent of within-species variation in genome assembly size, and the relative contributions of neutral vs. adaptive processes to it, remains poorly understood. We assembled the pangenome for the nine-spined stickleback (Pungitius pungitius) from whole-genome resequencing data obtained from range-wide sampling of 1,478 individuals across 47 populations. Our analysis recovered approximately 234.15 Mb of novel sequence and identified 11,151 protein-coding genes annotated in non-reference-represented regions, which accounted for 28.8% of all annotated pangenomic genes, corresponding to a 40.6% expansion relative to the 27,450 protein-coding genes annotated in the updated v8 reference genome. The identified presence\/absence variation (PAV) genes exhibited a higher incidence of deleterious and non-synonymous mutations than core genes. Freshwater populations with smaller effective population sizes had lost more genes and had smaller assembly sizes relative to larger marine populations. Larger genome sizes of marine populations were primarily associated with higher transposable element content. Across gene categories, patterns of molecular variation were consistent with weaker purifying selection in freshwater populations than in marine populations, while recurrent freshwater-biased loss of a subset of PAV genes suggested that gene loss is not entirely random. Together, these results indicate that demographic history explains the overall pattern of gene loss, whereas negative natural selection may contribute to repeated loss of a subset of genes.","rel_num_authors":5,"rel_authors":[{"author_name":"Hongbo Wang","author_inst":"The University of Hong Kong"},{"author_name":"Chaowei Zhang","author_inst":"The University of Hong Kong, Area of Ecology & Biodiversity, School of Biological Sciences"},{"author_name":"Dandan Wang","author_inst":"The University of Hong Kong, Area of Ecology & Biodiversity, School of Biological Sciences"},{"author_name":"Kerry Reid","author_inst":"The University of Hong Kong"},{"author_name":"Juha Merila","author_inst":"The University of Hong Kong"}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"Multigenerational machine learning-based genomic prediction for dermo resistance in eastern oyster Crassostrea virginica","rel_doi":"10.64898\/2026.09.08.750100","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750100","rel_abs":"Dermo disease caused by the protist Perkinsus marinus poses a major threat to Eastern oyster aquaculture. We previously conducted genomic selection for dermo resistance and found increased effectiveness over phenotypic selection. Here, we report improved genomic predictions using combined data from three successive generations. We evaluated nine different genomic selection models, including three supervised machine learning architectures: gradient boosting, logistic regression, and random forest. Combining data across multiple generations did not, by itself, substantially improve the accuracy of most models, but the increased sample size provided genotyping confidence of loci with rare alleles. Correlation accuracy of all models significantly increased with the inclusion of low-frequency variants and strong-effect markers identified through a genome-wide association study. Gradient boosting machine learning models outperformed other genomic selection models across all training scenarios, suggesting enhanced capacity to learn generalizable genomic signals associated with dermo resistance. The best gradient boosting model achieved a peak correlation accuracy of 0.410, a substantial improvement over the previous peak accuracy of 0.274 from traditional models. Together, our results highlight the potential of machine learning for genomic selection and the significance of rare variants in determining dermo resistance.","rel_num_authors":10,"rel_authors":[{"author_name":"Henry Sun","author_inst":"Duke University"},{"author_name":"Paul Coyne","author_inst":"Rutgers University"},{"author_name":"Zhenwei Wang","author_inst":"Rutgers University"},{"author_name":"Sandra Casas","author_inst":"Louisiana State University"},{"author_name":"Jerome La Peyre","author_inst":"Louisiana State University"},{"author_name":"Mason L Williams","author_inst":"Auburn University"},{"author_name":"Scott Rikard","author_inst":"Auburn University"},{"author_name":"David Bushek","author_inst":"Rutgers University"},{"author_name":"Juliet Wong","author_inst":"Duke University"},{"author_name":"Ximing Guo","author_inst":"Rutgers University"}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"Delta rhythm and voice familiarity organize neural entrainment in the infant brain","rel_doi":"10.64898\/2026.09.10.750698","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.10.750698","rel_abs":"The delta frequency band (~0.5-3.5 Hz) represents a phylogenetically conserved tempo of biological communication, and neural entrainment to this timescale would be a key mechanism through which the brain might generate temporal predictions. While entrainment at different levels has been characterized in adults, the mechanisms of auditory temporal prediction remain poorly studied across developmental trajectories, particularly regarding the roles of stimulus rhythmicity, frequency specificity, and voice familiarity. Using high-density EEG, we examined neural entrainment in thirty 6-month-old infants exposed to vocally rhythmic syllables produced by their mother or a stranger at delta (2 Hz) or theta (4 Hz) rates, as well as a non-rhythmic control. Auditory temporal regularity elicited a broad frontotemporal entrainment response. Critically, delta-band entrainment was frequency-specific across frontal and temporal clusters, with right-frontal selectivity progressively strengthening throughout the entrainment period as expected if this region actively refines a temporal model of the input rather than passively resonating to it; no significant theta-band specificity was observed. Entrainment was further shaped by voice familiarity: the left temporal cortex entrained selectively to the mother's voice, whereas the right frontal cluster responded selectively to the stranger's voice. This is consistent with an implementation in which familiarity-based processing within mid-temporal language-related regions interfaces with novelty-sensitive frontal mechanisms, and reflects the ongoing updating of internal predictive models rather than passive sensory registration. The co-occurrence of frequency-specific delta entrainment and experience-dependent hemispheric asymmetries reveals a neural functional network for hierarchical temporal predictions, shaped by early auditory experience and already in place at 6 months.","rel_num_authors":7,"rel_authors":[{"author_name":"Isabelle Rambosson","author_inst":"University of Geneva"},{"author_name":"Damien Benis","author_inst":"University of Geneva"},{"author_name":"Francisca Barcos-Munoz","author_inst":"University Hospitals of Geneva"},{"author_name":"Claire Kabdebon","author_inst":"CNRS"},{"author_name":"Leonardo Ceravolo","author_inst":"Universoty of Geneva"},{"author_name":"Didier Grandjean","author_inst":"University of Geneva"},{"author_name":"Manuela Filippa","author_inst":"University of Geneva"}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"Neural tracking of surprisal and semantic distance in naturalistic movie viewing","rel_doi":"10.64898\/2026.09.09.749230","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.749230","rel_abs":"Understanding speech requires listeners to integrate incoming input with prior linguistic and thematic knowledge to access meaning, a task greatly aided by prediction. Surprisal and related phenomena (e.g., next word prediction) tend to be associated with broad activation of language regions during listening. A major challenge for interpreting the neural correlates of surprisal is that lexical expectancies are constrained both by syntactic and semantic information. In contrast, semantic distance yields more of a pure metric of relatedness between one language constituent (e.g., word, phrase, n-gram) and another within a high-dimensional semantic space. We contrasted surprisal and semantic distance in running discourse during naturalistic audiovisual language comprehension. We analyzed fMRI scans from 20 English-speaking adults who viewed the full-length film 500 Days of Summer. Our focus was on brain sensitivity to either surprisal or semantic distance as language unfolded word-by-word. To this end, we implemented a series of hierarchical voxelwise encoding models. After accounting for low-level auditory and visual features, the addition of either surprisal or semantic distance improved prediction in bilateral superior temporal gyrus (STG), left inferior frontal gyrus, and right cerebellum. Critically, both semantic distance and surprisal explained unique variation in bilateral temporal cortex after accounting for the other. These results support the notion that the brain tracks both broad probabilistic prediction as well as semantic integration. More generally, these findings extend previous work on auditory-only speech by demonstrating that surprisal and semantic distance predict meaningful neural variation even within a rich audiovisual context.","rel_num_authors":5,"rel_authors":[{"author_name":"Ryan M. O'Leary","author_inst":"Northeastern"},{"author_name":"Hailey C. Smith","author_inst":"Northeastern University"},{"author_name":"Emily B. Myers","author_inst":"University of Connecticut"},{"author_name":"Jamie Reilly","author_inst":"Temple"},{"author_name":"Jonathan E Peelle","author_inst":"Northeastern University"}],"rel_date":"2026-09-13","rel_site":"biorxiv"},{"rel_title":"Speech Intelligibility Index (SII) as a Potential Referral Metric for Adult Cochlear Implant Candidacy Evaluation","rel_doi":"10.64898\/2026.09.10.26362790","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362790","rel_abs":"Objectives: The purpose of this pilot study was to investigate (1) if the Speech Intelligibility Index (SII) could be used to identify ears that meet cochlear implant (CI) candidacy beyond the \"60\/60\" referral guidelines and (2) investigate the relationship between SII from patients' own hearing aids (HAs) and SII from optimally fit clinic-stock HAs such that a patient's own HAs can act as a proxy for an optimally fit HA and thus as a referral metric. Design: Prospective study of 23 participants ([&ge;] 18 years) with bilateral moderate to profound sensorineural hearing loss who were CI candidates in at least one ear. SII-Clinic (SII-C) values were recorded with probe-microphone measures using a Verifit II device (NAL-N2 targets) with speech stimuli presented at 60 dB A during patient CI evaluation in either their own HAs or clinic-stock HAs. SII values from participants' own HAs were recorded as part of a larger research protocol, thus SII-Personal (SII-P), with probe-microphone measures using a Verifit I device (NAL-RP targets) with pink noise stimuli presented at 65 dB A. Participants that did not wear HAs did not have SII-P calculated. Data was collapsed across ears. Correlation analysis between SII and best-aided consonant-nucleus-consonant (CNC) was conducted. Benchmark SII values were extrapolated using a best-fit line and CI candidacy rates reflecting various aided CNC scores that could be applied across CI centers. Nested logistic regression models were used to determine if the SII-C could improve model fit beyond the revised ear-specific 60\/60 referral guideline. The relationship between SII-C and SII-P was assessed with Wilcoxon signed-rank test and Spearman correlation. Results: Correlation between SII-C and aided CNC score was r = 0.82 (p < 0.001), and the correlation between SII-P and aided CNC was r = 0.46 (p = 0.014). Extrapolated benchmarks of SII were calculated based on different CNC candidacy cutoffs, and benchmarks were able to capture at least 83% of the ears that met CNC candidacy cutoffs. SII was also found to improve model fit with word recognition score (WRS) and pure tone average (PTA) for 60% CNC candidacy cutoff ({chi}2 = 9.7; p = 0.002) and increased discrimination (AUC = 0.89 to AUC = 0.99). There was no significant difference between SII-C and SII-P using the Wilcoxon signed-rank test (p = 0.559). Conclusions: A larger study is needed that includes more ears that do not qualify for a CI; however, the results of this study demonstrate that (1) SII has the potential to be used in conjunction with the 60\/60 referral guideline for CI candidacy evaluations and (2) SII can be used as a marker of audibility across different devices, including patients' own HAs, making SII an accessible metric during HA fittings and fine tunings.","rel_num_authors":4,"rel_authors":[{"author_name":"Jennifer A Kong","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Terrin N Tamati","author_inst":"The Ohio State University"},{"author_name":"Aaron C Moberly","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jonathan D Neukam","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-09-12","rel_site":"medrxiv"},{"rel_title":"AI detects a distributed blood metabolomic Systemotype associated with early stage ovarian cancer","rel_doi":"10.64898\/2026.09.10.26362758","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362758","rel_abs":"Early detection of ovarian cancer remains a clinical challenge because available blood biomarkers lack the sensitivity and specificity required for population screening. We tested whether early-stage ovarian cancer is associated with a distributed physiological state in the circulating metabolome. We analyzed untargeted metabolomic profiles from two independent retrospective cohorts: 91 serum samples (59 ovarian cancer, 32 healthy controls) and 83 plasma samples (63 ovarian cancer, 20 healthy controls). Assay-specific boosted decision trees were trained and evaluated independently within each cohort using five-fold cross-validation repeated over 50 randomized rounds. At selected operating points, mean cross-validated sensitivity and specificity were 99.0% and 99.8% in serum and 97.7% and 99.7% in plasma. Restricting inputs to strongly dysregulated features did not improve the overall sensitivity false positive rate trade off, and smaller panels reduced sensitivity. The cohorts shared 239 concordantly altered annotated features spanning lipid, amino-acid, steroid, central-carbon, and redox metabolism. These findings are consistent with a distributed metabolic response involving tumor and host, although tissue contributions were not measured. We propose that the classifier recognizes a metabolomic Systemotype, an integrated physiological state reflected in circulating metabolites. The results support further investigation of this framework.","rel_num_authors":4,"rel_authors":[{"author_name":"Hongyi Zhou","author_inst":"Georgia Institute of Technology"},{"author_name":"Jean-Luc Chaubard","author_inst":"OmicsIQ LLC"},{"author_name":"Benedict Benigno","author_inst":"Ovarian Cancer Institute"},{"author_name":"Jeffrey Skolnick","author_inst":"Georgia Tech"}],"rel_date":"2026-09-12","rel_site":"medrxiv"},{"rel_title":"Polygenic Risk and Genetic Predisposition in Post-Traumatic Epilepsy: A Framework for Risk Estimation","rel_doi":"10.64898\/2026.09.10.26362755","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362755","rel_abs":"Background Post-traumatic epilepsy (PTE) can be a lifelong complication of traumatic brain injury (TBI). We hypothesize that PTE develops according to a Two-Hit Hypothesis, in which the first hit is a genetic predisposition and the second hit is the TBI. Using two independent datasets, we provide the first evidence that PTE is a polygenic disorder, and we propose a whole-exome sequencing (WES) based framework to estimate the risk of developing PTE. Methods From a pool of thousands of screened veterans, we recruited a cohort of PTE subjects (n=28) and a control cohort of TBI subjects without PTE (n=22) and then performed WES. Approximately 375000 variants identified in each subject were compared to approximately 15000 verified epilepsy-associated variants from ClinVar. Fisher's exact test was used to identify variants associated with PTE, which were subsequently classified as either PTE-prone or PTE-protective. Odds ratios (ORs) were calculated at both the variant and subject levels. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive model. A second dataset was used to validate the model, and logistic calibration was performed to estimate the probability of developing PTE. Results Thirty PTE-prone and 56 PTE-protective variants were identified, with corresponding large-effect ORs. ROC analysis demonstrated excellent discrimination (AUC=0.97). Polygenic variant patterns differed between cohorts, with a predominance of PTE-prone variants in affected individuals and PTE-protective variants in controls. Conclusion Our findings support a polygenic framework consistent with the Two-Hit Hypothesis. In addition, we developed a framework to estimate individual polygenic risk for PTE.","rel_num_authors":6,"rel_authors":[{"author_name":"James WY Chen","author_inst":"VAGLAHS"},{"author_name":"Cindy Le","author_inst":"VAGLAHS"},{"author_name":"Kathleen Cui","author_inst":"VAGLAHS"},{"author_name":"Olga M Alexeeva","author_inst":"VAGLAHS"},{"author_name":"Janice Joo","author_inst":"VAGLAHS"},{"author_name":"Julia Bailey","author_inst":"VAGLAHS"}],"rel_date":"2026-09-12","rel_site":"medrxiv"},{"rel_title":"Caregiver-Rated Inappropriate Speech and Post-cTBS Motor Cortical Facilitation in Autism: A Pilot Biomarker Study","rel_doi":"10.64898\/2026.09.10.26362749","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362749","rel_abs":"Transcranial magnetic stimulation can provide noninvasive measures of cortical excitability and plasticity, but relationships between these measures and clinically observable features of autism are not fully characterized. Nineteen autistic participants aged 15 to 40 years were included in the analysis of a left primary motor cortex continuous theta-burst stimulation (cTBS) biomarker protocol. Motor evoked potentials were measured at baseline and at seven assessments from 5 to 60 min after stimulation. Linear mixed-effects models evaluated whether clinical measures moderated the post-stimulation motor evoked potential log-response ratio over time. Aberrant Behavior Checklist (ABC) and Attenuated Behavior Questionnaire (ABQ) analyses were restricted to the same 15 participants with caregiver-informant assessments. Catatonia severity, social impairment, ABQ Motor Total, ABQ Total, and cognitive ability did not significantly moderate the post-stimulation response. ABC Inappropriate Speech was associated with progressively greater post-stimulation facilitation (standardized Time-by-Inappropriate Speech interaction: beta = +0.688, SE = 0.210, 95% CI +0.276 to +1.099; Holm-adjusted P = .008 across eight informant-rated models). Two individual speech-related items (\"Talks excessively\" and \"Talks to self loudly\") survived false-discovery-rate correction. An exploratory eight-item ABC phenotype showed a large descriptive in-sample association (beta = +0.904, SE = 0.200, P less than .001) and directionally positive held-out performance. However, full-pipeline permutation tests were nonsignificant for both Pearson (r = .357, two-sided empirical P = .360) and Spearman correlations (rho = .446, two-sided empirical P = .261). Caregiver-rated inappropriate speech may be associated with altered post-cTBS motor cortical facilitation in autism. The candidate phenotype remains hypothesis-generating and requires independent validation.","rel_num_authors":12,"rel_authors":[{"author_name":"Joshua Ryan Smith","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Maria Bonnee","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sarah Marler","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rowan Atwood","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Brianna Lewis","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Seri Lim","author_inst":"Widener University, Institute of Graduate Clinical Psychology"},{"author_name":"Isaac Baldwin","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Hao Wu","author_inst":"Vanderbilt University"},{"author_name":"Jinyuan Liu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Carissa Cascio","author_inst":"University of Kansas"},{"author_name":"Gagan Joshi","author_inst":"Massachusetts General Hospital"},{"author_name":"Paul Ryan Croarkin","author_inst":"Mayo Clinic Rochester"}],"rel_date":"2026-09-12","rel_site":"medrxiv"},{"rel_title":"Caregiver-Rated Inappropriate Speech and Post-cTBS Motor Cortical Facilitation in Autism: A Pilot Biomarker Study","rel_doi":"10.64898\/2026.09.10.26362749","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362749","rel_abs":"Transcranial magnetic stimulation can provide noninvasive measures of cortical excitability and plasticity, but relationships between these measures and clinically observable features of autism are not fully characterized. Nineteen autistic participants aged 15 to 40 years were included in the analysis of a left primary motor cortex continuous theta-burst stimulation (cTBS) biomarker protocol. Motor evoked potentials were measured at baseline and at seven assessments from 5 to 60 min after stimulation. Linear mixed-effects models evaluated whether clinical measures moderated the post-stimulation motor evoked potential log-response ratio over time. Aberrant Behavior Checklist (ABC) and Attenuated Behavior Questionnaire (ABQ) analyses were restricted to the same 15 participants with caregiver-informant assessments. Catatonia severity, social impairment, ABQ Motor Total, ABQ Total, and cognitive ability did not significantly moderate the post-stimulation response. ABC Inappropriate Speech was associated with progressively greater post-stimulation facilitation (standardized Time-by-Inappropriate Speech interaction: beta = +0.688, SE = 0.210, 95% CI +0.276 to +1.099; Holm-adjusted P = .008 across eight informant-rated models). Two individual speech-related items (\"Talks excessively\" and \"Talks to self loudly\") survived false-discovery-rate correction. An exploratory eight-item ABC phenotype showed a large descriptive in-sample association (beta = +0.904, SE = 0.200, P less than .001) and directionally positive held-out performance. However, full-pipeline permutation tests were nonsignificant for both Pearson (r = .357, two-sided empirical P = .360) and Spearman correlations (rho = .446, two-sided empirical P = .261). Caregiver-rated inappropriate speech may be associated with altered post-cTBS motor cortical facilitation in autism. The candidate phenotype remains hypothesis-generating and requires independent validation.","rel_num_authors":12,"rel_authors":[{"author_name":"Joshua Ryan Smith","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Maria Bonnee","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sarah Marler","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rowan Atwood","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Brianna Lewis","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Seri Lim","author_inst":"Widener University, Institute of Graduate Clinical Psychology"},{"author_name":"Isaac Baldwin","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Hao Wu","author_inst":"Vanderbilt University"},{"author_name":"Jinyuan Liu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Carissa Cascio","author_inst":"University of Kansas"},{"author_name":"Gagan Joshi","author_inst":"Massachusetts General Hospital"},{"author_name":"Paul Ryan Croarkin","author_inst":"Mayo Clinic Rochester"}],"rel_date":"2026-09-12","rel_site":"medrxiv"},{"rel_title":"Atrial Cardiomyopathy Refines Cardiovascular Mortality Risk Across Cardiometabolic Risk Factor Burden","rel_doi":"10.64898\/2026.09.09.26362666","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26362666","rel_abs":"Background: Electrocardiographic markers of atrial cardiomyopathy (AtCM) are associated with adverse cardiovascular outcomes. Whether AtCM further refines cardiovascular disease (CVD) mortality risk across increasing cardiometabolic risk factor (CMRF) burden is unclear. Methods: We analyzed 7,083 adults free of baseline CVD. AtCM was defined by the presence of [&ge;]1 ECG marker: prolonged P-wave duration [&ge;]120 ms in lead II, abnormal P-wave axis outside 0-75, or deep terminal negativity of the P wave in V1 <-100 V. CMRF burden was defined as the presence of 0, 1, or [&ge;]2 of hypertension, diabetes, and obesity. CVD mortality was ascertained through December 31, 2006. Results: Among 7,083 participants (mean age 58 years and 48% men), CVD mortality rates increased progressively across the six combined exposure groups. In a multivariable adjusted Cox proportional hazard analysis, AtCM identified higher-risk subgroups within each CMRF burden category, with risk increasing progressively across combined exposure groups and highest among participants with [&ge;]2 risk factors and AtCM (HR 2.25, 95% CI 1.75-2.87). In secondary analyses, a similar pattern was observed for individual CMRFs, with the combination of AtCM and hypertension, diabetes, or obesity conferring the highest risk compared with participants with neither condition (HR (95% CI): 1.58 (1.31-1.89); 2.08 (1.62-2.68); and 1.47 (1.19-1.82), respectively). Conclusions: ECG-defined AtCM refined CVD mortality risk across increasing CMRF burden. Individuals with both AtCM and multiple CMRFs had the highest risk. These findings support the potential role of ECG-based AtCM assessment as a scalable approach to improve cardiovascular risk stratification among individuals with CMRFs.","rel_num_authors":9,"rel_authors":[{"author_name":"Asem M Mohsen","author_inst":"Epidemiological Cardiology Research Center (EPICARE), Department of Cardiovascular Medicine, Wake Forest University School of Medicine"},{"author_name":"Moustafa Elnewishy","author_inst":"Epidemiological Cardiology Research Center (EPICARE), Department of Cardiovascular Medicine, Wake Forest University School of Medicine"},{"author_name":"Tarek Zaho","author_inst":"Cardiology department, Wake Forest School of Medicine"},{"author_name":"Patrick Cheon","author_inst":"Wake Forest School of Medicine"},{"author_name":"Brian C. Boursiquot","author_inst":"Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center"},{"author_name":"Parag A. Chevli","author_inst":"Department of Cardiovascular Medicine, Wake Forest University School of Medicine"},{"author_name":"Richard Kazibwe","author_inst":"Department of Internal Medicine, Wake Forest University School of Medicine"},{"author_name":"Prashant D. Bhave","author_inst":"Department of Cardiovascular Medicine, Wake Forest University School of Medicine"},{"author_name":"Elsayed Z. Soliman","author_inst":"Epidemiological Cardiology Research Center (EPICARE), Department of Cardiovascular Medicine, Wake Forest University School of Medicine"}],"rel_date":"2026-09-12","rel_site":"medrxiv"},{"rel_title":"Factors associated with a willingness to accept latent tuberculosis infection treatment among non-U.S.-born individuals: a situational choice experiment","rel_doi":"10.64898\/2026.09.09.26362665","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26362665","rel_abs":"Introduction Despite efforts to eliminate tuberculosis (TB) in the United States (U.S.), many individuals diagnosed with latent TB infection (LTBI) who are at increased risk of progressing to TB disease do not initiate TB preventive treatment. Methods Among adults receiving primary care in a federally qualified community health center in the San Francisco Bay Area, California, we conducted a cross-sectional online survey using a situational choice experiment to assess the circumstances in which individuals at risk for TB based on nativity would accept LTBI treatment. In 10 randomized choice tasks, participants answered whether or not they would accept LTBI treatment. In situations where LTBI treatment was accepted, participants were asked a follow-up question about whether they would change their response knowing that reinfection is still possible with LTBI treatment. Attributes assessed included risk level of progression to TB, side effects, changes to co-medication, cost, number of clinic visits, blood draws, and reinfection risk. We conducted a mixed-effects logistic regression to estimate factors associated with treatment acceptance and predicted acceptance across scenarios. Results Of 852 individuals who consented, 458 (53.8%) had complete responses and were included in the analysis. LTBI treatment was accepted in 69.4% of choice scenarios (3180\/4580); among scenarios where treatment was initially accepted, 91.5% of scenarios (2911\/3180) remained accepted when reinfection possibility was introduced. Compared to situations with low risk of TB progression, high TB progression risk increased the acceptance of LTBI treatment (adjusted odds ratio aOR 2.55, 95% Confidence Interval (CI) = 2.03-3.19). Compared with fatigue as a referent, risk of any liver injury\/inflammation (aOR 0.29, 95% CI = 0.22-0.38), gastrointestinal side effects (aOR 0.53, 95% CI 0.41-0.69), rash (aOR 0.62, 95% CI 0.48-0.80) and out-of-pocket cost of $100 (aOR 0.32, 95% CI = 0.26-0.41 compared to $0) were associated with lower acceptance of LTBI treatment. Conclusions The decision to accept LTBI treatment was sensitive to treatment characteristics, suggesting that shared decision-making should be broadly promoted among individuals diagnosed with or at risk of LTBI, particularly in diverse primary care settings serving individuals born in high TB burden countries, with attention to individual concerns such as cost and side effects to improve LTBI treatment uptake.","rel_num_authors":15,"rel_authors":[{"author_name":"Sutina Chou","author_inst":"University of California, San Francisco"},{"author_name":"H\u00e9l\u00e8ne E Aschmann","author_inst":"University of California, San Francisco"},{"author_name":"Amy Tang","author_inst":"North East Medical Services"},{"author_name":"Meagan Lee","author_inst":"North East Medical Services"},{"author_name":"Zinnia Dong","author_inst":"North East Medical Services"},{"author_name":"Kit Lui","author_inst":"North East Medical Services"},{"author_name":"Yuqian Ouyang","author_inst":"North East Medical Services"},{"author_name":"Gina Chen","author_inst":"North East Medical Services"},{"author_name":"Katya L Salcedo","author_inst":"California Department of Public Health"},{"author_name":"Matthew T Murrill","author_inst":"University of California, San Francisco"},{"author_name":"Mehabuba Rahman","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Jennifer Flood","author_inst":"California Department of Public Health"},{"author_name":"Andrew Kerkhoff","author_inst":"University of California, San Francisco"},{"author_name":"Priya B Shete","author_inst":"University of California San Franciso"},{"author_name":"Tracy K Lin","author_inst":"University of California, San Francisco"}],"rel_date":"2026-09-12","rel_site":"medrxiv"},{"rel_title":"Co-Designing Pay-It-Forward Strategies to Improve Retention in Cervical Cancer Care in Kenya: A Formative Participatory Study","rel_doi":"10.64898\/2026.09.10.26362751","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362751","rel_abs":"Background: Retention is the bridge between diagnosis and survival in low and middle-income countries, including Kenya, where the cost of cervical cancer treatment can amount to several years of an average woman's earnings. Pay-it-forward (PIF), a prosocial approach in which an individual receives a gift and then considers supporting another person, offers a community-driven strategy to reduce barriers and improve engagement and retention in cancer care. This study explored opportunities to integrate PIF strategies into cervical cancer care through a human-centered design (HCD) workshop. Methods: We conducted a two-day HCD workshop in Kenya, informed by the WHO\/UNICEF normative guide on co-creation with women with cervical cancer (on treatment or survivors), community representatives, and oncology care providers. Experience diagramming mapped the patient journey and identified barriers to retention. A designer-led team then developed the initial PIF prototypes, which were iteratively co-designed and refined with participants to align with their needs and preferences. Audio recordings and photographs of the co-design activities were transcribed and analyzed using rapid, team-based qualitative synthesis. Results: Among 25 participants, 52% (n=13) were women with cervical cancer and 48% (n=12) were health care providers or community representatives. Participants identified costs, extenuating circumstances, treatment side effects, health system challenges, discrimination, fear, and anxiety as barriers to retention. These barriers informed the co-design of six PIF component strategies: peer navigation, transport voucher fund, integrated service gift, a message board in clinic waiting areas, health insurance support fund, and a basket of kindness at checkout. Three of these (peer navigation, transport voucher fund, and health insurance support) have been effectively implemented in Kenya before for other health services. Participants noted that including both monetary and non-monetary nudges was essential but emphasized the need for transparency and oversight in monetary approaches. Conclusion: The Kenyan context provided rich opportunities for PIF component strategies to explore and enhance retention in cancer care. We hypothesize that PIF may improve retention by activating social capital through reciprocity, empathy, and a sense of belonging. Future work should pilot these PIF strategies to assess feasibility, acceptability, and appropriateness, and determine whether reciprocal giving can be sustained. Keywords: Pay-it-forward, cervical cancer, retention, engagement, and co-design Contributions to Literature We propose a hypothesized mechanism through which pay-it-forward may improve engagement and retention in care by activating social capital through reciprocity, empathy, trust, commitment, and belonging. We provide a menu of monetary and non-monetary pay-it-forward strategies that can be adapted and tested across different health care settings, offering practical options for addressing financial and psychosocial barriers to retention. We extend the pay-it-forward literature beyond one-time, low-cost preventive services by applying the approach to long-term, high-cost cancer care, where sustained engagement presents distinct implementation challenges.","rel_num_authors":17,"rel_authors":[{"author_name":"Harriet  Fridah Adhiambo","author_inst":"Kenya Medical Research Institute, Washington University in St. Louis"},{"author_name":"Anne Trolard","author_inst":"Washington University In St Louis: Washington University in St Louis"},{"author_name":"Dorothy  Imbuka Mangale","author_inst":"Washington University in St Louis"},{"author_name":"Eric Thuo","author_inst":"Washington University in St. Louis"},{"author_name":"Philippa Kadama Makanga","author_inst":"Infectious Diseases Institute"},{"author_name":"Lucy Akoo","author_inst":"Jaramogi Oginga Odinga Teaching and Referral Hospital"},{"author_name":"Jerome Katumba","author_inst":"Maseno University, School of Medicine"},{"author_name":"Phiona Adagi","author_inst":"Jaramogi Oginga Odinga Teaching and Referral Hospital"},{"author_name":"Betsy Abente","author_inst":"Washington University in St. Louis"},{"author_name":"Beryne Odeny","author_inst":"Washington University in St. Louis"},{"author_name":"Elizabeth Bukusi","author_inst":"Kenya Medical Research Institute"},{"author_name":"Byron Powell","author_inst":"Washington University in St. Louis"},{"author_name":"Bettina Drake","author_inst":"Washington University in St. Louis"},{"author_name":"Dickens Onyango","author_inst":"County Department of Health, Kisumu County Government"},{"author_name":"Elvin Geng","author_inst":"Washington University in St. Louis"},{"author_name":"Joseph D. Tucker","author_inst":"University of North Carolina, Chapel Hill"},{"author_name":"Thomas Odeny","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-09-12","rel_site":"medrxiv"},{"rel_title":"Evidence of Chemical Wave-Electric Field Interaction in Bacterial Cells","rel_doi":"10.64898\/2026.09.05.749092","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.05.749092","rel_abs":"Charge neutrality is widely assumed in living cells, yet this approximation breaks down in micron-scale bacteria where charge imbalance and spatial confinement are significant. Using Poisson-Nernst-Planck modeling, we show that unequal cation-anion effectiveness and bounded geometry generate extended intracellular diffuse layers and steady electric fields. We demonstrate that such fields couple directly to intracellular chemical waves, focusing on the Min-protein oscillator of Escherichia coli. Electric-field-driven transport skews the dispersion-mode structure, induces mode crossings, and selectively amplifies Turing and Hopf-Turing instabilities over intermediate length scales, constraining the permitted {omega}-k spectrum and setting optimal wavelengths and modal growth-rate velocities. Experiments in wild-type, anucleate, and antibiotic-treated cells, together with simulations of nucleoid-dependent charge density and field strength, quantitatively validate these predictions and explain observed pattern asymmetries and frequency modulations. Crucially, asymmetric wave-field coupling promotes quasi-periodicity through controlled mode competition, enhancing robustness to noise, cell-size variation, and growth. These findings identify intracellular electric fields as active regulators of biochemical patterning and suggest a general role for wave-field interactions in cellular self-organization.","rel_num_authors":2,"rel_authors":[{"author_name":"Jie-Pan Shen","author_inst":"Academia Sinica"},{"author_name":"Chia-Fu Chou","author_inst":"Academia Sinica"}],"rel_date":"2026-09-12","rel_site":"biorxiv"},{"rel_title":"Mapping tsetse fly connectivity in Uganda with machine learning landscape genetics","rel_doi":"10.64898\/2026.09.11.750686","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.750686","rel_abs":"Introduction - Tsetse flies (genus Glossina) are biting insects that transmit human and animal trypanosomiases across sub-Saharan Africa, and sustainable vector control depends on understanding dispersal barriers and reinvasion routes. Despite major progress toward elimination, Uganda remains at risk for both human forms of the disease (Trypanosoma brucei gambiense and T. b. rhodesiense) and planners still lack reliable maps of tsetse movement and reinvasion risk. Methods and Results - We address this gap with machine-learning landscape genetics and species distribution models, integrating estimates of population genetic distance and geospatial environmental data to predict and map Glossina fuscipes fuscipes connectivity across Uganda and western Kenya. Inputs included microsatellite genotypes from 11 loci genotyped in 2,736 flies sampled from 87 localities and remotely sensed environmental predictors summarized along least-cost paths. Random forest models predicted patterns of genetic differentiation better than distance-only models, supporting the use of a machine-learning framework for connectivity inference across complex heterogeneous landscapes, and identified variables related to temperature and water availability as the strongest predictors of genetic connectivity. Conclusions - Combining landscape genetics predictions of connectivity with a species distribution model revealed regions with high habitat suitability but low connectivity that represent priority zones for area-wide integrated pest management strategies, including established riverine control tools such as tiny targets and other targeted interventions aimed at reducing reinvasion risk. These results provide biologically interpretable maps and quantitative uncertainty metrics that can guide targeted tsetse control, while providing a transferable analytical pipeline for modeling and mapping genetic connectivity across other species and landscapes.","rel_num_authors":15,"rel_authors":[{"author_name":"Norah P. Saarman","author_inst":"Utah State University"},{"author_name":"Ryan Griffiths","author_inst":"Utah State University; Purdue University"},{"author_name":"Anusha Bishop","author_inst":"University of California, Davis"},{"author_name":"Camilla Moses","author_inst":"Utah State University"},{"author_name":"Emily Calhoun","author_inst":"Utah State University"},{"author_name":"Ethan Meredith","author_inst":"Utah State University"},{"author_name":"Rosemary Bateta","author_inst":"Kenya Agricultural and Livestock Research Organization"},{"author_name":"Winnie A. Okeyo","author_inst":"Kenya Agricultural and Livestock Research Organization; Maseno University"},{"author_name":"Paul O. Mireji","author_inst":"Kenya Agricultural and Livestock Research Organization; Kenya Medical Research Institute"},{"author_name":"Grace Murilla","author_inst":"Kenya Agricultural and Livestock Research Organization"},{"author_name":"Sylvance Okoth","author_inst":"Kenya Agricultural and Livestock Research Organization"},{"author_name":"Robert Opiro","author_inst":"Gulu University"},{"author_name":"Richard Echodu","author_inst":"Gulu University"},{"author_name":"Serap Aksoy","author_inst":"Yale School of Public Health"},{"author_name":"Adalgisa Caccone","author_inst":"Yale University"}],"rel_date":"2026-09-12","rel_site":"biorxiv"},{"rel_title":"Genomic characterization reveals high clonal redundancy in two Acropora cervicornis nurseries in the Dominican Republic","rel_doi":"10.64898\/2026.09.11.750210","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.750210","rel_abs":"Acropora cervicornis is often propagated through fragmentation (i.e., clonal propagation), a common practice implemented by restoration projects. Known as asexual propagation, this strategy may rapidly increase coral cover but reduces genetic variation. We used 2b-RAD sequencing to characterize multilocus genotypic variation among 45 A. cervicornis colonies maintained in two in-situ nurseries (Cap Cana, Acuario) in Punta Cana, Dominican Republic. After reference-based SNP discovery and filtering, 2,515 high-quality SNPs were retained in the dataset. Principal coordinate analysis (PCoA), hierarchical clustering, identity-by-state (IBS) distances, and relatedness estimates identified only three multilocus genets among the 45 colonies (AC1, AC2, and AC3). Of these, AC2 was the most abundant (n = 23; 51.1%), followed by AC3 (n = 14; 31.1%) and lastly AC1 (n = 8; 17.8%). Within-genet IBS distances (0.153-0.227) did not overlap with between-genet distances (0.406-0.497). AC1 and AC2 were detected in both nurseries, whereas AC3 was limited to Acuario. These results reveal substantial clonal redundancy among sampled nursery colonies that determines local reef conservation efforts. These data highlight the value of incorporating genotype identification in nursery-based coral restoration projects.","rel_num_authors":6,"rel_authors":[{"author_name":"Shamwari Anseeuw Carrasco","author_inst":"Rutgers University"},{"author_name":"Kasey H Walsh","author_inst":"Rutgers University"},{"author_name":"Rebecca Garcia-Camps","author_inst":"Fundacion Punta Cana"},{"author_name":"Ainhoa L Zubillaga","author_inst":"Fundacion Puntacana"},{"author_name":"Aldo Croquer","author_inst":"The Nature Conservancy"},{"author_name":"Debashish Bhattacharya","author_inst":"Rutgers University"}],"rel_date":"2026-09-12","rel_site":"biorxiv"},{"rel_title":"Impact of Australias 60-Day Dispensing Policy on Medicine Use: An Interrupted Time Series of the Stage 1 Roll-out","rel_doi":"10.64898\/2026.09.09.26362679","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26362679","rel_abs":"ObjectiveTo evaluate the real-world impact of Stage 1 of Australias 60-day dispensing policy on medicine utilisation and contextualise changes in dispensing with medicine shortages.\n\nMethodsWe conducted an interrupted time series analysis of aggregated national monthly dispensing data from the Pharmaceutical Benefits Scheme and Repatriation Pharmaceutical Benefits Scheme for the 247 medicines included in Stage 1 of the 60-day dispensing policy. Data from January 2020 to October 2025 were analysed, with September 2023 defined as policy implementation. Linear regression assessed changes in monthly dispensing trends before and after implementation, accounting for autocorrelation and seasonal variation. A relative change of at least {+\/-}5% in the post-intervention dispensing slope compared with the pre-intervention slope was prespecified as a potentially clinically meaningful change. Therapeutic Goods Administration shortage reports were used to contextualise observed changes.\n\nResultsOf 247 medicines, 131 (53%) had increasing and 116 (47%) had decreasing post-intervention dispensing trends; of which 86 (66%) and 71 (61%), were statistically significant, respectively. However, only 8 medicines (3%) demonstrated at least {+\/-}5% relative change in dispensing slope, six of which had reported shortages. Medicine-specific changes coincided with shortages, product deletions and therapeutic substitution, complicated attribution of changes to the 60-day dispensing policy.\n\nConclusionStage 1 of Australias 60-day dispensing policy was not associated with widespread changes in dispensing for most included medicines. Limited changes were plausibly influenced by concurrent shortages and other supply-related events. These findings provide reassurance that extended dispensing did not result in major increases in medicine utilisation at the population level, although continued monitoring is warranted as policy uptake expands.\n\nShort summary for non-expertsAustralia introduced 60-day dispensing in September 2023, allowing eligible patients to receive up to two months of some medicines at one time. We examined whether this changed overall usage of medicines across Australia.\n\nWe found that for almost all of the 247 medicines included in the first stage of the policy, there was no meaningful change in usage after 60-day dispensing was introduced. Only eight medicines showed a potentially meaningful change, and most of these changes occurred alongside medicine shortages or other supply problems. Overall, the findings suggest that 60- day dispensing did not lead to major increases in medicine usage, although ongoing monitoring is important as the policy expands.","rel_num_authors":6,"rel_authors":[{"author_name":"Jack Janetzki","author_inst":"Adelaide University"},{"author_name":"Nicole Pratt","author_inst":"Adelaide University"},{"author_name":"Lachlan Dalli","author_inst":"Monash University"},{"author_name":"Pilar Cataldo Miranda","author_inst":"Monash University"},{"author_name":"Sallie-Anne Pearson","author_inst":"University of New South Wales"},{"author_name":"Lisa Kalisch Ellett","author_inst":"Adelaide University"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Out-of-pocket costs and productivity losses associated with influenza illness and caregiving in a household study in the United States, 2024-2025","rel_doi":"10.64898\/2026.09.10.26362662","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362662","rel_abs":"Background: Non-medically attended (NMA) and outpatient medically attended (MA) influenza illnesses contribute substantially to influenza disease burden in the United States. We leveraged a household study to estimate out-of-pocket and lost productivity costs of NMA and MA influenza illness. Methods: The Respiratory Virus Transmission Network for Influenza was a 2024-2025 case-ascertained household study at 3 U.S. sites. Influenza-positive index patients and household contacts self-reported daily symptoms, over-the-counter (OTC) medication use, medical care-seeking, time missed from work or activities, and self-collected nasal swabs for PCR testing. We included participants with PCR-confirmed influenza infection and influenza-like-illness symptoms who ever (MA) or never (NMA) sought medical care during follow-up. We obtained costs of OTC medications from retail websites and productivity costs from published values. We calculated OTC medication and lost productivity costs in 2025 USD for MA and NMA influenza separately and household-level lost productivity costs among caregivers for MA and NMA household members. Results: Median out-of-pocket OTC medication costs were $6.38 (interquartile range [IQR] $2.92-$11.60) among 594 MA and $3.72 (IQR $1.50-$7.05) among 153 NMA influenza illnesses. Among participants [&ge;]15 years of age, median lost productivity was $315 ($149-$743) for MA and $248 ($0-$624) for NMA illnesses. Median household-level lost productivity for caregiving was $148 (households with 1 ill child), $379 (multiple ill children), and $0 ([&ge;]1 ill adult). Conclusions: Influenza causes substantial lost productivity costs within households. These estimates can inform future economic burden and cost effectiveness analyses.","rel_num_authors":18,"rel_authors":[{"author_name":"Elizabeth B White","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Jamison Pike","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Celibell Y Vargas","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Yuwei Zhu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Caroline A O'Neil","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Jessica E Biddle","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Lydia Bristol","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Emily McNair","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Son H McLaren","author_inst":"Columbia University Irving Medical Cetner"},{"author_name":"Ellen Sano","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Theresa A Scott","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rachel Presti","author_inst":"Washington University School of Medicine"},{"author_name":"Stephanie A Fritz","author_inst":"Washington University School of Medicine"},{"author_name":"Lisa A Prosser","author_inst":"University of Michigan"},{"author_name":"Melissa S Stockwell","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Carlos G Grijalva","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jennie H Kwon","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Alexandra Mellis","author_inst":"Centers for Disease Control and Prevention"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Out-of-pocket costs and productivity losses associated with influenza illness and caregiving in a household study in the United States, 2024-2025","rel_doi":"10.64898\/2026.09.10.26362662","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362662","rel_abs":"Background: Non-medically attended (NMA) and outpatient medically attended (MA) influenza illnesses contribute substantially to influenza disease burden in the United States. We leveraged a household study to estimate out-of-pocket and lost productivity costs of NMA and MA influenza illness. Methods: The Respiratory Virus Transmission Network for Influenza was a 2024-2025 case-ascertained household study at 3 U.S. sites. Influenza-positive index patients and household contacts self-reported daily symptoms, over-the-counter (OTC) medication use, medical care-seeking, time missed from work or activities, and self-collected nasal swabs for PCR testing. We included participants with PCR-confirmed influenza infection and influenza-like-illness symptoms who ever (MA) or never (NMA) sought medical care during follow-up. We obtained costs of OTC medications from retail websites and productivity costs from published values. We calculated OTC medication and lost productivity costs in 2025 USD for MA and NMA influenza separately and household-level lost productivity costs among caregivers for MA and NMA household members. Results: Median out-of-pocket OTC medication costs were $6.38 (interquartile range [IQR] $2.92-$11.60) among 594 MA and $3.72 (IQR $1.50-$7.05) among 153 NMA influenza illnesses. Among participants [&ge;]15 years of age, median lost productivity was $315 ($149-$743) for MA and $248 ($0-$624) for NMA illnesses. Median household-level lost productivity for caregiving was $148 (households with 1 ill child), $379 (multiple ill children), and $0 ([&ge;]1 ill adult). Conclusions: Influenza causes substantial lost productivity costs within households. These estimates can inform future economic burden and cost effectiveness analyses.","rel_num_authors":18,"rel_authors":[{"author_name":"Elizabeth B White","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Jamison Pike","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Celibell Y Vargas","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Yuwei Zhu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Caroline A O'Neil","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Jessica E Biddle","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Lydia Bristol","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Emily McNair","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Son H McLaren","author_inst":"Columbia University Irving Medical Cetner"},{"author_name":"Ellen Sano","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Theresa A Scott","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rachel Presti","author_inst":"Washington University School of Medicine"},{"author_name":"Stephanie A Fritz","author_inst":"Washington University School of Medicine"},{"author_name":"Lisa A Prosser","author_inst":"University of Michigan"},{"author_name":"Melissa S Stockwell","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Carlos G Grijalva","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jennie H Kwon","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Alexandra Mellis","author_inst":"Centers for Disease Control and Prevention"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Out-of-pocket costs and productivity losses associated with influenza illness and caregiving in a household study in the United States, 2024-2025","rel_doi":"10.64898\/2026.09.10.26362662","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362662","rel_abs":"Background: Non-medically attended (NMA) and outpatient medically attended (MA) influenza illnesses contribute substantially to influenza disease burden in the United States. We leveraged a household study to estimate out-of-pocket and lost productivity costs of NMA and MA influenza illness. Methods: The Respiratory Virus Transmission Network for Influenza was a 2024-2025 case-ascertained household study at 3 U.S. sites. Influenza-positive index patients and household contacts self-reported daily symptoms, over-the-counter (OTC) medication use, medical care-seeking, time missed from work or activities, and self-collected nasal swabs for PCR testing. We included participants with PCR-confirmed influenza infection and influenza-like-illness symptoms who ever (MA) or never (NMA) sought medical care during follow-up. We obtained costs of OTC medications from retail websites and productivity costs from published values. We calculated OTC medication and lost productivity costs in 2025 USD for MA and NMA influenza separately and household-level lost productivity costs among caregivers for MA and NMA household members. Results: Median out-of-pocket OTC medication costs were $6.38 (interquartile range [IQR] $2.92-$11.60) among 594 MA and $3.72 (IQR $1.50-$7.05) among 153 NMA influenza illnesses. Among participants [&ge;]15 years of age, median lost productivity was $315 ($149-$743) for MA and $248 ($0-$624) for NMA illnesses. Median household-level lost productivity for caregiving was $148 (households with 1 ill child), $379 (multiple ill children), and $0 ([&ge;]1 ill adult). Conclusions: Influenza causes substantial lost productivity costs within households. These estimates can inform future economic burden and cost effectiveness analyses.","rel_num_authors":18,"rel_authors":[{"author_name":"Elizabeth B White","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Jamison Pike","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Celibell Y Vargas","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Yuwei Zhu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Caroline A O'Neil","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Jessica E Biddle","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Lydia Bristol","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Emily McNair","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Son H McLaren","author_inst":"Columbia University Irving Medical Cetner"},{"author_name":"Ellen Sano","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Theresa A Scott","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rachel Presti","author_inst":"Washington University School of Medicine"},{"author_name":"Stephanie A Fritz","author_inst":"Washington University School of Medicine"},{"author_name":"Lisa A Prosser","author_inst":"University of Michigan"},{"author_name":"Melissa S Stockwell","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Carlos G Grijalva","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jennie H Kwon","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Alexandra Mellis","author_inst":"Centers for Disease Control and Prevention"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Estrogen interactions with breast cancer risk variants in regulatory DNA","rel_doi":"10.64898\/2026.09.09.26362309","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26362309","rel_abs":"Insight into population-level gene-environment (GxE) interactions is a major goal in understanding polygenic diseases, such as breast cancer. We integrated massively parallel reporter assays (MPRA), chromatin profiling, and network analysis to identify estrogen-responsive breast cancer variants. Screening 1,604 GWAS-identified breast cancer variants identified 73 estrogen-modulated SNVs (emSNVs). Chromatin accessibility modeling validated allele-specific effects, identifying variants that disrupt pioneer factor binding to chromatin and others that modulate transcription factor (TF) recruitment to pre-accessible enhancers. emSNV targets converged on pathways including mitochondrial metabolism, NF-{kappa}B signaling, and chromatin regulation. Aggregating emSNVs into a polygenic risk score (PRSE2) revealed interactions with reproductive risk factors in 13,026 post-menopausal BRCA cases and 108,265 controls, including age at first birth (p=0.0052); a control PRS lacking estrogen-responsive variants showed no interactions. This framework bridges molecular and epidemiological GxE studies to uncover variants whose disease associations depend on environmental context, with implications for understanding polygenic disease risk.","rel_num_authors":20,"rel_authors":[{"author_name":"Ibtihal M Elfaki","author_inst":"Stanford University"},{"author_name":"Laura Kellman","author_inst":"Stanford University"},{"author_name":"Robin Meyers","author_inst":"Stanford University"},{"author_name":"Luca Ducoli","author_inst":"Stanford University"},{"author_name":"Martina Fu","author_inst":"Stanford University"},{"author_name":"Kamal Obbad","author_inst":"Stanford University"},{"author_name":"Smarajit Mondal","author_inst":"Stanford University"},{"author_name":"Xue Yang","author_inst":"Stanford University"},{"author_name":"Douglas F Porter","author_inst":"Stanford University"},{"author_name":"David Reynolds","author_inst":"Stanford University"},{"author_name":"Suhas Srinivasan","author_inst":"Stanford University"},{"author_name":"Taishi Nakase","author_inst":"Stanford University"},{"author_name":"Mineto Ota","author_inst":"The University of Tokyo"},{"author_name":"Tania Fabo","author_inst":"Stanford University"},{"author_name":"Jordan Meyers","author_inst":"Stanford University"},{"author_name":"Lu Yang","author_inst":"Stanford University"},{"author_name":"Nasa Sinnot-Armstrong","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Kenneth Westerman","author_inst":"Massachusetts General Hospital"},{"author_name":"Linda Kachuri","author_inst":"Stanford University"},{"author_name":"Paul Khavari","author_inst":"Stanford University"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Lived experiences and occupational pressures among Vietnamese nail salon workers in Maryland","rel_doi":"10.64898\/2026.09.10.26362742","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362742","rel_abs":"Individuals of Vietnamese descent comprise a majority of the United States nail salon workforce. Whereas prior research has centered on chemical exposures, thematic analysis of interviews with Vietnamese nail salon workers around Baltimore, Maryland examined the lived experiences of nail salon workers. Six themes were identified: (1) nail work as a familial livelihood and a sacrifice-oriented pathway towards intergenerational mobility; (2) perceived flexibility within the workplace with low control; (3) professional pride grounded in artistry, detail, and customer care; (4) cumulative occupational risks; (5) emotional labor as an expected and core component of nail salon work; and (6) limited perceived capacity to change working conditions. These findings suggest that the occupational pressures in nail salon work cannot be solely framed as a lack of worker knowledge or motivation towards adopting safer practices. Intervention success depends on a holistic view of workers lives, whose choices are shaped by family obligations, customer demands, and conditions largely outside their control. Therefore, efforts to improve nail salon health may benefit from shifting the burden of risk management away from individual workers and engaging the wider community.","rel_num_authors":2,"rel_authors":[{"author_name":"Kevin K. Nguyen","author_inst":"The Johns Hopkins University"},{"author_name":"Emily M. Agree","author_inst":"The Johns Hopkins University"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"The Impact of Opioid, Opioid Agonist Therapy, and Cannabis Exposure on Fetal Growth: A Population-Based Cohort Study","rel_doi":"10.64898\/2026.09.10.26362743","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362743","rel_abs":"ObjectivesThe primary objective is to determine the extent to which fetal growth profiles in opioid and opioid agonist (OAT) exposed pregnancies are influenced by cannabis exposure. Secondary objectives are to examine differences in fetal and neonatal morbidity and mortality.\n\nDesignPopulation-based cohort study.\n\nSettingOntario, Canada, in a public healthcare system.\n\nParticipantsAll live\/stillborn births between April 1st, 2013, and March 31st, 2021.\n\nExposuresSubstance exposure in pregnancy, including opioids, opioid agonist therapy, cannabis, and nicotine.\n\nMain Outcome MeasuresPrimary outcome measures included incidence of small for gestational age (<3rd and <10th percentile for sex) and intrauterine growth restriction. Secondary outcome measures included incidence of stillbirth, severe neonatal morbidity (SNM), neonatal mortality, and neonatal abstinence syndrome (NAS).\n\nResults959,731 births are included with exposures classified as 864,508 (88.0%) no substance, 73,815 (7.7%) nicotine, 23,003 (2.4%) cannabis, 7,694 (0.8%) opioid, and 5,353 (0.6%) OAT. Cannabis co-exposure was reported in 1 out of every 6 opioid and\/or OAT exposed births. The observed proportions of SGA and IUGR were approximately doubled across substance-exposed groups compared with the no substance exposure group. In adjusted analyses, cannabis exposure alone was associated with an 84% increased risk of IUGR, compared with 14% for opioid exposure alone and 60% for OAT exposure alone. SNM was observed in 7.2% of no substance exposure neonates, compared to 13.9% and 14.2% of opioid and OAT exposed neonates, respectively. NAS was diagnosed in 70.6% of all OAT exposed neonates, compared to 34.3% of all opioid exposed neonates. Risks for all outcomes across all cannabis co-exposure groups were significantly elevated relative to the no substance exposure group, with estimates ranging from 43% to 107% increased risk.\n\nConclusionsPrenatal co-exposure to opioid and\/or OAT along with cannabis appears to place infants at the highest risk. Isolated cannabis use has similar, if not more significant, impacts on fetal growth as opioid and\/or OAT use. This information may serve as an important starting point in the design of effective harm reduction strategies in this patient population.\n\nTweetable abstractPrenatal co-exposure to cannabis and opioid and\/or opioid agonist therapy (OAT) use places infants at increased risk for impaired fetal growth and severe neonatal morbidity. Isolated cannabis use in pregnancy has similar, if not greater, impacts on fetal growth than opioid and\/or OAT use.\n\nSummary BoxesO_ST_ABSSection 1: What is already known on this topicC_ST_ABSAcross North America, rates of opioid exposure during pregnancy range from 1.1-42%. Multi-substance use is common, with concurrent cannabis exposure estimated at 36-75% among opioid users. Opioid use in pregnancy is associated with altered fetal growth, including low birthweight and small for gestational age (SGA) infants. Cannabis use in pregnancy is likewise associated with compromised fetal and neonatal growth, along with neurocognitive developmental deficits in offspring. Despite these known risks in isolation, little is known about the impact of co-use, which is concerning given the high rates of concurrent substance exposure.\n\nSection 2: What this study addsThis study demonstrates that babies exposed to cannabis, opioids and\/or OAT in pregnancy are more likely to experience complications, including failure to reach ideal growth potential, stillbirth, difficulties adapting to life after birth, readmission to hospital within 42 days of delivery, and neonatal death. Prenatal cannabis co-exposure with opioid and\/or OAT places infants at the highest risk. Isolated cannabis use has similar, if not greater, impacts on fetal growth than isolated opioid or OAT use, significantly increasing the risks of impaired fetal growth (including fetal growth restriction (FGR) and SGA) and severe neonatal morbidity (SNM).","rel_num_authors":6,"rel_authors":[{"author_name":"Jessica Pudwell","author_inst":"Queen's University"},{"author_name":"Kira King","author_inst":"Queen's University"},{"author_name":"Wenbin Li","author_inst":"Queen's University"},{"author_name":"Maria P. Velez","author_inst":"McGill University"},{"author_name":"Shannon Bainbridge","author_inst":"University of Ottawa"},{"author_name":"Laura Gaudet","author_inst":"Queen's University"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"The Impact of Opioid, Opioid Agonist Therapy, and Cannabis Exposure on Fetal Growth: A Population-Based Cohort Study","rel_doi":"10.64898\/2026.09.10.26362743","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362743","rel_abs":"ObjectivesThe primary objective is to determine the extent to which fetal growth profiles in opioid and opioid agonist (OAT) exposed pregnancies are influenced by cannabis exposure. Secondary objectives are to examine differences in fetal and neonatal morbidity and mortality.\n\nDesignPopulation-based cohort study.\n\nSettingOntario, Canada, in a public healthcare system.\n\nParticipantsAll live\/stillborn births between April 1st, 2013, and March 31st, 2021.\n\nExposuresSubstance exposure in pregnancy, including opioids, opioid agonist therapy, cannabis, and nicotine.\n\nMain Outcome MeasuresPrimary outcome measures included incidence of small for gestational age (<3rd and <10th percentile for sex) and intrauterine growth restriction. Secondary outcome measures included incidence of stillbirth, severe neonatal morbidity (SNM), neonatal mortality, and neonatal abstinence syndrome (NAS).\n\nResults959,731 births are included with exposures classified as 864,508 (88.0%) no substance, 73,815 (7.7%) nicotine, 23,003 (2.4%) cannabis, 7,694 (0.8%) opioid, and 5,353 (0.6%) OAT. Cannabis co-exposure was reported in 1 out of every 6 opioid and\/or OAT exposed births. The observed proportions of SGA and IUGR were approximately doubled across substance-exposed groups compared with the no substance exposure group. In adjusted analyses, cannabis exposure alone was associated with an 84% increased risk of IUGR, compared with 14% for opioid exposure alone and 60% for OAT exposure alone. SNM was observed in 7.2% of no substance exposure neonates, compared to 13.9% and 14.2% of opioid and OAT exposed neonates, respectively. NAS was diagnosed in 70.6% of all OAT exposed neonates, compared to 34.3% of all opioid exposed neonates. Risks for all outcomes across all cannabis co-exposure groups were significantly elevated relative to the no substance exposure group, with estimates ranging from 43% to 107% increased risk.\n\nConclusionsPrenatal co-exposure to opioid and\/or OAT along with cannabis appears to place infants at the highest risk. Isolated cannabis use has similar, if not more significant, impacts on fetal growth as opioid and\/or OAT use. This information may serve as an important starting point in the design of effective harm reduction strategies in this patient population.\n\nTweetable abstractPrenatal co-exposure to cannabis and opioid and\/or opioid agonist therapy (OAT) use places infants at increased risk for impaired fetal growth and severe neonatal morbidity. Isolated cannabis use in pregnancy has similar, if not greater, impacts on fetal growth than opioid and\/or OAT use.\n\nSummary BoxesO_ST_ABSSection 1: What is already known on this topicC_ST_ABSAcross North America, rates of opioid exposure during pregnancy range from 1.1-42%. Multi-substance use is common, with concurrent cannabis exposure estimated at 36-75% among opioid users. Opioid use in pregnancy is associated with altered fetal growth, including low birthweight and small for gestational age (SGA) infants. Cannabis use in pregnancy is likewise associated with compromised fetal and neonatal growth, along with neurocognitive developmental deficits in offspring. Despite these known risks in isolation, little is known about the impact of co-use, which is concerning given the high rates of concurrent substance exposure.\n\nSection 2: What this study addsThis study demonstrates that babies exposed to cannabis, opioids and\/or OAT in pregnancy are more likely to experience complications, including failure to reach ideal growth potential, stillbirth, difficulties adapting to life after birth, readmission to hospital within 42 days of delivery, and neonatal death. Prenatal cannabis co-exposure with opioid and\/or OAT places infants at the highest risk. Isolated cannabis use has similar, if not greater, impacts on fetal growth than isolated opioid or OAT use, significantly increasing the risks of impaired fetal growth (including fetal growth restriction (FGR) and SGA) and severe neonatal morbidity (SNM).","rel_num_authors":6,"rel_authors":[{"author_name":"Jessica Pudwell","author_inst":"Queen's University"},{"author_name":"Kira King","author_inst":"Queen's University"},{"author_name":"Wenbin Li","author_inst":"Queen's University"},{"author_name":"Maria P. Velez","author_inst":"McGill University"},{"author_name":"Shannon Bainbridge","author_inst":"University of Ottawa"},{"author_name":"Laura Gaudet","author_inst":"Queen's University"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Immune Profiling after treatment with an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy in Treatment-Refractory Progressive Multiple Sclerosis","rel_doi":"10.64898\/2026.09.11.26361992","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26361992","rel_abs":"Treatment targeting progressive multiple sclerosis (MS) have limited efficacy, as central nervous system (CNS) resident B cells are resistant to peripheral B cell depletion by anti-CD20 monoclonal antibodies. CD19-targeted chimeric antigen receptor (CAR)-T cells offer the promise to deplete B cells more extensively in both the peripheral and CNS compartments. Two adult participants with treatment-refractory progressive MS were treated with 0.33x10^8 autologous anti-CD19 CAR-T cells (mivocabtagene autoleucel, miv-cel) intravenously after a preconditioning regimen. Participant 1 (50s year old female, EDSS 6) had no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Participant 2 (60s year old female, EDSS 4.5) had grade 1 CRS and no ICANS. Expansion of CAR-T cells in the cerebrospinal fluid (CSF) at Day 14 was noted in both participants, remarkably with sustained disappearance of disease-associated oligoclonal band (OCB) or normalization of IgG index despite peripheral naive B cell reconstitution. MRI and clinical outcomes showed sustained stability at Week 48. Serologic studies showed a decline in anti-Epstein Barr Virus seropositivity. Single cell myeloid and proteomic signatures showed a decline in proinflammatory profiles.\n\nIn the 2 subjects with progressive MS reported here, low dose anti-CD19 CAR-T cell therapy (miv-cel) was safe, penetrated the CSF effectively, reduced intrathecal humoral activity, modulated peripheral immune tone, and appeared to stabilize EDSS scores. Overall, these results support the continued investigation of CAR-T cell therapy in MS.\n\nOne Sentence SummaryAnti-CD19 CAR-T cell was safe in two progressive MS patients with CSF penetration, OCB\/IgG index resolution, and improved inflammatory background.","rel_num_authors":25,"rel_authors":[{"author_name":"Sasha Gupta","author_inst":"University of California, San Fransisco"},{"author_name":"Madhav R Seshadri","author_inst":"University of California, San Fransisco"},{"author_name":"Ravi Dandekar","author_inst":"University of California, San Fransisco"},{"author_name":"Leonie Mueller-Jensen","author_inst":"University of California, San Fransisco"},{"author_name":"Krista McCutcheon","author_inst":"University of California, San Fransisco"},{"author_name":"Leslie A Scarffe","author_inst":"University of California, San Fransisco"},{"author_name":"ShiLu Vanasupa","author_inst":"University of California, San Fransisco"},{"author_name":"Megumi Sunahara","author_inst":"University of California, San Fransisco"},{"author_name":"Fumie Hayashi","author_inst":"University of California, San Fransisco"},{"author_name":"Colette Caspar","author_inst":"University of California, San Fransisco"},{"author_name":"Robin Lincoln","author_inst":"University of California, San Fransisco"},{"author_name":"Naomi Okinishi","author_inst":"University of California, San Fransisco"},{"author_name":"Nancy Thomas","author_inst":"University of California, San Fransisco"},{"author_name":"Samantha Shenoy","author_inst":"University of California, San Fransisco"},{"author_name":"Samantha Zylberman","author_inst":"University of California, San Fransisco"},{"author_name":"Camille Fouassier","author_inst":"University of California, San Fransisco"},{"author_name":"Ebtesam Hassan","author_inst":"University of California, San Fransisco"},{"author_name":"Sam Klauer","author_inst":"University of California, San Fransisco"},{"author_name":"Jenai Wilmoth","author_inst":"University of California, San Fransisco"},{"author_name":"Joseph J Sabatino Jr.","author_inst":"University of California, San Fransisco"},{"author_name":"Aaron Bodansky","author_inst":"University of California, San Fransisco"},{"author_name":"Ahmed Abdelhak","author_inst":"University of California, San Francisco"},{"author_name":"Stephen L Hauser","author_inst":"University of California, San Fransisco"},{"author_name":"Michael R Wilson","author_inst":"University of California, San Fransisco"},{"author_name":"Bruce A.C. Cree","author_inst":"University of California, San Fransisco"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Evaluation of Urinary Circulating Tumor DNA to Detect Minimal Residual Disease in Patients with High-Risk Non-Muscle Invasive Bladder Cancer","rel_doi":"10.64898\/2026.09.09.26362655","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26362655","rel_abs":"PurposeRestaging transurethral resection of bladder tumor (reTURBT) is the standard-of-care for some patients with high-risk non-muscle invasive bladder cancer (NMIBC). However, it may lead to complications and biomarkers to avoid unnecessary reTURBT are needed.\n\nMaterials and MethodsPatients with high-risk NMIBC undergoing reTURBT were prospectively enrolled. Whole-exome sequencing along with low-pass whole-genome sequencing were performed on index TURBT samples to generate mutational profiles and copy number variation. Up to 50 personalized mutations and a fixed panel of 500 hotspot mutations were used for detecting variants from urine samples collected prior to reTURBT. Using a prespecified algorithm, tumor fraction (TF) and copy number burden (CNB) score were used to measure minimal residual disease and correlated with reTURBT pathology.\n\nResultsOverall, 72\/76 urine samples collected from patients with high-risk NMIBC prior to reTURBT passed quality check. From the indext TURBT specimens, a median of 39 personalized variants from the index TURBT were used for disease tracking. Overall, median TF was 0.206 vs. 0.001 in patients with and without residual tumor, respectively (p<0.001). Similarly, CNB score was elevated (7.34 vs. 4.02, p<0.001). utDNA achieved sensitivity of 97.8% and specificity of 69.2%, with area under the curve (AUC) of 0.932 in predicting disease found on reTURBT. Analyses of the index and reTURBT tissue and urine mutational profiles provided evidence for underdiagnosis of subclinical disease at the time of reTURBT.\n\nConclusionPaired personalized and panel utDNA can be used to accurately detect residual disease in patients with high-risk NMIBC with potentially wide-ranging clinical applications.","rel_num_authors":24,"rel_authors":[{"author_name":"Roger Li","author_inst":"Moffitt"},{"author_name":"Josh Linscott","author_inst":"Moffitt"},{"author_name":"Prithvi Murthy","author_inst":"Moffitt"},{"author_name":"Kyle Rose","author_inst":"Moffitt"},{"author_name":"Young Pak","author_inst":"Moffitt"},{"author_name":"Frank Zhang","author_inst":"Predicine"},{"author_name":"Yong Huang","author_inst":"Predicine"},{"author_name":"G Daniel Grass","author_inst":"Moffitt"},{"author_name":"Jon Chatzkel","author_inst":"Moffitt"},{"author_name":"Noah Hahn","author_inst":"Johns Hopkins"},{"author_name":"David McConkey","author_inst":"Rochester"},{"author_name":"Josh Meeks","author_inst":"Northwestern"},{"author_name":"Siamak Daneshmand","author_inst":"USC"},{"author_name":"Tom Flaig","author_inst":"Colorado"},{"author_name":"Seth Lerner","author_inst":"Baylor"},{"author_name":"Logan Zemp","author_inst":"Moffitt"},{"author_name":"Michael Poch","author_inst":"Moffitt"},{"author_name":"Philippe Spiess","author_inst":"Moffitt"},{"author_name":"Wade Sexton","author_inst":"Moffitt"},{"author_name":"Scott Gilbert","author_inst":"Moffitt"},{"author_name":"Hongzhi Xu","author_inst":"Moffitt"},{"author_name":"Pan Du","author_inst":"Predicine"},{"author_name":"Shidong Jia","author_inst":"Predicine"},{"author_name":"Xuefeng Wang","author_inst":"Moffitt"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"A Systems Biology Model Linking Peripheral NIMETOX Biomarkers to Multilevel Brain Structural and Functional Alterations Across Major Depression and Schizophrenia","rel_doi":"10.64898\/2026.09.09.26362608","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26362608","rel_abs":"Peripheral lipid and antioxidant-related biomarkers may help contextualize brain abnormalities across psychiatric disorders, but their relationships with brain structure, intrinsic activity, and dimensional symptoms remain incompletely characterized. In this cross-sectional study, 93 adults were recruited: 38 with major depressive disorder, 29 with schizophrenia, and 26 healthy controls. Eighty-seven participants met resting-state functional MRI quality-control criteria. Assessments included structural and functional MRI, serum lipids, albumin, apolipoprotein A-I, childhood maltreatment, psychological resilience, and clinical symptoms. Exploratory analyses combined regional imaging measures, within-network connectivity, statistical mediation, and partial least squares structural equation modeling. Group-related functional abnormalities involved parietal, sensorimotor, cingulate, insular, and temporal regions. Peripheral lipid and antioxidant-related measures were associated with regional gray matter measures and intrinsic activity. Childhood maltreatment and resilience were associated with mood-related symptom burden, whereas lower connectivity and nodal strength within the selected 11-region network were associated with psychosis-related and overall illness severity. Exploratory structural equation models accounted for 66.4% of the variance in the mood-related composite and 25.3% of the variance in local intrinsic activity. These findings describe cross-sectional relationships among peripheral biological measures, regional brain characteristics, developmental adversity, and psychopathology. They provide a framework for further investigation rather than evidence of a causal blood-to-brain sequence. Independent replication with prospectively defined measures and longitudinal assessments is needed.","rel_num_authors":17,"rel_authors":[{"author_name":"Hongzhou Wu","author_inst":"University of Electronic Science and Technology of China"},{"author_name":"Chenghui Yang","author_inst":"Sichuan Provincial People's Hospital"},{"author_name":"Ying He","author_inst":"Sichuan Provincial People's Hospital"},{"author_name":"Xianfeng Qu","author_inst":"Sichuan Provincial People's Hospital"},{"author_name":"Abbas F. Almulla","author_inst":"Sichuan Provincial People's Hospital"},{"author_name":"Yingqiang Zhang","author_inst":"Sichuan Provincial People's Hospital"},{"author_name":"Jinming Xiao","author_inst":"Sichuan Normal University"},{"author_name":"Chengxiao Yang","author_inst":"University of Electronic Science and Technology of China"},{"author_name":"Drozdstoj Stoyanov","author_inst":"Medical University of Plovdiv"},{"author_name":"Bharat B Biswal","author_inst":"University of Electronic Science and Technology of China"},{"author_name":"Benjamin Klugah-Brown","author_inst":"University of electronic science and technology of China"},{"author_name":"Andre F. Carvalho","author_inst":"Deakin University"},{"author_name":"Licia Pacheco Luna","author_inst":"Johns Hopkins Hospital"},{"author_name":"Stefania Ferraro","author_inst":"University of Electronic Science and Technology"},{"author_name":"Yuting Wang","author_inst":"Sichuan Provincial People's Hospital"},{"author_name":"Elijah Agoalikum","author_inst":"University of Electronic Science and Technology of China"},{"author_name":"Michael Maes","author_inst":"University of Electronic Science and Technology of China"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Validation of Algorithms to Identify Small or Large for Gestational Age in the Korean Nationwide Healthcare Database","rel_doi":"10.64898\/2026.09.09.26362678","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26362678","rel_abs":"ObjectiveSmall for gestational age (SGA) and large for gestational age (LGA) are critical endpoints in perinatal pharmacoepidemiology, yet gestational age is frequently missing in administrative databases. This study validated algorithms for identifying SGA and LGA in the Korean National Health Information Database (NHID).\n\nMethodsWe linked the NHID with national vaccination and infant health screening registries (2018-2021) to create a validation cohort of 94,159 pregnancies with reference standard gestational age and birth weight; infants with birth weights below the 10th or above the 90th percentile were considered SGA or LGA, respectively. We evaluated four algorithms: ICD-10 diagnosis codes from infant claims (Method A), maternal claims (Method B), either infant or maternal claims (Method C), and birth weight combined with estimated gestational age (Method D).\n\nResultsICD-10-based algorithms consistently underestimated prevalence, showing high specificity but low sensitivity (<17%). In contrast, Method D demonstrated superior performance: for SGA, sensitivity was 89.3%, specificity 96.8%, and positive predictive value (PPV) 71.6%; for LGA, sensitivity was 77.5%, specificity 98.3%, and PPV 84.7%.\n\nConclusionSGA and LGA can be identified with reasonable accuracy in the NHID using birth weight and estimated gestational age, whereas diagnosis codes alone can underestimate prevalence.","rel_num_authors":5,"rel_authors":[{"author_name":"Yongtai Cho","author_inst":"Department of Pharmacy, School of Pharmacy, Sungkyunkwan University, Suwon, South Korea"},{"author_name":"HyunJoo Lim","author_inst":"Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, South Korea."},{"author_name":"Bohyun Suh","author_inst":"Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, South Korea."},{"author_name":"Yubin Lee","author_inst":"Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, South Korea."},{"author_name":"Ju-Young Shin","author_inst":"College of Pharmacy, Seoul National University"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Effectiveness and safety of a New Standardised TrEatment Protocol based on initial\/early therapy with single-pill combinations of blood pressure-lowering drugs for improving blood pressure control (NewSTeP): Rationale, design of a randomized clinical trial and baseline characteristics of the trial participants","rel_doi":"10.64898\/2026.09.10.26362712","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362712","rel_abs":"BackgroundHypertension is the leading modifiable risk factor for cardiovascular disease (CVD). Despite availability of blood pressure (BP)-lowering therapies, BP control rates remain suboptimal. Reluctance to initiate treatment with combination therapy and delayed treatment intensification contribute to poor control. Early use of single-pill combinations (SPCs) within standardised treatment protocols (STPs) may improve outcomes, but evidence from India is limited.\n\nObjectiveTo evaluate the effectiveness and safety of a new STP incorporating initial or early use of SPCs compared with usual care among adults with hypertension.\n\nMethodsThe New Standardised TrEatment Protocol (NewSTeP) trial is a pragmatic, multicentre, randomized, parallel-group, open-label trial conducted in tertiary healthcare centres in India. Adults with hypertension who are untreated or receiving one BP-lowering drug and require treatment initiation or intensification (n = 300) will be randomized 1:1 to either a new STP incorporating early SPC therapy or usual care. Participants will be followed for 6 months. The primary effectiveness outcome is change in home-measured mean systolic BP from randomization to month 6. The primary safety outcome is discontinuation of trial drug due to adverse events. Secondary outcomes include proportion of participants achieving BP control, change in diastolic BP, incidence of adverse events of special interest, treatment adherence, treatment modification, and time to BP control. A process evaluation will assess reach, implementation, acceptability, and sustainability, while an economic evaluation will assess cost-effectiveness.\n\nResultsBetween October 2025 and March 2026, 300 participants were randomized across nine sites (150 to New STP; 150 usual care) from 360 screened individuals. Final follow-up is expected in September 2026, with results anticipated in October 2026.\n\nConclusionsThe NewSTeP trial will provide evidence on the effectiveness, safety, implementation, and cost-effectiveness of an SPC-based STP for hypertension management in India and inform future hypertension control strategies and policies.\n\nTrial RegistrationThe trial is registered with the Clinical Trials Registry-India (CTRI\/2025\/07\/091649).","rel_num_authors":23,"rel_authors":[{"author_name":"Rupasvi Dhurjati","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Rashmi Pant","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Amit Kumar","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Anshika Mittal","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Krishnaiah Chappidi","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Gautam Satheesh","author_inst":"University of Sydney"},{"author_name":"Parul Puri","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Sasi Kumar Tiruttani","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Shwetha Rajaram","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Aneesh Basheer","author_inst":"1.\tDepartment of Medicine, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalpet, Chennai, India"},{"author_name":"Prabhdeep kaur","author_inst":"IISc, Bengaluru, India"},{"author_name":"Andrew Moran","author_inst":"Resolve to Save Lives, New York, NY; Division of General Medicine, Columbia University Medical Center, New York, NY"},{"author_name":"Andres Rosende","author_inst":"Department of Noncommunicable Diseases and Mental Health, Pan American Health Organization, Washington, D.C., United States of America"},{"author_name":"Poongothai Subramani","author_inst":"Madras Diabetes Research Foundation, ICMR-Collaborating Centre of Excellence, Chennai, India"},{"author_name":"Sandeep Mahajan","author_inst":"All India Institute of Medical Sciences, New Delhi, India"},{"author_name":"Nupur Lalvani","author_inst":"Blue Circle Diabetes Foundation"},{"author_name":"Sandeep Bansal","author_inst":"VMMC and Safdarjung Hospital, New Delhi, India"},{"author_name":"Dorairaj Prabhakaran","author_inst":"Centre for Chronic Disease Control"},{"author_name":"Jayagopal Pathiyil Balagopalan","author_inst":"Lakshmi Hospital, Palakkad, Kerala, India"},{"author_name":"Stephen Jan","author_inst":"The George Institute for Global Health"},{"author_name":"Mark D Huffman","author_inst":"Washington University in Saint Louis"},{"author_name":"Vivekanand Jha","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India; Prasanna School of Public Health, Manipal Academy of Higher Education, India; School of Pub"},{"author_name":"Abdul Salam","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India; Prasanna School of Public Health, Manipal Academy of Higher Education, India; The George In"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Effectiveness and safety of a New Standardised TrEatment Protocol based on initial\/early therapy with single-pill combinations of blood pressure-lowering drugs for improving blood pressure control (NewSTeP): Rationale, design of a randomized clinical trial and baseline characteristics of the trial participants","rel_doi":"10.64898\/2026.09.10.26362712","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362712","rel_abs":"BackgroundHypertension is the leading modifiable risk factor for cardiovascular disease (CVD). Despite availability of blood pressure (BP)-lowering therapies, BP control rates remain suboptimal. Reluctance to initiate treatment with combination therapy and delayed treatment intensification contribute to poor control. Early use of single-pill combinations (SPCs) within standardised treatment protocols (STPs) may improve outcomes, but evidence from India is limited.\n\nObjectiveTo evaluate the effectiveness and safety of a new STP incorporating initial or early use of SPCs compared with usual care among adults with hypertension.\n\nMethodsThe New Standardised TrEatment Protocol (NewSTeP) trial is a pragmatic, multicentre, randomized, parallel-group, open-label trial conducted in tertiary healthcare centres in India. Adults with hypertension who are untreated or receiving one BP-lowering drug and require treatment initiation or intensification (n = 300) will be randomized 1:1 to either a new STP incorporating early SPC therapy or usual care. Participants will be followed for 6 months. The primary effectiveness outcome is change in home-measured mean systolic BP from randomization to month 6. The primary safety outcome is discontinuation of trial drug due to adverse events. Secondary outcomes include proportion of participants achieving BP control, change in diastolic BP, incidence of adverse events of special interest, treatment adherence, treatment modification, and time to BP control. A process evaluation will assess reach, implementation, acceptability, and sustainability, while an economic evaluation will assess cost-effectiveness.\n\nResultsBetween October 2025 and March 2026, 300 participants were randomized across nine sites (150 to New STP; 150 usual care) from 360 screened individuals. Final follow-up is expected in September 2026, with results anticipated in October 2026.\n\nConclusionsThe NewSTeP trial will provide evidence on the effectiveness, safety, implementation, and cost-effectiveness of an SPC-based STP for hypertension management in India and inform future hypertension control strategies and policies.\n\nTrial RegistrationThe trial is registered with the Clinical Trials Registry-India (CTRI\/2025\/07\/091649).","rel_num_authors":23,"rel_authors":[{"author_name":"Rupasvi Dhurjati","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Rashmi Pant","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Amit Kumar","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Anshika Mittal","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Krishnaiah Chappidi","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Gautam Satheesh","author_inst":"University of Sydney"},{"author_name":"Parul Puri","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Sasi Kumar Tiruttani","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Shwetha Rajaram","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Aneesh Basheer","author_inst":"1.\tDepartment of Medicine, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalpet, Chennai, India"},{"author_name":"Prabhdeep kaur","author_inst":"IISc, Bengaluru, India"},{"author_name":"Andrew Moran","author_inst":"Resolve to Save Lives, New York, NY; Division of General Medicine, Columbia University Medical Center, New York, NY"},{"author_name":"Andres Rosende","author_inst":"Department of Noncommunicable Diseases and Mental Health, Pan American Health Organization, Washington, D.C., United States of America"},{"author_name":"Poongothai Subramani","author_inst":"Madras Diabetes Research Foundation, ICMR-Collaborating Centre of Excellence, Chennai, India"},{"author_name":"Sandeep Mahajan","author_inst":"All India Institute of Medical Sciences, New Delhi, India"},{"author_name":"Nupur Lalvani","author_inst":"Blue Circle Diabetes Foundation"},{"author_name":"Sandeep Bansal","author_inst":"VMMC and Safdarjung Hospital, New Delhi, India"},{"author_name":"Dorairaj Prabhakaran","author_inst":"Centre for Chronic Disease Control"},{"author_name":"Jayagopal Pathiyil Balagopalan","author_inst":"Lakshmi Hospital, Palakkad, Kerala, India"},{"author_name":"Stephen Jan","author_inst":"The George Institute for Global Health"},{"author_name":"Mark D Huffman","author_inst":"Washington University in Saint Louis"},{"author_name":"Vivekanand Jha","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India; Prasanna School of Public Health, Manipal Academy of Higher Education, India; School of Pub"},{"author_name":"Abdul Salam","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India; Prasanna School of Public Health, Manipal Academy of Higher Education, India; The George In"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Effectiveness and safety of a New Standardised TrEatment Protocol based on initial\/early therapy with single-pill combinations of blood pressure-lowering drugs for improving blood pressure control (NewSTeP): Rationale, design of a randomized clinical trial and baseline characteristics of the trial participants","rel_doi":"10.64898\/2026.09.10.26362712","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362712","rel_abs":"BackgroundHypertension is the leading modifiable risk factor for cardiovascular disease (CVD). Despite availability of blood pressure (BP)-lowering therapies, BP control rates remain suboptimal. Reluctance to initiate treatment with combination therapy and delayed treatment intensification contribute to poor control. Early use of single-pill combinations (SPCs) within standardised treatment protocols (STPs) may improve outcomes, but evidence from India is limited.\n\nObjectiveTo evaluate the effectiveness and safety of a new STP incorporating initial or early use of SPCs compared with usual care among adults with hypertension.\n\nMethodsThe New Standardised TrEatment Protocol (NewSTeP) trial is a pragmatic, multicentre, randomized, parallel-group, open-label trial conducted in tertiary healthcare centres in India. Adults with hypertension who are untreated or receiving one BP-lowering drug and require treatment initiation or intensification (n = 300) will be randomized 1:1 to either a new STP incorporating early SPC therapy or usual care. Participants will be followed for 6 months. The primary effectiveness outcome is change in home-measured mean systolic BP from randomization to month 6. The primary safety outcome is discontinuation of trial drug due to adverse events. Secondary outcomes include proportion of participants achieving BP control, change in diastolic BP, incidence of adverse events of special interest, treatment adherence, treatment modification, and time to BP control. A process evaluation will assess reach, implementation, acceptability, and sustainability, while an economic evaluation will assess cost-effectiveness.\n\nResultsBetween October 2025 and March 2026, 300 participants were randomized across nine sites (150 to New STP; 150 usual care) from 360 screened individuals. Final follow-up is expected in September 2026, with results anticipated in October 2026.\n\nConclusionsThe NewSTeP trial will provide evidence on the effectiveness, safety, implementation, and cost-effectiveness of an SPC-based STP for hypertension management in India and inform future hypertension control strategies and policies.\n\nTrial RegistrationThe trial is registered with the Clinical Trials Registry-India (CTRI\/2025\/07\/091649).","rel_num_authors":23,"rel_authors":[{"author_name":"Rupasvi Dhurjati","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Rashmi Pant","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Amit Kumar","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Anshika Mittal","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Krishnaiah Chappidi","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Gautam Satheesh","author_inst":"University of Sydney"},{"author_name":"Parul Puri","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Sasi Kumar Tiruttani","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Shwetha Rajaram","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India"},{"author_name":"Aneesh Basheer","author_inst":"1.\tDepartment of Medicine, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalpet, Chennai, India"},{"author_name":"Prabhdeep kaur","author_inst":"IISc, Bengaluru, India"},{"author_name":"Andrew Moran","author_inst":"Resolve to Save Lives, New York, NY; Division of General Medicine, Columbia University Medical Center, New York, NY"},{"author_name":"Andres Rosende","author_inst":"Department of Noncommunicable Diseases and Mental Health, Pan American Health Organization, Washington, D.C., United States of America"},{"author_name":"Poongothai Subramani","author_inst":"Madras Diabetes Research Foundation, ICMR-Collaborating Centre of Excellence, Chennai, India"},{"author_name":"Sandeep Mahajan","author_inst":"All India Institute of Medical Sciences, New Delhi, India"},{"author_name":"Nupur Lalvani","author_inst":"Blue Circle Diabetes Foundation"},{"author_name":"Sandeep Bansal","author_inst":"VMMC and Safdarjung Hospital, New Delhi, India"},{"author_name":"Dorairaj Prabhakaran","author_inst":"Centre for Chronic Disease Control"},{"author_name":"Jayagopal Pathiyil Balagopalan","author_inst":"Lakshmi Hospital, Palakkad, Kerala, India"},{"author_name":"Stephen Jan","author_inst":"The George Institute for Global Health"},{"author_name":"Mark D Huffman","author_inst":"Washington University in Saint Louis"},{"author_name":"Vivekanand Jha","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India; Prasanna School of Public Health, Manipal Academy of Higher Education, India; School of Pub"},{"author_name":"Abdul Salam","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India; Prasanna School of Public Health, Manipal Academy of Higher Education, India; The George In"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Conserved roles of cardiac endothelial ETS factors in ventricular development and disease","rel_doi":"10.64898\/2026.09.08.26361286","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.08.26361286","rel_abs":"We previously identified ETS1 as a candidate gene in the rare chromosomal deletion disorder, Jacobsen syndrome (JS, OMIM#147791). Here, we present data from four model systems that define roles for ETS factors in normal heart development and suggest how defects in these genes contribute to congenital heart disease. In frog, knockdown of Ets1 in cardiac mesoderm led to a hypoplastic ventricle with impaired cardiac function and loss of trabecular myocardium. Grafting of wildtype cardiac mesodermal tissue restored the integrity of the ventricular endocardial layer and normal development. In zebrafish, KD of ETS1 and two related ETS factor genes caused severely underdeveloped, poorly functioning ventricles with decreased numbers of endocardial cells that failed to contact the myocardium. Genetic ablation of the endocardium in mice also caused a hypoplastic ventricle with loss of the trabecular myocardium. In Drosophila, loss of the ETS1 ortholog pointed (pnt) affected specification of cardiac precursors and decreased Notch signaling, a pathway previously implicated in some forms of hypoplastic left heart syndrome (HLHS). We also demonstrated genetic interactions between pnt and tinman, the NKX2.5 ortholog, associated with HLHS. Finally, our examination of the heart from a newborn with JS\/HLHS showed myofibrillar disarray and myocardial maturation defects. Furthermore, there was a reduction in the coronary vascular endothelium in the LV myocardium from the JS\/HLHS patient compared to an age-matched normal heart. Taken together, our studies demonstrate a critical and conserved role of ETS factors for cardiac endothelial function and in ventricular morphogenesis.","rel_num_authors":15,"rel_authors":[{"author_name":"Lu Wang","author_inst":"University of California San Diego"},{"author_name":"Analyne Schroeder","author_inst":"SBP Medical Discovery Institute"},{"author_name":"Katya Marchetti","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Ingolf Reim","author_inst":"Philipps-Universitat Marburg"},{"author_name":"Matthias Blanc","author_inst":"Stanford University"},{"author_name":"K'leigh Guillotte","author_inst":"SBP Medical Discovery Institute"},{"author_name":"Amelie Muck","author_inst":"Philipps-Universitat Marburg"},{"author_name":"Elaina Bao","author_inst":"Rady Children's Health"},{"author_name":"Wenhao Liu","author_inst":"Georgia Institute of Technology"},{"author_name":"Shu Jia","author_inst":"Georgia Institute of Technology"},{"author_name":"Denise Malicki","author_inst":"Rady Children's Health"},{"author_name":"Rolf Bodmer","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Shuyi Nie","author_inst":"Georgia Institute of Technology"},{"author_name":"Karen Ocorr","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Paul Grossfeld","author_inst":"UCSD School of Medicine"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Conserved roles of cardiac endothelial ETS factors in ventricular development and disease","rel_doi":"10.64898\/2026.09.08.26361286","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.08.26361286","rel_abs":"We previously identified ETS1 as a candidate gene in the rare chromosomal deletion disorder, Jacobsen syndrome (JS, OMIM#147791). Here, we present data from four model systems that define roles for ETS factors in normal heart development and suggest how defects in these genes contribute to congenital heart disease. In frog, knockdown of Ets1 in cardiac mesoderm led to a hypoplastic ventricle with impaired cardiac function and loss of trabecular myocardium. Grafting of wildtype cardiac mesodermal tissue restored the integrity of the ventricular endocardial layer and normal development. In zebrafish, KD of ETS1 and two related ETS factor genes caused severely underdeveloped, poorly functioning ventricles with decreased numbers of endocardial cells that failed to contact the myocardium. Genetic ablation of the endocardium in mice also caused a hypoplastic ventricle with loss of the trabecular myocardium. In Drosophila, loss of the ETS1 ortholog pointed (pnt) affected specification of cardiac precursors and decreased Notch signaling, a pathway previously implicated in some forms of hypoplastic left heart syndrome (HLHS). We also demonstrated genetic interactions between pnt and tinman, the NKX2.5 ortholog, associated with HLHS. Finally, our examination of the heart from a newborn with JS\/HLHS showed myofibrillar disarray and myocardial maturation defects. Furthermore, there was a reduction in the coronary vascular endothelium in the LV myocardium from the JS\/HLHS patient compared to an age-matched normal heart. Taken together, our studies demonstrate a critical and conserved role of ETS factors for cardiac endothelial function and in ventricular morphogenesis.","rel_num_authors":15,"rel_authors":[{"author_name":"Lu Wang","author_inst":"University of California San Diego"},{"author_name":"Analyne Schroeder","author_inst":"SBP Medical Discovery Institute"},{"author_name":"Katya Marchetti","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Ingolf Reim","author_inst":"Philipps-Universitat Marburg"},{"author_name":"Matthias Blanc","author_inst":"Stanford University"},{"author_name":"K'leigh Guillotte","author_inst":"SBP Medical Discovery Institute"},{"author_name":"Amelie Muck","author_inst":"Philipps-Universitat Marburg"},{"author_name":"Elaina Bao","author_inst":"Rady Children's Health"},{"author_name":"Wenhao Liu","author_inst":"Georgia Institute of Technology"},{"author_name":"Shu Jia","author_inst":"Georgia Institute of Technology"},{"author_name":"Denise Malicki","author_inst":"Rady Children's Health"},{"author_name":"Rolf Bodmer","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Shuyi Nie","author_inst":"Georgia Institute of Technology"},{"author_name":"Karen Ocorr","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Paul Grossfeld","author_inst":"UCSD School of Medicine"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"HemOncAgent: an artificial intelligence system for retrieving structured and narrative oncology knowledge","rel_doi":"10.64898\/2026.09.09.26362651","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26362651","rel_abs":"Oncology knowledge spans structured and unstructured datasets of drugs, regimens, conditions, and identifiers, as well as clinician-authored narratives describing treatment sequencing across disease settings. Answering clinical questions may require accessing both databases and free-text narratives, but existing intelligent retrieval systems favor either relational facts or narrative context. We developed HemOncAgent, an artificial intelligence agent that selects among retrieval tools for the HemOnc knowledge ecosystem: HemOncKB, a curated knowledge graph for pharmacologic relationships, and HemOnc.org, a narrative resource for care pathways. Across structured and narrative benchmarks, HemOncAgent maintained high-fidelity retrieval across question types for which single-source systems showed domain-specific limitations, supporting hybrid tool-based retrieval for more reliable oncology knowledge access.","rel_num_authors":9,"rel_authors":[{"author_name":"Andrew J Yang","author_inst":"The Warren Alpert Medical School of Brown University"},{"author_name":"Hossam A Zaki","author_inst":"The Warren Alpert Medical School of Brown University"},{"author_name":"Aaron Seto","author_inst":"The Warren Alpert Medical School of Brown University"},{"author_name":"Taemin Kim","author_inst":"The Warren Alpert Medical School of Brown University"},{"author_name":"Irbaz Bin Riaz","author_inst":"Mayo Clinic Comprehensive Cancer Center"},{"author_name":"Andrew Srisuwananukorn","author_inst":"The Ohio State University Comprehensive Cancer Center"},{"author_name":"Andrew J Cowan","author_inst":"BC Cancer\/University of British Columbia"},{"author_name":"Peter C Yang","author_inst":"Massachusetts General Hospital"},{"author_name":"Jeremy L Warner","author_inst":"Center for Clinical Cancer Informatics and Data Science, Legorreta Cancer Center, Brown University"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Multi-trait Polygenic Profiling and Survival Free of Dementia and Disability: Results from the Health and Retirement Study","rel_doi":"10.64898\/2026.09.09.26362686","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26362686","rel_abs":"ObjectiveTo determine whether a multi-trait polygenic profile for dementia is associated with dementia- and disability-free survival in middle-aged and older adults.\n\nBackgroundClinical trials of brain health and aging increasingly use holistic, patient-centered outcomes that capture overall health status. Survival free of dementia and disability is one such outcome. We hypothesized that adverse polygenic profiles for dementia would be associated with higher risk of dementia, disability, or death.\n\nDesign\/MethodsWe conducted a genetic association study within the Health and Retirement Study, a prospective, nationally representative longitudinal cohort of U.S. adults. Polygenic profiling used the previously validated integrated polygenic risk score for dementia (iPRS-DEM), which incorporates neurodegenerative and vascular genetic components. Participants were categorized as having favorable ([&le;]20th percentile), intermediate (20th-80th percentile), or poor (>80th percentile) polygenic profiles. The primary outcome was a composite of dementia, disability, or death. Cox proportional hazards models were adjusted for age, sex, genetic ancestry, and genetic principal components. Interaction between continuous iPRS-DEM and APOE {varepsilon}4 status was assessed for 31-year outcome risk.\n\nResultsAmong 45,234 HRS participants, 15,620 provided DNA samples, 15,565 had genotype data after quality control and imputation, and 14,333 were free of dementia and disability at baseline (median age 55 years; 58% female). Compared with a favorable polygenic profile, intermediate and poor profiles were associated with higher risk of the composite outcome (HR 1.14, 95% CI 1.07-1.21 and HR 1.43, 95% CI 1.26-1.63, respectively). The relative association was strongest for dementia; for poor versus favorable profiles, HRs were 1.58 (95% CI 1.21-2.05) for dementia, 1.43 (95% CI 1.14-1.79) for disability, and 1.33 (95% CI 1.15-1.54) for death. An interaction between continuous iPRS-DEM and APOE {varepsilon}4 status was observed for 31-year dementia risk (P=0.016). Relative to favorable-profile APOE {varepsilon}4 non-carriers, dementia risk was highest among participants with a poor profile who were APOE {varepsilon}4 carriers (HR 2.32, 95% CI 1.73-3.12).\n\nConclusionsAdverse polygenic profiles for dementia were associated with higher composite risk of dementia, disability, or death in a large population-based cohort, with the strongest association observed for dementia. Joint consideration of iPRS-DEM and APOE {varepsilon}4 further identified individuals at elevated dementia risk. These findings support the potential value of polygenic profiling for risk stratification while highlighting limitations related to ancestry, generalizability, and clinical translation.","rel_num_authors":10,"rel_authors":[{"author_name":"Yome Tawaldemedhen","author_inst":"Yale University"},{"author_name":"Santiago Clocchiatti-Tuozzo","author_inst":"Yale School of Medicine"},{"author_name":"Cyprien Rivier","author_inst":"Yale School of Medicine"},{"author_name":"Shufan Huo","author_inst":"Yale School of Medicine"},{"author_name":"Andrew Silberfeld","author_inst":"Yale School of Medicine"},{"author_name":"Tim D'Aoust","author_inst":"University of Bordeaux"},{"author_name":"Stephanie Debette","author_inst":"University of Bordeaux"},{"author_name":"Adam de Havenon","author_inst":"Yale School of Medicine"},{"author_name":"Thomas M. Gill","author_inst":"Yale School of Medicine"},{"author_name":"Guido J. Falcone","author_inst":"Yale School of Medicine"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Absolute Benefit of Androgen Deprivation Therapy With Radiotherapy for Localized Prostate Cancer","rel_doi":"10.64898\/2026.09.10.26362669","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362669","rel_abs":"ObjectivesTo estimate the absolute benefit of adding and prolonging androgen deprivation therapy (ADT) to radiation therapy (RT) for men with localized prostate cancer by integrating cancer-specific risk, other-cause mortality (OCM) risk, and relative treatment efficacy.\n\nSubjects and MethodsIndividualized risks were estimated by integrating cause-specific hazard estimates from a validated staging system (STAR-CAP) with those from a validated non-cancer mortality model (OCCAM). ADT treatment efficacy was then incorporated using published hazard ratio estimates from the MARCAP meta-analysis. Model utility was illustrated using the Prostate, Lung, Colon, and Ovarian (PLCO) cancer screening trial cohort (n=5468 prostate cancer patients with complete covariates). The primary outcome was the estimated 10-year absolute risk reduction (ARR) in distant metastasis (DM) from adding short-term ADT (STADT) to RT or extending STADT to long term ADT (LTADT).\n\nResultsWithin PLCO, model estimated risk of DM at 10 years ranged from <1% to 56% under guideline concordant care and OCM risk ranged from 3% to 80% independent of treatment. For patients with NCCN unfavorable intermediate-risk (n=1814), adding STADT to RT reduced estimated 10 year DM risk by a median of 4%, but the ARR estimates for individuals ranged from <1% to almost 15%. Similar variation was seen within NCCN high-risk patients (n=1289) with a median ARR of 9% [Range: 0.4%-17.2%] when prolonging ADT treatment. Moreover, 25% of NCCN unfavorable intermediate-risk patients have less than a 2.4% ARR while 25% of NCCN high-risk patients experience less than a 5% ARR.\n\nConclusionAn integrated model accounting for both prostate cancer aggressiveness and comorbidities demonstrates substantial heterogeneity in the estimated absolute benefit of ADT within conventional risk groups. This approach provides individualized estimates to support treatment discussions; external validation is needed before clinical implementation.","rel_num_authors":10,"rel_authors":[{"author_name":"Jessica Aldous","author_inst":"Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"William C Jackson","author_inst":"Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA"},{"author_name":"Elizabeth Chase","author_inst":"Department of Economics, Sociology, & Statistics, RAND Corporation, Arlington, VA, USA"},{"author_name":"Elise Covert","author_inst":"IQVIA, Madison, WI, USA"},{"author_name":"Joseph Tang","author_inst":"Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA"},{"author_name":"Udit Singhal","author_inst":"Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA"},{"author_name":"Todd M Morgan","author_inst":"Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA"},{"author_name":"Daniel E Spratt","author_inst":"Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine Cleveland, Cleveland, OH, USA"},{"author_name":"Robert T Dess","author_inst":"Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA"},{"author_name":"Matthew J Schipper","author_inst":"Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Relationship between mental health and unmet need for contraception and method type among women living with HIV in Kenya","rel_doi":"10.64898\/2026.09.10.26362702","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362702","rel_abs":"Contraception is important for preventing unintended pregnancies and reducing maternal and infant mortality. Among women living with HIV (WLHIV), it is also central to preventing vertical HIV transmission. Yet unmet need for contraception remains high among WLHIV in sub-Saharan Africa. Mental health symptoms may contribute to unmet need, but evidence among WLHIV remains limited. We examined the relationship between depression and anxiety and unmet need for contraception.\n\nWe used baseline survey data from Kenyan WLHIV receiving routine HIV care participating in a cluster randomized clinical trial evaluating a reproductive health counselling intervention at 10 HIV clinics. Women who were fecund, did not desire a pregnancy within two years, and not using a modern method of contraception were considered to have unmet need for contraception and were eligible for this analysis. Surveys captured data on depression, anxiety, fertility intentions and contraceptive use. We constructed separate generalized linear models to assess the relationship between depression and\/or anxiety and unmet need for contraception.\n\nAmong 2,334 women in the analysis, the median age was 34; 9% (n=221) reported symptoms of at least mild depression, 9% (n=200) anxiety, 13% (n=305) either condition, and 5% (n=116) both. Overall, 84% (n=1,952) used a modern contraceptive method, 16% (n=378) had an unmet need for contraception, and 41% (n=784) used LARC. In univariate analysis, unmet need for contraception was 43% higher among women with either at least mild depression or at least mild anxiety (Prevalence Ratio [PR]=1.43, 95% Confidence Interval [CI]: 1.22-1.67); results were similar in the adjusted model (adjusted PR [aPR]=1.30, 95% CI: 1.08-1.58). No relationships were detected between anxiety or depression alone and unmet need.\n\nWLHIV with either depression or anxiety had higher unmet need which suggests that mental health conditions may pose barriers to contraceptive use and may need additional support to achieve their reproductive health goals. Additional attention to mental health needs during contraceptive counselling may support informed contraceptive decision-making.","rel_num_authors":11,"rel_authors":[{"author_name":"Agnes Karingo Karume","author_inst":"Kenyatta National Hospital"},{"author_name":"Aparna Seth","author_inst":"University of Washington Seattle Campus: University of Washington"},{"author_name":"Nancy Ngumbau","author_inst":"Kenyatta National Hospital"},{"author_name":"Celestine Atieno","author_inst":"Kenyatta National Hospital"},{"author_name":"June Moraa","author_inst":"Kenyatta National Hospital"},{"author_name":"Kristin Beima-Sofie","author_inst":"University of Washington Seattle Campus: University of Washington"},{"author_name":"Barbra  A. Richardson","author_inst":"University of Washington Seattle Campus: University of Washington"},{"author_name":"Jennifer  A. Unger","author_inst":"Warren Alpert Medical School of Brown University: Brown University Warren Alpert Medical School"},{"author_name":"Amritha Bhat","author_inst":"University of Washington Seattle Campus: University of Washington"},{"author_name":"John Kinuthia","author_inst":"Kenyatta National Hospital"},{"author_name":"Alison  L. Drake","author_inst":"University of Washington Seattle Campus: University of Washington"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Symptom burden, Psychosocial Distress, Resilience and Health-Related Quality of Life in Women with Metastatic Breast Cancer Receiving Contemporary Systemic Therapy","rel_doi":"10.64898\/2026.09.08.26362524","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.08.26362524","rel_abs":"AimsTargeted therapies and immunotherapies have extended survival of women with metastatic breast cancer. However, the role of resilience among women receiving those contemporary treatments remains understudied. We aimed to examine the interrelationships among physical symptom burden, psychosocial distress, resilience and health-related quality of life in women with metastatic breast cancer receiving contemporary systemic cancer treatment.\n\nDesignCross-sectional study.\n\nMethodsWomen with metastatic breast cancer receiving systemic treatment were recruited across the United States from February to September 2024. Data was collected using validated measures. Psychosocial distress was constructed as a latent variable indicated by anxiety, depression and uncertainty, using confirmatory factor analysis. We conducted structural equation modeling to examine multiple pathways between physical symptom burden, latent psychosocial distress, resilience and health-related quality of life.\n\nResultsOf 217 participants, 209 were included in the analysis (mean age = 50.1 years, SD=14.1). Physical symptom burden, psychosocial distress and resilience were significantly associated with health-related quality of life. Significant indirect associations of physical symptom burden and psychosocial distress with health-related quality of life through resilience were identified. Structural equation modeling showed indirect associations between physical symptom burden and health-related quality of life through psychosocial distress and resilience ({beta} =-0.137, 95% CI: -0.217, -0.078, p<0.001).\n\nConclusionPsychosocial distress appeared to be more proximally associated with resilience than physical symptom burden among this population. Resilience interventions may be strengthened by identifying and addressing anxiety, depression and uncertainty as proximal intervention points for preserving resilience, rather than only including generic stress management components.\n\nImpactThis study highlighted the need of resilience interventions that prioritize anxiety and depression screening, mental health referral, and distress focused supportive care alongside symptom management for this population.\n\nReporting MethodSTROBE, Cross-sectional guidelines.\n\nPatient or Public ContributionThis study involved women with metastatic breast cancer and breast cancer patient advocacy groups participated in recruitment.","rel_num_authors":7,"rel_authors":[{"author_name":"Yan Zhan","author_inst":"Yale School of Nursing"},{"author_name":"Shelli Feder","author_inst":"Yale School of Nursing"},{"author_name":"Sangchoon Jeon","author_inst":"Yale School of Nursing"},{"author_name":"Maryam Lustberg","author_inst":"Yale School of Medicine, Medical Oncology Division, Yale Cancer Center"},{"author_name":"Margaret Rosenzweig","author_inst":"University of Pittsburgh School of Nursing"},{"author_name":"Djin Tay","author_inst":"University of Utah, College of Nursing"},{"author_name":"Tish Knobf","author_inst":"Yale School of Nursing"}],"rel_date":"2026-09-11","rel_site":"medrxiv"},{"rel_title":"Association between Plasmodium falciparum Kelch13 mutations and malaria parasite clearance half-life after artemisinin-based therapy: an updated WWARN systematic review and individual patient data meta-analysis","rel_doi":"10.64898\/2026.09.08.26362414","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.08.26362414","rel_abs":"BackgroundArtemisinin-based combination therapies remain the first-line treatment for uncomplicated Plasmodium falciparum malaria. Plasmodium falciparum Kelch13 mutations emerge and spread within distinct malaria epidemiological and immunological contexts, shaping the expression of artemisinin resistance (ART-R). Understanding the clinical phenotypes of these mutations requires evaluation across diverse transmission settings and geographic regions.\n\nMethodsA systematic review (SR) and individual patient data meta-analysis (IPDMA) were conducted (PROSPERO: CRD42019133366) to identify studies that included serial parasite density measurements and Kelch13 genotyping. Associations between Kelch13 mutations and parasite clearance half-lives (PC1\/2) and Day 3 parasite positivity were assessed. Receiver operating characteristic (ROC) analyses identified PC1\/2 thresholds most strongly associated with relevant Kelch13 mutations.\n\nFindingsThe SR identified 86 eligible studies, and individual patient data were obtained from 45 studies (n=16,823 patients from 539 study sites in 33 countries). After excluding hyperparasitaemia, Day 3 parasite positivity exceeded 10% overall across all WHO-validated, candidate, and potential mutations, but not for other Kelch13 mutations. Parasite clearance rates were consistently shorter in moderate-to-high-transmission than in lower-transmission areas. The WHO threshold PC1\/2>5h had a sensitivity of 36% (27.9-44.6) for detecting WHO-validated mutations in moderate-to-high transmission areas and 81% (78.5-82.8) in lower transmission areas. In moderate-to-high transmission settings, a PC1\/2 threshold of 3.1h optimally discriminated WHO-validated mutations (ROC AUC 0.78; 95% CI 0.74-0.82; sensitivity 75% (95% CI:67%-82%); specificity 71%, 95% CI: 69%-73%). Additional emerging Kelch13 mutations associated with delayed parasite clearance were identified in relatively small African and Asian sample sets.\n\nInterpretationCompared with WT parasites, parasites carrying WHO-validated ART-R mutations were associated with a 34%-59% longer mean PC1\/2, regardless of endemicity, treatment regimen, or age. Given the low sensitivity of the PC1\/2>5h threshold for identifying WHO-validated ART-R parasites in moderate-to-high transmission settings, where its recalibration is indicated. Broader genotyping is warranted for identifying emerging Kelch13 mutations associated with delayed parasite clearance.\n\nResearch in Context: PanelO_ST_ABSEvidence before this studyC_ST_ABSArtemisinin-based combination therapies (ACTs) remain the first-line treatment for Plasmodium falciparum malaria. The emergence and spread of artemisinin partial resistance (ART-R), characterised by delayed parasite clearance after treatment and mediated primarily by non-synonymous mutations in the Kelch13 propeller domain, pose a major threat to global malaria control. Previous individual-patient data meta-analyses (IPDMAs) have established an association between Kelch13 mutations and delayed clearance, but these analyses were largely restricted to low-transmission settings in Southeast Asia (SEA). Comprehensive evaluation of these relationships in Africa, which bears 95% of the global falciparum malaria burden and where transmission intensity, host immunity, and infection complexity differ, is needed.\n\nAdded value of this studyThis study represents the largest and most geographically comprehensive IPDMA of Kelch13-associated ART-R to date, integrating published and unpublished data from 16,823 patients at 539 sites across 33 countries, including 22 in Africa. Extending on the previous analysis and incorporating the newly updated WHO compendium of relevant Kelch13 mutations, this study evaluated parasite clearance phenotypes across diverse transmission intensities, including underrepresented African populations. WHO-listed mutations of ART-R were strongly associated with Day 3 positivity and prolonged parasite clearance half-life (PC1\/2) after treatment, while additional Kelch13 mutants were also associated with delayed clearance, thereby expanding the contemporary molecular landscape of ART-R. The WHO-recommended PC1\/2 threshold of >5h showed low sensitivity for detecting ART-R in moderate-to-high transmission settings. Our findings support transmission-specific interpretation of PC1\/2 and indicate that a threshold of 3.1 h more accurately identifies WHO-validated ART-R mutations in moderate-to-high transmission settings, which bear the greatest global malaria burden.\n\nImplications of all the available evidenceART-R is now established across much of SEA and is emerging independently in multiple African parasite populations. Building on the previous WorldWide Antimalarial Resistance Network (WWARN) IPDMA and the expanding WHO evidence base on drug-resistance molecular markers, this study strengthens the evidence linking Kelch13 mutations to delayed parasite clearance following treatment in Africa, while demonstrating that the phenotypic expression of ART-R varies with transmission intensity and epidemiological context. These findings support context-specific interpretation of parasite clearance metrics, integrated with molecular surveillance and therapeutic efficacy studies, to improve early detection of emerging ART-R and guide timely public health responses.","rel_num_authors":7,"rel_authors":[{"author_name":"Stephanie van Wyk","author_inst":"University of Cape Town"},{"author_name":"- WWARN KELCH13 STUDY GROUP","author_inst":"-"},{"author_name":"Philip J. Rosenthal","author_inst":"University of California, San Francisco"},{"author_name":"Philippe Guerin","author_inst":"University of Oxford"},{"author_name":"Mehul Dhorda","author_inst":"University of Oxford"},{"author_name":"Karen I Barnes","author_inst":"University of Cape Town"},{"author_name":"Prabin Dahal","author_inst":"University of Oxford"}],"rel_date":"2026-09-10","rel_site":"medrxiv"},{"rel_title":"Expanded Access use of Intravenous Gene Transfer with AAV9-GLB1 in a Juvenile GM1 Gangliosidosis Participant","rel_doi":"10.64898\/2026.09.04.26361573","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26361573","rel_abs":"GM1 gangliosidosis is an inherited and progressively neurodegenerative lysosomal storage disorder with no approved therapy. We report 5-year safety and 3-year clinical, biochemical, and neuroimaging efficacy outcomes following expanded-access intravenous AAV9-GLB1 gene therapy in GT01, a 6-10-year-old female with juvenile-onset GM1 gangliosidosis. During participation in a natural history study before gene transfer, GT01 developed seizures, dysarthria, loss of ambulation, and progressive neurodegeneration. She received a single intravenous administration of AAV9-GLB1 at 1.5x1013 vector genomes per kilogram of body weight. Early improvements included the resolution of dysphagia, increased interactions with others, assisted ambulation, and gains in specific domains of adaptive functioning. She was seizure-free without anti-epileptic drugs 18 months post dosing with sustained seizure freedom at the study completion. Cerebrospinal fluid concentrations of GM1 ganglioside and H3N2b (a pentasaccharide biomarker indicative of biochemical improvement in this disorder) concentrations decreased by 50% and {beta}-galactosidase reached normal activity. Brain, thalamic, and net fiber tract volume assessed by differential tractography increased and ventriculomegaly improved three years post-dosing. These results indicate that meaningful benefit can be achieved even in advanced neurologic disease.","rel_num_authors":22,"rel_authors":[{"author_name":"Connor J Lewis","author_inst":"National Human Genome Research Institute (NHGRI)"},{"author_name":"Hera Akmal","author_inst":"National Human Genome Research Institute (NHGRI)"},{"author_name":"Precilla D'Souza","author_inst":"National Human Genome Research Institute (NHGRI)"},{"author_name":"Jean M Johnston","author_inst":"National Human Genome Research Institute (NHGRI)"},{"author_name":"Sumaiya Ashraf","author_inst":"National Human Genome Research Institute (NHGRI)"},{"author_name":"Gilbert Vezina","author_inst":"Childrens National Hospital"},{"author_name":"Selby I Chipman","author_inst":"National Human Genome Research Institute"},{"author_name":"Meghan Blackwood","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Muhammad H Yousef","author_inst":"National Institutes of Health Clinical Center"},{"author_name":"Zenaide Quezado","author_inst":"National Institutes of Health Clinical Center"},{"author_name":"William A Gahl","author_inst":"National Human Genome Research Institute (NHGRI)"},{"author_name":"Barry J Byrne","author_inst":"University of Florida"},{"author_name":"Terence R Flotte","author_inst":"UMass Chan Medical School"},{"author_name":"Xuntian R Jiang","author_inst":"Washington University In St Louis"},{"author_name":"Audrey Thurm","author_inst":"National Institute of Mental Health (NIMH)"},{"author_name":"Amanda L Gross","author_inst":"Auburn University"},{"author_name":"Allison Keeler","author_inst":"UMass Chan Medical School"},{"author_name":"Douglas R Martin","author_inst":"Auburn University"},{"author_name":"Miguel Sena-Esteves","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Heather L Gray-Edwards","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Raymond Y Wang","author_inst":"Childrens Hospital of Orange County"},{"author_name":"Cynthia J Tifft","author_inst":"National Human Genome Research Institute (NHGRI)"}],"rel_date":"2026-09-10","rel_site":"medrxiv"},{"rel_title":"Expanded Access use of Intravenous Gene Transfer with AAV9-GLB1 in a Juvenile GM1 Gangliosidosis Participant","rel_doi":"10.64898\/2026.09.04.26361573","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26361573","rel_abs":"GM1 gangliosidosis is an inherited and progressively neurodegenerative lysosomal storage disorder with no approved therapy. We report 5-year safety and 3-year clinical, biochemical, and neuroimaging efficacy outcomes following expanded-access intravenous AAV9-GLB1 gene therapy in GT01, a 6-10-year-old female with juvenile-onset GM1 gangliosidosis. During participation in a natural history study before gene transfer, GT01 developed seizures, dysarthria, loss of ambulation, and progressive neurodegeneration. She received a single intravenous administration of AAV9-GLB1 at 1.5x1013 vector genomes per kilogram of body weight. Early improvements included the resolution of dysphagia, increased interactions with others, assisted ambulation, and gains in specific domains of adaptive functioning. She was seizure-free without anti-epileptic drugs 18 months post dosing with sustained seizure freedom at the study completion. Cerebrospinal fluid concentrations of GM1 ganglioside and H3N2b (a pentasaccharide biomarker indicative of biochemical improvement in this disorder) concentrations decreased by 50% and {beta}-galactosidase reached normal activity. Brain, thalamic, and net fiber tract volume assessed by differential tractography increased and ventriculomegaly improved three years post-dosing. These results indicate that meaningful benefit can be achieved even in advanced neurologic disease.","rel_num_authors":22,"rel_authors":[{"author_name":"Connor J Lewis","author_inst":"National Human Genome Research Institute (NHGRI)"},{"author_name":"Hera Akmal","author_inst":"National Human Genome Research Institute (NHGRI)"},{"author_name":"Precilla D'Souza","author_inst":"National Human Genome Research Institute (NHGRI)"},{"author_name":"Jean M Johnston","author_inst":"National Human Genome Research Institute (NHGRI)"},{"author_name":"Sumaiya Ashraf","author_inst":"National Human Genome Research Institute (NHGRI)"},{"author_name":"Gilbert Vezina","author_inst":"Childrens National Hospital"},{"author_name":"Selby I Chipman","author_inst":"National Human Genome Research Institute"},{"author_name":"Meghan Blackwood","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Muhammad H Yousef","author_inst":"National Institutes of Health Clinical Center"},{"author_name":"Zenaide Quezado","author_inst":"National Institutes of Health Clinical Center"},{"author_name":"William A Gahl","author_inst":"National Human Genome Research Institute (NHGRI)"},{"author_name":"Barry J Byrne","author_inst":"University of Florida"},{"author_name":"Terence R Flotte","author_inst":"UMass Chan Medical School"},{"author_name":"Xuntian R Jiang","author_inst":"Washington University In St Louis"},{"author_name":"Audrey Thurm","author_inst":"National Institute of Mental Health (NIMH)"},{"author_name":"Amanda L Gross","author_inst":"Auburn University"},{"author_name":"Allison Keeler","author_inst":"UMass Chan Medical School"},{"author_name":"Douglas R Martin","author_inst":"Auburn University"},{"author_name":"Miguel Sena-Esteves","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Heather L Gray-Edwards","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Raymond Y Wang","author_inst":"Childrens Hospital of Orange County"},{"author_name":"Cynthia J Tifft","author_inst":"National Human Genome Research Institute (NHGRI)"}],"rel_date":"2026-09-10","rel_site":"medrxiv"},{"rel_title":"Childhood Anemia and Maternal Media Exposure in Sub-Saharan Africa: A Multi-Country Cross-Sectional Analysis Across Ghana, Nigeria, and Tanzania","rel_doi":"10.64898\/2026.09.08.26362530","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.08.26362530","rel_abs":"ObjectivesTo examine the association between maternal media exposure and childhood anemia in three sub-Saharan African countries, and to develop a two-stage multiple imputation approach for substantial hemoglobin outcome missingness in Demographic and Health Survey (DHS) data.\n\nDesignMulti-country cross-sectional analysis of nationally representative DHS data.\n\nSettingCommunity-based household surveys in Ghana (2022), Nigeria (2023-24), and Tanzania (2022).\n\nParticipants42,944 children aged 6-59 months across 2,621 clusters.\n\nPrimary and secondary outcome measuresThe primary outcome was anemia (altitude-adjusted hemoglobin <11.0 g\/dL, WHO criteria); the primary exposure was a composite maternal media score (0-4 channels). Given 61.5% hemoglobin missingness, we imputed altitude-adjusted hemoglobin using multilevel Gaussian models and derived anemia deterministically, then estimated associations using population-averaged generalized estimating equations (pre-specified primary analysis), with six sensitivity analyses and exploratory mediation analysis.\n\nResultsMedia exposure was significantly associated with reduced anemia odds (OR 0.946, 95% CI 0.917 to 0.976, p<0.001; FMI 32.5%), a 5.4% reduction per additional weekly channel. Estimates were consistent across six sensitivity analyses (OR range 0.914-0.961), with no heterogeneity by country (I{superscript 2}=0%, p=0.482). Media exposure predicted antenatal care attendance and iron supplementation (both p<0.001), but neither mediated the anemia association.\n\nConclusionsMaternal media exposure was consistently associated with reduced childhood anemia across three sub-Saharan African settings. A two-stage multiple imputation approach addressed substantial (61.5%) outcome missingness while maintaining stable estimates, offering a transferable framework for DHS-based analyses. Prospective and intervention studies are needed before media-based communication can be recommended as a complementary anemia-control strategy.\n\nStrengths and Limitations of This StudyO_LIThis is among the first multi-country analyses to directly examine maternal media exposure and childhood anemia using nationally representative biomarker data from three sub-Saharan African countries.\nC_LIO_LIA validated two-stage multiple imputation approach addressed substantial (61.5%) hemoglobin missingness, with robustness confirmed across six pre-specified sensitivity analyses.\nC_LIO_LIThe cross-sectional design precludes establishing temporality and cannot rule out reverse causation or residual confounding from unmeasured household factors.\nC_LIO_LIMaternal media exposure was measured as frequency of channel use only, without capturing content, quality, or health-specific programming.\nC_LIO_LIMediation analysis relied on a single imputed dataset with non-clustered models, limiting direct comparability with the primary GEE-based estimate.\nC_LI","rel_num_authors":3,"rel_authors":[{"author_name":"Enock Adu Bonsu","author_inst":"University of Arizona"},{"author_name":"Daniel Ebo","author_inst":"Georgia State University"},{"author_name":"Dorcas Doku","author_inst":"University of Iowa"}],"rel_date":"2026-09-10","rel_site":"medrxiv"},{"rel_title":"Epigenetic misprogramming of progenitor cells links transient viral infection to chronic diseases across tissues","rel_doi":"10.64898\/2026.09.08.26362522","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.08.26362522","rel_abs":"Chronic diseases are increasingly linked to a transient viral exposure, yet known mechanisms do not explain how this exposure eventually leads to chronic pathologies in unrelated tissues. Using Epstein-Barr virus (EBV) as a model, I show that diverse EBV-associated diseases arise from epigenetic misprogramming of progenitor cells. These alterations persist independently of active infection and propagate across cell lineages, generating latent vulnerabilities later unmasked by secondary insults. Breast cancer provided an unresolved test case for EBV involvement: invasive tumors carried EBV-like methylation signatures already present in precursor lesions, independent of lymphocytic infiltration. In EBV-associated multiple sclerosis, three independent cohorts (brain, white matter, and blood) each revealed progenitor-cell methylation anomalies at sites shared with breast and classic EBV-associated cancers. Epigenetic vulnerability in progenitor cells thus emerges as a shared mechanism linking fundamentally different diseases, offering a candidate biomarker and a new target for early intervention.","rel_num_authors":1,"rel_authors":[{"author_name":"Bernard Friedenson","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-09-10","rel_site":"medrxiv"},{"rel_title":"Genetic discovery using deep learning-derived optic nerve integrity phenotypes","rel_doi":"10.64898\/2026.09.08.26362398","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.08.26362398","rel_abs":"The peripapillary retinal nerve fibre layer (pRNFL) thickness and Bruchs membrane opening-minimum rim width (BMO-MRW) are three-dimensional retinal biomarkers for glaucoma. We aimed to demonstrate that AI-derived thickness from two-dimensional fundus images can act as proxies, enabling the discovery of novel neurodegenerative loci. AI-derived pRNFL and BMO-MRW strongly correlated with OCT-derived thickness (r: 0.69 and 0.79, respectively). After validation, these phenotypes were predicted in two cohorts lacking disc-centred OCT: the UK Biobank and the Canadian Longitudinal Study on Aging. The predicted phenotypes showed strong genetic correlations with directly measured phenotypes from a previous study for both phenotypes (0.70 and 0.96, respectively). This data increased statistical power, identifying 29 loci for pRNFL thickness and 122 loci for BMO-MRW, including 14 loci that were independent of VCDR. We observed shared and sector-specific thickness loci overlapping glaucoma loci and revealed loci independent of known risk factors. Together, these results emphasise that multidimensional inferences can be drawn from 2D imaging, enabling downstream genetic analyses.","rel_num_authors":48,"rel_authors":[{"author_name":"Asma M Aman","author_inst":"QIMR Berghofer"},{"author_name":"Eslam Zaher","author_inst":"ARC Training Centre for Information Resilience (CIRES)"},{"author_name":"Santiago Diaz-Torres","author_inst":"QIMR Berghofer"},{"author_name":"Sjoerd J Driessen","author_inst":"Erasmus Medical Center"},{"author_name":"Victor A de Vries","author_inst":"Erasmus Medical Center"},{"author_name":"Frank CT van der Heide","author_inst":"Maastricht University"},{"author_name":"Antonia Kolovos","author_inst":"Flinders University"},{"author_name":"Joshua M Schmidt","author_inst":"Flinders University"},{"author_name":"Henry N Marshall","author_inst":"Flinders University"},{"author_name":"Lania Saleh","author_inst":"King's College London"},{"author_name":"Alicia Schulze","author_inst":"University Medical Center of the Johannes Gutenberg-University Mainz"},{"author_name":"Gabriella AM Blokland","author_inst":"Faculty of Health, Medicine and Life Sciences, Maastricht University"},{"author_name":"Carroll A.B Webers","author_inst":"Maastricht University Medical Center +"},{"author_name":"Carla J.H van der Kallen","author_inst":"Maastricht University Medical Center+"},{"author_name":"Anke Wesselius","author_inst":"Maastricht University"},{"author_name":"Ilja Arts","author_inst":"Maastricht University"},{"author_name":"Freekje van Asten","author_inst":"Maastricht University Medical Center +"},{"author_name":"Mathias Gorski","author_inst":"University of Regensburg"},{"author_name":"Martina E Zimmermann","author_inst":"University of Regensburg"},{"author_name":"Klaus J Stark","author_inst":"University of Regensburg"},{"author_name":"Iris M Heid","author_inst":"University of Regensburg"},{"author_name":"Terri L Young","author_inst":"University of Wisconsin-Madison"},{"author_name":"Louis R Pasquale","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Ayellet V Segre","author_inst":"Harvard Medical School"},{"author_name":"Janey L Wiggs","author_inst":"Harvard Medical School"},{"author_name":"Anthony P Khawaja","author_inst":"Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology"},{"author_name":"Donald J Zack","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Raymond C.B Wong","author_inst":"Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital"},{"author_name":"Alex W Hewitt","author_inst":"University of Tasmania"},{"author_name":"Alexander K Schuster","author_inst":"University Medical Center of the Johannes Gutenberg-University Mainz"},{"author_name":"Tos T.J.M Berendschot","author_inst":"Maastricht University Medical Center +"},{"author_name":"Alberta A.H.J Thiadens","author_inst":"Erasmus Medical Center"},{"author_name":"Karin A van Garderen","author_inst":"Erasmus Medical Center"},{"author_name":"Caroline C.W Klaver","author_inst":"Erasmus Medical Center"},{"author_name":"Pirro G Hysi","author_inst":"King's College London"},{"author_name":"Christopher J Hammond","author_inst":"King's College London"},{"author_name":"Caroline Brandl","author_inst":"University Hospital Regensburg"},{"author_name":"Jamie E Craig","author_inst":"Flinders University"},{"author_name":"Wishal D Ramdas","author_inst":"Erasmus Medical Center"},{"author_name":"Ya Xing Wang","author_inst":"Beijing Tsinghua Changgung Hospital, Tsinghua Medicine, Tsinghua University"},{"author_name":"Jost B Jonas","author_inst":"Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science"},{"author_name":"Fred Roosta","author_inst":"ARC Training Centre for Information Resilience (CIRES)"},{"author_name":"Michael L Hunter","author_inst":"Busselton Population Medical Research Foundation, Department of Respiratory Medicine, Sir Charles Gairdner Hospital"},{"author_name":"Stuart MacGregor","author_inst":"QIMR Berghofer"},{"author_name":"Samantha Sze-Yee Lee","author_inst":"University of Western Australia, Lions Eye Institute"},{"author_name":"David A Mackey","author_inst":"University of Tasmania"},{"author_name":"Maciej Trzaskowski","author_inst":"Profenso Pty Ltd"},{"author_name":"Puya Gharahkhani","author_inst":"QIMR Berghofer"}],"rel_date":"2026-09-10","rel_site":"medrxiv"}]}