{"gname":"University of Massachusetts Chan Medical School ","grp_id":"44","rels":[{"rel_title":"Distinct Anaerobic Microbial Signature Differentiates Anal Squamous Cell Carcinoma From High-Grade Squamous Intraepithelial Lesions: A Prospective Metagenomic Study","rel_doi":"10.64898\/2026.09.14.26363082","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363082","rel_abs":"Background: Anal squamous cell carcinoma (ASCC) develops from high-grade squamous intraepithelial lesions (HSIL), but only a subset of patients with HSIL progress to invasive cancer, suggesting that factors beyond persistent human papillomavirus (HPV) infection contribute to disease progression. The anal microbiome may be a contributing factor; however, direct comparisons between HSIL and treatment-naive ASCC remain limited. Methods: Anal canal swabs were collected from adults with histologically confirmed HSIL or nonmetastatic ASCC prospectively enrolled at Montefiore Medical Center from September 2022 through October 2024. Shotgun metagenomic sequencing was performed after human-read removal. Microbial diversity and community composition were compared between disease groups. Differentially abundant species were identified using ANCOM-BC2 and validated using adjusted centered log-ratio regression. Longitudinal changes and MetaCyc pathways associated with persistent ASCC-enriched species were also evaluated. Multivariable analyses adjusted for age, sex, tobacco use, HIV status, and HPV status. Results: Among 121 participants, 102 had HSIL and 19 had ASCC. Observed richness was lower in ASCC (adjusted beta = -21.28; p = 0.035), while Shannon and inverse Simpson diversity did not differ. Microbial community composition differed by disease group using Bray-Curtis (R2 = 0.100; p = 0.001), Jaccard (R2 = 0.133; p = 0.002), and Aitchison distances (R2 = 0.172; p = 0.001). Of 60 species identified by ANCOM-BC2, 58 were validated, including six enriched in ASCC: Fusobacterium nucleatum, Parvimonas micra, Peptococcus niger, Porphyromonas asaccharolytica, Porphyromonas levii, and Porphyromonas sp. CAG:1061. All six remained associated with ASCC longitudinally, and five demonstrated greater baseline-to-month-6 decreases in ASCC than HSIL. Twenty-six MetaCyc pathways were linked to the persistent ASCC-enriched species and were also enriched in ASCC, highlighting shared functions in amino acid metabolism, anaerobic degradation, and carbohydrate and energy metabolism. Conclusion: ASCC was characterized by lower observed richness and enrichment of a distinct anaerobic microbial signature that persisted across longitudinal sampling and declined following treatment initiation. These taxa were linked to a shared functional profile dominated by amino acid metabolism and anaerobic metabolic pathways. These findings identify microbial features associated with invasive anal cancer and provide a foundation for evaluating their relationship with disease progression, tumor burden, and treatment response.","rel_num_authors":11,"rel_authors":[{"author_name":"Bryan Nolasco","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Travis Lambert","author_inst":"Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"},{"author_name":"Kai Luo","author_inst":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine"},{"author_name":"N Patrik Brodin","author_inst":"Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"},{"author_name":"Dean Hosgood","author_inst":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine"},{"author_name":"Chandan Guha","author_inst":"Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"},{"author_name":"Madhur Garg","author_inst":"Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"},{"author_name":"Shalom Kalnicki","author_inst":"Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"},{"author_name":"Qibin Qi","author_inst":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine"},{"author_name":"Rebecca Levine","author_inst":"Department of Surgery, Montefiore Medical Center"},{"author_name":"Rafi Kabarriti","author_inst":"Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Leader and Follower Roles in Adapted Tango Reveal Complementary Neural Routes to Motor Improvement in Parkinson's Disease","rel_doi":"10.64898\/2026.09.14.26362964","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362964","rel_abs":"Parkinson's disease (PD) disrupts internally generated (IG) movement through impaired striato-thalamo-cortical circuitry, while externally guided (EG) movement may recruit relatively preserved cerebello-thalamo-cortical pathways. We tested whether IG and EG movement strategies differentially shape clinical outcomes and resting-state functional connectivity by using partnered adapted tango as a naturalistic IG\/EG movement manipulation. People with mild-to-moderate PD were randomized to 12 weeks of adapted tango as Leaders, adapted tango as Followers, or a non-dance health education Control condition. During therapeutic adaptango classes, Leaders self-initiated movement direction, timing, and amplitude, whereas Followers used auditory, tactile, and proprioceptive cues from the partner to guide their movement. We identified significant clinical improvement in both dance groups, with Leaders and Followers showing reduced overall disease severity and motor impairment, while Controls did not show a corresponding significant pattern. When Leaders and Followers were pooled, the Dance group also showed overall clinical and motor improvement, in addition to enhanced lower-limb motor outcomes. Connectivity findings suggested partly distinct neural routes to benefit. Leaders showed relative network stability and shifted directionally toward lower connectivity values resembling those of healthy older adults on cerebellar-sensorimotor connections that are typically strengthened in PD. Followers showed increased connectivity across sensorimotor and caudate-motor circuits, consistent with cue-supported action updating. Controls showed overlapping connectivity increases in some motor-network regions of interest, but without comparable clinical gains, suggesting that increased connectivity alone may not be adaptive. These findings indicate that adapted tango can improve motor outcomes in PD through complementary IG and EG movement-weighted mechanisms, with Leader training potentially supporting neural normalization and Follower training engaging distributed cue-to-action networks.","rel_num_authors":8,"rel_authors":[{"author_name":"Constantina Theofanopoulou","author_inst":"The Rockefeller University"},{"author_name":"Neha Bajaj","author_inst":"Emory University"},{"author_name":"Alberto Munoz Sanchez","author_inst":"The Rockefeller University\/Howard Hughes Medical Institute"},{"author_name":"Bruce Crosson","author_inst":"Atlanta VA Health Care System\/Emory University"},{"author_name":"Steven L Wolf","author_inst":"Atlanta VA Health Care System\/Emory University"},{"author_name":"Venkatagiri Krishnamurthy","author_inst":"Atlanta VA Health Care System\/Emory University"},{"author_name":"Keith McGregor","author_inst":"UAB"},{"author_name":"Madeleine E. Hackney","author_inst":"Emory University School of Medicine"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Catatonic Features That May Be Mistaken for Worsening Autism Show Treatment-Associated Improvement: Implications for Later Regression","rel_doi":"10.64898\/2026.09.14.26363007","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363007","rel_abs":"Catatonia in autistic individuals may resemble worsening autism yet represent a potentially treatable departure from baseline functioning. We compared item-level catatonic signs in autistic and non-autistic patients and evaluated treatment-associated change during electroconvulsive therapy (ECT). This single-center observational cohort included patients with catatonia who received ECT from May 2022 through April 2026. The 23-item Bush-Francis Catatonia Rating Scale (BFCRS) was assessed longitudinally. Pretreatment BFCRS data were available for 104 patients, including 41 autistic and 63 non-autistic patients, with 993 near-complete repeated assessments available. Pretreatment item presence was modeled using a three-level clinical-group variable with adjustment for age, biologic sex, and calendar year. Compared with non-autistic patients, patients with autism and intellectual disability had higher adjusted odds of eight activated, repetitive, or behaviorally dysregulated signs and lower odds of immobility\/stupor. Among 96 patients with paired first and last eligible BFCRS assessments, multiple items improved in both cohorts. Generalized estimating equations demonstrated longitudinal declines in total BFCRS scores and multiple psychomotor-domain scores, with no clinical-group-by-time interaction surviving false-discovery rate correction in unrestricted or 30-, 60-, 90-, and 180-day models. Autism-specific Kanner analyses identified seven significant fixed-endpoint severity-item improvements after false-discovery rate correction, six of which were reproduced longitudinally. Catatonia in autism with intellectual disability was characterized by a phenotype that may resemble worsening autism during later regression, and many constituent signs demonstrated treatment-associated improvement during ECT.","rel_num_authors":16,"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":"Seri Lim","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Catherine Fuchs","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rafael Tamargo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Isaac Baldwin","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Maley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ashley VanHaverbeck","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Courtney Hamilton","author_inst":"Vanderbilt University Medical Center"},{"author_name":"timothy Adegoke","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Haozheng Xu","author_inst":"Vanderbilt University"},{"author_name":"Jinyuan Liu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Zachary Williams","author_inst":"University of California Los Angeles"},{"author_name":"Jo Ellen Wilson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"James Ryan Luccarelli","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"The APOL1 protective M1 modifier occurs exclusively with the KIK protein haplotype to suppress channel conductance","rel_doi":"10.64898\/2026.09.14.26362999","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362999","rel_abs":"Introduction. Genetic studies have shown the APOL1 variant p.N264K, also called M1, is associated with markedly lower kidney disease risk when co-inherited with the G2-risk allele. Empirical studies show M1 in cis with G2 blocks APOL1 cation channel flux. To date M1 only occurs on a specific APOL1 haplotype defined by three amino acid positions: p.Lys150 (K), p.Ile228 (I) and p.Lys255 (K). We analyzed two large community datasets to determine if M1 occurs on other APOL1 protein haplotypes and used a cell model to assess if the M1 variant alone is sufficient to block channel activity or if its haplotype context modifies its function. Methods. Phased APOL1 haplotypes frequencies were examined in the Alzheimer Disease Sequencing Project Release 5 (ASDP R5) participants (n=40,909) and confirmed in All of Us Research Program (All of Us) enrollees (n=72,538). Reported race was compared with genetically inferred ancestry. Local APOL1 genealogies were inferred and allele age determined. Thallium flux was measured in 293 cells after induced expression of APOL1-G2 on natural and engineered haplotype backgrounds. Results. The M1 variant occurred exclusively on the KIK APOL1 protein haplotype in all ADSP R5 participants (n=330) and 99.5% of All of Us participants (n=3,560). Local genealogies placed these chromosomes within the lineage carrying p.150K. In vitro thallium flux assays demonstrated that M1 alone and p.Lys150 alone each partially reduced thallium flux but completely abrogated thallium flux when on the same haplotype. Conclusions. M1 is inherited almost exclusively with a single haplotype background. Both the p.150K and p.264K (M1) are needed to completely block APOL1-G2-mediated thallium flux. Studies aimed at examining and exploiting the protective mechanisms of M1 for possible treatments need to consider its distinct haplotype context.","rel_num_authors":17,"rel_authors":[{"author_name":"Diya Yang","author_inst":"Case Western Reserve University"},{"author_name":"Korey R Bartolomeo","author_inst":"Cleveland Clinic"},{"author_name":"Shiying Liu","author_inst":"Case Western Reserve University"},{"author_name":"Agustin Gonzalez-Vicente","author_inst":"Case Western Reserve University"},{"author_name":"Nicholas R Wheeler","author_inst":"Case Western Reserve University"},{"author_name":"Penelope Benchek","author_inst":"Case Western Reserve University"},{"author_name":"Xiaofeng Zhu","author_inst":"Case Western Reserve university"},{"author_name":"Jonathan Haines","author_inst":"CWRU"},{"author_name":"Jessica N Cooke-Bailey","author_inst":"East Carolina University"},{"author_name":"Thomas Nader","author_inst":"Cleveland Clinic"},{"author_name":"Nurdan Cam","author_inst":"Cleveland Clinic"},{"author_name":"Leslie A Bruggeman","author_inst":"Cleveland Clinic"},{"author_name":"Scott M Williams","author_inst":"Case Western Reserve University"},{"author_name":"Dana C Crawford","author_inst":"Case Western Reserve University"},{"author_name":"William S Bush","author_inst":"Case Western Reserve University"},{"author_name":"John F O'Toole","author_inst":"Cleveland Clinic"},{"author_name":"John R Sedor","author_inst":"Cleveland Clinic"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Nasal transcriptomics characterize T-helper (T)2-low asthma endotypes in a study of Puerto Rican and Dominican adults living in the U.S.","rel_doi":"10.64898\/2026.09.14.26363037","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363037","rel_abs":"IMPORTANCE: CD4+ T helper (T) 1, T2 and T17 cells have helped identify asthma endotypes in predominantly non-Hispanic White adults. Identifying asthma endotypes in diverse subgroups should help develop personalized medicine in asthma. OBJECTIVE: To characterize asthma endotypes and their association with selected variables and asthma severity\/control in adults. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional and longitudinal analyses of nasal samples from the SOL-Asthma study of Puerto Rican and Dominican adults with (cases, n=313) and without (controls, n=371) asthma in the Bronx (NY) and Chicago (IL), with replication of selected findings in 376 adults of African ancestry in CAAPA. MAIN OUTCOMES AND MEASURES: Our primary outcome was asthma endotypes identified through nasal expression of \"signature genes\" for 3 T2, 5 T1, and 5 T17 pathways. Multinomial logistic regression was used for the analysis of asthma endotypes (with controls as the reference outcome category) at a baseline visit, as well as for the analysis of severe asthma exacerbations (SAEs) at baseline and during a 1-year follow-up. We attempted to replicate the identified profiles in CAAPA. RESULTS: In SOL-Asthma, cases were more likely to be female, Puerto Rican, and current\/former smokers, and to have physician-diagnosed COPD than controls. Five transcriptomic profiles were identified in cases: T2HIGH (n=16 [5.1%]), T1HIGH (n=71 [22.7%]), T17HIGH (n=96 [30.7%]), T1HIGH\/T17HIGH (n=53 [16.9%]), and T2LOW\/T1LOW\/T17LOW (n=77 [24.6%]). In a multivariable analysis, Puerto Ricans were more likely to have a T17HIGH profile than Dominicans (odds ratio [OR]=2.48, 95% confidence interval [CI]=1.08-5.74) and female sex was associated with T1HIGH (OR=3.44, 95% CI=1.33-8.88), T1HIGH\/T17HIGH and T2LOW\/T1LOW\/T17LOW profiles, while COPD was associated with profiles other than T2HIGH or T1HIGH. The T1HIGH profile was associated with [&ge;]1 SAE in the year prior to baseline and during the one-year follow-up (OR=4.31, 95% CI=1.26-14.77). Each profile had unique differentially expressed genes (DEGs), with substantial replication of the profile distribution and DEGs in CAAPA. CONCLUSIONS AND RELEVANCE: Nasal transcriptomics identified profiles corresponding to five asthma endotypes in a cohort of Puerto Rican and Dominican adults. Puerto Rican background, female sex, and physician-diagnosed COPD were associated with non-T2HIGH (T2LOW) asthma endotypes, and T1HIGH asthma was strongly associated with SAEs.","rel_num_authors":11,"rel_authors":[{"author_name":"Sheng Yang","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Yueh-Ying Han","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Soheil Farid Azar","author_inst":"National Institute of Allergy and Infectious Diseases, National Institutes of Health"},{"author_name":"Amber Pirzada","author_inst":"University of Illinois College of Medicine"},{"author_name":"Franziska J. Rosser","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Golda Hudes","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Robert Kaplan","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Wei Chen","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Carmen R. Isasi","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Rasika A. Mathias","author_inst":"National Institute of Allergy and Infectious Diseases, National Institutes of Health"},{"author_name":"Juan C. Celedon","author_inst":"UMPC Children's Hospital of Pittsburgh, University of Pittsburgh"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Nasal transcriptomics characterize T-helper (T)2-low asthma endotypes in a study of Puerto Rican and Dominican adults living in the U.S.","rel_doi":"10.64898\/2026.09.14.26363037","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363037","rel_abs":"IMPORTANCE: CD4+ T helper (T) 1, T2 and T17 cells have helped identify asthma endotypes in predominantly non-Hispanic White adults. Identifying asthma endotypes in diverse subgroups should help develop personalized medicine in asthma. OBJECTIVE: To characterize asthma endotypes and their association with selected variables and asthma severity\/control in adults. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional and longitudinal analyses of nasal samples from the SOL-Asthma study of Puerto Rican and Dominican adults with (cases, n=313) and without (controls, n=371) asthma in the Bronx (NY) and Chicago (IL), with replication of selected findings in 376 adults of African ancestry in CAAPA. MAIN OUTCOMES AND MEASURES: Our primary outcome was asthma endotypes identified through nasal expression of \"signature genes\" for 3 T2, 5 T1, and 5 T17 pathways. Multinomial logistic regression was used for the analysis of asthma endotypes (with controls as the reference outcome category) at a baseline visit, as well as for the analysis of severe asthma exacerbations (SAEs) at baseline and during a 1-year follow-up. We attempted to replicate the identified profiles in CAAPA. RESULTS: In SOL-Asthma, cases were more likely to be female, Puerto Rican, and current\/former smokers, and to have physician-diagnosed COPD than controls. Five transcriptomic profiles were identified in cases: T2HIGH (n=16 [5.1%]), T1HIGH (n=71 [22.7%]), T17HIGH (n=96 [30.7%]), T1HIGH\/T17HIGH (n=53 [16.9%]), and T2LOW\/T1LOW\/T17LOW (n=77 [24.6%]). In a multivariable analysis, Puerto Ricans were more likely to have a T17HIGH profile than Dominicans (odds ratio [OR]=2.48, 95% confidence interval [CI]=1.08-5.74) and female sex was associated with T1HIGH (OR=3.44, 95% CI=1.33-8.88), T1HIGH\/T17HIGH and T2LOW\/T1LOW\/T17LOW profiles, while COPD was associated with profiles other than T2HIGH or T1HIGH. The T1HIGH profile was associated with [&ge;]1 SAE in the year prior to baseline and during the one-year follow-up (OR=4.31, 95% CI=1.26-14.77). Each profile had unique differentially expressed genes (DEGs), with substantial replication of the profile distribution and DEGs in CAAPA. CONCLUSIONS AND RELEVANCE: Nasal transcriptomics identified profiles corresponding to five asthma endotypes in a cohort of Puerto Rican and Dominican adults. Puerto Rican background, female sex, and physician-diagnosed COPD were associated with non-T2HIGH (T2LOW) asthma endotypes, and T1HIGH asthma was strongly associated with SAEs.","rel_num_authors":11,"rel_authors":[{"author_name":"Sheng Yang","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Yueh-Ying Han","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Soheil Farid Azar","author_inst":"National Institute of Allergy and Infectious Diseases, National Institutes of Health"},{"author_name":"Amber Pirzada","author_inst":"University of Illinois College of Medicine"},{"author_name":"Franziska J. Rosser","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Golda Hudes","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Robert Kaplan","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Wei Chen","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Carmen R. Isasi","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Rasika A. Mathias","author_inst":"National Institute of Allergy and Infectious Diseases, National Institutes of Health"},{"author_name":"Juan C. Celedon","author_inst":"UMPC Children's Hospital of Pittsburgh, University of Pittsburgh"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Separating the effects of immune waning and viral evolution on COVID-19 vaccine effectiveness reveals improved effectiveness of updated vaccines","rel_doi":"10.64898\/2026.09.14.26363077","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363077","rel_abs":"The continued evolution of SARS-CoV-2 has led to regular updates of the COVID-19 vaccine immunogen. However, the exact benefits of these updates for vaccine effectiveness in a real world context are difficult to evaluate. We performed a comprehensive meta-analysis of booster vaccine effectiveness in studies identified through the ViewHub systematic review. We integrated evidence from 44 studies reporting on effectiveness of mRNA booster vaccines containing XBB.1.5, JN.1 and KP.2 immunogens to assess the combined impact of booster immunogen, time since vaccination and calendar time at which a study was conducted. We estimate that the relative risk of severe disease increases by 9% [95%CI 7.4-10.5] each month following booster administration, likely due to antibody waning, and by an additional 2.4% [95%CI 1.2-3.6] for each calendar month, likely due to antigenic drift. Our findings show that COVID-19 booster vaccine effectiveness declines both with time after vaccination as well as calendar time since the vaccine immunogen emerged. This reinforces the need for regularly and timely vaccine immunogen updates.","rel_num_authors":7,"rel_authors":[{"author_name":"Wang Jin","author_inst":"University of New South Wales"},{"author_name":"Ainslie Mitchell","author_inst":"Kirby Institute, University of New South Wales"},{"author_name":"Eva Stadler","author_inst":"University of New South Wales"},{"author_name":"Charles S.P. Foster","author_inst":"University of New South Wales"},{"author_name":"Timothy E. Schlub","author_inst":"The University of Sydney"},{"author_name":"Miles Philip Davenport","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Deborah Philip Cromer","author_inst":"UNSW Australia"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Separating the effects of immune waning and viral evolution on COVID-19 vaccine effectiveness reveals improved effectiveness of updated vaccines","rel_doi":"10.64898\/2026.09.14.26363077","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363077","rel_abs":"The continued evolution of SARS-CoV-2 has led to regular updates of the COVID-19 vaccine immunogen. However, the exact benefits of these updates for vaccine effectiveness in a real world context are difficult to evaluate. We performed a comprehensive meta-analysis of booster vaccine effectiveness in studies identified through the ViewHub systematic review. We integrated evidence from 44 studies reporting on effectiveness of mRNA booster vaccines containing XBB.1.5, JN.1 and KP.2 immunogens to assess the combined impact of booster immunogen, time since vaccination and calendar time at which a study was conducted. We estimate that the relative risk of severe disease increases by 9% [95%CI 7.4-10.5] each month following booster administration, likely due to antibody waning, and by an additional 2.4% [95%CI 1.2-3.6] for each calendar month, likely due to antigenic drift. Our findings show that COVID-19 booster vaccine effectiveness declines both with time after vaccination as well as calendar time since the vaccine immunogen emerged. This reinforces the need for regularly and timely vaccine immunogen updates.","rel_num_authors":7,"rel_authors":[{"author_name":"Wang Jin","author_inst":"University of New South Wales"},{"author_name":"Ainslie Mitchell","author_inst":"Kirby Institute, University of New South Wales"},{"author_name":"Eva Stadler","author_inst":"University of New South Wales"},{"author_name":"Charles S.P. Foster","author_inst":"University of New South Wales"},{"author_name":"Timothy E. Schlub","author_inst":"The University of Sydney"},{"author_name":"Miles Philip Davenport","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Deborah Philip Cromer","author_inst":"UNSW Australia"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Epidemiology of Shigella sonnei and Shigella flexneri in the Global Pediatric Diarrhea Surveillance network, 2017-2022","rel_doi":"10.64898\/2026.09.14.26363009","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363009","rel_abs":"Background Shigella is a leading cause of diarrhea in children in low- and middle-income countries (LMICs). Optimizing the impact of vaccines necessitates an accurate characterization of Shigella serotype prevalence. We describe the burden, epidemiology and characteristics of S. sonnei and S. flexneri diarrhea in the Global Pediatric Diarrhea Surveillance (GPDS) network. Methods GPDS is a World Health Organization-coordinated surveillance network investigating the etiology of hospitalized diarrhea among children aged <5 years. GPDS enrolls children hospitalized with diarrhea at 38 sentinel surveillance sites in 31 LMICs. Randomly selected stool specimens from these children were tested by quantitative polymerase chain reaction to detect a broad range of enteropathogens as well as to identify S. sonnei and S. flexneri serotypes. We estimated pathogen-specific attributable fractions and incidence of diarrheal hospitalizations. Results During 2017-2022, GPDS enrolled 70,750 children aged <5 years hospitalized with diarrhea, of which 16,458 (23.3%) were randomly selected for qPCR testing. Globally, Shigella caused 9.8% (95% Confidence Interval [CI]: 8.4, 11.3) of hospitalized diarrhea, with 28.3% of cases occurring in children aged {pound}12 months. The estimated attributable incidence of Shigella-associated diarrhea hospitalizations decreased from 1.27 (95% CI: 0.95, 1.64) per 1,000 child years in 2017-2018 to 0.88 (0.67, 1.10) in 2021-2022. Among typeable Shigella cases, 34.8% were S. sonnei, 24.2% were S. flexneri 2a, and 9.9% were S. flexneri 1b. Vaccines currently in development would cover an estimated 59.0% to 72.2% of cases. Conclusions These findings support the role of Shigella as an important cause of the most severe diarrhea in young children. The breadth of homotypic protection provided by Shigella vaccines in clinical development varied by region, and these broadly representative data can aid in prioritization. Non-dysenteric Shigella could not be readily differentiated from other causes of hospitalized diarrhea based on clinical characteristics.","rel_num_authors":38,"rel_authors":[{"author_name":"Jie Liu","author_inst":"Qingdao University"},{"author_name":"Myra Lewontin","author_inst":"University of Virginia"},{"author_name":"Sarah  E Elwood","author_inst":"University of Virginia"},{"author_name":"Shilpa  S Iyer","author_inst":"World Health Organization"},{"author_name":"S\u00e9bastien Antoni","author_inst":"World Health Organization"},{"author_name":"Gloria Rey-Bonito","author_inst":"Pan American Health Organization"},{"author_name":"Claudia Ortiz","author_inst":"Pan American Health Organization"},{"author_name":"Goitom Weldegebriel","author_inst":"World Health Organization Regional Office for Africa: Organisation mondiale de la Sante pour Afrique"},{"author_name":"Joseph Biey","author_inst":"World Health Organization Regional Office for Africa: Organisation mondiale de la Sante pour Afrique"},{"author_name":"Jason  M Mwenda","author_inst":"World Health Organization Regional Office for Africa: Organisation mondiale de la Sante pour Afrique"},{"author_name":"Roberta Pastore","author_inst":"World Health Organization Regional Office for Europe"},{"author_name":"Dovile Videbaek","author_inst":"World Health Organization Regional Office for Europe"},{"author_name":"Samarjit Singh","author_inst":"World Health Organization Regional Office for Europe"},{"author_name":"Emmanuel Njambe","author_inst":"World Health Organization Regional Office for South-East Asia"},{"author_name":"Lucky Sangal","author_inst":"World Health Organization Regional Office for South-East Asia"},{"author_name":"Deepak Dhongde","author_inst":"World Health Organization Regional Office for South-East Asia"},{"author_name":"Varja Grabovac","author_inst":"World Health Organization Regional Office for the Western Pacific"},{"author_name":"Josephine Logronio","author_inst":"World Health Organization Regional Office for the Western Pacific"},{"author_name":"Kamal Fahmy","author_inst":"World Health Organisation Regional Office for the Eastern Mediterranean"},{"author_name":"Amany Ghoniem","author_inst":"World Health Organisation Regional Office for the Eastern Mediterranean"},{"author_name":"George Armah","author_inst":"University of Ghana College of Health Sciences"},{"author_name":"Francis  E Dennis","author_inst":"University of Ghana College of Health Sciences"},{"author_name":"Mapaseka  L Seheri","author_inst":"Sefako Makgatho Health Sciences University"},{"author_name":"Nonkululeko Magagula","author_inst":"Sefako Makgatho Health Sciences University"},{"author_name":"Kebareng Rakau-Nondela","author_inst":"Sefako Makgatho Health Sciences University"},{"author_name":"Tulio  M Fumian","author_inst":"Instituto Oswaldo Cruz"},{"author_name":"Irene  T.A. Maciel","author_inst":"Instituto Oswaldo Cruz"},{"author_name":"Elena Samoilovich","author_inst":"Ministry of Health"},{"author_name":"Galina Semeiko","author_inst":"Ministry of Health"},{"author_name":"Tintu Varghese","author_inst":"Christian Medical College Vellore"},{"author_name":"Sarah Thomas","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Julie  E Bines","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Dandi Li","author_inst":"China CDC: Chinese Center for Disease Control and Prevention"},{"author_name":"Furqan Kabir","author_inst":"Aga Khan University"},{"author_name":"Eric  R Houpt","author_inst":"University of Virginia"},{"author_name":"Mick  N Mulders","author_inst":"World Health Organization"},{"author_name":"Heidi  M. Soeters","author_inst":"Independent Researcher"},{"author_name":"James  A Platts-Mills","author_inst":"University of Virginia"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Epidemiology of Shigella sonnei and Shigella flexneri in the Global Pediatric Diarrhea Surveillance network, 2017-2022","rel_doi":"10.64898\/2026.09.14.26363009","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363009","rel_abs":"Background Shigella is a leading cause of diarrhea in children in low- and middle-income countries (LMICs). Optimizing the impact of vaccines necessitates an accurate characterization of Shigella serotype prevalence. We describe the burden, epidemiology and characteristics of S. sonnei and S. flexneri diarrhea in the Global Pediatric Diarrhea Surveillance (GPDS) network. Methods GPDS is a World Health Organization-coordinated surveillance network investigating the etiology of hospitalized diarrhea among children aged <5 years. GPDS enrolls children hospitalized with diarrhea at 38 sentinel surveillance sites in 31 LMICs. Randomly selected stool specimens from these children were tested by quantitative polymerase chain reaction to detect a broad range of enteropathogens as well as to identify S. sonnei and S. flexneri serotypes. We estimated pathogen-specific attributable fractions and incidence of diarrheal hospitalizations. Results During 2017-2022, GPDS enrolled 70,750 children aged <5 years hospitalized with diarrhea, of which 16,458 (23.3%) were randomly selected for qPCR testing. Globally, Shigella caused 9.8% (95% Confidence Interval [CI]: 8.4, 11.3) of hospitalized diarrhea, with 28.3% of cases occurring in children aged {pound}12 months. The estimated attributable incidence of Shigella-associated diarrhea hospitalizations decreased from 1.27 (95% CI: 0.95, 1.64) per 1,000 child years in 2017-2018 to 0.88 (0.67, 1.10) in 2021-2022. Among typeable Shigella cases, 34.8% were S. sonnei, 24.2% were S. flexneri 2a, and 9.9% were S. flexneri 1b. Vaccines currently in development would cover an estimated 59.0% to 72.2% of cases. Conclusions These findings support the role of Shigella as an important cause of the most severe diarrhea in young children. The breadth of homotypic protection provided by Shigella vaccines in clinical development varied by region, and these broadly representative data can aid in prioritization. Non-dysenteric Shigella could not be readily differentiated from other causes of hospitalized diarrhea based on clinical characteristics.","rel_num_authors":38,"rel_authors":[{"author_name":"Jie Liu","author_inst":"Qingdao University"},{"author_name":"Myra Lewontin","author_inst":"University of Virginia"},{"author_name":"Sarah  E Elwood","author_inst":"University of Virginia"},{"author_name":"Shilpa  S Iyer","author_inst":"World Health Organization"},{"author_name":"S\u00e9bastien Antoni","author_inst":"World Health Organization"},{"author_name":"Gloria Rey-Bonito","author_inst":"Pan American Health Organization"},{"author_name":"Claudia Ortiz","author_inst":"Pan American Health Organization"},{"author_name":"Goitom Weldegebriel","author_inst":"World Health Organization Regional Office for Africa: Organisation mondiale de la Sante pour Afrique"},{"author_name":"Joseph Biey","author_inst":"World Health Organization Regional Office for Africa: Organisation mondiale de la Sante pour Afrique"},{"author_name":"Jason  M Mwenda","author_inst":"World Health Organization Regional Office for Africa: Organisation mondiale de la Sante pour Afrique"},{"author_name":"Roberta Pastore","author_inst":"World Health Organization Regional Office for Europe"},{"author_name":"Dovile Videbaek","author_inst":"World Health Organization Regional Office for Europe"},{"author_name":"Samarjit Singh","author_inst":"World Health Organization Regional Office for Europe"},{"author_name":"Emmanuel Njambe","author_inst":"World Health Organization Regional Office for South-East Asia"},{"author_name":"Lucky Sangal","author_inst":"World Health Organization Regional Office for South-East Asia"},{"author_name":"Deepak Dhongde","author_inst":"World Health Organization Regional Office for South-East Asia"},{"author_name":"Varja Grabovac","author_inst":"World Health Organization Regional Office for the Western Pacific"},{"author_name":"Josephine Logronio","author_inst":"World Health Organization Regional Office for the Western Pacific"},{"author_name":"Kamal Fahmy","author_inst":"World Health Organisation Regional Office for the Eastern Mediterranean"},{"author_name":"Amany Ghoniem","author_inst":"World Health Organisation Regional Office for the Eastern Mediterranean"},{"author_name":"George Armah","author_inst":"University of Ghana College of Health Sciences"},{"author_name":"Francis  E Dennis","author_inst":"University of Ghana College of Health Sciences"},{"author_name":"Mapaseka  L Seheri","author_inst":"Sefako Makgatho Health Sciences University"},{"author_name":"Nonkululeko Magagula","author_inst":"Sefako Makgatho Health Sciences University"},{"author_name":"Kebareng Rakau-Nondela","author_inst":"Sefako Makgatho Health Sciences University"},{"author_name":"Tulio  M Fumian","author_inst":"Instituto Oswaldo Cruz"},{"author_name":"Irene  T.A. Maciel","author_inst":"Instituto Oswaldo Cruz"},{"author_name":"Elena Samoilovich","author_inst":"Ministry of Health"},{"author_name":"Galina Semeiko","author_inst":"Ministry of Health"},{"author_name":"Tintu Varghese","author_inst":"Christian Medical College Vellore"},{"author_name":"Sarah Thomas","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Julie  E Bines","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Dandi Li","author_inst":"China CDC: Chinese Center for Disease Control and Prevention"},{"author_name":"Furqan Kabir","author_inst":"Aga Khan University"},{"author_name":"Eric  R Houpt","author_inst":"University of Virginia"},{"author_name":"Mick  N Mulders","author_inst":"World Health Organization"},{"author_name":"Heidi  M. Soeters","author_inst":"Independent Researcher"},{"author_name":"James  A Platts-Mills","author_inst":"University of Virginia"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Impact of Social Determinants of Health in Early Pregnancy on Racial and Ethnic Differences in Post-pregnancy Cardiovascular Health","rel_doi":"10.64898\/2026.09.14.26363034","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363034","rel_abs":"Background: Social determinants of health (SDOH) influence maternal cardiovascular health (CVH), but the extent to which SDOH in early pregnancy may explain racial and ethnic differences in post-pregnancy CVH has not been defined. Methods: This secondary analysis used data from the prospective multisite Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study. CVH was assessed in early pregnancy and 2-7 years after delivery using the American Heart Association's Life's Essential 8 (LE8) framework. We used the Oaxaca-Blinder decomposition to quantify the statistical contributions of differences in early pregnancy CVH, SDOH, psychosocial factors, and demographic covariates to racial and ethnic differences in post-pregnancy CVH between the two largest minoritized racial and ethnic groups (non-Hispanic [NH] Black and Hispanic) compared with NH White women. Results: Among 4,088 women (14.4% Black, 17.6% Hispanic, and 68.0% White), the mean (SD) post-pregnancy LE8 score was lower in Black (70.1 [14.1]) and Hispanic (77.8 [12.7]) women compared with White women (82.4 [12.7]) (all p<0.01). Independent of early pregnancy CVH, maternal age, and nativity, differences in SDOH were associated with 4.5 (95% CI, 2.8-6.2) points of the Black-White gap (37% of the observed post-pregnancy CVH difference) and 3.2 (95% CI, 1.1-5.3) points of the Hispanic-White gap (70% of the observed post-pregnancy CVH difference), respectively. Conclusions: Most racial and ethnic differences in post-pregnancy CVH 2 to 7 years after a first birth were explained by differences in early pregnancy CVH and SDOH. Independent of early pregnancy CVH, SDOH remained the largest measured contributor to the residual difference.","rel_num_authors":20,"rel_authors":[{"author_name":"Xiaoning Huang","author_inst":"Northwestern University"},{"author_name":"Lucia C Petito","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Natalie Cameron","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of General Internal Medicine"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine, Department of Obstetrics and Gynecology"},{"author_name":"Brian M Mercer","author_inst":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology"},{"author_name":"Samuel Parry","author_inst":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"George R Saade","author_inst":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Robert M Silver","author_inst":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Yi Qiao","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine"},{"author_name":"Xiaomeng Huang","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine"},{"author_name":"Hyagriv N Simhan","author_inst":"University of Pittsburg School of Medicine, Magee-Women's Research Institute & Foundation, Department of Obstetrics and Gynecology"},{"author_name":"Uma M. Reddy","author_inst":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology"},{"author_name":"Judith Chung","author_inst":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology; Northwestern University Feinberg School of Medicine, Depart"},{"author_name":"Donald M Lloyd-Jones","author_inst":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Kiarri N Kershaw","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine"},{"author_name":"William A Grobman","author_inst":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Sadiya S Khan","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology; Northwestern University Feinberg School of Medicine, Depart"},{"author_name":"Kartik K Venkatesh","author_inst":"The Ohio State University Wexner Medical Center, College of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Impact of Social Determinants of Health in Early Pregnancy on Racial and Ethnic Differences in Post-pregnancy Cardiovascular Health","rel_doi":"10.64898\/2026.09.14.26363034","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363034","rel_abs":"Background: Social determinants of health (SDOH) influence maternal cardiovascular health (CVH), but the extent to which SDOH in early pregnancy may explain racial and ethnic differences in post-pregnancy CVH has not been defined. Methods: This secondary analysis used data from the prospective multisite Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study. CVH was assessed in early pregnancy and 2-7 years after delivery using the American Heart Association's Life's Essential 8 (LE8) framework. We used the Oaxaca-Blinder decomposition to quantify the statistical contributions of differences in early pregnancy CVH, SDOH, psychosocial factors, and demographic covariates to racial and ethnic differences in post-pregnancy CVH between the two largest minoritized racial and ethnic groups (non-Hispanic [NH] Black and Hispanic) compared with NH White women. Results: Among 4,088 women (14.4% Black, 17.6% Hispanic, and 68.0% White), the mean (SD) post-pregnancy LE8 score was lower in Black (70.1 [14.1]) and Hispanic (77.8 [12.7]) women compared with White women (82.4 [12.7]) (all p<0.01). Independent of early pregnancy CVH, maternal age, and nativity, differences in SDOH were associated with 4.5 (95% CI, 2.8-6.2) points of the Black-White gap (37% of the observed post-pregnancy CVH difference) and 3.2 (95% CI, 1.1-5.3) points of the Hispanic-White gap (70% of the observed post-pregnancy CVH difference), respectively. Conclusions: Most racial and ethnic differences in post-pregnancy CVH 2 to 7 years after a first birth were explained by differences in early pregnancy CVH and SDOH. Independent of early pregnancy CVH, SDOH remained the largest measured contributor to the residual difference.","rel_num_authors":20,"rel_authors":[{"author_name":"Xiaoning Huang","author_inst":"Northwestern University"},{"author_name":"Lucia C Petito","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Natalie Cameron","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of General Internal Medicine"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine, Department of Obstetrics and Gynecology"},{"author_name":"Brian M Mercer","author_inst":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology"},{"author_name":"Samuel Parry","author_inst":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"George R Saade","author_inst":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Robert M Silver","author_inst":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Yi Qiao","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine"},{"author_name":"Xiaomeng Huang","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine"},{"author_name":"Hyagriv N Simhan","author_inst":"University of Pittsburg School of Medicine, Magee-Women's Research Institute & Foundation, Department of Obstetrics and Gynecology"},{"author_name":"Uma M. Reddy","author_inst":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology"},{"author_name":"Judith Chung","author_inst":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology; Northwestern University Feinberg School of Medicine, Depart"},{"author_name":"Donald M Lloyd-Jones","author_inst":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Kiarri N Kershaw","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine"},{"author_name":"William A Grobman","author_inst":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Sadiya S Khan","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology; Northwestern University Feinberg School of Medicine, Depart"},{"author_name":"Kartik K Venkatesh","author_inst":"The Ohio State University Wexner Medical Center, College of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Impact of Social Determinants of Health in Early Pregnancy on Racial and Ethnic Differences in Post-pregnancy Cardiovascular Health","rel_doi":"10.64898\/2026.09.14.26363034","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363034","rel_abs":"Background: Social determinants of health (SDOH) influence maternal cardiovascular health (CVH), but the extent to which SDOH in early pregnancy may explain racial and ethnic differences in post-pregnancy CVH has not been defined. Methods: This secondary analysis used data from the prospective multisite Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study. CVH was assessed in early pregnancy and 2-7 years after delivery using the American Heart Association's Life's Essential 8 (LE8) framework. We used the Oaxaca-Blinder decomposition to quantify the statistical contributions of differences in early pregnancy CVH, SDOH, psychosocial factors, and demographic covariates to racial and ethnic differences in post-pregnancy CVH between the two largest minoritized racial and ethnic groups (non-Hispanic [NH] Black and Hispanic) compared with NH White women. Results: Among 4,088 women (14.4% Black, 17.6% Hispanic, and 68.0% White), the mean (SD) post-pregnancy LE8 score was lower in Black (70.1 [14.1]) and Hispanic (77.8 [12.7]) women compared with White women (82.4 [12.7]) (all p<0.01). Independent of early pregnancy CVH, maternal age, and nativity, differences in SDOH were associated with 4.5 (95% CI, 2.8-6.2) points of the Black-White gap (37% of the observed post-pregnancy CVH difference) and 3.2 (95% CI, 1.1-5.3) points of the Hispanic-White gap (70% of the observed post-pregnancy CVH difference), respectively. Conclusions: Most racial and ethnic differences in post-pregnancy CVH 2 to 7 years after a first birth were explained by differences in early pregnancy CVH and SDOH. Independent of early pregnancy CVH, SDOH remained the largest measured contributor to the residual difference.","rel_num_authors":20,"rel_authors":[{"author_name":"Xiaoning Huang","author_inst":"Northwestern University"},{"author_name":"Lucia C Petito","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Natalie Cameron","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of General Internal Medicine"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine, Department of Obstetrics and Gynecology"},{"author_name":"Brian M Mercer","author_inst":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology"},{"author_name":"Samuel Parry","author_inst":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"George R Saade","author_inst":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Robert M Silver","author_inst":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Yi Qiao","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine"},{"author_name":"Xiaomeng Huang","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine"},{"author_name":"Hyagriv N Simhan","author_inst":"University of Pittsburg School of Medicine, Magee-Women's Research Institute & Foundation, Department of Obstetrics and Gynecology"},{"author_name":"Uma M. Reddy","author_inst":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology"},{"author_name":"Judith Chung","author_inst":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology; Northwestern University Feinberg School of Medicine, Depart"},{"author_name":"Donald M Lloyd-Jones","author_inst":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Kiarri N Kershaw","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine"},{"author_name":"William A Grobman","author_inst":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Sadiya S Khan","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology; Northwestern University Feinberg School of Medicine, Depart"},{"author_name":"Kartik K Venkatesh","author_inst":"The Ohio State University Wexner Medical Center, College of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Plasma Proteomic Mediators of the Association Between Early-Pregnancy Psychosocial Stress and Cardiovascular Health 2 to 7 Years After Delivery: The nuMoM2b-HHS Study","rel_doi":"10.64898\/2026.09.14.26363041","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363041","rel_abs":"Importance: Psychosocial exposures in early pregnancy are associated with worse maternal cardiovascular health (CVH), but the biological pathways linking early-pregnancy stressors to long-term CVH are not defined. Objective: To determine whether plasma proteins measured in early pregnancy mediate the association between early-pregnancy psychosocial stressors and CVH 2 to 7 years after delivery. Design, Setting, and Participants: This was a secondary analysis of the prospective multicenter Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study (nuMoM2b-HHS), which enrolled nulliparous individuals at eight US academic centers (2010-2014) and followed them 2 to 7 years after delivery. The analytic sample comprised participants with first-trimester plasma proteomics. Analyses were conducted from January to June 2026. Exposures: Perceived stress (Perceived Stress Scale-10 >13) as the primary exposure; Early-pregnancy depression (Edinburgh Postnatal Depression Scale >10) and anxiety (State-Trait Anxiety Inventory >37) as secondary exposures. Main Outcomes and Measures: Post-pregnancy CVH quantified by the American Heart Association Life's Essential 8 (LE8) composite score (0-100) and its clinical components: blood pressure, lipid, glucose, and body mass index (BMI) scores. A four-way decomposition partitioned the total effect of stress into a controlled direct effect, reference interaction, mediated interaction, and pure indirect effect operating through a proteomic mediator. Results: Among 1662 participants (mean [SD] age, 27.1 [5.5] years), 41.6% screened positive for stress. Of 6874 aptamers, 17 (representing 14 unique, predominantly neuronal and synaptic proteins) were associated with both stress and the LE8 composite as well as four clinical components after false discovery rate correction. No aptamers met criteria for depression or anxiety. Stress was associated with lower levels of all 14 proteins, and higher protein levels were associated with better CVH scores. The 14 proteins reduced to a single principal component (57% of variance) used as the mediator. Stress was associated with a lower post-pregnancy LE8 composite score (total effect, -3.74 [95% CI, -5.03 to -2.45]); the proteomic factor accounted for a pure indirect effect of -1.20 (95% CI, -1.68 to -0.72), approximately 32% of the total effect, and approximately 56% of the larger association with the BMI score. Significant indirect effects through the proteomic factor were also observed for the blood pressure, lipid, and glucose scores despite nonsignificant total effects.","rel_num_authors":18,"rel_authors":[{"author_name":"Xiaoning Huang","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL"},{"author_name":"Lucia C Petito","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL"},{"author_name":"Weihua Guan","author_inst":"University of Minnesota, School of Public Health, Division of Biostatistics & Health Data Science"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Chicago, IL"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine, Department of Obstetrics and Gynecology, Indianapolis, IN"},{"author_name":"Brian M Mercer","author_inst":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology, Cleveland, OH"},{"author_name":"Samuel Parry","author_inst":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Philadelphia, PA"},{"author_name":"George R Saade","author_inst":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Galveston, TX"},{"author_name":"Robert M Silver","author_inst":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Salt Lake City, UT"},{"author_name":"Yi Qiao","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"},{"author_name":"Xiaomeng Huang","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"},{"author_name":"Hyagriv N Simhan","author_inst":"University of Pittsburgh School of Medicine, Magee-Women's Research Institute & Foundation, Department of Obstetrics and Gynecology, Pittsburgh, PA"},{"author_name":"Uma M Reddy","author_inst":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology, New York, NY"},{"author_name":"Judith Chung","author_inst":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Irvine, CA"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL; Northwestern University Feinberg School of Med"},{"author_name":"Donald M Lloyd-Jones","author_inst":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"},{"author_name":"William A Grobman","author_inst":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Providence, RI"},{"author_name":"Sadiya S Khan","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL; Northwestern University Feinberg School of Med"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Plasma Proteomic Mediators of the Association Between Early-Pregnancy Psychosocial Stress and Cardiovascular Health 2 to 7 Years After Delivery: The nuMoM2b-HHS Study","rel_doi":"10.64898\/2026.09.14.26363041","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363041","rel_abs":"Importance: Psychosocial exposures in early pregnancy are associated with worse maternal cardiovascular health (CVH), but the biological pathways linking early-pregnancy stressors to long-term CVH are not defined. Objective: To determine whether plasma proteins measured in early pregnancy mediate the association between early-pregnancy psychosocial stressors and CVH 2 to 7 years after delivery. Design, Setting, and Participants: This was a secondary analysis of the prospective multicenter Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study (nuMoM2b-HHS), which enrolled nulliparous individuals at eight US academic centers (2010-2014) and followed them 2 to 7 years after delivery. The analytic sample comprised participants with first-trimester plasma proteomics. Analyses were conducted from January to June 2026. Exposures: Perceived stress (Perceived Stress Scale-10 >13) as the primary exposure; Early-pregnancy depression (Edinburgh Postnatal Depression Scale >10) and anxiety (State-Trait Anxiety Inventory >37) as secondary exposures. Main Outcomes and Measures: Post-pregnancy CVH quantified by the American Heart Association Life's Essential 8 (LE8) composite score (0-100) and its clinical components: blood pressure, lipid, glucose, and body mass index (BMI) scores. A four-way decomposition partitioned the total effect of stress into a controlled direct effect, reference interaction, mediated interaction, and pure indirect effect operating through a proteomic mediator. Results: Among 1662 participants (mean [SD] age, 27.1 [5.5] years), 41.6% screened positive for stress. Of 6874 aptamers, 17 (representing 14 unique, predominantly neuronal and synaptic proteins) were associated with both stress and the LE8 composite as well as four clinical components after false discovery rate correction. No aptamers met criteria for depression or anxiety. Stress was associated with lower levels of all 14 proteins, and higher protein levels were associated with better CVH scores. The 14 proteins reduced to a single principal component (57% of variance) used as the mediator. Stress was associated with a lower post-pregnancy LE8 composite score (total effect, -3.74 [95% CI, -5.03 to -2.45]); the proteomic factor accounted for a pure indirect effect of -1.20 (95% CI, -1.68 to -0.72), approximately 32% of the total effect, and approximately 56% of the larger association with the BMI score. Significant indirect effects through the proteomic factor were also observed for the blood pressure, lipid, and glucose scores despite nonsignificant total effects.","rel_num_authors":18,"rel_authors":[{"author_name":"Xiaoning Huang","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL"},{"author_name":"Lucia C Petito","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL"},{"author_name":"Weihua Guan","author_inst":"University of Minnesota, School of Public Health, Division of Biostatistics & Health Data Science"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Chicago, IL"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine, Department of Obstetrics and Gynecology, Indianapolis, IN"},{"author_name":"Brian M Mercer","author_inst":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology, Cleveland, OH"},{"author_name":"Samuel Parry","author_inst":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Philadelphia, PA"},{"author_name":"George R Saade","author_inst":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Galveston, TX"},{"author_name":"Robert M Silver","author_inst":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Salt Lake City, UT"},{"author_name":"Yi Qiao","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"},{"author_name":"Xiaomeng Huang","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"},{"author_name":"Hyagriv N Simhan","author_inst":"University of Pittsburgh School of Medicine, Magee-Women's Research Institute & Foundation, Department of Obstetrics and Gynecology, Pittsburgh, PA"},{"author_name":"Uma M Reddy","author_inst":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology, New York, NY"},{"author_name":"Judith Chung","author_inst":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Irvine, CA"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL; Northwestern University Feinberg School of Med"},{"author_name":"Donald M Lloyd-Jones","author_inst":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"},{"author_name":"William A Grobman","author_inst":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Providence, RI"},{"author_name":"Sadiya S Khan","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL; Northwestern University Feinberg School of Med"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Plasma Proteomic Mediators of the Association Between Early-Pregnancy Psychosocial Stress and Cardiovascular Health 2 to 7 Years After Delivery: The nuMoM2b-HHS Study","rel_doi":"10.64898\/2026.09.14.26363041","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363041","rel_abs":"Importance: Psychosocial exposures in early pregnancy are associated with worse maternal cardiovascular health (CVH), but the biological pathways linking early-pregnancy stressors to long-term CVH are not defined. Objective: To determine whether plasma proteins measured in early pregnancy mediate the association between early-pregnancy psychosocial stressors and CVH 2 to 7 years after delivery. Design, Setting, and Participants: This was a secondary analysis of the prospective multicenter Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study (nuMoM2b-HHS), which enrolled nulliparous individuals at eight US academic centers (2010-2014) and followed them 2 to 7 years after delivery. The analytic sample comprised participants with first-trimester plasma proteomics. Analyses were conducted from January to June 2026. Exposures: Perceived stress (Perceived Stress Scale-10 >13) as the primary exposure; Early-pregnancy depression (Edinburgh Postnatal Depression Scale >10) and anxiety (State-Trait Anxiety Inventory >37) as secondary exposures. Main Outcomes and Measures: Post-pregnancy CVH quantified by the American Heart Association Life's Essential 8 (LE8) composite score (0-100) and its clinical components: blood pressure, lipid, glucose, and body mass index (BMI) scores. A four-way decomposition partitioned the total effect of stress into a controlled direct effect, reference interaction, mediated interaction, and pure indirect effect operating through a proteomic mediator. Results: Among 1662 participants (mean [SD] age, 27.1 [5.5] years), 41.6% screened positive for stress. Of 6874 aptamers, 17 (representing 14 unique, predominantly neuronal and synaptic proteins) were associated with both stress and the LE8 composite as well as four clinical components after false discovery rate correction. No aptamers met criteria for depression or anxiety. Stress was associated with lower levels of all 14 proteins, and higher protein levels were associated with better CVH scores. The 14 proteins reduced to a single principal component (57% of variance) used as the mediator. Stress was associated with a lower post-pregnancy LE8 composite score (total effect, -3.74 [95% CI, -5.03 to -2.45]); the proteomic factor accounted for a pure indirect effect of -1.20 (95% CI, -1.68 to -0.72), approximately 32% of the total effect, and approximately 56% of the larger association with the BMI score. Significant indirect effects through the proteomic factor were also observed for the blood pressure, lipid, and glucose scores despite nonsignificant total effects.","rel_num_authors":18,"rel_authors":[{"author_name":"Xiaoning Huang","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL"},{"author_name":"Lucia C Petito","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL"},{"author_name":"Weihua Guan","author_inst":"University of Minnesota, School of Public Health, Division of Biostatistics & Health Data Science"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Chicago, IL"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine, Department of Obstetrics and Gynecology, Indianapolis, IN"},{"author_name":"Brian M Mercer","author_inst":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology, Cleveland, OH"},{"author_name":"Samuel Parry","author_inst":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Philadelphia, PA"},{"author_name":"George R Saade","author_inst":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Galveston, TX"},{"author_name":"Robert M Silver","author_inst":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Salt Lake City, UT"},{"author_name":"Yi Qiao","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"},{"author_name":"Xiaomeng Huang","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"},{"author_name":"Hyagriv N Simhan","author_inst":"University of Pittsburgh School of Medicine, Magee-Women's Research Institute & Foundation, Department of Obstetrics and Gynecology, Pittsburgh, PA"},{"author_name":"Uma M Reddy","author_inst":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology, New York, NY"},{"author_name":"Judith Chung","author_inst":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Irvine, CA"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL; Northwestern University Feinberg School of Med"},{"author_name":"Donald M Lloyd-Jones","author_inst":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"},{"author_name":"William A Grobman","author_inst":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Providence, RI"},{"author_name":"Sadiya S Khan","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL; Northwestern University Feinberg School of Med"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Detection of Severe Structural Heart Disease Using an AI-Enhanced Portable 1-Lead ECG: The ACCESS-SHD Study","rel_doi":"10.64898\/2026.09.14.26361683","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26361683","rel_abs":"Aims: Structural heart disease (SHD) often remains undetected until symptoms develop. Portable 1-lead ECG devices return an automated rhythm-based interpretation, but whether AI-ECG adds diagnostic value beyond this interpretation is unknown. We prospectively evaluated a noise-adapted 1-lead AI-ECG algorithm for detecting severe SHD from portable KardiaMobile 6L recordings, and its relative diagnostic value beyond the device's rhythm interpretation. Methods and Results: Adults undergoing outpatient echocardiography between June 2024 and January 2025 recorded a 30-second, 1-lead ECG with real-time AI-ECG inference. The primary endpoint was discrimination for echocardiography-defined severe SHD. Secondary analyses assessed net reclassification improvement (NRI) versus the native interpretation and the number needed to test (NNT). Among 597 participants (median age 61.7 years; 51.4% women), 30 (5.1%) had severe SHD. AI-ECG achieved an AUROC of 0.872 (95% CI: 0.806-0.938), meeting the prespecified endpoint, with 86.7% (70.3-94.7) sensitivity, 72.5% (68.7-76.0) specificity, 99.0% (97.5-99.6) negative predictive value, and 14.4% (10.1-20.3) positive predictive value, with comparable performance across subgroups. AI-ECG increased sensitivity by 34.6 percentage points (95% CI: 13.0-56.0) over the native interpretation and yielded a categorical NRI of 24.3% (95% CI: 2.8-45.9), with 76.9% sensitivity and 80.0% specificity among tracings the device read as normal. An AI-ECG-guided strategy for detecting severe SHD reduced the NNT from 19.7 to 6.9 (a 64.8% reduction). Conclusions: A noise-adapted AI-ECG algorithm detected severe SHD from real-world portable 1-lead ECGs and substantially improved case finding beyond the device's rhythm interpretation, supporting AI-ECG-guided triage as a potential scalable screening strategy.","rel_num_authors":11,"rel_authors":[{"author_name":"Arya Aminorroaya","author_inst":"Yale School of Medicine"},{"author_name":"Sumukh Vasisht Shankar","author_inst":"Yale University"},{"author_name":"Mariam Khan","author_inst":"Yale School of Medicine"},{"author_name":"Madeleine Carter","author_inst":"Yale School of Medicine"},{"author_name":"Lovedeep Singh Dhingra","author_inst":"Yale School of Medicine"},{"author_name":"Akshay Khunte","author_inst":"Yale School of Medicine"},{"author_name":"Bernardo Lombo","author_inst":"Yale University"},{"author_name":"Robert L McNamara","author_inst":"Yale School of Medicine"},{"author_name":"Evangelos K Oikonomou","author_inst":"Yale School of Medicine"},{"author_name":"Aline F Pedroso","author_inst":"Yale School of Medicine"},{"author_name":"Rohan Khera","author_inst":"Yale School of Medicine"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Evidence for cross-reactivity and protection against Bundibugyo virus disease after heterologous vaccination: a systematic review and meta-analysis","rel_doi":"10.64898\/2026.09.14.26362805","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362805","rel_abs":"There are currently no approved vaccines or medical countermeasures for use in prevention or treatment of Bundibugyo virus disease. A critical question is whether the existing vaccines approved for use against Ebola virus disease could provide sufficient cross-reactivity and cross-protection against Bundibugyo virus disease. We performed a systematic review and meta-analysis of published studies of antibody cross-reactivity to Bundibugyo virus (BDBV) after vaccination with previously approved Ebola vaccines (Ervebo or Zabdeno\/Mvabea). We find on average a 2.8-fold (95% predictive interval, PI: 2.6-3.0) drop in binding (n = 8 observations from 4 studies) and 3.1-fold drop (95% PI: 2.0-4.8) in neutralization (n = 2 observations from 1 study) between Ebola virus and BDBV antigens after Ervebo vaccination, which appears maintained over time after vaccination. Very limited data on cross reactivity after Zabdeno\/Mvabea vaccination suggests a higher drop in recognition of BDBV (39.7-fold, 95% PI: 24.8-63.8; n = 3 observations from 2 studies). In addition to analysis of antibody recognition in humans, we also investigated evidence for vaccine protection from BDBV challenge in animal models after Ervebo or other recombinant vesicular stomatitis virus (rVSV) based vaccines containing only Ebola antigen. A single study in NHP showed non-significant vaccine protection from BDBV challenge, while a study in ferrets showed significant protection after both one and two doses. The available data demonstrate immune cross-reactivity and some evidence for protection in animals, although further clinical and pre-clinical data is urgently needed to inform decisions on the use of Ervebo to protect against Bundibugyo virus disease.","rel_num_authors":10,"rel_authors":[{"author_name":"Eva Stadler","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Mariah Csolle","author_inst":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia"},{"author_name":"Ainslie Mitchell","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Ece Egilmezer","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Karen M Elias","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Bronwyn A Bailey","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Deborah Cromer","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Tari Turner","author_inst":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia"},{"author_name":"David S Khoury","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Miles Philip Davenport","author_inst":"Kirby Institute, UNSW Sydney"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Late Life Learning, Cognition, and Aging: A Longitudinal study of middle and older-aged adults in Beirut, Lebanon (3LC study)","rel_doi":"10.64898\/2026.09.10.26362603","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362603","rel_abs":"Background: Lebanon is undergoing substantial demographic and social change, with older adults comprising approximately 10% of the population. The Late Life Learning, Cognition, and Aging (3LC) study was established around the University for Seniors (UfS), a longstanding late-life learning program at the American University of Beirut. The cohort was designed to leverage variation in late-life learning exposure by including both UfS participants and community-dwelling adults without prior participation in the program. This provides a unique opportunity to investigate how late-life learning, lifecourse social and biological factors, and health behaviors relate to cognitive aging, dementia risk, mental health, and resilience in Lebanon. Methods: Participants aged 50 years and older are recruited from the UfS program and the surrounding community in Lebanon. Baseline assessments include an interviewer-administered questionnaire, standardized anthropometric and sensory assessments, and blood collection for biomarker measurement and biobanking. The questionnaire captures health, psychosocial, cognitive, social engagement, and lifecourse factors, including exposure to war, conflict, and socioeconomic adversity. Longitudinal follow-up includes planned phone-based and in-person assessments at approximately two-year intervals. Results: The cohort comprised 1,871 participants, including 536 UfS participants (350 previously enrolled and 186 newly enrolled) and 1,335 community participants, of whom 1,041 were age-, sex-, and education-matched to UfS participants and 294 were additionally recruited without matching. The mean age was 65.6 years (SD=9.0), and 70.1% of participants were women. Blood samples were obtained from 1,541 participants (82.3%). Conclusion: The 3LC study provides a unique platform to examine how late-life learning and lifecourse factors shape cognitive aging, well-being, and dementia risk in Lebanon. By integrating social, psychosocial, health, and biological measures, the cohort offers opportunities to identify modifiable determinants of cognitive aging and inform dementia prevention in Lebanon and other under-resourced settings.","rel_num_authors":9,"rel_authors":[{"author_name":"Adina Zeki Al Hazzouri","author_inst":"Department of Epidemiology, Mailman School of Public Health, Columbia University, NY, NY"},{"author_name":"Abla Mehio Sibai","author_inst":"Department of Epidemiology and Biostatistics, Faculty of Health Sciences, American University of Beirut, Beirut, Lebanon"},{"author_name":"Darina T Bassil","author_inst":"Department of Epidemiology, Mailman School of Public Health, Columbia University, NY, NY"},{"author_name":"M Maria Glymour","author_inst":"Department of Epidemiology, Boston School of Public Health, Boston University, Boston, MA"},{"author_name":"Jennifer J Manly","author_inst":"Department of Neurology, the Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Irving Medical Center"},{"author_name":"Maya Abi Chahine","author_inst":"University for Seniors, Faculty of Health Sciences, American University of Beirut, Beirut, Lebanon"},{"author_name":"Lara Chehabeddine","author_inst":"Clinical Research Institute, American University of Beirut Medical Center, Beirut, Lebanon"},{"author_name":"Mira Bekdache","author_inst":"Clinical Research Institute, American University of Beirut Medical Center, Beirut, Lebanon"},{"author_name":"Martine Elbejjani","author_inst":"Clinical Research Institute, American University of Beirut Medical Center, Beirut, Lebanon"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Surgically Modifiable Insertion Geometry Drives Thrombogenic Flow in the Modified Blalock-Taussig-Thomas Shunt","rel_doi":"10.64898\/2026.09.11.26362753","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362753","rel_abs":"ABSTRACT Background: The modified Blalock-Taussig-Thomas shunt (mBTTS) sustains pulmonary blood flow in infants with cyanotic or single-ventricle heart disease, but shunt thrombosis occurs in 8-12% of cases and carries substantial mortality. Systemic anticoagulation has limited efficacy. Objectives: This study tested whether surgically modifiable shunt geometry might form a second, patient-specific approach to maintaining shunt patency, via management of thrombogenic hemodynamics. Methods: Three-dimensional mBTTS anatomies were reconstructed from computed tomography in 10 infants (4 thrombosed, 6 patent). Pulsatile inlet waveforms derived from Doppler ultrasound were coupled with three-element Windkessel outlet models individually calibrated to catheter-derived pressures. Transient computational fluid dynamics simulations predicted wall shear rate (WSR) and elongational strain rate (ESR). Associations between surgically relevant geometric parameters and hemodynamic metrics were evaluated. Results: Simulated pressures closely matched clinical measurements at all four outlets in all 10 models. Despite substantial anatomic variability, peak WSR and ESR consistently localized to the shunt-subclavian junction in 8 of 10 patients, including all 4 thrombosed shunts. Greater deviation of shunt insertion angle from perpendicular was associated with higher systolic and cycle-averaged normalized WSR ({rho} = 0.94, p < 0.001; {rho} = 0.88, p = 0.002) and ESR ({rho} = 0.82, p = 0.007; {rho} = 0.70, p = 0.03). Larger shunt diameter was associated with lower WSR and ESR. Thrombosed shunts demonstrated higher shear-related metrics than patent shunts, particularly during systole. Conclusions: In patient-specific mBTTS anatomies, insertion angle and shunt diameter are determinants of local abnormal flow, concentrated at the shunt-subclavian junction. Patient-specific hemodynamic assessment may inform shunt construction and interstage risk stratification.","rel_num_authors":11,"rel_authors":[{"author_name":"Yi Qiao","author_inst":"Colorado State University"},{"author_name":"Ethan Penn","author_inst":"Washington University in St Louis"},{"author_name":"Jacob Miller","author_inst":"Washington University School of Medicine, St Louis Children's Hospital"},{"author_name":"Scott Bugenhagen","author_inst":"Washington University School of Medicine"},{"author_name":"Ram Rohatgi","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Kelsey Mercer","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Blaire Kulp","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Pirooz Eghtesady","author_inst":"Washington University School of Medicine"},{"author_name":"Guy M Genin","author_inst":"Washington University in St. Louis"},{"author_name":"David Lawrence Bark Jr.","author_inst":"Monash University"},{"author_name":"Edon Rabinowitz","author_inst":"Washington University in St Louis"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Mechanistical and structural basis of Kv channel inhibition by 4 aminopyridine","rel_doi":"10.64898\/2026.09.12.751153","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.12.751153","rel_abs":"Inhibition of Kv channels by 4-aminopyridine (4AP) improves motor function in multiple sclerosis by enhancing neuronal excitability. The mechanism of inhibition and the structural basis of 4AP binding to Kv channels remain unclear. Here, we determined the structure of the Shaker V369I-I372L-S376T (ILT) mutant bound to 4AP at 3.3 [A], demonstrating that 4AP binds to the closed state of the channel. This structure is inconsistent with an open channel block mechanism. Electrophysiology experiments show that 4AP binds even when intracellular pore access is constitutively blocked, suggesting that 4AP enters the pore through membrane-facing fenestrations. MD simulations and mutational analysis agree with the proposed fenestration pathway and suggest that 4AP binds in its neutral form. These results support a mechanism where 4AP binds to a partially activated closed state that prevents complete activation of Kv channels, explaining its pharmacological activity.","rel_num_authors":6,"rel_authors":[{"author_name":"Bernardo I Pinto-Anwandter","author_inst":"University of Chicago"},{"author_name":"Richa Agrawal","author_inst":"University of Chicago"},{"author_name":"Trayder Thomas","author_inst":"University of Chicago"},{"author_name":"Eduardo Perozo","author_inst":"University of Chicago"},{"author_name":"Benoit Roux","author_inst":"University of Chicago"},{"author_name":"Francisco Bezanilla","author_inst":"University of Chicago"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Meta-analysis of gut microbiome in largemouth bass (Micropterus salmoides) under different aquaculture systems","rel_doi":"10.64898\/2026.09.13.751318","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.13.751318","rel_abs":"The teleost gastrointestinal tract hosts metabolically active microbial assemblages that play critical roles in nutrient use, immune regulation, physiology, behavior, growth, reproduction, and health status. However, the extent to which aquaculture production systems restructure these communities remains poorly defined. In this study, metagenomic sequencing was applied to characterize gut microbiota in largemouth bass (Micropterus salmoides) reared under four representative farming conditions: industrial aquaculture (IA), captive pond-based farming (CA), ordinary pond aquaculture with healthy fish (PH), and ordinary pond aquaculture with diseased fish (PD). Results revealed that the four groups exhibited pronounced differences in microbial diversity, taxonomic composition, functional capacity, carbohydrate-active enzyme profiles, and antibiotic resistance genes (ARGs). Notably, bacterial taxa accounted for more than 95% of the gut microbial communities across all groups. IA fish showed greater microbial richness and diversity than CA and PH fish, consistent with a more complex and potentially more stable intestinal ecosystem under industrialized rearing conditions. Taxonomic profiling at both the phylum and genus levels identified production system-specific microbial signatures. In particular, opportunistic pathogens, including Aeromonas veronii and Aeromonas hydrophila, were disproportionately enriched in CA fish, suggesting a microbiota profile associated with increased disease vulnerability. Functional prediction analysis further indicated distinct metabolic states among groups, with purine and fatty acid metabolism enriched in PD fish, potentially reflecting disease-associated disruption of host-microbiota interactions. Carbohydrate-active enzyme analysis revealed substantial variation in microbial carbohydrate-processing potential, whereas ARG profiling indicated that farming conditions were linked to distinct gut resistome patterns. Collectively, these findings identify aquaculture regimes as a key ecological driver of intestinal microbiome structure in largemouth bass and provide a mechanistic basis for optimizing microbiome-informed health management in aquaculture systems. Keywords: Largemouth bass (Micropterus salmoides); gut microbiota; aquaculture modes","rel_num_authors":4,"rel_authors":[{"author_name":"Xiangnan Liu","author_inst":"City University of Hong Kong"},{"author_name":"Liang Zhong","author_inst":"City University of Hong Kong"},{"author_name":"Weiwei Zeng","author_inst":"Foshan University"},{"author_name":"Wenlong Cai","author_inst":"City University of Hong Kong"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Ribosome profiling reveals translational dynamics between an archaeal virus and its host","rel_doi":"10.64898\/2026.09.13.751334","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.13.751334","rel_abs":"Host-virus interactions remain poorly understood in archaea, whose information processing systems harbor a mosaic of bacterial and eukaryotic features. Here, we used complementary multiomics to investigate interactions between Haloferax tailed virus 1 (HFTV1) and the halophilic archaeon Haloferax gibbonsii (Hg), capturing global translational and transcriptional dynamics across the infection cycle. This revealed co-regulatory expression patterns across HFTV1 and Hg genes. Post-transcriptional regulation was observed for several early HFTV1 genes and the late HFTV1 gene gp17, and the HFTV1 tRNA co-sedimented with Hg ribosome complexes. Infection reshaped the translational landscape of Hg, causing a slow decline in information processing activity, a complex transcriptional response, and amino acid starvation. An unannotated Tat-dependent fimbrial system of Hg was co-regulated with early HFTV1 genes and was correlated with increased biofilm formation, suggesting a potential antiviral defense system. These findings provide high-resolution insight into archaeal host-virus interactions at the evolutionary interface between bacteria and eukaryotes.","rel_num_authors":5,"rel_authors":[{"author_name":"Matthew F Isada","author_inst":"Johns Hopkins University"},{"author_name":"Pavlina Gregorova","author_inst":"University of Helsinki"},{"author_name":"Palak Sadana","author_inst":"Johns Hopkins University"},{"author_name":"Peter Sarin","author_inst":"University of Helsinki"},{"author_name":"Jocelyne DiRuggiero","author_inst":"Johns Hopkins University"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Clustered heterogeneity, spiking history and efficient silencing maximize mutual information in adaptive time encoding","rel_doi":"10.64898\/2026.09.09.750511","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750511","rel_abs":"Neurons involved in a computation are remarkably diverse. They display a range of thresholds, time scales and spiking history dependence, and often exhibit adaptation that enhances computational power by concentrating spikes at transient stimuli. We seek basic organizational principles for coding with cellular heterogeneity by focusing on the encoding and retrieval of inter-event time interval sequences by adaptive neurons. We formulate the general input-output mutual information maximization problem for parallel neurons with a fading memory of past intervals. The solution reveals an unexpected multi-variate heterogeneity that is tailored to encode information efficiently. Gradient ascent on mutual information produces a number of parameterized clusters bounded by the sequence length. Correlations between parameters emerge naturally. The predicted covariation of adaptation time with spiking history strength, and the optimal combination of history and non-history cells, agree with experiments. Threshold optimization yields a continuum of time constants and thresholds within each cluster. Strikingly, division of labour between neurons arises where subsets respond selectively to different interval ranges. This creates cell-specific interval ranges that tile reasonably well a uniform prior of intervals, and almost perfectly a scale-free prior, producing a code that is efficient in cell number and reduces metabolic cost by limiting spike rates.","rel_num_authors":3,"rel_authors":[{"author_name":"Raphael Lafond-Mercier","author_inst":"University of Ottawa"},{"author_name":"Andre Longtin","author_inst":"University of Ottawa"},{"author_name":"Len Maler","author_inst":"University of Ottawa"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Clustered heterogeneity, spiking history and efficient silencing maximize mutual information in adaptive time encoding","rel_doi":"10.64898\/2026.09.09.750511","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750511","rel_abs":"Neurons involved in a computation are remarkably diverse. They display a range of thresholds, time scales and spiking history dependence, and often exhibit adaptation that enhances computational power by concentrating spikes at transient stimuli. We seek basic organizational principles for coding with cellular heterogeneity by focusing on the encoding and retrieval of inter-event time interval sequences by adaptive neurons. We formulate the general input-output mutual information maximization problem for parallel neurons with a fading memory of past intervals. The solution reveals an unexpected multi-variate heterogeneity that is tailored to encode information efficiently. Gradient ascent on mutual information produces a number of parameterized clusters bounded by the sequence length. Correlations between parameters emerge naturally. The predicted covariation of adaptation time with spiking history strength, and the optimal combination of history and non-history cells, agree with experiments. Threshold optimization yields a continuum of time constants and thresholds within each cluster. Strikingly, division of labour between neurons arises where subsets respond selectively to different interval ranges. This creates cell-specific interval ranges that tile reasonably well a uniform prior of intervals, and almost perfectly a scale-free prior, producing a code that is efficient in cell number and reduces metabolic cost by limiting spike rates.","rel_num_authors":3,"rel_authors":[{"author_name":"Raphael Lafond-Mercier","author_inst":"University of Ottawa"},{"author_name":"Andre Longtin","author_inst":"University of Ottawa"},{"author_name":"Len Maler","author_inst":"University of Ottawa"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Host soluble inositol phosphate signaling promotes coronavirus replication","rel_doi":"10.64898\/2026.09.12.751050","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.12.751050","rel_abs":"Coronaviruses rely extensively on host pathways for replication, making host-directed therapies an attractive strategy for broad-spectrum antivirals with reduced risk of viral resistance. Here we identify the host soluble inositol phosphate pathway as a previously unrecognized dependency for coronavirus infection. Genetic or pharmacologic inhibition of several kinases in this pathway markedly suppresses replication of both alpha- and betacoronaviruses, while increasing pathway activity promotes viral replication. We developed UNC7844, a potent multi-target inhibitor of these kinases, which reduces coronavirus replication by more than four orders of magnitude in cultured cells and suppresses coronavirus infection in mice. Mechanistically, UNC7844 suppresses inositol (pyro)phosphates production, disrupts phosphoinositide homeostasis, and impairs late endosomal dynamics, blocking early post-entry steps required for viral genome release and replication. Together, our findings establish the soluble inositol (pyro)phosphate pathway as an important regulator of coronavirus infection and highlight its inhibition as a promising host-directed antiviral strategy.","rel_num_authors":12,"rel_authors":[{"author_name":"Igor Shats","author_inst":"National Institute of Environmental Health Sciences"},{"author_name":"Huanchen Wang","author_inst":"National Institute of Environmental Health Sciences"},{"author_name":"Yubai Zhou","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Chunfang Gu","author_inst":"National Institute of Environmental Health Sciences"},{"author_name":"Adam Carr","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Carlos M. Guardia","author_inst":"National Institute of Environmental Health Sciences"},{"author_name":"Stephen Shears","author_inst":"National Institute of Environmental Health Sciences"},{"author_name":"Robin E Stanley","author_inst":"NIEHS\/NIH"},{"author_name":"Qisheng Zhang","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Raymond Blind","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Xiaodong Wang","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Xiaoling Li","author_inst":"National Institute of Environmental Health Sciences"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"A rational design strategy and validation for protease-resistant fusion-inhibitor antiviral peptides","rel_doi":"10.64898\/2026.09.12.750390","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.12.750390","rel_abs":"Peptide-based fusion inhibitors are promising pharmaceuticals in the fight against enveloped viruses relying on membrane fusion for host infection. However, peptide therapeutic applications have long been hindered by their poor stability in vivo. Here, we discovered that peptide inhibitors with the wildtype sequence of the heptad repeat 2 (HR2) domain of the SARS-CoV-2 spike protein are efficiently cleaved by Transmembrane Protease, Serine 2 (TMPRSS2), a key protease involved in the SARS-CoV-2 virus-cell fusion pathway. We then identified the corresponding cleavage sites and designed three protease-resistant peptides using ranking based on deep mutational scanning and natural occurrence. The three candidates all exhibit inhibitory activity in a cell-cell fusion assay. A high-resolution cryo-EM structure of the top candidate, HR2-NHN, bound to its HR1 target reveals the molecular basis for its potent activity. The top candidate of the cell-based screening assay significantly improved efficacy relative to the wildtype peptide when administered 12 h before infection in both an authentic virus-cell infection assay and a mouse assay. More broadly, our results suggest that the design strategies for protease-resistant peptides could be applied to a broad spectrum of other enveloped viruses and pave the way for the development of safe, prophylactic antivirals that can be administered before exposure.","rel_num_authors":22,"rel_authors":[{"author_name":"Kailu Yang","author_inst":"Stanford University"},{"author_name":"Chuchu Wang","author_inst":"Stanford University"},{"author_name":"Francesco Topi","author_inst":"University of Helsinki"},{"author_name":"Serena Muratcioglu","author_inst":"Vanderbilt University"},{"author_name":"Ravi Kant","author_inst":"University of Helsinki"},{"author_name":"Tomas Strandin","author_inst":"University of Helsinki"},{"author_name":"Yih Tyng Bong","author_inst":"University of Helsinki"},{"author_name":"Lauri Kareinen","author_inst":"University of Helsinki"},{"author_name":"Sanna M\u00e4ki","author_inst":"University of Helsinki"},{"author_name":"Saber H. Saber","author_inst":"Queensland Brain Institute"},{"author_name":"Tobias Binder","author_inst":"University of Helsinki"},{"author_name":"Tarja Sironen","author_inst":"Haartman Institute, University of Helsinki"},{"author_name":"Subu Subramanian","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"K Ian White","author_inst":"Stanford University"},{"author_name":"Richard Pfuetzner","author_inst":"Stanford University"},{"author_name":"Luis Esquivies","author_inst":"Stanford University"},{"author_name":"Olli Vapalahti","author_inst":"University of Helsinki"},{"author_name":"Merja Joensuu","author_inst":"The Univeristy of Queensland"},{"author_name":"John Kuriyan","author_inst":"Vanderbilt University"},{"author_name":"Jussi Hepojoki","author_inst":"University of Helsinki \/ Medicum"},{"author_name":"Giuseppe Balistreri","author_inst":"University of Helsinki"},{"author_name":"Axel T Brunger","author_inst":"Stanford University"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"PRDM9-mediated meiotic hotspot specification is constrained in humans despite extensive sequence diversity","rel_doi":"10.64898\/2026.09.10.750150","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.10.750150","rel_abs":"PRDM9 specifies meiotic recombination hotspots through a rapidly evolving C2H2 zinc-finger (ZNF) coding minisatellite that determines DNA-binding specificity. Although this minisatellite harbors extraordinary allelic diversity in humans, the functional consequences of most naturally occurring variants remain unknown. Here we functionally characterize 80 human PRDM9 alleles using genome-wide chromatin profiling. Despite extensive sequence diversity within the ZNF array, most alleles function indistinguishably from common A and C hotspot-specifying alleles, revealing that human PRDM9 function is more constrained than its sequence diversity predicts. In contrast, rare and infertility-associated variants occupy two functional extremes: either abundant and novel DNA binding specificity or minimal DNA binding, suggesting that both gain- and loss-of-function alleles may disrupt symmetric hotspot specification during meiosis, thus representing a plausible contributor to human infertility. Together, our findings define the functional landscape of human PRDM9 variation and provide a framework for interpreting the impact of newly discovered PRDM9 alleles.","rel_num_authors":11,"rel_authors":[{"author_name":"Rachel L Cosby","author_inst":"The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Marja Brolinson King","author_inst":"The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Alexandra M Poch","author_inst":"The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, MD, USA"},{"author_name":"M. Blake Evans","author_inst":"The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Dawn E Watkins-Chow","author_inst":"The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Briana Young","author_inst":"The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Sherry Ralls","author_inst":"The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Veronica Gomez-Lobo","author_inst":"The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Kenneth I Aston","author_inst":"Andrology Laboratory, Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA"},{"author_name":"Donald F Conrad","author_inst":"Oregon Health & Science University"},{"author_name":"Todd S Macfarlan","author_inst":"The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, MD, USA"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Inter-regional interactions uncouple within-region inhibition stabilization and paradoxical responses","rel_doi":"10.64898\/2026.09.09.750483","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750483","rel_abs":"Paradoxical responses, in which excitatory perturbations of inhibitory neurons reduce their firing rates, are widely regarded as a hallmark of inhibition-stabilized networks (ISNs) and have been observed in multiple brain regions. However, because brain regions are interconnected by long-range projections, it remains unclear whether a paradoxical response observed in a given region reflects inhibition stabilization within that region or instead arises from distributed interactions among regions. Here, using analytically tractable multi-region population models and numerical simulations, we show that inter-regional connections can dissociate local inhibition stabilization from paradoxical responses. The condition for a paradoxical response in a given region is jointly determined by recurrent excitation within that region, feedback mediated through other regions, and the dynamics of those other regions. Consequently, inter-regional coupling can generate a paradoxical response in a region that is not locally inhibition-stabilized or abolish it in a region that is. Thus, in an interconnected network, a paradoxical response is neither necessary nor sufficient for local inhibition stabilization. These findings demonstrate that local perturbation responses cannot generally be interpreted solely in terms of local circuit dynamics and highlight the importance of accounting for inter-regional connections when inferring the local circuit properties of individual brain regions.","rel_num_authors":2,"rel_authors":[{"author_name":"Yue Kris Wu","author_inst":"Columbia University"},{"author_name":"Kenneth D Miller","author_inst":"Columbia University"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Arginine methyltransferase signalling is hyperactive in conditions of neuromuscular junction instability and muscle atrophy","rel_doi":"10.64898\/2026.09.09.750242","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750242","rel_abs":"Background: The neuromuscular junction (NMJ) is the site of communication between myofibers and a-motor neurons. Cellular and molecular mechanisms that determine, maintain, and remodel the neuromuscular synapse are poorly understood. Coactivator-associated arginine methyltransferase 1 (CARM1) post-translationally modifies target proteins by methylating arginine residues and has emerged as a key determinant of skeletal muscle biology. Methylarginine signalling is required for the maintenance and repair of the NMJ, but the direct role of CARM1 on the NMJ in health and disease remains unexplored, particularly in humans. Methods: We generated Carm1 skeletal muscle-specific knockout-out (mKO) mice to gain a basic understanding for the role of the enzyme in NMJ biology under homeostatic and denervated conditions. Additionally, we investigated CARM1 activity in severe mouse models of neuromuscular disorders (NMDs) including D2.mdx and Smn2B\/- mice, which replicate Duchenne's muscular dystrophy (DMD) and spinal muscular atrophy (SMA), respectively, and exhibit chronic remodelling of the NMJ. Lastly, to evaluate if methylarginine signalling is implicated during NMJ instability in human skeletal muscle, we obtained samples from healthy volunteers before and after 14 days of single leg immobilization as well as from patients with myotonic dystrophy type 1. Results: Our results demonstrated that Carm1 mRNA expression and activity are elevated (P<0.05) in NMJ-enriched regions of healthy murine skeletal muscle. Carm1 muscle-specific deletion reduced NMJ compactness (-9.3%; P<0.05), increased fragmentation (+33%; P<0.05), and disrupted the expression of synapse-specific transcripts basally and following sciatic nerve transection. In skeletal muscle from pre-clinical models of NMDs, we observed a compensatory upregulation in CARM1-dependent arginine methylation as evident by +54% and +71 increases (P<0.05) in asymmetric dimethylarginine (ADMA)-marked CARM1 substrates in DMD and SMA mice, respectively. Similarly, muscle CARM1 was hyperactive with increased NMJ instability during neuromuscular disuse (+22%; P<0.05), and disease (+30%; P<0.05), in humans. In a cohort of muscular dystrophy patients and healthy volunteers, elevated CARM1 signalling was negatively correlated with clinical metrics of skeletal muscle health including grip strength (r = -0.583; P<0.05) as well as positively correlated with mRNA expression of NMJ machinery such as CHRNA1 (r = 0.578; P<0.05). Conclusion: In summary, we highlight that muscle-specific CARM1 is required for maintaining NMJ morphology and transcriptional regulation. Insults to NMJ stability during muscle disuse or in myopathic conditions were associated with enhanced CARM1-mediated methylarginine signalling in mice and humans. Collectively, our findings demonstrate CARM1 as a key mediator of NMJ biology and plasticity in health and disease.","rel_num_authors":12,"rel_authors":[{"author_name":"Andrew I Mikhail","author_inst":"McMaster University"},{"author_name":"Sean Y Ng","author_inst":"McMaster University"},{"author_name":"Magda A Lesinski","author_inst":"McMaster University"},{"author_name":"Stephanie R Mattina","author_inst":"McMaster University"},{"author_name":"Derek W Stouth","author_inst":"McMaster University"},{"author_name":"Rozhin Raziee","author_inst":"McMaster University"},{"author_name":"Changhyun Lim","author_inst":"Newcastle University"},{"author_name":"Gautham Vasam","author_inst":"University of Ottawa"},{"author_name":"Keir J Menzies","author_inst":"Univeristy of Ottawa"},{"author_name":"Stuart M Phillips","author_inst":"McMaster University"},{"author_name":"Mark A Tarnopolsky","author_inst":"McMaster University"},{"author_name":"Vladimir Ljubicic","author_inst":"McMaster University"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Arginine methyltransferase signalling is hyperactive in conditions of neuromuscular junction instability and muscle atrophy","rel_doi":"10.64898\/2026.09.09.750242","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750242","rel_abs":"Background: The neuromuscular junction (NMJ) is the site of communication between myofibers and a-motor neurons. Cellular and molecular mechanisms that determine, maintain, and remodel the neuromuscular synapse are poorly understood. Coactivator-associated arginine methyltransferase 1 (CARM1) post-translationally modifies target proteins by methylating arginine residues and has emerged as a key determinant of skeletal muscle biology. Methylarginine signalling is required for the maintenance and repair of the NMJ, but the direct role of CARM1 on the NMJ in health and disease remains unexplored, particularly in humans. Methods: We generated Carm1 skeletal muscle-specific knockout-out (mKO) mice to gain a basic understanding for the role of the enzyme in NMJ biology under homeostatic and denervated conditions. Additionally, we investigated CARM1 activity in severe mouse models of neuromuscular disorders (NMDs) including D2.mdx and Smn2B\/- mice, which replicate Duchenne's muscular dystrophy (DMD) and spinal muscular atrophy (SMA), respectively, and exhibit chronic remodelling of the NMJ. Lastly, to evaluate if methylarginine signalling is implicated during NMJ instability in human skeletal muscle, we obtained samples from healthy volunteers before and after 14 days of single leg immobilization as well as from patients with myotonic dystrophy type 1. Results: Our results demonstrated that Carm1 mRNA expression and activity are elevated (P<0.05) in NMJ-enriched regions of healthy murine skeletal muscle. Carm1 muscle-specific deletion reduced NMJ compactness (-9.3%; P<0.05), increased fragmentation (+33%; P<0.05), and disrupted the expression of synapse-specific transcripts basally and following sciatic nerve transection. In skeletal muscle from pre-clinical models of NMDs, we observed a compensatory upregulation in CARM1-dependent arginine methylation as evident by +54% and +71 increases (P<0.05) in asymmetric dimethylarginine (ADMA)-marked CARM1 substrates in DMD and SMA mice, respectively. Similarly, muscle CARM1 was hyperactive with increased NMJ instability during neuromuscular disuse (+22%; P<0.05), and disease (+30%; P<0.05), in humans. In a cohort of muscular dystrophy patients and healthy volunteers, elevated CARM1 signalling was negatively correlated with clinical metrics of skeletal muscle health including grip strength (r = -0.583; P<0.05) as well as positively correlated with mRNA expression of NMJ machinery such as CHRNA1 (r = 0.578; P<0.05). Conclusion: In summary, we highlight that muscle-specific CARM1 is required for maintaining NMJ morphology and transcriptional regulation. Insults to NMJ stability during muscle disuse or in myopathic conditions were associated with enhanced CARM1-mediated methylarginine signalling in mice and humans. Collectively, our findings demonstrate CARM1 as a key mediator of NMJ biology and plasticity in health and disease.","rel_num_authors":12,"rel_authors":[{"author_name":"Andrew I Mikhail","author_inst":"McMaster University"},{"author_name":"Sean Y Ng","author_inst":"McMaster University"},{"author_name":"Magda A Lesinski","author_inst":"McMaster University"},{"author_name":"Stephanie R Mattina","author_inst":"McMaster University"},{"author_name":"Derek W Stouth","author_inst":"McMaster University"},{"author_name":"Rozhin Raziee","author_inst":"McMaster University"},{"author_name":"Changhyun Lim","author_inst":"Newcastle University"},{"author_name":"Gautham Vasam","author_inst":"University of Ottawa"},{"author_name":"Keir J Menzies","author_inst":"Univeristy of Ottawa"},{"author_name":"Stuart M Phillips","author_inst":"McMaster University"},{"author_name":"Mark A Tarnopolsky","author_inst":"McMaster University"},{"author_name":"Vladimir Ljubicic","author_inst":"McMaster University"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"HrasG12V induces follicular thyroid cancer with attenuated MAPK activation and increased latency compared to KrasG12D","rel_doi":"10.64898\/2026.09.09.750413","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750413","rel_abs":"RAS mutations are found in nearly 50% of follicular thyroid cancers (FTCs), frequently accompanied by secondary mutations in the P13K\/AKT pathway as tumors advance to more poorly differentiated states. To examine the role that oncogenic Hras plays in thyroid tumor initiation and progression, we developed murine models with thyroid-specific expression of HrasG12V combined with heterozygous or homozygous loss of Pten. Loss of Pten cooperated with HrasG12V in a dose-dependent manner to induce the development of follicular thyroid carcinoma and poorly-differentiated thyroid carcinoma. Histopathology of HrasG12V\/PtenHom tumors closely resembled those from the established KrasG12D\/PtenHom model, but tumor onset was significantly delayed in HrasG12V\/PtenHom mice. At three weeks of age, downregulation of MAPK pathway inhibitors was observed in KrasG12D\/PtenHom thyroids, accompanied by increased MAPK pathway activation compared to HrasG12V\/PtenHom mice. Furthermore, amplification of oncogenic Ras was found in HrasG12V tumors and cell lines, while allelic balance was maintained in KrasG12D models. These studies demonstrate clear phenotypic differences between mutant Hras and Kras in the thyroid and suggest that delayed MAPK activation may mediate the increased tumor latency observed in the HrasG12V\/PtenHom model.","rel_num_authors":7,"rel_authors":[{"author_name":"Nicholas E Bambach","author_inst":"Department of Pediatrics, Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA"},{"author_name":"Katherine Labella","author_inst":"Department of Pediatrics, Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA"},{"author_name":"Lee Ann Jolly","author_inst":"Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR"},{"author_name":"Diana Isabel Cruz","author_inst":"Department of Pediatrics, Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA"},{"author_name":"Nicole Massol","author_inst":"Department of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR"},{"author_name":"Antonio Di Cristofano","author_inst":"Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY"},{"author_name":"Aime T Franco","author_inst":"Department of Pediatrics, Abramson Cancer Center, University of Pennsylvania, Philadephia, PA; Department of Pediatrics, Division of Endocrinology and Diabetes,"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"HrasG12V induces follicular thyroid cancer with attenuated MAPK activation and increased latency compared to KrasG12D","rel_doi":"10.64898\/2026.09.09.750413","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750413","rel_abs":"RAS mutations are found in nearly 50% of follicular thyroid cancers (FTCs), frequently accompanied by secondary mutations in the P13K\/AKT pathway as tumors advance to more poorly differentiated states. To examine the role that oncogenic Hras plays in thyroid tumor initiation and progression, we developed murine models with thyroid-specific expression of HrasG12V combined with heterozygous or homozygous loss of Pten. Loss of Pten cooperated with HrasG12V in a dose-dependent manner to induce the development of follicular thyroid carcinoma and poorly-differentiated thyroid carcinoma. Histopathology of HrasG12V\/PtenHom tumors closely resembled those from the established KrasG12D\/PtenHom model, but tumor onset was significantly delayed in HrasG12V\/PtenHom mice. At three weeks of age, downregulation of MAPK pathway inhibitors was observed in KrasG12D\/PtenHom thyroids, accompanied by increased MAPK pathway activation compared to HrasG12V\/PtenHom mice. Furthermore, amplification of oncogenic Ras was found in HrasG12V tumors and cell lines, while allelic balance was maintained in KrasG12D models. These studies demonstrate clear phenotypic differences between mutant Hras and Kras in the thyroid and suggest that delayed MAPK activation may mediate the increased tumor latency observed in the HrasG12V\/PtenHom model.","rel_num_authors":7,"rel_authors":[{"author_name":"Nicholas E Bambach","author_inst":"Department of Pediatrics, Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA"},{"author_name":"Katherine Labella","author_inst":"Department of Pediatrics, Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA"},{"author_name":"Lee Ann Jolly","author_inst":"Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR"},{"author_name":"Diana Isabel Cruz","author_inst":"Department of Pediatrics, Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA"},{"author_name":"Nicole Massol","author_inst":"Department of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR"},{"author_name":"Antonio Di Cristofano","author_inst":"Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY"},{"author_name":"Aime T Franco","author_inst":"Department of Pediatrics, Abramson Cancer Center, University of Pennsylvania, Philadephia, PA; Department of Pediatrics, Division of Endocrinology and Diabetes,"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Transdermal diagnosis and therapy using an integrated acoustofluidic patch","rel_doi":"10.64898\/2026.09.09.750438","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750438","rel_abs":"Transdermal biosensing and drug delivery provide convenient, pain-free, and user-friendly solutions for personalized therapy. However, challenges remain in detecting and treating acute diseases, primarily due to current limitations in effective detection of transdermal biomarkers and administration of therapeutics to an individual within a short time window in a real-world environment. Here, we integrate a compact acoustofluidic patch for transdermal sampling, sensing, and delivery in a rapid and automated manner. By leveraging acoustic streaming and 3D-printed microfluidic designs, acoustofluidic sampler and injector modules are assembled for penetration of the skin stratum corneum, precise sampling of skin interstitial fluids, and controlled percutaneous release of therapeutics, respectively. By incorporating an electrochemical sensing module, the integrated patch can be further developed to achieve in situ and rapid detection of transdermal biomarkers and automated transdermal delivery of therapeutics via closed-loop control. As a proof-of-concept application, we demonstrate our approach can detect and reverse life-threatening acute allergic reactions in a mouse model of anaphylaxis by rapid sampling and sensing transdermal histamine followed by automated transdermal delivery of epinephrine. The innovative acoustofluidic patch may enable a new kind of transdermal devices for personalized therapy of various acute diseases.","rel_num_authors":12,"rel_authors":[{"author_name":"Yang Yang","author_inst":"Harvard Medical School"},{"author_name":"Yantao Xing","author_inst":"Indiana University Bloomington"},{"author_name":"Xiang Li","author_inst":"Indiana University Bloomington"},{"author_name":"Zhuhao Wu","author_inst":"Indiana University Bloomington"},{"author_name":"Hongwei Cai","author_inst":"Indiana University Bloomington"},{"author_name":"Vivian Niu","author_inst":"Indiana University Bloomington"},{"author_name":"Jack Crystal","author_inst":"Indiana University Bloomington"},{"author_name":"Nian Wang","author_inst":"UTSW"},{"author_name":"Ken Mackie","author_inst":"IU Bloomington"},{"author_name":"Weihua Guan","author_inst":"Indiana University"},{"author_name":"James Friend","author_inst":"Washington University in St. Louis"},{"author_name":"Feng Guo","author_inst":"Indiana University Bloomington"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Bramble: projection of spliced genomic alignments into transcriptomic space for improved transcript quantification","rel_doi":"10.64898\/2026.09.09.750464","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750464","rel_abs":"Accurate transcript abundance estimation is central to many transcriptomic studies. Many current quantification methods rely on reads mapped directly to the transcriptome, but transcriptome alignment can misassign reads from unannotated transcripts to annotated isoforms, leading to biased abundance estimates. We introduce Bramble, a method that projects spliced genomic alignments into transcriptomic coordinates to produce alignments compatible with downstream transcript quantification tools. Across simulated short- and long-read RNA-seq datasets and multiple levels of reference annotation completeness, incorporating Bramble into quantification pipelines consistently improved accuracy and reduced error. These results suggest that genome-derived transcriptomic alignments can improve transcript quantification by preserving compatible alignments to annotated transcripts while filtering alignments likely originating from unannotated transcripts.","rel_num_authors":4,"rel_authors":[{"author_name":"Zoe Rudnick","author_inst":"Johns Hopkins University"},{"author_name":"Ales Varabyou","author_inst":"Johns Hopkins University"},{"author_name":"Rob Patro","author_inst":"University of Maryland"},{"author_name":"Mihaela Pertea","author_inst":"Johns Hopkins University"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Developing a behavioral measure of social memory from narrative video","rel_doi":"10.64898\/2026.09.09.750409","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750409","rel_abs":"Understanding other people relies on long-term memory: we use learned information about others' personalities, preferences, and personal histories to make inferences about the causes of their behavior. However, little is known about individual differences in memory for high-level social information. Here, we develop and psychometrically evaluate a behavioral measure of social memory from narrative video content. Participants (N = 103) watched the pilot episode of the TV show Friday Night Lights, and answered multiple choice questions about characters' actions, statements, inferred mental states, relationships, and personalities immediately after viewing and following a 21-day delay. To assess convergent and divergent validity of this measure, participants performed several additional tasks probing memory for other aspects of show content including face-name associations and face image recognition, as well as a standard measure of verbal episodic memory. Performance on the social memory task showed moderate split-half reliability, demonstrating feasibility as an individual difference measure. Memory for information about specific events in the narrative showed a decline across the delay, while memory for abstract information remained stable. Memory for different types of event-related information (actions, statements, and mental states) were correlated, providing evidence for a unified construct. Social memory performance was correlated with face-name association and verbal episodic memory, but not with face image recognition memory. These results provide a proof of concept for a novel behavioral measure of social memory and suggest that the measure relates to episodic and relational memory but not image recognition.","rel_num_authors":4,"rel_authors":[{"author_name":"Taylor Marcus","author_inst":"Tulane University"},{"author_name":"Didi Ross","author_inst":"Tulane University"},{"author_name":"Roma Kolluru","author_inst":"Tulane University"},{"author_name":"Ben Deen","author_inst":"Tulane University"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Sarcomere length, fascicle length, and serial sarcomere number are preserved in paretic hindlimb muscles following chronic stroke in rats despite persistent motor impairment","rel_doi":"10.64898\/2026.09.09.750457","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750457","rel_abs":"Stroke causes motor impairments that are commonly attributed to altered neural control, but chronic changes in neural activation and muscle use may also influence skeletal muscle structure. This study examined whether chronic stroke alters sarcomere length and dispersion, fascicle length, or serial sarcomere number in adult skeletal muscle. Twenty-four female Sprague-Dawley rats underwent photothrombotic stroke or sham surgery. Limb-specific motor impairment was assessed longitudinally using a beam traversal task. At 4.5 months post-surgery, the lateral gastrocnemius and extensor digitorum longus muscles were harvested from paretic and non-paretic limbs. We measured fascicle length directly from isolated fascicle bundles and quantified sarcomere length and dispersion using laser diffraction. Stroke animals exhibited persistent impairment of the paretic limb during beam traversal with elevated misstep rates. Despite this persistent motor impairment, sarcomere length and dispersion did not differ between stroke and sham animals or between limbs. Fascicle length and serial sarcomere number were greater in stroke than sham animals, but these differences were not limb-specific and were therefore unlikely to reflect stroke-related changes. Fascicle length, sarcomere length and dispersion, and serial sarcomere number differed between the lateral gastrocnemius and extensor digitorum longus, consistent with differences in architecture or relative length at the selected joint angles. These findings indicate that persistent neural impairment following adult-onset stroke does not necessarily result in substantial changes in sarcomere length or sarcomeres in series. Instead, sarcomere changes may depend on additional factors, including the timing of neural injury relative to growth and the mechanical environment experienced by the muscle.","rel_num_authors":6,"rel_authors":[{"author_name":"Stephanie A. Ross","author_inst":"University of Calgary"},{"author_name":"Sydney N. Dorscher","author_inst":"University of Calgary"},{"author_name":"Timothy R. Leonard","author_inst":"University of Calgary"},{"author_name":"Ruth A. Seerattan","author_inst":"University of Calgary"},{"author_name":"Dale Corbett","author_inst":"University of Ottawa"},{"author_name":"Walter Herzog","author_inst":"University of Calgary"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Sarcomere length, fascicle length, and serial sarcomere number are preserved in paretic hindlimb muscles following chronic stroke in rats despite persistent motor impairment","rel_doi":"10.64898\/2026.09.09.750457","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750457","rel_abs":"Stroke causes motor impairments that are commonly attributed to altered neural control, but chronic changes in neural activation and muscle use may also influence skeletal muscle structure. This study examined whether chronic stroke alters sarcomere length and dispersion, fascicle length, or serial sarcomere number in adult skeletal muscle. Twenty-four female Sprague-Dawley rats underwent photothrombotic stroke or sham surgery. Limb-specific motor impairment was assessed longitudinally using a beam traversal task. At 4.5 months post-surgery, the lateral gastrocnemius and extensor digitorum longus muscles were harvested from paretic and non-paretic limbs. We measured fascicle length directly from isolated fascicle bundles and quantified sarcomere length and dispersion using laser diffraction. Stroke animals exhibited persistent impairment of the paretic limb during beam traversal with elevated misstep rates. Despite this persistent motor impairment, sarcomere length and dispersion did not differ between stroke and sham animals or between limbs. Fascicle length and serial sarcomere number were greater in stroke than sham animals, but these differences were not limb-specific and were therefore unlikely to reflect stroke-related changes. Fascicle length, sarcomere length and dispersion, and serial sarcomere number differed between the lateral gastrocnemius and extensor digitorum longus, consistent with differences in architecture or relative length at the selected joint angles. These findings indicate that persistent neural impairment following adult-onset stroke does not necessarily result in substantial changes in sarcomere length or sarcomeres in series. Instead, sarcomere changes may depend on additional factors, including the timing of neural injury relative to growth and the mechanical environment experienced by the muscle.","rel_num_authors":6,"rel_authors":[{"author_name":"Stephanie A. Ross","author_inst":"University of Calgary"},{"author_name":"Sydney N. Dorscher","author_inst":"University of Calgary"},{"author_name":"Timothy R. Leonard","author_inst":"University of Calgary"},{"author_name":"Ruth A. Seerattan","author_inst":"University of Calgary"},{"author_name":"Dale Corbett","author_inst":"University of Ottawa"},{"author_name":"Walter Herzog","author_inst":"University of Calgary"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Brain organoid computing for robotic decision-making","rel_doi":"10.64898\/2026.09.09.750426","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750426","rel_abs":"Biomimicry has inspired the evolution of robotics toward greater autonomy, adaptability, and symbiosis with humans and dynamic environments. However, current robotic systems still face major challenges in recapitulating the high-efficiency decision-making capabilities of the human brain under complex and dynamic conditions. Here, we present Brainobot, a biohybrid robotic system that establishes a brain organoid controller as a high-level robotic decision-making layer for closed-loop embodiment. By leveraging brain organoid reservoir computing, Brainobot interacts with dynamic environments by receiving and processing sensory inputs and generating motor actions. As a proof-of-concept demonstration, Brainobot is implemented in a humanoid robotic system to perform real-world tasks, including object grasping and laser chasing. Interestingly, Brainobot exhibits unique features, including cross-task adaptivity, high computing efficiency, and low energy consumption. Thus, our approach may provide insights for advancing robotic embodiment and understanding biological decision-making.","rel_num_authors":16,"rel_authors":[{"author_name":"Hongwei Cai","author_inst":"Indiana University Bloomington"},{"author_name":"Chunhui Tian","author_inst":"Indiana University Bloomington"},{"author_name":"Yang Yang","author_inst":"Harvard Medical School"},{"author_name":"Yantao Xing","author_inst":"Indiana University Bloomington"},{"author_name":"Zichen Hong","author_inst":"Indiana University Bloomington"},{"author_name":"Huiyu Chu","author_inst":"Indiana University Bloomington"},{"author_name":"Jiansen Wang","author_inst":"Indiana University Bloomington"},{"author_name":"Zheng Ao","author_inst":"Indiana University Bloomington"},{"author_name":"Jason S Meyer","author_inst":"Indiana University School of Medicine"},{"author_name":"James Friend","author_inst":"Washington University in St. Louis"},{"author_name":"Jason Tchieu","author_inst":"Cincinnati Children's Hospital Medical Center"},{"author_name":"Mingxia Gu","author_inst":"UCLA"},{"author_name":"Insoo Hyun","author_inst":"Harvard Medical School"},{"author_name":"Ken Mackie","author_inst":"IU Bloomington"},{"author_name":"Lantao Liu","author_inst":"Indiana University Bloomington"},{"author_name":"Feng Guo","author_inst":"Indiana University Bloomington"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Patterns of subcortical tissue iron levels across the lifespan measured with functional MRI","rel_doi":"10.64898\/2026.09.09.750391","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750391","rel_abs":"Iron is essential for neurophysiological health. Prior work has shown that subcortical tissue iron levels are the highest among all brain regions but also change over the lifespan. Recent functional MRI (fMRI) studies have provided evidence that an fMRI-derived iron-sensitive signal may index relative iron concentration in subcortical regions. In this context, we aimed to characterize the lifespan trajectory of this fMRI-derived iron-sensitive signal (relative iron quantification) in 10 subcortical regions and 14 thalamic nuclei from 881 healthy participants aged 12 to 88 years, using resting-state fMRI. Regressions were run with age as a predictor, separately for males (N = 429) and females (N = 452). The main results show non-linear effects of age, with an overall increase in iron levels across most subcortical regions within each sex. Six of the 14 thalamic nuclei in male participants had similar slopes of their lifespan iron levels, showing some homogeneity. The thalamic nuclei of female participants showed less agreement in slopes. This study provides new insight into the typical trajectory of iron levels across all major subcortical regions throughout the lifespan.","rel_num_authors":8,"rel_authors":[{"author_name":"Attakias T. Mertens","author_inst":"Boys Town National Research Hospital"},{"author_name":"Derek J Pavelka","author_inst":"Boys Town National Research Hospital"},{"author_name":"Lauren Foley","author_inst":"Boys Town National Research Hospital"},{"author_name":"Katrina Myers","author_inst":"Boys Town National Research Hospital"},{"author_name":"Callum Goldsmith","author_inst":"Boys Town National Research Hospital"},{"author_name":"Tatiana Wolfe","author_inst":"University of Arkansas for Medical Sciences"},{"author_name":"Jacob J Oleson","author_inst":"The University of Iowa"},{"author_name":"Gaelle E Doucet","author_inst":"Boys Town National Research Hospital"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"A dimensional link between gain-loss economic preferences and psychopathology","rel_doi":"10.64898\/2026.09.09.750300","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750300","rel_abs":"Human decision-makers differ in how they value and trade off reward, risk, and information when evaluating future gains and losses, and these preferences are central to well-being. However, how multi-attribute economic valuation relates to psychopathology remains unclear. Here, 1,954 individuals completed a transdiagnostic symptom battery and a multi-attribute decision-making task that independently manipulated expected reward, reward uncertainty, and non-instrumental information under matched gain and loss contexts. On average, when choosing among gains, participants preferred larger rewards, avoided risk, and sought advance information. When choosing among losses, they still preferred better outcomes and advance information, but less strongly. Their risk preference, by contrast, reversed, from risk-averse to risk-seeking. Substantial individual variability accompanied these population-level context effects, and different patterns of variability were associated with separate dimensions of psychopathology. Anxious-depressive and social withdrawal symptoms were associated with increased reward sensitivity across contexts, whereas compulsive-intrusive symptoms were associated with reduced reward sensitivity. Symptom-related differences in risk and information preferences were not fully explained by a uniform scaling of overall economic sensitivity, revealing additional attribute- and context-specific variation. A data-driven analysis summarized these symptom-preference associations in a single latent dimension that contrasted compulsive-intrusive symptoms with anxious-depressive and social withdrawal symptoms. An independently identified subgroup that strongly sought information about gains but avoided it about losses mirrored this profile and was enriched for compulsive-intrusive symptoms. These findings reveal structured, low-dimensional variation linking multi-attribute decision-making to psychopathology and could support a dimensional, task-based approach to psychiatric nosology.","rel_num_authors":2,"rel_authors":[{"author_name":"Yang-Yang Feng","author_inst":"Stanford University"},{"author_name":"Ilya E Monosov","author_inst":"Johns Hopkins University"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Prevention of Unc13a cryptic splicing is sufficient to preserve memory","rel_doi":"10.64898\/2026.09.11.751031","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.751031","rel_abs":"TDP-43 dysfunction is thought to underlie frontotemporal dementia and limbic-predominant age-related TDP-43 encephalopathy, neurodegenerative dementias currently without effective therapy. Therapeutic strategies are designed to correct individual cryptic targets of TDP-43, such as UNC13A, whereby its cryptic splicing compromises synaptic function, yet the sufficiency of such an approach to prevent memory deficits is unclear. Using a forebrain neuron-specific TDP-43 knockout mouse model that recapitulates TDP-43 dysfunction occurring during early stages of human disorders, we found here that prevention of cryptic splicing to include that of Unc13a attenuated memory deficits. We show that genetic ablation of Unc13a cryptic exon solely in such TDP-43 knockout mice is sufficient to preserve cognition, supporting the clinical value of targeting UNC13A to mitigate memory deficits. Prevention of cryptic splicing of multiple targets of TDP-43 additionally attenuate neuron loss. For optimal outcomes in TDP-43 related dementias, these findings thus strongly support strategies designed to repress cryptic splicing of multiple targets of TDP-43, including UNC13A.","rel_num_authors":18,"rel_authors":[{"author_name":"Tianyu Cao","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Meghraj Singh Baghel","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Rashmi Thapa","author_inst":"University of Wyoming"},{"author_name":"Sishir Gautam","author_inst":"University of Wyoming"},{"author_name":"Aswathy Peethambaran Mallika","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Yijun Wei","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Xiaoke K Chen","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Irika R Sinha","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Grace D Burns","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Shruti Renganathan","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Xinrui Wen","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Bo Pang","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Jihee Choi","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Jonathan P Ling","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Da-Ting Ling","author_inst":"National Institute on Drug Abuse"},{"author_name":"Rongsong Liu","author_inst":"University of Wyoming"},{"author_name":"Yun Li","author_inst":"University of Wyoming"},{"author_name":"Philip C Wong","author_inst":"The Johns Hopkins University School of Medicine"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Cyanogenic clovers invest more in rhizobia but do not affect rhizobium evolution","rel_doi":"10.64898\/2026.09.11.751034","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.751034","rel_abs":"Nitrogen governs the interactions between leguminous plants and their nitrogen-fixing resource mutualists, rhizobia. While most work has focused on how soil nitrogen availability shapes the ecology and evolution of the legume-rhizobium mutualism, the nitrogen demands of plants may also influence the mutualism. Plants differ in nitrogen demand, in part because of variation in specialized metabolite production, particularly in species that produce nitrogen-based defense compounds such as cyanogenic glycosides. Plants with high nitrogen demand might be expected to be more reliant on rhizobia, potentially investing more in rhizobia and exerting stronger preferences for high-quality mutualists. Here, we use white clover (Trifolium repens), which is polymorphic for cyanogenesis, from two biparental F3 mapping populations to examine whether nitrogen-based chemical defenses affect plant investment in the mutualism or rhizobium evolution. By inoculating cyanogenic and acyanogenic clover lines with a single strain of Rhizobium leguminosarum, we found that cyanogenic clovers produced larger root nodules than acyanogenic clover, suggesting that cyanogensis is associated with increased investment in rhizobia. Greater investment in rhizobia could select for more cooperative mutualists if accompanied by partner choice or sanctions allowing plants to preferentially reward more cooperative rhizobia. We conditioned soils with cyanogenic and acyanogenic clover lines for five plant growth cycles and compared the partner quality of rhizobia isolated from these soils. Rhizobia evolved in association with cyanogenic versus acyanogenic clover did not differ in quality. Overall, our results show that N-based anti-herbivore defense traits can influence plant investment in resource mutualists but suggest that differences in investment do not necessarily translate into long-term evolutionary changes in mutualist quality.","rel_num_authors":4,"rel_authors":[{"author_name":"Julia Eckberg","author_inst":"University of Michigan"},{"author_name":"Jennifer Lau","author_inst":"Indiana University"},{"author_name":"Kenneth M. Olsen","author_inst":"Washington University in St. Louis"},{"author_name":"Mia Howard","author_inst":"University of Michigan"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"A hypothalamic circuit links hunger to mesolimbic dopamine to drive feeding","rel_doi":"10.64898\/2026.09.10.750730","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.10.750730","rel_abs":"Hunger enhances the motivational value of food, but the neural circuits linking homeostatic hunger neurons to dopamine systems remain poorly understood. Here, we identify a hypothalamic-midbrain neural circuit through which AgRP neurons engage the mesolimbic dopamine system. We demonstrate that AgRP neuron activity is both necessary and sufficient for the potentiated dopamine response to food by hunger, and that they achieve this by reducing inhibitory drive onto midbrain dopamine neurons. Importantly, this AgRP neuron-evoked dopamine signaling is required for subsequent food intake. Mechanistically, we find that AgRP neuron projections to NPY-sensitive paraventricular hypothalamic neurons selectively amplify food-evoked dopamine release to promote feeding behavior. These findings reveal a circuit mechanism through which hunger recruits dopamine signaling to transform physiological need into motivated feeding behavior.","rel_num_authors":9,"rel_authors":[{"author_name":"Sam Z Bacharach","author_inst":"Monell Chemical Senses Center"},{"author_name":"Katherine A Zappetti","author_inst":"Monell Chemical Senses Center"},{"author_name":"Laryssa O Coutinho","author_inst":"Monell Chemical Senses Center"},{"author_name":"Amanda Bacherer","author_inst":"Monell Chemical Senses Center"},{"author_name":"Joseph I Wahba","author_inst":"Monell Chemical Senses Center"},{"author_name":"Heather M Schneps","author_inst":"Monell Chemical Senses Center"},{"author_name":"Zhong-Wu Liu","author_inst":"Yale University"},{"author_name":"Marcelo O Dietrich","author_inst":"Yale University"},{"author_name":"Amber L Alhadeff","author_inst":"Monell Chemical Senses Center"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"A single cortical circuit implements fast and slow visual search","rel_doi":"10.64898\/2026.09.09.750509","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.09.750509","rel_abs":"How the brain produces different behaviors from a fixed anatomical substrate is a foundational question in neuroscience. The dominant account holds that behavioral flexibility requires distinct neural circuits: dedicated systems selectively recruited for different processing modes. An alternative proposes that flexibility arises not from switching between circuits, but from dynamically controlling the speed at which a shared circuit operates. Here, we test this account directly using intracranial EEG recordings from nineteen human patients performing two visual search tasks of markedly different difficulty: an easy color-singleton search and a difficult orientation search, a fast vs. slow dissociation attributed for four decades to distinct anatomical and oscillatory neural systems. We show that both search tasks recruit the same cortical regions, oscillatory frequencies, and processing hierarchy. Dynamic time warping reveals that the two neural trajectories are time-stretched versions of one another; the same temporal scaling appears within each condition between faster and slower trials, indexing response speed rather than the distinction between tasks. Alpha-band oscillations (~8-10 Hz) support this temporal scaling through two coordinated mechanisms: synchronizing activity across a posterior cortical network and phase-gating local high-frequency activity (70-150 Hz) within those regions at the same preferred phase in both conditions. These findings establish that, for the two tasks studied here, fast and slow visual search are not implemented by selecting between distinct dedicated circuits, but by adjusting the speed of a single alpha-coordinated architecture. The same principle may apply to other search tasks, and to other domains in which dual-process architectures have been invoked, a testable prediction for future studies.","rel_num_authors":9,"rel_authors":[{"author_name":"Mattia Federico Pagnotta","author_inst":"University of California, Berkeley"},{"author_name":"Haojun Zhuang","author_inst":"University of California Berkeley, USA"},{"author_name":"S. J. Katarina Slama","author_inst":"University of California Berkeley, USA"},{"author_name":"David King-Stephens","author_inst":"University of California Irvine, USA"},{"author_name":"Kenneth D. Laxer","author_inst":"California Pacific Medical Center, San Francisco, USA"},{"author_name":"Tor Endestad","author_inst":"University of Oslo, Norway"},{"author_name":"Anne-Kristin Solbakk","author_inst":"University of Oslo, Norway"},{"author_name":"Jack J. Lin","author_inst":"University of California Davis, USA"},{"author_name":"Robert T. Knight","author_inst":"University of California Berkeley, USA"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Matrix Viscoelasticity Regulates the Stemness and Multilineage differentiation of Primary Neural Progenitor-Stem Cells in 3D","rel_doi":"10.64898\/2026.09.11.750834","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.750834","rel_abs":"Neural progenitor-stem cells (NPSCs) reside in mechanically dynamic brain microenvironments and give rise to neurons, astrocytes, and oligodendrocytes. Although recent studies have shown that matrix viscoelasticity can influence neural maturation and neurogenic differentiation, its role in primary NPSCs beyond neurogenesis remains less defined. How matrix viscoelasticity or stress relaxation regulates primary NPSC stemness, neuronal and glial differentiation, and the associated matrix-cell mechanotransduction pathways are not well understood. Here, we use alginate hydrogels with independently tunable stiffness and stress relaxation properties to investigate how matrix stress relaxation regulates the fate of primary subventricular zone (SVZ)-derived NPSCs in 3D. The results suggested that matrices with faster stress relaxation enhances stemness maintenance, radial glial-like marker expression, and differentiation of NPSCs toward neuronal, astrocytic, and oligodendrocytic lineages in the corresponding biochemical environments. In mixed neuronal\/astrocytic differentiation conditions, fast-relaxing matrices preferentially promote neuronal differentiation. Mechanistically, NPSC responses to matrix stress relaxation involve integrin-mediated adhesion, actomyosin contractility, actin polymerization, and Piezo1 activity, with distinct contributions across differentiation lineages. Together, these findings reveal how matrix stress relaxation regulates primary NPSC stemness and multilineage differentiation through multiple mechanotransduction pathways in 3D.","rel_num_authors":4,"rel_authors":[{"author_name":"Supeng Ding","author_inst":"UC San Diego"},{"author_name":"Joo Ho Kim","author_inst":"Johns Hopkins University"},{"author_name":"Mengke Wang","author_inst":"Johns Hopkins University"},{"author_name":"Luo Gu","author_inst":"Johns Hopkins University"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"rel_title":"Matrix Viscoelasticity Regulates the Stemness and Multilineage differentiation of Primary Neural Progenitor-Stem Cells in 3D","rel_doi":"10.64898\/2026.09.11.750834","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.750834","rel_abs":"Neural progenitor-stem cells (NPSCs) reside in mechanically dynamic brain microenvironments and give rise to neurons, astrocytes, and oligodendrocytes. Although recent studies have shown that matrix viscoelasticity can influence neural maturation and neurogenic differentiation, its role in primary NPSCs beyond neurogenesis remains less defined. How matrix viscoelasticity or stress relaxation regulates primary NPSC stemness, neuronal and glial differentiation, and the associated matrix-cell mechanotransduction pathways are not well understood. Here, we use alginate hydrogels with independently tunable stiffness and stress relaxation properties to investigate how matrix stress relaxation regulates the fate of primary subventricular zone (SVZ)-derived NPSCs in 3D. The results suggested that matrices with faster stress relaxation enhances stemness maintenance, radial glial-like marker expression, and differentiation of NPSCs toward neuronal, astrocytic, and oligodendrocytic lineages in the corresponding biochemical environments. In mixed neuronal\/astrocytic differentiation conditions, fast-relaxing matrices preferentially promote neuronal differentiation. Mechanistically, NPSC responses to matrix stress relaxation involve integrin-mediated adhesion, actomyosin contractility, actin polymerization, and Piezo1 activity, with distinct contributions across differentiation lineages. Together, these findings reveal how matrix stress relaxation regulates primary NPSC stemness and multilineage differentiation through multiple mechanotransduction pathways in 3D.","rel_num_authors":4,"rel_authors":[{"author_name":"Supeng Ding","author_inst":"UC San Diego"},{"author_name":"Joo Ho Kim","author_inst":"Johns Hopkins University"},{"author_name":"Mengke Wang","author_inst":"Johns Hopkins University"},{"author_name":"Luo Gu","author_inst":"Johns Hopkins University"}],"rel_date":"2026-09-15","rel_site":"biorxiv"},{"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":"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":"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":"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":"BackgroundNon-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.\n\nMethodsThe 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.\n\nResultsMedian 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).\n\nConclusionsInfluenza 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":"BackgroundNon-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.\n\nMethodsThe 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.\n\nResultsMedian 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).\n\nConclusionsInfluenza 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":"BackgroundNon-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.\n\nMethodsThe 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.\n\nResultsMedian 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).\n\nConclusionsInfluenza 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"}]}