{"gname":"Albert Einstein College of Medicine","grp_id":"4","rels":[{"rel_title":"Diabetes is associated with increased nocturnal respiratory rate","rel_doi":"10.64898\/2026.06.16.26355548","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355548","rel_abs":"Background and Objective: Diabetes mellitus (DM) causes autonomic neuropathy, which may alter nocturnal respiratory rate (NRR). To test the association between DM and NRR, we analyzed elective polysomnograms of four large observational cohorts. Research Design and Methods: We performed cross-sectional analysis of over 25,000 individuals with polysomnograms (PSGs) from the Sleep Heart Health Study (SHHS), Hispanic Community Health Study\/Study of Latinos (HCHS\/SOL), Osteoporotic Fractures in Men Study (MrOS), and Wisconsin Sleep Cohort (WSC). Patient-level NRRs were derived from inductance plethysmography waveforms. DM status was determined by self-report, physician diagnosis, medication use, or laboratory values, depending on the cohort. We related DM and NRR (continuous and dichotomized) using logistic regression models and adjusted for potential confounders. Cohort-specific results were combined using random-effects meta-analysis. Results: Meta-analysis of unadjusted models showed a pooled odds ratio (OR) of 1.10 (95% CI:1.04-1.17) for each breath-per-minute (brpm) increase in NRR. This association remained significant after multivariable adjustment (OR:1.06, 95% CI:1.02-1.11). Dichotomized analyses similarly showed higher odds of DM across dichotomization thresholds ranging from 15 to 21 brpm. At a threshold of 18 brpm, the unadjusted pooled OR was 1.77 (95% CI:1.23-2.55, P=0.0022), and the adjusted OR was 1.49 (95% CI:1.10-2.02, P=0.0098). Conclusions: Clinically stable outpatients with elevated NRR have an increased prevalence of DM. Additional studies are needed to investigate whether the mechanism is autonomic neuropathy and whether monitoring NRR can detect early complications of DM.","rel_num_authors":5,"rel_authors":[{"author_name":"Keshav S Gupta","author_inst":"University of California San Diego"},{"author_name":"Raimon Pedros-Valls","author_inst":"University of California San Diego"},{"author_name":"Nicholas Harrington","author_inst":"University of California San Diego"},{"author_name":"David Torres Barba","author_inst":"University of California San Diego"},{"author_name":"Kevin R King","author_inst":"UC San Diego"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Antimicrobial-resistant E. coli in human, animal and environmental reservoirs in rural Bangladeshi households with young children","rel_doi":"10.64898\/2026.06.16.26355831","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355831","rel_abs":"In low-income countries, ESBL-producing Escherichia coli (ESBL-EC) is frequently detected in humans, animals and household environments, indicating widespread exposure to antimicrobial resistance (AMR). Established risk factors such as antibiotic use do not explain the high community carriage of AMR in all settings; identifying the dominant exposure pathways can inform interventions against AMR. We aimed to investigate (i) animal-human-environment sharing of AMR by assessing associations between the abundance of ESBL-EC in the household environment, domestic animal feces and young children's stool and (ii) household factors associated with ESBL-EC abundance in these reservoirs. We enrolled 112 households from the CRADLE trial in rural Bangladesh. We enumerated ESBL-EC in drinking water, food, child hand rinses, outdoor soil, indoor floor swabs, chicken and cow feces, and stool from children aged 6 months. We recorded indicators of sanitation, animal ownership\/management, human and animal antibiotic use, and child exposure behaviors using structured questionnaires and spot checks. The highest prevalence of ESBL-EC was in child stool (95.6%) and animal feces (82.3-96.9%), followed by soil (48.2%) and floors (36.6%); < 10% of food, child hands and drinking water harbored ESBL-EC. The abundance of ESBL-EC in child stool was not associated with its abundance in any sampled matrix; the abundance in chicken but not cow feces showed positive correlations with soil, floors, child hands, and drinking water (correlation coefficients: 0.19-0.39, p-values < 0.05). Higher-quality latrines (improved, pour-flush, with slab) were associated with lower ESBL-EC abundance across matrices; unsafe animal management (animals roaming or spending the night inside the home) was associated with higher abundance. Child antibiotic use and exposure behaviors (soil ingestion, time spent on floor) were not associated with ESBL-EC abundance in child stool. We observed high AMR colonization among young children and domestic animals in rural Bangladesh not explained by traditional fecal-oral exposure pathways. Future studies should explore additional pathways and assess whether sanitation and animal management improvements can reduce AMR.","rel_num_authors":17,"rel_authors":[{"author_name":"Sumaiya Tazin","author_inst":"NC State University"},{"author_name":"Md. Sakib Hossain","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Laboratory of Environmental Health Dhaka, Bangladesh"},{"author_name":"Ashrin Haque","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Laboratory of Environmental Health Dhaka, Bangladesh"},{"author_name":"Md. Hajbiur Rahman","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Laboratory of Environmental Health Dhaka, Bangladesh"},{"author_name":"Tahani Tabassum","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Laboratory of Environmental Health Dhaka, Bangladesh"},{"author_name":"Amanta Rahman","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Laboratory of Environmental Health Dhaka, Bangladesh"},{"author_name":"Claire Anderson","author_inst":"Stanford University Department of Civil and Environmental Engineering Stanford, CA, USA"},{"author_name":"Suhi Hanif","author_inst":"Stanford University Department of Epidemiology and Population Health Stanford, CA, USA"},{"author_name":"Gabriella R Barratt Heitmann","author_inst":"Stanford University"},{"author_name":"Md. Rana Miah","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Environmental Health and WASH Dhaka, Bangladesh"},{"author_name":"Afsana Yeamin","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Environmental Health and WASH Dhaka, Bangladesh"},{"author_name":"Farjana Jahan","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Environmental Health and WASH Dhaka, Bangladesh"},{"author_name":"Abul Kasham Shoab","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Environmental Health and WASH Dhaka, Bangladesh"},{"author_name":"Mahbubur Rahman","author_inst":"ICDDRB: International Centre for Diarrhoeal Disease Research Bangladesh"},{"author_name":"Zahid Hayat Mahmud","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Laboratory of Environmental Health Dhaka, Bangladesh"},{"author_name":"Jade Benjamin-Chung","author_inst":"Stanford University"},{"author_name":"Ayse Ercumen","author_inst":"North Carolina State University"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Digital self-efficacy as a potential intermediary between vision impairment and daily internet use among older adults: A cross-sectional analysis of HINTS 2024","rel_doi":"10.64898\/2026.06.09.26353388","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26353388","rel_abs":"Background: Older adults with vision impairment often experience barriers to using digital technology. The indirect associations between vision impairment and digital access and skills via digital self-efficacy and frustration among older adults remain largely unknown. Objective: This study aimed to 1) explore factors associated with digital access, skills, self-efficacy, and frustration among older adults with vision impairment; 2) examine associations between vision impairment and digital access, skills, self-efficacy, and frustration among older adults; and 3) examine whether digital self-efficacy and frustration may help explain associations between vision impairment and digital access and skills among older adults. Methods: This was a cross-sectional study using nationally representative data from the Health Information National Trends Survey (HINTS) 2024. Respondents aged 60 and older were included. Vision impairment was assessed using a self-reported item. Outcomes included self-reported digital access, skills, self-efficacy, and frustration. Survey-weighted multivariable logistic regression and generalized structural equation modeling were conducted, adjusting for age, sex, race\/ethnicity, education, and the number of comorbidities. Results: Among 3,149 older adults (mean [SD] age, 70.7 [10.0] years; 45.6% female), 7.1% (n=223) reported vision impairment. Among older adults with vision impairment, 65.6% (95% CI, 53.5% to 75.9%) used the internet daily, and 79.5% (95% CI, 66.8% to 88.2%) used a smartphone in the past 12 months. In multivariable logistic regression analyses among older adults with vision impairment, older age was associated with lower odds of daily internet use (OR, 0.84; 95% CI, 0.79 to 0.90), smartphone use (OR, 0.85; 95% CI, 0.75 to 0.97), wearable device use (OR, 0.88; 95% CI, 0.79 to 0.97), and using the internet to send a message to a healthcare provider (OR, 0.87; 95% CI, 0.80 to 0.93). Older adults who self-identified as racial and ethnic minority groups (e.g., Black\/African American, Hispanic) had lower odds of daily internet use (OR, 0.15; 95% CI, 0.05 to 0.50) and using the internet to send a message to a healthcare provider (OR, 0.17; 95% CI, 0.04 to 0.73) compared with Non-Hispanic White older adults. Vision impairment was associated with lower odds of daily internet use (OR, 0.60; 95% CI, 0.37 to 0.99) and digital self-efficacy (OR, 0.53; 95% CI, 0.32 to 0.86). Digital self-efficacy was associated with higher odds of daily internet use (OR, 2.95; 95% CI, 2.04 to 4.26). Generalized structural equation modeling identified an indirect association between vision impairment and daily internet use via digital self-efficacy (coefficient, -0.68; 95% CI, -1.24 to -0.12). Conclusions: Findings suggest that reduced digital self-efficacy may help explain the observed association between vision impairment and daily internet use among older adults. Interventions targeting digital self-efficacy, including accessible interface designs, personalized coaching, and peer support, may help bridge the digital divide among older adults with vision impairment.","rel_num_authors":4,"rel_authors":[{"author_name":"Haruno Suzuki","author_inst":"University of California, San Francisco"},{"author_name":"Thomas Hoffmann","author_inst":"University of California, San Francisco"},{"author_name":"Heather Leutwyler","author_inst":"University of California, San Francisco"},{"author_name":"Margaret Wallhagen","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Avidity of anti-pertussis toxin antibodies is associated with symptomatic Bordetella pertussis infection in a novel controlled human infection model","rel_doi":"10.64898\/2026.06.17.26355173","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.17.26355173","rel_abs":"Background The association between functional antibody responses following Bordetella pertussis infection and symptomatic disease remains unclear. We characterized the maturation of anti-pertussis toxin (PT) IgG avidity after human challenge with B. pertussis and determined its association with symptomatic infection. Methods Healthy adults were intranasally inoculated with live B. pertussis organisms in a controlled human infection model and monitored for development of pertussis symptoms (NCT05136599). Serum samples were collected one day before inoculation and at 14, 28, 56, 180, and 365 days post challenge. Anti PT IgG avidity was tested using a titration of ammonium isothiocyanate (the bond breaking agent) to quantify a wide range of antibody avidities from low to very-high. Associations between covariates and avidity were examined using linear regression models, and high dimensional analyses were used to integrate all data. Findings Anti PT IgG avidity increased in both symptomatic (n=20) and asymptomatic (n=10) participants after the challenge, reached maximum levels at day 56, and then declined through day 365. Symptomatic participants developed significantly higher levels of high- and very high-avidity anti-PT antibodies at 28, 56, 180, and 365 days post-challenge compared with those who remained asymptomatic. In multivariate analyses, symptomatic infection was associated with higher levels of high and very high avidity anti-PT IgG at day180 and365 after challenge. Distinct avidity profiles in symptomatic vs asymptomatic participants emerged at day28 onwards, with the former group having higher levels of antibodies with higher avidities. However, levels of medium-high, high and very high avidity antibodies in symptomatic participants were lower at day 365 after challenge compared to their peak levels. Interpretation Anti-PT IgG avidity was associated with symptomatic B. pertussis infection and thus may serve as a surrogate of clinical disease outcome. These results highlight that antibody avidity provides an additional functional assay besides antibody quantitation to dissect immune responses to pertussis. Further investigation of anti PT IgG avidity should be pursued in natural pertussis outbreaks to determine whether it might be used to differentiate symptomatic from asymptomatic infections for epidemiologic purposes.","rel_num_authors":7,"rel_authors":[{"author_name":"Carlos Espinosa--Vinals","author_inst":"Dalhousie University"},{"author_name":"Hala Obeid","author_inst":"Dalhousie University"},{"author_name":"Kara L Redden","author_inst":"Dalhousie University"},{"author_name":"May S ElSherif","author_inst":"Dalhousie University"},{"author_name":"Kathryn M Edwards","author_inst":"Vanderbilt University"},{"author_name":"Scott Halperin","author_inst":"Dalhousie University"},{"author_name":"Bahaa Abu-Raya","author_inst":"Dalhousie University"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Hard to Halt: Automation Bias in Agent-Driven Sequencing Prior Authorization Workflows","rel_doi":"10.64898\/2026.06.16.26355782","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355782","rel_abs":"Purpose: Prior authorization (PA) for exome or genome sequencing is a time-consuming process that impedes timely rare disease diagnosis. Large language model-based browser agents offer potential for automating these workflows, but their clinical reliability remain uncharacterized. Methods: We developed a sandbox compromising a simulated ES\/GS PA submission payer portal and a synthetic EHR containing 836 patient records spanning compliant profiles and deficient profiles with different types of issues. Gemini 3 Pro, Gemini 3 Flash, and Claude Opus 4.5 were evaluated on task completion rate, form completion accuracy, and appropriate withholding for deficient profiles. Results: Larger models achieved much higher task completion rates (Gemini 3 Pro 95.45%, Claude Opus 4.5 93.67%) compared to Gemini 3 Flash (56.05%), but nearly universally failed to withhold submission for deficient profiles whereas Gemini 3 Flash ironically demonstrated superior withholding performance (17.33%). In a non-agentic setting, Gemini 3 Pro correctly identified 91% of the issues in deficient profiles, indicating that withholding failure is attributable to the browser interaction rather than the model's reasoning limitations. Conclusion: Current LLM-based browser agents exhibit a systematic bias towards form submission that poses risks in PA workflows. A modular, multi-agent architecture with human supervision is necessary for a safe clinical deployment.","rel_num_authors":9,"rel_authors":[{"author_name":"Mengshu Nie","author_inst":"Boston Childrens Hospital"},{"author_name":"Wendy Chung","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Jessica Waxler","author_inst":"Boston Children's Hospital"},{"author_name":"Michael Lee","author_inst":"Boston Children's Hospital"},{"author_name":"Chunhua Weng","author_inst":"Columbia University"},{"author_name":"Rachel Lewis","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Priyanka Ahimaz","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Kai Wang","author_inst":"Children's Hospital of Philadelphia; University of Pennsylvania"},{"author_name":"Cong Liu","author_inst":"Boston Children's Hospital; Harvard Medical School"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Cost-effectiveness of a virtual fracture clinic versus traditional in-person fracture clinic care for adults with acute simple fractures: a protocol for a health economic evaluation within the RECITAL trial","rel_doi":"10.64898\/2026.06.16.26355732","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355732","rel_abs":"ABSTRACT Introduction Traditional in-person fracture clinics are often overcrowded and inconvenient for patients. Virtual fracture clinics aim to address some of these concerns by improving the efficiency of the orthopaedic service and reducing unnecessary interventions while maintaining safety and quality of care. The RECITAL trial is a non-inferiority randomised controlled trial comparing follow-up care provided at a virtual fracture clinic for people with acute simple fractures to follow-up care provided at an in-person fracture clinic. This study describes the protocol for an economic evaluation of RECITAL where the primary aim is to investigate the cost-effectiveness of a virtual fracture clinic compared with traditional in-person fracture clinic care from a health system perspective. Methods and analysis The RECITAL trial recruited 312 participants with acute simple fractures and randomised them to receive follow-up care provided at a virtual fracture clinic or follow-up care provided at an in-person fracture clinic. We will conduct a within-trial analysis from a health system perspective (primary analysis), as well as a health service, patient and societal perspective. The economic evaluation will estimate the difference in the cost of resource inputs on an intention to treat basis used by participants in the two arms of the trial, allowing comparisons to be made between the in-person and virtual fracture clinics. Data for intervention costs and healthcare utilisation will be collected from trial records, hospital electronic medical records and district performance units. The results of the economic evaluation will be expressed in terms of incremental cost per utility weight gained at 12 weeks and will be plotted on a cost-effectiveness plane. Bootstrapping by resampling will be used to estimate 95% confidence intervals around costs and outcomes, and to calculate the confidence intervals around the incremental cost-effectiveness ratio. A cost-effectiveness acceptability curve (CEAC) will be plotted, which will provide information about the probability that an intervention is cost-effective, given the level of a decision makers willingness to pay for each additional outcome. Ethics and Dissemination The trail was approved by the SLHD Ethics Review Committee (RPAH Zone) (X23-0200 and 2023\/ETH01038). The findings will be disseminated through a peer-reviewed journal and conference presentations. Trial registration number The trial was prospectively registered on the Australian New Zealand Clinical Trials Registry (ANZCTR; 12623000934640)","rel_num_authors":15,"rel_authors":[{"author_name":"Rowena Charteris","author_inst":"The University of Sydney"},{"author_name":"Adrian C Traeger","author_inst":"The University of Sydney"},{"author_name":"Christopher G Maher","author_inst":"The University of Sydney"},{"author_name":"Tessa Copp","author_inst":"The University of Sydney"},{"author_name":"Kristen Pickles","author_inst":"The University of Sydney"},{"author_name":"Min Jiat Teng","author_inst":"The University of Sydney"},{"author_name":"Isabella Khoudair","author_inst":"Sydney Local Health District Virtual Hospital"},{"author_name":"Ben Warnock","author_inst":"Sydney Local Health District Virtual Hospital"},{"author_name":"Miranda Shaw","author_inst":"Sydney Local Health District Virtual Hospital"},{"author_name":"Owen Hutchings","author_inst":"Sydney Local Health District Virtual Hospital"},{"author_name":"Mark Horsley","author_inst":"Royal Prince Alfred Hospital"},{"author_name":"Ilana N Ackerman","author_inst":"Monash University"},{"author_name":"Ray Thomas","author_inst":"Consumer Representative"},{"author_name":"Philip Haywood","author_inst":"The University of Sydney"},{"author_name":"Joshua Zadro","author_inst":"The University of Sydney"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Device assessed 24-hour movement behaviour and cardiovascular disease mortality amongst cancer survivors.","rel_doi":"10.64898\/2026.06.09.26355299","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355299","rel_abs":"Background: Cancer survivors face elevated risks of mortality from cardiovascular disease (CVD). The potential importance of physical activity (PA) and other behaviours across the 24-hour day (e.g. sedentary behaviour (SB) and sleep) for CVD-mortality risk is not well understood in this at-risk population. Objectives: To assess the importance of 24-hour movement behaviour, using a compositional approach, for mitigating CVD-mortality amongst cancer survivors. Methods: Participants with a prior cancer diagnosis were drawn from the UK Biobank accelerometry sub-study (n=6,158). Accelerometer-derived movement (moderate-to-vigorous PA (MVPA), vigorous PA (VPA), moderate PA (MPA), light PA (LPA), SB, sleep) was examined in relation to CVD-mortality, identified from health record linkage data (using Fine-Gray Cox proportional-hazards models adjusted for demographic, health, lifestyle covariates). Results: Median follow-up was 8.0 years (Q1-Q3: 7.4-8.5), with n=500 (8.2%) deaths (CVD-deaths: n=118). Greater MVPA, in place of any other behaviour, was inversely associated with CVD-mortality with e.g. 10% lower hazard if MVPA theoretically replaced 7 minutes (mins)\/day SB (Hazard ratio (HR): 0.91, (95% Confidence Interval: 0.86-0.95)), 9 mins\/day LPA (HR: 0.90, 0.83-0.97), or 11 mins\/day sleep (HR: 0.90, 0.83-0.97). The VPA component of MVPA proved critical, requiring only ~1-2 additional mins\/day for equivalent hazard reduction. Sleep duration, was also inversely associated with CVD-mortality. A 10% lower hazard required replacing 29 mins\/day of SB with sleep (HR: 0.90, 0.84-0.96); no other behavioural replacement amongst SB, sleep or LPA could provide an equivalent risk reduction. Conclusions: Among cancer survivors, the most potent reduction in CVD-mortality followed theoretically reallocating time to higher intensity movement.","rel_num_authors":17,"rel_authors":[{"author_name":"John J Mitchell","author_inst":"University College London"},{"author_name":"Raaj Kishore Biswas","author_inst":"University of Sydney"},{"author_name":"Joanna  M Blodgett","author_inst":"University College London"},{"author_name":"Nicholas A. Koemel","author_inst":"Monash University"},{"author_name":"Matthew N. Ahmadi","author_inst":"Monash University"},{"author_name":"Abigail Fisher","author_inst":"University College London"},{"author_name":"Christine M. Friedenreich","author_inst":"University of Calgary"},{"author_name":"Karen Canfell","author_inst":"The University of Sydney School of Public Health"},{"author_name":"I-Min Lee","author_inst":"Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;"},{"author_name":"Peter A. Cistulli","author_inst":"University of Sydney"},{"author_name":"Dorothea Dumuid","author_inst":"Adelaide University"},{"author_name":"Anthony  D. Okely","author_inst":"University of Wollongong"},{"author_name":"Armando Teixera-Pinto","author_inst":"University of Sydney"},{"author_name":"Julia Steinberg","author_inst":"University of Sydney"},{"author_name":"Anne  E. Cust","author_inst":"The University of Sydney"},{"author_name":"Emmanuel Stamatakis","author_inst":"Monash University"},{"author_name":"Mark Hamer","author_inst":"University College London"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Distinct Neuronal, Proliferative, and Secretory Pathways are Perturbed in Cancer Survivors with Depressive Symptoms","rel_doi":"10.64898\/2026.06.16.26355016","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355016","rel_abs":"Introduction Depression is highly prevalent among cancer survivors and may be biologically distinct, although clinical studies investigating these mechanisms remain limited. Thus, the aims of this study were to (1) identify perturbed biological pathways associated with depressive symptom severity in cancer survivors, and (2) investigate whether these pathways are common or distinct to those perturbed in an age-matched non-cancer cohort. Methods We analyzed cross-sectional self-reported and transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (PHD #39341). Cancer survivors and an age-matched non-cancer cohort (target ratio 1:2) were identified. The 20-item Center for Epidemiologic Studies Depression Scale (CES-D) was used to split participants into low (CES-D<16) and high ([&ge;]16) depressive symptom groups. Analyses were conducted separately for survivor and non-cancer cohorts. Differential gene expression between depressive symptom groups was evaluated with adjustments for covariates significantly associated with depression (survivor cohort: BMI; non-cancer cohort: marital status), with pathway impact analysis identifying perturbed pathways (FDR < 0.025). Results Ninety-three cancer survivors (11.8% with high depressive symptoms) and 176 non-cancer participants (9.7% with high depressive symptoms) were included. Sixty-eight and 72 perturbed pathways were associated with depression among survivor and non-cancer cohorts, respectively. Twenty-one of these pathways were perturbed uniquely among cancer survivors, which were related to neurodegeneration, reward circuitry, proliferation, and secretion. Inflammatory pathways were consistently perturbed across both cohorts. Conclusions Distinct biological mechanisms related to neurodegeneration, reward circuitry, autonomic secretion, and proliferative signaling may underlie depression in cancer survivors. Inflammation was implicated as a shared mechanism of depression across cancer and non-cancer populations. This study identifies potential therapeutic targets and highlights the need for precision medicine in treating depression among cancer survivors.","rel_num_authors":10,"rel_authors":[{"author_name":"Julia Trudeau","author_inst":"University of California, Irvine"},{"author_name":"Nidhi Thati","author_inst":"University of California, San Francisco"},{"author_name":"Ding Quan Ng","author_inst":"Yale University"},{"author_name":"Esther Chavez-Iglesias","author_inst":"University of California, San Francisco"},{"author_name":"Adam B Olshen","author_inst":"University of California, San Francisco"},{"author_name":"Anand Dhruva","author_inst":"University of California, San Francisco"},{"author_name":"Jason W Chan","author_inst":"University of California, San Francisco"},{"author_name":"Raymond J Chan","author_inst":"Flinders University"},{"author_name":"Alexandre Chan","author_inst":"University of California, Irvine"},{"author_name":"Kord M Kober","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Distinct Neuronal, Proliferative, and Secretory Pathways are Perturbed in Cancer Survivors with Depressive Symptoms","rel_doi":"10.64898\/2026.06.16.26355016","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355016","rel_abs":"Introduction Depression is highly prevalent among cancer survivors and may be biologically distinct, although clinical studies investigating these mechanisms remain limited. Thus, the aims of this study were to (1) identify perturbed biological pathways associated with depressive symptom severity in cancer survivors, and (2) investigate whether these pathways are common or distinct to those perturbed in an age-matched non-cancer cohort. Methods We analyzed cross-sectional self-reported and transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (PHD #39341). Cancer survivors and an age-matched non-cancer cohort (target ratio 1:2) were identified. The 20-item Center for Epidemiologic Studies Depression Scale (CES-D) was used to split participants into low (CES-D<16) and high ([&ge;]16) depressive symptom groups. Analyses were conducted separately for survivor and non-cancer cohorts. Differential gene expression between depressive symptom groups was evaluated with adjustments for covariates significantly associated with depression (survivor cohort: BMI; non-cancer cohort: marital status), with pathway impact analysis identifying perturbed pathways (FDR < 0.025). Results Ninety-three cancer survivors (11.8% with high depressive symptoms) and 176 non-cancer participants (9.7% with high depressive symptoms) were included. Sixty-eight and 72 perturbed pathways were associated with depression among survivor and non-cancer cohorts, respectively. Twenty-one of these pathways were perturbed uniquely among cancer survivors, which were related to neurodegeneration, reward circuitry, proliferation, and secretion. Inflammatory pathways were consistently perturbed across both cohorts. Conclusions Distinct biological mechanisms related to neurodegeneration, reward circuitry, autonomic secretion, and proliferative signaling may underlie depression in cancer survivors. Inflammation was implicated as a shared mechanism of depression across cancer and non-cancer populations. This study identifies potential therapeutic targets and highlights the need for precision medicine in treating depression among cancer survivors.","rel_num_authors":10,"rel_authors":[{"author_name":"Julia Trudeau","author_inst":"University of California, Irvine"},{"author_name":"Nidhi Thati","author_inst":"University of California, San Francisco"},{"author_name":"Ding Quan Ng","author_inst":"Yale University"},{"author_name":"Esther Chavez-Iglesias","author_inst":"University of California, San Francisco"},{"author_name":"Adam B Olshen","author_inst":"University of California, San Francisco"},{"author_name":"Anand Dhruva","author_inst":"University of California, San Francisco"},{"author_name":"Jason W Chan","author_inst":"University of California, San Francisco"},{"author_name":"Raymond J Chan","author_inst":"Flinders University"},{"author_name":"Alexandre Chan","author_inst":"University of California, Irvine"},{"author_name":"Kord M Kober","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Hospital-Level Variation in Antenatal Corticosteroids for Late Preterm Births","rel_doi":"10.64898\/2026.06.09.26355014","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355014","rel_abs":"Objective: To determine whether and to what extent hospitals across the United States vary in their use of late-preterm steroids using a novel data set in which the timing of steroid administration relative to delivery can be observed. Methods: This was a retrospective cohort study of singleton births with known gestational ages identified in the Premier Healthcare Database from 2015 to 2022. The primary variable of interest was hospital-level adoption of antenatal corticosteroids for late-preterm singleton deliveries, calculated as the proportion of late-preterm singleton births (34-36 completed weeks of gestation) with any betamethasone exposure during the same late-preterm period. Hospital adoption was defined as the weighted average rate of ALPS administration among late-preterm infants across the entire post-period. Hospitals were ranked by their late-preterm steroid adoption rates and categorized by quartile based on the empirical distribution. Temporal trends were assessed using annual hospital-level adoption rates and visualized using time-series plots and distributional plots. A logistic regression model was constructed to determine hospital characteristics associated with being a highest-quartile adopting hospital. Results: The analysis cohort included 728 hospitals and 5,452,791 births, of which 361,006 (6.6%) were singleton late preterm births. Hospital steroid exposure rates ranged from 0 to 82% and were categorized into quartiles based on overall exposure rate, with cutoffs at 20.6%, 29.8%, and 40.1%. Median exposure rates increased progressively across quartiles from 14.1% (IQR 9.3-17.4%) in the lowest adopting hospitals (Q1) to 47.6% (IQR 43.7-53.2%) in the highest adopting hospitals (Q4), with substantial within-quartile variation. In the multivariable model, urban location was a strong predictor of high adoption after adjustment (aOR 2.05; 95% CI 1.11-3.83, p=0.02). Compared to Midwest hospitals, Southern hospitals had significantly lower odds of being high adopters (aOR 0.37; 95% CI 0.20-0.69, p<0.01). Among clinical case mix variables, a higher proportion of late preterm births at 34 weeks' gestation was strongly associated with high adoption (aOR 2.21; 95% CI 1.58-3.14, p<0.001). Conclusion: Following publication of the ALPS Trial, there was heterogeneous adoption of late preterm steroids among US hospitals. These findings highlight the need for a more in-depth exploration of local factors that drive the adoption of evidence-based practices outside of observable hospital characteristics.","rel_num_authors":10,"rel_authors":[{"author_name":"Mark Allen Clapp","author_inst":"Massachusetts General Hospital"},{"author_name":"Dohyun Lee","author_inst":"Massachusetts General Hospital"},{"author_name":"Siguo Li","author_inst":"Massachusetts General Hospital"},{"author_name":"Kaitlyn E James","author_inst":"Massachusetts General Hospital"},{"author_name":"Scott A Lorch","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Jessica L Cohen","author_inst":"Harvard TH Chan School of Public Health"},{"author_name":"Jason D Wright","author_inst":"Tufts Medical Center"},{"author_name":"Cynthia Allen Gyamfi-Bannerman","author_inst":"UC San Diego"},{"author_name":"Anjali J Kaimal","author_inst":"University of South Florida"},{"author_name":"Alexander Melamed","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Development and Initial Validation of the Quality of life Evaluation in NF2-related Schwannomatosis Trials (QUEST) Assessment","rel_doi":"10.64898\/2026.06.09.26355287","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355287","rel_abs":"Individuals with NF2-related schwannomatosis (NF2-SWN) experience a complex constellation of physical, emotional, and social symptoms that substantially impact quality of life (QoL). Although disease-specific patient-reported outcome measures are increasingly important for evaluating treatment benefit in clinical trials, existing NF2-SWN QoL measures have limitations in content coverage and sensitivity to change. This study describes the development and initial validation a new disease-specific QoL assessment -- the Quality of Life Evaluation in NF2-related Schwannomatosis Trials (QUEST). Using a three-phase, mixed-methods approach, items were generated through concept elicitation interviews with individuals with NF2-SWN and clinicians, prioritized via patient survey data, and refined through iterative cognitive debriefing procedures. The resulting 21-item QUEST assesses the extent to which NF2-SWN has negatively impacted a persons daily life over the past seven days. Initial psychometric evaluation was conducted in an international sample of 174 individuals with NF2-SWN aged 15 years and older (117 women (67%), 158 White individuals (89%)). Exploratory factor analysis supported a four-factor structure, and the total score demonstrated excellent internal consistency and strong test-retest reliability. Evidence of construct validity was demonstrated through hypothesized associations with disease-specific, generic, and domain-specific QoL measures, as well as known-groups validity based on self-reported disease severity and number of prior surgeries. Incremental validity analyses indicated that QUEST explained unique variance beyond existing measures. Together, findings support the QUEST as a reliable and valid disease-specific QoL measure with strong content validity and feasibility for use as a clinical trial endpoint in NF2-SWN.","rel_num_authors":6,"rel_authors":[{"author_name":"Vanessa L Merker","author_inst":"Massachusetts General Hospital"},{"author_name":"Sophia Caetano Carias","author_inst":"Massachusetts General Hospital"},{"author_name":"Rosalie E. Ferner","author_inst":"Guys and St. Thomas NHS Foundation Trust"},{"author_name":"John F. Golding","author_inst":"University of Westminster"},{"author_name":"Scott R. Plotkin","author_inst":"Massachusetts General Hospital"},{"author_name":"Frank D. Buono","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Entrainment of cortical gamma oscillations predicts improved bradykinesia and dyskinesia in Parkinson's disease","rel_doi":"10.64898\/2026.06.10.26354720","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26354720","rel_abs":"Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is hypothesized to improve motor symptoms in Parkinson's disease (PD) by suppressing pathologically elevated beta activity and promoting \"prokinetic\" gamma activity in the cortico-basal ganglia-thalamo-cortical loop. Advances in bidirectional DBS devices have revealed that stimulation can modify gamma oscillations via subharmonic entrainment, though entrainment's therapeutic role remains unclear. Objectives: To identify stimulation parameters that entrain motor cortical and STN gamma oscillations in PD at rest and during movement, and examine their association with motor function. Methods: Sensorimotor cortex and STN field potentials were collected using a bidirectional DBS system in four subjects with PD over a range of stimulation amplitudes and frequencies. Entrainment amplitude at half the stimulation frequency was quantified at rest and during a finger-tapping task in the ON-medication state. The presence or absence of entrainment was studied as a physiomarker of motor symptom severity. Results: The amplitude of stimulation-entrained gamma oscillations was non-linearly related to stimulation intensity and frequency and varied by stimulation contact choice. Entrainment amplitude was highest in precentral gyrus and increased with movement. In the ON-medication state, precentral gyrus gamma entrainment was associated with reduced bradykinesia, dyskinesia, and dystonia. Subthalamic gamma entrainment predicted improved dystonia but was a less significant marker for motor benefit than cortical entrainment. Conclusions: Stimulation-entrained gamma oscillations in the motor network are a physiomarker for optimal DBS response in PD, and could have a role in physiology-guided DBS programming, complementing existing strategies based on suppression of basal ganglia beta activity.","rel_num_authors":5,"rel_authors":[{"author_name":"Maria Shcherbakova","author_inst":"University of Pennsylvania"},{"author_name":"Stephanie Cernera","author_inst":"University of California San Francisco"},{"author_name":"Amelia G. Hahn","author_inst":"Loyola University Chicago"},{"author_name":"Simon Little","author_inst":"University of California San Francisco"},{"author_name":"Philip A. Starr","author_inst":"University of California San Francisco"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Factor Analysing Predictive Processing: No Evidence for a General Factor Across Tasks","rel_doi":"10.64898\/2026.06.09.26354804","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26354804","rel_abs":"Background & Hypothesis: Dysfunctional predictive processing (PP), specifically the aberrant weighting of priors, is a frequently-proposed mechanism for psychosis and psychosis-like phenomena (schizotypy). Evidence for this theory mostly originates from single-task studies, which assume that all tasks load onto a single latent construct of PP performance, but the underlying factor structure of PP tasks is unknown. PP deficits in psychosis may be better described by a two-factor, hierarchical model: weakened lower-level (perceptual) priors compensated by higher-level (cognitive) priors. Study Design: This study implements a multi-paradigm approach in healthy participants to investigate latent constructs underlying PP and their relationship to schizotypy. Participants (N = 73) completed 6 tasks measuring reliance on priors across language, memory, visual, and auditory domains. A factor analysis investigated whether performance across tasks is captured by a single or two-factor model. Study Results: Although a two-factor model best described performance, factors reflected within-task correlations rather than a PP hierarchy. Cross-task PP measures were poorly correlated, suggesting that individuals' weighting of priors was task-specific. A full model including all task outcomes (not factors) significantly predicted the severity of schizotypal aberrant beliefs but no other schizotypal measures. Conclusions: These results do not evidence a single factor underpinning PP performance. It is therefore inappropriate to use results from single tasks to propose a generalised PP deficit in psychosis. Variation was also not captured by a two-factor hierarchical model of priors. Further multi-paradigm research is required to evaluate alternative models or additional variables that describe aberrant PP in psychosis.","rel_num_authors":10,"rel_authors":[{"author_name":"Chantal Miller-Silva","author_inst":"University of Cambridge"},{"author_name":"Franziska Knolle","author_inst":"Technical University of Munich"},{"author_name":"Andrea Greve","author_inst":"Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge"},{"author_name":"Franciska de Beer","author_inst":"Center for Clinical Neuroscience and Cognition, University Medical Centre Groningen"},{"author_name":"Tamara Mujirishvili","author_inst":"Faculty of Health Sciences, University of Alicante"},{"author_name":"Lucy J MacGregor","author_inst":"Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge"},{"author_name":"Philip R Corlett","author_inst":"Department of Psychiatry, Yale University"},{"author_name":"Joost Haarsma","author_inst":"Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University"},{"author_name":"Albert R Powers","author_inst":"Department of Psychiatry, Yale University"},{"author_name":"Graham K Murray","author_inst":"University of Cambridge"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Validation of a multiscale Hill-type actuator against comprehensive benchmarks of motor unit and muscle force measurements","rel_doi":"10.64898\/2026.06.15.732276","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732276","rel_abs":"Computational Hill-type muscle models are widely used to simulate muscle force production because of their efficiency and physiological interpretability. However, their formulation relies on limiting assumptions, including debated multiscale simplifications, a simplified excitation-activation dynamics and an inability to capture slow and fast fibres. Moreover, existing Hill-type models remain insufficiently validated across physiological scales, fibre types, and contraction modes. We addressed these limitations by developing a multiscale fibre-type specific Hill-type neuromuscular actuator with mechanistic excitation-activation dynamics and systematically validated it against comprehensive experimental benchmarks. The model built upon a previously proposed motoneuron-driven actuator incorporating calcium-kinetics-based activation dynamics. The excitation-activation formulation was further refined to strengthen its physiological basis, while the contraction dynamics was extended by including an activation- and length-dependent force-velocity relationship, elastic tendon, passive elastic element, and the fibre-type-specific effects of yielding and sag. Validation was performed against four benchmark datasets spanning motor-unit and whole-muscle scales, including slow and fast fibres under both isometric and dynamic conditions. Experimental force traces were obtained from six muscles of rats and cats using a broad range of stimulation frequencies, muscle lengths, and imposed length changes, combining previous literature datasets with experiments performed ad hoc for this study. Overall, the model reproduced forces across all benchmark conditions, with mean absolute errors typically below 15% of the maximum isometric force, although larger errors were observed in specific submaximal and dynamic trials. The inclusion of physiologically based excitation-activation dynamics, together with yielding and sag, improved model performance under submaximal activation conditions. This study presents the first systematic validation of a single multiscale Hill-type neuromuscular actuator against comprehensive experimental motor unit and muscle force data, providing a benchmark framework for the development and assessment of future models.","rel_num_authors":10,"rel_authors":[{"author_name":"Andrea Sgarzi","author_inst":"University of New South Wales - Kensington Campus"},{"author_name":"Arnault Hubert Caillet","author_inst":"Imperial College London Department of Bioengineering"},{"author_name":"Matthew Millard","author_inst":"Universitat Stuttgart"},{"author_name":"Sven Weidner","author_inst":"Universitat Stuttgart"},{"author_name":"Nicos Haralabidis","author_inst":"University of New South Wales - Kensington Campus"},{"author_name":"Th\u00e9o Meranger","author_inst":"University of New South Wales - Kensington Campus"},{"author_name":"Bart Bolsterlee","author_inst":"University of New South Wales - Kensington Campus"},{"author_name":"Dario Farina","author_inst":"Imperial College London Department of Bioengineering"},{"author_name":"Nigel  H. Lovell","author_inst":"University of New South Wales - Kensington Campus"},{"author_name":"Luca Modenese","author_inst":"University of New South Wales - Kensington Campus"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Predicting optimal growth temperatures of bacteria using learned structural information from a single protein","rel_doi":"10.64898\/2026.06.15.732269","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732269","rel_abs":"Temperature is a fundamental determinant of bacterial physiology and ecology. Optimal growth temperature (OGT) is highly variable across species, contributing to differences in where and when species are most likely to thrive. Although the OGTs for most bacteria remain unknown, the increasing availability of genomes from uncultivated and cultivated taxa has made it advantageous to build genomic, cultivation-independent models to infer OGT. However, pre-existing genomic models often lack the generalizability and mechanistic grounding required for robust inferences of OGT. We propose a novel framework for predicting bacterial OGT which uses learned protein structural signatures of thermal adaptation. We hypothesize that biophysical tradeoffs which dictate enzymatic functions across variable temperatures provide a more robust empirical basis for OGT prediction than broad genomic features. Our OGT-predicting model, ROSEATE, is based on a single gene, adenylate kinase (ADK), that encodes for a ubiquitous enzyme essential for energy homeostasis. ROSEATE uses high-dimensional latent space encoding via MSA Transformer, a protein language model which embeds ADKs in a manner which preserves biophysical information about embedded proteins. We show that the accuracy of the ROSEATE model is on par with other genome-based models, has a high degree of phylogenetic generalizability, and the ESM embeddings effectively capture key temperature-adaptive enzyme characteristics derived from AlphaFold structures. Because ROSEATE is based on analyses of a single ubiquitous protein, it can be used with metagenomic data to infer the community-level variation in bacterial OGTs. We demonstrate this feature of ROSEATE by reconstructing ADK sequences from over 500 environmental and host-associated metagenomes, successfully distinguishing community-wide thermal preferences across diverse habitats, from polar oceans to mammalian guts. By transitioning from genomic proxies to informationally dense protein structural features, this work provides an efficient, interpretable tool for predicting bacterial OGTs across taxa and whole communities.","rel_num_authors":6,"rel_authors":[{"author_name":"Michael Hoffert","author_inst":"University of Colorado Boulder"},{"author_name":"Dru Myerscough","author_inst":"University of California San Francisco"},{"author_name":"Nicholas B Dragone","author_inst":"Monash University"},{"author_name":"Matthew J Gebert","author_inst":"The University of Utah"},{"author_name":"Jonathan J Silberg","author_inst":"Rice University"},{"author_name":"Noah Fierer","author_inst":"University of Colorado Boulder"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Differential efficiency of sampling devices in the measurement of microbial diversity of Yellowstone National Park hot springs","rel_doi":"10.64898\/2026.06.15.732322","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732322","rel_abs":"Metagenomic characterization of low-biomass Yellowstone National Park (YNP) hot spring waters remains challenging because microbial recovery is influenced by filtration methodology, sample preservation, DNA extraction, and sequencing strategy. We characterized thermophilic microbial communities in alkaline YNP hot spring waters (62-90.5{degrees}C) using three high-temperature-compatible filtration systems (Sterivex, Supor, and polycarbonate membranes), automated onsite DNA extraction (Titan), and shotgun metagenomic sequencing with Illumina short-read and Oxford Nanopore Technologies (ONT) long-read platforms. Across all filtration systems and sequencing workflows, microbial communities were consistently dominated by Bacteria (~90% of reads), whereas Archaea represented <10% of recovered sequences. Dominant microbial populations were reproducibly recovered across all approaches; however, recovery of lower-abundance taxa varied among methods. This variability was most evident in polycarbonate-filtered samples, which exhibited greater replicate-to-replicate variation and less consistent detection of microbial species. Thermocrinis ruber and related Aquificae-associated thermophiles dominated the hottest waters (78.5-90.5{degrees}C), whereas warmer effluent-channel waters (63.5-66.5{degrees}C) contained T. ruber together with photosynthetic taxa, including Synechococcus spp. and Candidatus Thermochlorobacter aerophilum. Archaeal communities were primarily represented by Pyrobaculum- and Thermoproteus-related taxa. Non-metric multidimensional scaling analyses indicated that overall community structure was largely unaffected by filtration or sequencing methodology, whereas alpha-diversity metrics showed that filter selection influenced richness and diversity estimates. These findings identify field-deployable workflows for metagenomic characterization of low-biomass thermophilic aquatic systems and demonstrate the importance of integrating filtration and sequencing strategies for studying extremophile microbiomes under remote sampling conditions.","rel_num_authors":8,"rel_authors":[{"author_name":"Jason M Wood","author_inst":"Jet Propulsion Laboratory"},{"author_name":"Scott Tighe","author_inst":"University of Vermont"},{"author_name":"Camilla Urbaniak","author_inst":"NASA Jet Propulsion Laboratory"},{"author_name":"Ceth W. Parker","author_inst":"JET PROPULSION LABORATORY-NASA"},{"author_name":"Nitin Kumar Singh","author_inst":"Jet Propulsion Laboratory"},{"author_name":"Season Wong","author_inst":"AI Biosciences, Inc."},{"author_name":"Brent M Peyton","author_inst":"Montana State University"},{"author_name":"Kasthuri Venkateswaran","author_inst":"California Institute of Technology"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Adaptive Neural Reorganization Enables Real-Time Finger-Level Robotic Control in BCI-Nai\u0308ve Stroke Survivors","rel_doi":"10.64898\/2026.06.15.732267","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732267","rel_abs":"Restoring hand function remains a major challenge for individuals with motor impairments following stroke. Noninvasive brain-computer interfaces (BCIs) aim to address this problem by translating neural signals into robotic assistance; however, control of individual fingers has not been demonstrated in BCI-naive populations. In this study, we investigated whether individuals with stroke and no prior BCI experience could achieve finger-level robotic control using motor imagery. Nine stroke-affected participants performed real-time BCI tasks to control a robotic hand through imagined finger movements decoded from electroencephalography. On average, participants achieved decoding accuracies of 84% for two-finger tasks and 61% for three-finger tasks, demonstrating reliable control at the level of individual fingers. These results indicate that discriminable neural signals for fine motor control persist after stroke and can be leveraged using data-driven deep learning decoders. Sensor-level and source-level electrophysiological analyses further reveal patterns of stroke-related neural reorganization. Overall, these findings support the potential of noninvasive, finger-level BCIs for post-stroke robotic assistance.","rel_num_authors":7,"rel_authors":[{"author_name":"Yidan Ding","author_inst":"Carnegie Mellon University"},{"author_name":"Maxim Karrenbach","author_inst":"Carnegie Mellon University"},{"author_name":"Zachary Johnson","author_inst":"Carnegie Mellon University"},{"author_name":"Hanwen Wang","author_inst":"Carnegie Mellon University"},{"author_name":"Jintao Zhang","author_inst":"Carnegie Mellon University"},{"author_name":"George F Wittenberg","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Bin He","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Variation in infant subcortical brain development from 6 to 12 months in Down syndrome","rel_doi":"10.64898\/2026.06.16.732759","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732759","rel_abs":"Introduction: Down syndrome (DS), arising from Trisomy 21, is the most common genetic condition associated with intellectual disability. While smaller total brain volumes have been consistently observed in DS, no longitudinal neuroimaging studies have examined volumetric brain development in DS during infancy, a period of rapid neural growth when interventions may have the greatest impact. Method: High-resolution T1- and T2-weighted images were acquired during natural sleep in a multisite longitudinal cohort of 44 infants with DS and 39 control infants without DS at ages 6 and 12 months. Neuroimaging data were harmonized to reduce batch effects, and a novel deep-learning, repeated-measures segmentation approach was applied to optimize neuroanatomical segmentations. Total intracranial volume (ICV) and bilateral absolute subcortical volumes (amygdala, caudate, hippocampus, pallidum, putamen, thalamus) were first directly compared in infants with and without DS at 6 and 12 months. Hierarchical linear modeling (HLM) evaluated longitudinal group differences for each structure, accounting for sex, gestational age, and laterality. Subcortical group differences estimated by HLM were also compared to group differences in total ICV. Results: ICV in infants with DS was lower than controls at 6 months (12.6%; p<.001) and 12 months (16.3%; p<.001). Subcortical structures displayed a range of lower volumes (6.9%-13.1%; p's<.003) in infants with DS, although the caudate and putamen were exceptions. Caudate volumes were on average lower in DS but not significantly different from controls, while putamen volumes were on average higher in DS but not significantly different from controls, except for the right putamen, which was significantly larger (5.3%; p=.018) at 6 months. In HLM, ICV and all subcortical structures showed slower growth in DS from 6 to 12 months, except for the amygdala and putamen, which displayed similar growth rates to controls. DS-associated reductions in subcortical volumes were similar in magnitude to ICV, although 12-month caudate and 6- and 12-month putamen volumes were enlarged relative to ICV. Conclusion: Infants with DS exhibited substantially reduced ICV and widespread reductions in subcortical volumes and growth from 6-12 months. Across a range of volumetric differences, findings were most distinct in the basal ganglia, for which volume reductions were attenuated in the caudate, while the putamen was uniquely enlarged with comparable growth to controls. These observations support early regional specificity in the neural impact of Trisomy 21 and underscore the utility of infant neuroimaging to inform biologically based interventions and clinical trial readiness in DS.","rel_num_authors":24,"rel_authors":[{"author_name":"Dea Garic","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Mengwei Ren","author_inst":"New York University"},{"author_name":"Zoe Hawks","author_inst":"Washington University in St. Louis"},{"author_name":"Yoonmi Hong","author_inst":"UNC-Chapel Hill: The University of North Carolina at Chapel Hill"},{"author_name":"Carolyn Lasch","author_inst":"Washington University in St. Louis"},{"author_name":"Rebecca Grzadzinski","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Sun Hyung Kim","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Omar Azrak","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Jed Elison","author_inst":"University of Minnesota"},{"author_name":"Jason Wolff","author_inst":"University of Minnesota"},{"author_name":"John R Pruett Jr.","author_inst":"Washington University in St. Louis"},{"author_name":"Robert C McKinstry III","author_inst":"Washington University in St. Louis"},{"author_name":"Annette Estes","author_inst":"University of Washington"},{"author_name":"Stephen Dager","author_inst":"University of Washington"},{"author_name":"Juhi Pandey","author_inst":"University of Pennsylvania"},{"author_name":"Robert Schultz","author_inst":"University of Pennsylvania"},{"author_name":"Alan C Evans","author_inst":"McGill University"},{"author_name":"Mark D Shen","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Martin Styner","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Joseph Piven","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Kelly Botteron","author_inst":"Washington University in St Louis"},{"author_name":"Heather Hazlett","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Guido Gerig","author_inst":"New York University"},{"author_name":"Natasha Marrus","author_inst":"Washington University in St Louis"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"A unified smoothing framework for protein domain bigram model","rel_doi":"10.64898\/2026.06.14.732219","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732219","rel_abs":"Biomolecular sequences can be represented as strings over an alphabet, an analogy that has motivated many applications of computational linguistic techniques to biological problems. However, such methods must be adapted to the characteristic scale and organization of biomolecular data. Here, we consider the problem of bigram smoothing for multidomain protein architectures, where domain bigram frequency data is extremely sparse and differs from textual data in alphabet size, string length distribution, the relationship between bigram and unigram frequencies, tandem repeat lengths, and the distribution of domain adjacencies. Moreover, some domain combinations are unobserved because they are biologically incompatible, others because the data are incomplete. A smoothing method that distinguishes these two cases is required. We propose a unified smoothing framework based on interpolation that can be tuned to accommodate different bigram data characteristics. Within this framework, we design specific model variants suited to protein domain bigram data: these assign low adjusted counts to pairs that are likely incompatible, while making appropriate adjustments for undersampled pairs. We demonstrate empirically that this approach distinguishes the two cases while preserving the characteristic signatures of multidomain data.","rel_num_authors":3,"rel_authors":[{"author_name":"Xiaoyue Cui","author_inst":"Carnegie Mellon University"},{"author_name":"Gautam Iyer","author_inst":"Carnegie Mellon University"},{"author_name":"Dannie Durand","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Looking beyond stereotyped neuron structures reveals links between beading and morphological rearrangements in aging phenotypes.","rel_doi":"10.64898\/2026.06.15.732273","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732273","rel_abs":"Understanding how neuronal morphology changes during aging and acute stress is essential for elucidating mechanisms of neurodegeneration. The highly branched PVD neuron of Caenorhabditis elegans provides a powerful model for studying dendritic remodeling and degeneration-associated phenotypes such as dendritic beading. However, the complexity of this arbor presents substantial challenges for automated segmentation and quantitative analysis. In this study, we adapted a convolutional neural network (CNN)-guided region growing framework for automated dendrite tracing, coupled with two topology-based algorithms for categorizing dendritic segments by branching degree. The segmentation algorithm achieved high accuracy relative to manual tracing, with a median Dice coefficient of 0.82, while reducing analysis time by approximately tenfold. Automated dendrite categorization demonstrated strong agreement with manual annotations across branching orders, though position-based mapping performance declined with age due to progressive morphological distortion. Leveraging this platform, we investigated mechanistic differences in dendritic beading patterns observed during aging and cold shock. Consistent with prior work, aging was associated with decreased inter-bead spacing, whereas cold shock produced increased bead dispersion with stress severity. Structural analysis revealed that these trends were not driven by dendritic pruning or reduced arbor complexity. Instead, while a traditional anatomically unflexible paradigm falsely implicated lower-degree dendrites as highly vulnerable, our branching-informed framework revealed that age-dependent beading is fundamentally dictated by a segments history of successive branching events. Conversely, acute cold shock triggered systemic beading that expanded across all dendritic orders in a severity-dependent manner. Together, these findings demonstrate that chronic aging and acute stress engage distinct degenerative pathways (compartment-specific lineage vulnerability versus global architectural collapse) rather than gross morphological loss, as well as highlighting the need for paradigms that enable reliable analysis of changing morphologies.","rel_num_authors":5,"rel_authors":[{"author_name":"Kin Gomez","author_inst":"North Carolina State University"},{"author_name":"Kyle Nguyen","author_inst":"North Carolina State University"},{"author_name":"John Lagergren","author_inst":"North Carolina State University"},{"author_name":"Kevin Flores","author_inst":"North Carolina State University"},{"author_name":"Adriana San Miguel","author_inst":"North Carolina State University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Sequence-encoded autoinhibition couples mRNA decapping activity to phase separation","rel_doi":"10.64898\/2026.06.16.732745","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732745","rel_abs":"Removal of the 5' mG cap by the Dcp1\/Dcp2 complex commits mRNAs to degradation, yet the mechanisms regulating decapping remain incompletely understood. Here, we identify residue-level determinants within the extended C-terminus of fission yeast Dcp2 that repress activity. Mutations in conserved inhibitory motifs relieve autoinhibition, enhance RNA binding, and bypass the requirement for the activator Edc3. Strikingly, this activation persists within phase-separated condensates, demonstrating that conformational relief in solution is propagated to the dense phase. We further show that long-range interactions between the intrinsically disordered region of Dcp2 and the catalytic core restrict RNA engagement, providing a mechanistic basis for negative regulation. Together, these findings establish that sequence-encoded elements within the Dcp2 C-terminus control catalytic activity and functional output within biomolecular condensates. More broadly, our results reveal that competing interactions encoded within intrinsically disordered regions of proteins are balanced to allosterically tune enzyme activity, providing a general mechanism by which proteins modulate distinct enzymatic functions within biological condensates.","rel_num_authors":5,"rel_authors":[{"author_name":"Trase Aguigam","author_inst":"University of California San Francisco"},{"author_name":"Katarzyna Grab","author_inst":"University of Warsaw"},{"author_name":"Joanna Kowalska","author_inst":"University of Warsaw"},{"author_name":"Jacek Jemielity","author_inst":"University of Warsaw"},{"author_name":"John D. Gross","author_inst":"University of California San Francisco"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"3dcon: tomogram denoising by deconvolution","rel_doi":"10.64898\/2026.06.15.732138","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732138","rel_abs":"Cryo-electron tomography is an expanding technology for the study of macromolecules, viruses, and cells. It is often applied to specimens that are too large or heterogeneous for methods based on 2D image averaging such as single particle analysis, e.g., intracellular membranes or organelles. Current practice records a tilt series of projection images in rotation. Reconstruction is normally an ill-posed mathematical problem. Particularly for the under-determined case of sparse data, discrete tilt angles, and a limited tilt range, characteristic artifacts appear in the reconstructed slices. Much of what appears as noise is in fact structural: the projection of contrast from different planes. Various schemes are employed to regularize the reconstruction, including machine-learning frameworks built on neural networks. To the extent that the noise is structural, it might be suppressed by deconvolution with a suitable kernel. This was demonstrated and has been used regularly in cryo-STEM tomography of thick specimens where the under-sampling problem is particularly acute. Here we present 3dcon as an open-source extension of the entropy-regularized deconvolution algorithm that had been adopted from fluorescence microscopy. It takes advantage of modern computing hardware for convenient and fast processing. Deconvolution is entirely algorithmic, meaning that successful processing of the data does not depend on the data itself. As such it should be robust in a wide variety of applications.","rel_num_authors":4,"rel_authors":[{"author_name":"Peter Kirchweger","author_inst":"Weizmann Institute of Science"},{"author_name":"Lev Melnikovsky","author_inst":"Weizmann Institute of Science"},{"author_name":"Shahar Seifer","author_inst":"Weizmann Institiute of Science"},{"author_name":"Michael Elbaum","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Characterising differential gene expression and alternative splicing in a sex reversing skink, Bassiana duperreyi","rel_doi":"10.64898\/2026.06.15.731768","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.731768","rel_abs":"In some reptiles, genetic and environmental sex determination interact whereby extreme incubation temperatures override genetic sex determination (GSD) to produce sex-reversed individuals. In one lizard with temperature-influenced GSD, the central bearded dragon, intron retention in the histone-modifier genes Kdm6b and Jarid2 has been implicated as a candidate signal linking temperature to sex. Equivalent intron retention is also present in two species with temperature-dependent sex determination, the red-eared slider turtle and the American alligator. The eastern three-lined skink, Bassiana duperreyi, represents another lizard with temperature induced sex reversal. It has an XY sex determination system in which low temperature incubation causes sex reversal of XX embryos to produce phenotypic males. In this study, we performed splice-aware analysis of RNA sequencing from hatchling brains of the three-lined skink. We investigated differences in alternative splicing and gene expression between the three sex conditions: XY males (XYm), XX females (XXf), and sex-reversed XX males (XXm). Sex reversal specific intron retention was observed in the gene, Ttll7, which only occurred in XXm and not in XYm or XXf. Intron retention in Ttll7 could alter the function of the encoded protein, a tubulin polyglutamylase, but its effect on sex reversal here is unknown. In addition, intron retention in the histone-modifier genes Jarid2 and Kdm6b occurred in all conditions. The presence of Kdm6b and Jarid2 intron retention in all sex conditions suggests that the pattern of intron retention in sex reversal in the eastern three-lined skink is distinct compared to the bearded dragon. We conclude that a different molecular pathway for sex reversal is induced in the three-lined skink, the details of which remain elusive.","rel_num_authors":6,"rel_authors":[{"author_name":"Benjamin J Hanrahan","author_inst":"University of New South Wales"},{"author_name":"J King Chang","author_inst":"University of New South Wales"},{"author_name":"Duminda S B Dissanayake","author_inst":"University of Canberra"},{"author_name":"Nicholas C Lister","author_inst":"University of New South Wales"},{"author_name":"Arthur Georges","author_inst":"University of Canberra"},{"author_name":"Paul D Waters","author_inst":"University of New South Wales"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Multitrophic interaction networks mediate biodiversity effects on ecosystem multifunctionality","rel_doi":"10.64898\/2026.06.15.732252","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732252","rel_abs":"Biodiversity loss threatens the multifunctionality of ecosystems on which human well-being ultimately depends. Changes in multitrophic species interactions may be key to explaining the ecological consequences of biodiversity loss, but research explicitly linking species interactions and ecosystem multifunctionality remains rare. To assess interaction-mediated biodiversity effects and underlying mechanisms, characterizing the structure of species interaction networks is invaluable. Using comprehensive species interaction and ecosystem functioning data from a large-scale tree biodiversity experiment, we find consistent effects of the structure of species interaction networks on ecosystem multifunctionality across multiple types of antagonistic and mutualistic interactions. While positive effects of network size align with expected positive effects of multitrophic species diversity, positive effects of niche overlap among interacting species and negative effects of highly connected species (i.e. high linkage density) reveal additional, interaction-mediated drivers of multifunctionality. Specifically, the effects of niche overlap suggest benefits of functionally similar species, and the effects of linkage density underscore the importance of specialized interactions in promoting ecosystem multifunctionality. These findings emphasize that to effectively safeguard ecosystem service provisioning, ecosystem management and biodiversity conservation not only need to account for biodiversity changes at multiple trophic levels, but also explicitly for how species interact among each other.","rel_num_authors":38,"rel_authors":[{"author_name":"Georg Albert","author_inst":"Department of Forest Nature Conservation, University of Goettingen, Goettingen, Germany"},{"author_name":"Michael Staab","author_inst":"Ecological Networks, Technical University of Darmstadt, Darmstadt, Germany; Institute of Ecology, Leuphana University of Lueneburg, Lueneburg, Germany"},{"author_name":"Arong Luo","author_inst":"Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Perttu Anttonen","author_inst":"Department of Forest Nature Conservation, University of Goettingen, Goettingen, Germany; German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-L"},{"author_name":"Remy Beugnon","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Leipzig Institute for Meteorology, Universitaet Leipzig, Leipzi"},{"author_name":"Simone Cesarz","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Institute of Biology, Leipzig University, Leipzig, Germany"},{"author_name":"Jingting Chen","author_inst":"Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; College of Biological Sciences, Unive"},{"author_name":"Nico Eisenhauer","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Institute of Biology, Leipzig University, Leipzig, Germany"},{"author_name":"Alexandra Erfmeier","author_inst":"Institute for Ecosystem Research, Department of Geobotany, Kiel University, Kiel, Germany"},{"author_name":"Felix Fornoff","author_inst":"Chair of Nature Conservation and Landscape Ecology, Faculty of Environment and Natural Resources, University of Freiburg, Freiburg, Germany"},{"author_name":"Pengfei Guo","author_inst":"Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; College of Pharmacy, Guizhou Universi"},{"author_name":"Werner Haerdtle","author_inst":"Institute of Ecology, Leuphana University of Lueneburg, Lueneburg, Germany"},{"author_name":"Lydia Hoenig","author_inst":"Institute of Biology\/Geobotany and Botanical Garden, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany; German Wildlife Foundation, Hamburg, Ger"},{"author_name":"Lin Jiang","author_inst":"School of Biological Sciences, Georgia Institute of Technology, Georgia, Atlanta, USA"},{"author_name":"Alexandra-Maria Klein","author_inst":"Chair of Nature Conservation and Landscape Ecology, Faculty of Environment and Natural Resources, University of Freiburg, Freiburg, Germany"},{"author_name":"Yi Li","author_inst":"State Key Laboratory of Vegetation and Environmental Change, Institute of Botany, Chinese Academy of Sciences, Xiangshan, Beijing, China"},{"author_name":"Yingbin Li","author_inst":"Key Laboratory of Forest Ecology Management, Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China"},{"author_name":"Qi Li","author_inst":"Key Laboratory of Forest Ecology Management, Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China"},{"author_name":"Lingli Liu","author_inst":"State Key Laboratory of Vegetation and Environmental Change, Institute of Botany, Chinese Academy of Sciences, Xiangshan, Beijing, China"},{"author_name":"Keping Ma","author_inst":"State Key Laboratory of Vegetation and Environmental Change, Institute of Botany, Chinese Academy of Sciences, Xiangshan, Beijing, China; College of Life Scienc"},{"author_name":"Goddert von Oheimb","author_inst":"Institute of General Ecology and Environmental Protection, TUD Dresden University of Technology, Tharandt, Germany"},{"author_name":"Gemma Rutten","author_inst":"Institute of Plant Sciences, University of Bern, Bern, Switzerland"},{"author_name":"Thomas Scholten","author_inst":"Soil Science and Geomorphology, Department of Geosciences, University of Tuebingen, Tuebingen, Germany"},{"author_name":"Steffen Seitz","author_inst":"Soil Science and Geomorphology, Department of Geosciences, University of Tuebingen, Tuebingen, Germany; Physical Geography, Institute of Geography, Osnabrueck U"},{"author_name":"Bala Singavarapu","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Institute of Biology\/Geobotany and Botanical Garden, Martin Lut"},{"author_name":"Stefan Trogisch","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Institute of Biology\/Geobotany and Botanical Garden, Martin Lut"},{"author_name":"Ming-Qiang Wang","author_inst":"Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Key Laboratory of Mountain Ecological"},{"author_name":"Pandeng Wang","author_inst":"State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-Sen University, Guangzhou, China"},{"author_name":"Donghao Wu","author_inst":"College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China; School of Ecology, Sun Yat-sen University, Guangzhou, China"},{"author_name":"Tesfaye Wubet","author_inst":"Department of Community Ecology, Helmholtz Centre for Environmental Research - UFZ, Halle (Saale), Germany; German Centre for Integrative Biodiversity Research "},{"author_name":"Xian Yang","author_inst":"School of Biological Sciences, Georgia Institute of Technology, Georgia, Atlanta, USA; State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-Sen Univer"},{"author_name":"Mingjian Yu","author_inst":"College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China"},{"author_name":"Naili Zhang","author_inst":"College of Forestry, Beijing Forestry University, Beijing, China"},{"author_name":"Bernhard Schmid","author_inst":"Department of Geography, University of Zurich, Zurich, Switzerland; Institute of Ecology, College of Urban and Environmental Sciences, Peking University, Beijin"},{"author_name":"Helge Bruelheide","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Institute of Biology\/Geobotany and Botanical Garden, Martin Lut"},{"author_name":"Xiaojuan Liu","author_inst":"State Key Laboratory of Vegetation and Environmental Change, Institute of Botany, Chinese Academy of Sciences, Xiangshan, Beijing, China; Zhejiang Qianjiangyuan"},{"author_name":"Chao-Dong Zhu","author_inst":"Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; College of Biological Sciences, Unive"},{"author_name":"Andreas Schuldt","author_inst":"Department of Forest Nature Conservation, University of Goettingen, Goettingen, Germany"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Programming Brain Cell-Type-Selective Delivery In Vivo with Transporter-Guided Therapeutics","rel_doi":"10.64898\/2026.06.14.732141","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732141","rel_abs":"Many diseases arise from dysfunction of defined cell populations, yet most therapeutics distribute broadly, limiting efficacy and causing toxicity. We developed ExACT, a platform for cell-type-selective intracellular delivery that exploits membrane transporters. In vivo screening of combinatorial fluorescent small-molecule libraries in mouse brain identified chemistries whose uptake is dictated by endogenous transporter expression, yielding compounds with preferential entry into neurons, astrocytes, pericytes and endothelial cells. One series showed strong selectivity for brain and retinal endothelium, where Slco1a4 mediated uptake. This selectivity principle extended to the human orthologue SLCO1A2, highly expressed in brain endothelium and oligodendrocytes, where it mediated selective uptake in a humanized mouse model and human iPSC-derived oligodendrocytes. Ectopic expression of SLCO1A2 in neurons via gene therapy created a synthetic entry port, conferring ExACT conjugate uptake on otherwise inaccessible cells. Bifunctional compounds linking transporter-targeting motifs to antisense oligonucleotides or small-molecule drugs retained pharmacological activity while conferring transporter-dependent cell-type selectivity, illustrating how transporter diversity can be harnessed for precision pharmacotherapy.","rel_num_authors":10,"rel_authors":[{"author_name":"Roshan W Gunasekara","author_inst":"Yale School of Medicine"},{"author_name":"Lejie Zhang","author_inst":"Yale School of Medicine"},{"author_name":"Lei Tong","author_inst":"Yale School of Medicine"},{"author_name":"John Zhou","author_inst":"Yale School of Medicine"},{"author_name":"Hoang Kim Trinh","author_inst":"Yale School of Medicine"},{"author_name":"Sean Pinon","author_inst":"Yale School of Medicine"},{"author_name":"Madison Gendreau","author_inst":"Yale School of Medicine"},{"author_name":"Emily Scott","author_inst":"Yale School of Medicine"},{"author_name":"John Chiari","author_inst":"Yale School of Medicine"},{"author_name":"Jaime Grutzendler","author_inst":"Yale University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Optimization of Functional Electric Stimulation for Foot Drop Patients using Inertial Measurement Unit.","rel_doi":"10.64898\/2026.06.14.732030","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732030","rel_abs":"Many people which are affected by drop foot syndrome, have to face difficulty while walking which leads to pathological gait. This type of syndrome is treated by means of an external artificial stimulation known as functional electric stimulator (FES). In this paper we are designing an online feedback control system which optimize the strength of a FES given to paretic muscle which results in correction of pathological gait of the patient in a tolerable domain. Different phases of gait are identified using inertial measurement unit (IMU) as a feedback sensor mounted on the foot. Data is collected form 8 different healthy subjects and average of collected data is used as a reference template. Different trajectories of drop foot patients are simulated (due to unavailability of patients) and corrected according to the reference template.","rel_num_authors":4,"rel_authors":[{"author_name":"Muhammad Shahzaib","author_inst":"Institute of Space Technology, Islamabad, Pakistan"},{"author_name":"Usman Shaikh","author_inst":"Auckland university of Technology"},{"author_name":"Sadia Shakil","author_inst":"Chinese University of Hong Kong"},{"author_name":"Sobia Jangsher","author_inst":"Dublin City University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"The motivational control of instrumental performance by nutrient-specific appetites depends on incentive learning","rel_doi":"10.64898\/2026.06.14.732213","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732213","rel_abs":"Considerable evidence suggests that the motivational control of instrumental action depends on incentive learning; i.e., on the opportunity to learn how the value of the consequences or outcome of an action, (e.g., a specific food) varies under different motivational conditions (e.g., under different degrees of hunger). The current study investigated whether learning the values of high-protein and high-carbohydrate rewards under different degrees of protein and carbohydrate appetite is also necessary for these nutrient-specific appetites to exert control over instrumental performance. Experiment 1 gave differing consummatory experience to whey protein and polycose carbohydrate outcomes under protein and carbohydrate appetite and found that, without the opportunity for incentive learning, the performance of actions earning these outcomes was insensitive to a shift in appetite. However, once the opportunity for incentive learning was provided, the rats increased their instrumental performance on a lever that earned the whey outcome relative to the polycose lever when protein hungry and on the polycose lever relative to the whey lever when carbohydrate hungry. Experiment 2 assessed how these nutrient-specific states exerted this control; whether, once learned, nutrient values were immediately controlled by nutrient appetite or whether this was based on conditional control acquired during experience with the outcomes under different nutrient appetites. We found that exposure to an outcome under a single nutrient-specific state was not sufficient to establish state-specific control. Instead, establishing the conditional control of outcome value required exposure to both the whey and polycose outcomes under both protein and carbohydrate appetites.","rel_num_authors":3,"rel_authors":[{"author_name":"Douglas John Roy","author_inst":"UNSW"},{"author_name":"Thomas Joseph Burton","author_inst":"The University of New South Wales"},{"author_name":"Bernard Balleine","author_inst":"UNSW Sydney"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Predicting pain location from resting-state brain fMRI","rel_doi":"10.64898\/2026.06.14.732139","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732139","rel_abs":"Low back pain is a prevalent issue with few reliable treatments. Although there is great variation in clinical presentation within the low back pain population, little is known about the neurobiological mechanisms underlying these differences. In this study, we sought to stratify chronic low back pain patients (N = 275) into phenotypes characterized by correlated patterns of resting-state brain activity and sensory abnormalities (pain, numbness, and pins and needles) indicated on hand-drawn body maps. Our cross-decomposition analysis yielded phenotypes that resemble previously documented mechanistic pain types, revealing distinct brain connectivity patterns associated with different clinical presentations. Our model was then used to predict pain body maps from fMRI data in a small novel dataset of chronic pain subjects, suggesting that these relationships may generalize to other chronic pain conditions. Our results support the utility of resting-state fMRI in understanding the heterogeneity of chronic pain, which may be leveraged to develop more targeted pain treatments.","rel_num_authors":7,"rel_authors":[{"author_name":"Jennifer A Cummings","author_inst":"University of California, San Francisco"},{"author_name":"Sharmila Majumdar","author_inst":"University of California, San Francisco"},{"author_name":"Andrew Bishara","author_inst":"University of California, San Francisco"},{"author_name":"Julian Motzkin","author_inst":"University of California, San Francisco"},{"author_name":"Ashish Raj","author_inst":"University of California, San Francisco"},{"author_name":"Prasad Shirvalkar","author_inst":"University of California, San Francisco"},{"author_name":"Jeffrey Lotz","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Clinical and primary cell evidence reveals complex CFTR function-phenotype relationships","rel_doi":"10.64898\/2026.06.17.732921","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732921","rel_abs":"Rationale: The CFTR function-phenotype relationship remains incompletely understood, with prior work yielding heterogeneous findings suggesting linear and nonlinear associations. Objective: Define the genotype-function-phenotype relationship using data from the Clinical and Functional TRanslation of CFTR (CFTR2) and human nasal epithelial (HNE) studies. Methods: Clinical data (sweat chloride, lung function, pancreatic status) from 84,418 individuals in CFTR2 were linked to CFTR functional measures derived from 289 CFTR genotypes. Total genotype function was calculated as the average percent wild-type chloride conductance of both variants in heterologous cell lines. This framework was applied to an HNE cohort including people with CF, CF heterozygotes, and controls. CFTR function was derived from short circuit measurements in HNEs from 153 individuals and correlated with phenotype for 415 individuals. Weighted linear and logarithmic regressions were applied to evaluate the function-phenotype relationship. Measurements and Main Results: Simple linear regression obscured marked heterogeneity across datasets. Piecewise linear regressions revealed marked attenuation of slope magnitude with increasing function across phenotypes. This pattern was well-described by a logarithmic function, such that modeling function on a log scale rendered the relationship approximately linear. HNE data demonstrated similar attenuation, corroborating this pattern. Conclusions: Large-scale natural history data integrated with primary cell findings show that the function-phenotype relationship is not sufficiently described by a single linear effect but is a proportional relationship, in which equivalent changes in CFTR function yield different phenotypic outcomes depending on baseline function. This framework provides precision in predicting clinical benefits from CFTR-directed therapies and identifying meaningful thresholds of CFTR rescue.","rel_num_authors":10,"rel_authors":[{"author_name":"Kristen Miller","author_inst":"Division of Maternal-Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."},{"author_name":"Audrey Pion","author_inst":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"author_name":"Ana Topasna","author_inst":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"author_name":"Alicia J Ostmann","author_inst":"Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cinci"},{"author_name":"Jessica D Meeker","author_inst":"Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cinci"},{"author_name":"Georgia Kelly","author_inst":"Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cinci"},{"author_name":"John J Brewington","author_inst":"Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cinci"},{"author_name":"Neeraj Sharma","author_inst":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"author_name":"Garry R Cutting","author_inst":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"author_name":"Karen S Raraigh","author_inst":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"CFTR function in nasal airway cells from symptomatic and asymptomatic CF heterozygotes","rel_doi":"10.64898\/2026.06.17.732907","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732907","rel_abs":"Rationale An estimated 25 million people worldwide have one deleterious variant in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Chronic respiratory disease symptoms are at an increased prevalence in cystic fibrosis (CF) heterozygotes. Objectives Determine the level of CFTR function in CF heterozygotes compared to individuals without CF-causing variants. Establish whether CFTR function differs between asymptomatic and symptomatic CF heterozygotes. Methods Individuals without respiratory symptoms or CF family history were recruited as controls. Heterozygotes were recruited from families with a CF individual harboring null alleles or c.1521_1523del (F508del) in CFTR. CFTR function was measured by short circuit current in primary human nasal epithelial cells (HNEs) from participants. Cell composition was assessed by single cell RNA sequencing. Measurements and Main Results CFTR function was variable in cells from control and heterozygous individuals. Mean CFTR function in asymptomatic null (8.8{+\/-}0.5A\/cm2 (SEM); n=30) and F508del (8.7{+\/-}1.0A\/cm2 ; n=22) heterozygotes was similar and significantly lower at 54.6% and 53.9% than controls (16.1{+\/-}1.1A\/cm2 ; n=24; p<0.0001). Mean CFTR function in symptomatic heterozygotes (8.4{+\/-}1.0A\/cm2 ; n =15) was 52.1% of controls and did not differ from asymptomatic heterozygotes (p=0.7803). Cell identities and proportions were equivalent between control and heterozygous cultures. HNEs from CF heterozygotes showed variable response to CFTR modulators. Conclusions CFTR function in primary airway cells exhibits substantial interindividual variability and overlaps between controls and CF heterozygotes. CF heterozygotes exhibit approximately 50% of CFTR function in controls, regardless of symptom status. These findings suggest that respiratory symptoms in CF heterozygotes are influenced by factors beyond CFTR dysfunction.","rel_num_authors":12,"rel_authors":[{"author_name":"Audrey Pion","author_inst":"Johns Hopkins University"},{"author_name":"Alyssa Chang","author_inst":"Johns Hopkins University"},{"author_name":"Piero Mejia","author_inst":"Johns Hopkins University"},{"author_name":"Alice C. Eastman","author_inst":"Johns Hopkins University"},{"author_name":"Erin Kavanagh","author_inst":"Johns Hopkins University"},{"author_name":"Ana Topasna","author_inst":"Johns Hopkins University"},{"author_name":"Katherine Starego","author_inst":"Johns Hopkins University"},{"author_name":"Alianna Parr","author_inst":"Johns Hopkins University"},{"author_name":"Karen S Raraigh","author_inst":"Johns Hopkins University"},{"author_name":"Christian Merlo","author_inst":"Johns Hopkins University"},{"author_name":"Neeraj Sharma","author_inst":"Johns Hopkins University"},{"author_name":"Garry Cutting","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"A mammalian-specific domain of MSH5 drives the transition from crossover licensing to designation during meiotic prophase I","rel_doi":"10.64898\/2026.06.16.731784","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.731784","rel_abs":"Meiotic recombination initiates with DNA double-strand breaks (DSBs) repaired as either crossovers (COs) or non-crossovers. Across eukaryotes, MSH4\/MSH5 (MutS{gamma}) licenses DSB repair intermediates, directing repair into the class I CO pathway via recruitment of MLH1\/MLH3 (MutL{gamma}). In mammals, excess MutS{gamma} sites relative to final MutL{gamma} foci suggest additional MutS{gamma} functions, including directing repair through the minor class II CO pathway. We investigated the role of a mammalian-specific 38-amino acid C-terminal domain of MSH5 using mice lacking this domain (Msh5{Delta}C\/{Delta}C). Spermatocytes and oocytes load MSH4 normally to achieve CO licensing in zygonema, but these numbers decline precipitously in pachynema, leading to dramatically reduced MutL{gamma} foci and associated pro-CO factors HEI10 and CNTD1. Despite this, licensing factors RNF212B and MutS{gamma}-associated kinase CDK4 remain persistently upregulated in pachynema. Strikingly, the switch from licensing-associated CDK4 to CO-site-associated CDK2 fails to occur in Msh5{Delta}C\/{Delta}C mice, even at residual class I CO events. The result is rapid germ cell death prior to prophase I completion in both sexes. Thus, the loss of the MSH5 C-terminus functionally uncouples the regulatory proteins that define the stepwise patterning of class I COs. Our findings reveal novel early roles for the C-terminus of mammalian MSH5 in converting licensed DSB repair intermediates to designated class I COs.","rel_num_authors":9,"rel_authors":[{"author_name":"Ky'ara D Carr","author_inst":"Cornell University"},{"author_name":"Maame Serwaa Adjei-Boadu","author_inst":"Cornell University"},{"author_name":"Eliza O'Donnell","author_inst":"Cornell University"},{"author_name":"Tegan S Horan","author_inst":"Cornell University"},{"author_name":"Anna J Wood","author_inst":"Cornell University"},{"author_name":"Yongwei Zhang","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Winfried Edelmann","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Maria de las Mercedes Carro","author_inst":"Cornell University"},{"author_name":"Paula Cohen","author_inst":"Cornell University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"A mammalian-specific domain of MSH5 drives the transition from crossover licensing to designation during meiotic prophase I","rel_doi":"10.64898\/2026.06.16.731784","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.731784","rel_abs":"Meiotic recombination initiates with DNA double-strand breaks (DSBs) repaired as either crossovers (COs) or non-crossovers. Across eukaryotes, MSH4\/MSH5 (MutS{gamma}) licenses DSB repair intermediates, directing repair into the class I CO pathway via recruitment of MLH1\/MLH3 (MutL{gamma}). In mammals, excess MutS{gamma} sites relative to final MutL{gamma} foci suggest additional MutS{gamma} functions, including directing repair through the minor class II CO pathway. We investigated the role of a mammalian-specific 38-amino acid C-terminal domain of MSH5 using mice lacking this domain (Msh5{Delta}C\/{Delta}C). Spermatocytes and oocytes load MSH4 normally to achieve CO licensing in zygonema, but these numbers decline precipitously in pachynema, leading to dramatically reduced MutL{gamma} foci and associated pro-CO factors HEI10 and CNTD1. Despite this, licensing factors RNF212B and MutS{gamma}-associated kinase CDK4 remain persistently upregulated in pachynema. Strikingly, the switch from licensing-associated CDK4 to CO-site-associated CDK2 fails to occur in Msh5{Delta}C\/{Delta}C mice, even at residual class I CO events. The result is rapid germ cell death prior to prophase I completion in both sexes. Thus, the loss of the MSH5 C-terminus functionally uncouples the regulatory proteins that define the stepwise patterning of class I COs. Our findings reveal novel early roles for the C-terminus of mammalian MSH5 in converting licensed DSB repair intermediates to designated class I COs.","rel_num_authors":9,"rel_authors":[{"author_name":"Ky'ara D Carr","author_inst":"Cornell University"},{"author_name":"Maame Serwaa Adjei-Boadu","author_inst":"Cornell University"},{"author_name":"Eliza O'Donnell","author_inst":"Cornell University"},{"author_name":"Tegan S Horan","author_inst":"Cornell University"},{"author_name":"Anna J Wood","author_inst":"Cornell University"},{"author_name":"Yongwei Zhang","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Winfried Edelmann","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Maria de las Mercedes Carro","author_inst":"Cornell University"},{"author_name":"Paula Cohen","author_inst":"Cornell University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Spatiotemporal Patterns and Structural Substrates of Individual Functional Variability in Youth","rel_doi":"10.64898\/2026.06.16.730254","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.730254","rel_abs":"Youth is a period of emerging individuality and extensive neural remodeling, yet how functional brain individuality is organized across development remains unclear. Prior work has often conflated variability in functional topography and connectivity, highlighting the need to examine them separately to better understand how functional individuality relates to brain structure and cognition. Here we used individualized functional parcellation in a large multimodal developmental cohort to separately quantify variability in individualized functional parcellation (vIFP) and variability in functional connectivity (vFC). Both forms of variability followed the sensorimotor-association axis and were greatest in the association cortex. vIFP increased significantly with age, whereas vFC showed regionally specific maturation without a significant whole-brain increase. Both trajectories showed a common mid-adolescent inflection at 14-16 years, marking a window of accelerated functional individualization. Despite shared spatial and temporal organization, vIFP and vFC showed dissociable links to structure and cognition. vIFP was more strongly coupled to structural variability, whereas vFC was more strongly associated with cognitive variability. These findings reveal convergent and divergent developmental principles of topographic and connectional functional variability, highlighting their complementary roles in structural constraints and cognitive specialization.","rel_num_authors":11,"rel_authors":[{"author_name":"Zekun Yang","author_inst":"Beijing Normal University"},{"author_name":"Xiaoxi Dong","author_inst":"Beijing Normal University"},{"author_name":"Debin Zeng","author_inst":"Fudan University"},{"author_name":"Lei Chu","author_inst":"Beihang University"},{"author_name":"Yirong He","author_inst":"South China Normal University"},{"author_name":"Jichang Zhang","author_inst":"Beijing Normal University"},{"author_name":"Qiongling Li","author_inst":"Beijing Normal University"},{"author_name":"Yiyu Zhang","author_inst":"Beijing Normal University"},{"author_name":"Lianglong Sun","author_inst":"Beijing Normal University"},{"author_name":"Xiuying Wang","author_inst":"The University of Sydney"},{"author_name":"Shuyu Li","author_inst":"Beijing Normal University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Distinct cortical patches for syntactic and semantic composition in the human brain","rel_doi":"10.64898\/2026.06.18.732834","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.732834","rel_abs":"Although the brain areas for language processing are well delimited, whether lexical-semantic and syntactic processes are spatially segregated remains debated. To clarify this issue, we conducted two experiments using 7-Tesla functional MRI in 20 participants performing: a functional localizer involving reading sequences of words of increasing linguistic complexity; and a presentation of short, semantically impoverished three-word mini-sentences, flashed in a single glance (e.g., \"he does it\"), whose grammaticality and syntactic complexity was manipulated through syntactic movement. Our results reveal two functionally dissociable sets of cortical patches within the language system: one sensitive to syntactic structure even in the absence of meaning, and the other involved in semantic composition. This dual-network architecture was consistently observed in the majority of participants, although its precise anatomical localization varied. The two types of voxels coexisted even within a given brain region of the Glasser atlas. Results were confirmed using subject-specific analyses and region-by-condition interactions, as voxels in those two systems displayed markedly different responses to mini-sentences. Thus, high-resolution functional imaging reveals a division of labor between syntactic and semantic composition within the classical language network.","rel_num_authors":5,"rel_authors":[{"author_name":"Thomas Dighiero-Becht","author_inst":"Sorbonne Universite, Paris, France"},{"author_name":"Naama Friedmann","author_inst":"Sagol School of Neuroscience and School of Education, Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Luigi Rizzi","author_inst":"Centro Interuniversitario di Studi Cognitivi sul Linguaggio, University of Siena, Siena, Italy"},{"author_name":"Christophe Pallier","author_inst":"Cognitive Neuroimaging Unit, INSERM, CEA, CNRS, Universite Paris-Saclay, NeuroSpin center, Gif sur Yvette, France"},{"author_name":"Stanislas Dehaene","author_inst":"College de France, Universite Paris Sciences Lettres (PSL), Paris, France"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Bayesian-enhanced closed-loop optimization of ultrasound protocols for targeted and precise neuromodulation","rel_doi":"10.64898\/2026.06.16.732762","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732762","rel_abs":"Low-intensity focused ultrasound (LIFU) is a promising neuromodulation modality, but challenges related to high response variability and the poorly understood parameter space undermine progress in clinical applications. To facilitate the development of therapeutic LIFU protocols, we developed an approach for Bayesian-enhanced adaptive control of ultrasound neuromodulation (BEACUN). BEACUN enables efficient, data-driven parameter mapping using a limited number of stimulation-response evaluations. We used functional ultrasound imaging (fUSI) to measure the neural responses to LIFU stimulation in real time, and we carried out in vivo experiments in rats to optimize and validate the performance of the BEACUN search. In live optimizations, we show that BEACUN produces more effective inhibitory LIFU neuromodulation protocols than conventional parameter exploration methods and converges to the optimal solution in 23 {+\/-} 3.67 stimulation-response evaluations. Our approach realizes a platform for efficient optimization of neuromodulation parameters that could pave the way for personalized LIFU protocol development in patients.","rel_num_authors":3,"rel_authors":[{"author_name":"Andrea Boscutti","author_inst":"University of California San Francisco"},{"author_name":"Valeria Grasso","author_inst":"University of California San Francisco"},{"author_name":"Tommaso Di Ianni","author_inst":"University of California San Francisco"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Muscle Loss as a Foundational Step in the Development and Evolution of the Turtle Shell","rel_doi":"10.64898\/2026.06.16.732726","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732726","rel_abs":"Modern biodiversity is built on a series of disparate body plans whose origins are obscured by deep time. Our most direct source of clarifying data is the fossilized skeleton, where morphology reflects an evolving functionality realized through the development of associated tissues. We apply this dualistic perspective to the shelled body plan of turtles whose Paleozoic initiation is marked by a derived relationship between ribs and dermis (Lyson & Bever, 2020). Current developmental models remain in conflict with an increasingly informative fossil record, suggesting critical steps remain unrecognized. Here we explore the hypothesis that the breakdown of rib-spanning muscles, an evolutionary transformation mirrored in embryogenesis, is one such step. Multi-modal imaging of turtle embryos, including a novel application of histology-based deep learning (Kiemen et al., 2022; Matos-Romero et al., 2025; Forjaz et al., 2026), establishes intercostal muscle degradation as preceding turtle-specific rib development and highlights the heuristic power of 3D, whole-embryo analysis (Forjaz et al., 2026). Quantified divergence from mouse pinpoints the timing and tempo of this organized, apoptotic breakdown. Initial evidence suggests an associated non-pathological inflammatory response, which has been shown capable of driving evolutionarily stable hyperossification (Rashid et al., 2023). These patterns support trunk muscles as a critical signalling centre whose ontogenetic loss set the phylogenetic stage for a morphogenetic transformation remarkable in a non-metamorphic species.","rel_num_authors":10,"rel_authors":[{"author_name":"William Foster","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Paul Gensbigler","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Max Bletcher","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Andre Forjaz","author_inst":"Johns Hopkins University"},{"author_name":"Biyi Li","author_inst":"Johns Hopkins University"},{"author_name":"Valentina Matos Romero","author_inst":"Johns Hopkins University"},{"author_name":"Chulan Kwon","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Tyler Lyson","author_inst":"Denver Museum of Nature and Science"},{"author_name":"Ashley L Kiemen","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Gabriel S Bever","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Striatal activity maintains a short-term action-outcome memory to guide future choice","rel_doi":"10.64898\/2026.06.16.731709","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.731709","rel_abs":"Adaptive behavior requires animals to use the outcomes of recent actions (action-outcomes) to guide future decisions. While the striatum is critical for decision-making, it is currently unclear how it is involved in the storage and retrieval of short-term associative memories. Here, we implemented a head-fixed memory-guided decision-making task in which mice use the outcome of a previous choice to determine whether to repeat or switch their next action. We show that dopamine fluctuations in the ventrolateral striatum are modulated by reward receipt or omission and recent outcome history, while the activity of direct and indirect pathway striatal projection neurons encodes recent action-outcome associations and predicts future switch\/repeat choices. Closed-loop optogenetic activation and inhibition of direct and indirect pathway neurons during either the action-outcome association period or the delay preceding the next choice bidirectionally biased future actions away from those favored by reward history. Together, these findings suggest that striatal activity maintains a short-term action-outcome associative memory that links completed actions to future motor plans during adaptive decision-making.","rel_num_authors":13,"rel_authors":[{"author_name":"Allison E Girasole","author_inst":"Harvard Medical School"},{"author_name":"Gil Mandelbaum","author_inst":"Harvard Medical School"},{"author_name":"Livia C Murray","author_inst":"Harvard Medical School"},{"author_name":"Celia C Beron","author_inst":"Harvard Medical School"},{"author_name":"Madeline A Albanese","author_inst":"Harvard Medical School"},{"author_name":"Rebekah Y Zhang","author_inst":"Harvard Medical School"},{"author_name":"Bastijn J G van den Boom","author_inst":"Harvard Medical School"},{"author_name":"Rebecca N Alvarado","author_inst":"Harvard Medical School"},{"author_name":"Daniel R Hochbaum","author_inst":"Harvard Medical School"},{"author_name":"Trevor M Haynes","author_inst":"Harvard Medical School"},{"author_name":"Maria Diaz Bobillo","author_inst":"Harvard Medical School"},{"author_name":"Wengang Wang","author_inst":"Harvard Medical School"},{"author_name":"Bernardo L Sabatini","author_inst":"Howard Hughes Medical Institute, Harvard Medical School"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Striatal activity maintains a short-term action-outcome memory to guide future choice","rel_doi":"10.64898\/2026.06.16.731709","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.731709","rel_abs":"Adaptive behavior requires animals to use the outcomes of recent actions (action-outcomes) to guide future decisions. While the striatum is critical for decision-making, it is currently unclear how it is involved in the storage and retrieval of short-term associative memories. Here, we implemented a head-fixed memory-guided decision-making task in which mice use the outcome of a previous choice to determine whether to repeat or switch their next action. We show that dopamine fluctuations in the ventrolateral striatum are modulated by reward receipt or omission and recent outcome history, while the activity of direct and indirect pathway striatal projection neurons encodes recent action-outcome associations and predicts future switch\/repeat choices. Closed-loop optogenetic activation and inhibition of direct and indirect pathway neurons during either the action-outcome association period or the delay preceding the next choice bidirectionally biased future actions away from those favored by reward history. Together, these findings suggest that striatal activity maintains a short-term action-outcome associative memory that links completed actions to future motor plans during adaptive decision-making.","rel_num_authors":13,"rel_authors":[{"author_name":"Allison E Girasole","author_inst":"Harvard Medical School"},{"author_name":"Gil Mandelbaum","author_inst":"Harvard Medical School"},{"author_name":"Livia C Murray","author_inst":"Harvard Medical School"},{"author_name":"Celia C Beron","author_inst":"Harvard Medical School"},{"author_name":"Madeline A Albanese","author_inst":"Harvard Medical School"},{"author_name":"Rebekah Y Zhang","author_inst":"Harvard Medical School"},{"author_name":"Bastijn J G van den Boom","author_inst":"Harvard Medical School"},{"author_name":"Rebecca N Alvarado","author_inst":"Harvard Medical School"},{"author_name":"Daniel R Hochbaum","author_inst":"Harvard Medical School"},{"author_name":"Trevor M Haynes","author_inst":"Harvard Medical School"},{"author_name":"Maria Diaz Bobillo","author_inst":"Harvard Medical School"},{"author_name":"Wengang Wang","author_inst":"Harvard Medical School"},{"author_name":"Bernardo L Sabatini","author_inst":"Howard Hughes Medical Institute, Harvard Medical School"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Adaptive Charge Modulation Enables Focal, Selective Spinal Cord Stimulation","rel_doi":"10.64898\/2026.06.16.732691","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732691","rel_abs":"Clinical neuromodulation primarily employs near-field low frequency electrical stimulation to activate neurons in the immediate vicinity of the electrode. We introduce Adaptive Charge Modulation (ACM), a spatiotemporal, charge-balanced stimulation strategy that focuses activation at deep tissue sites distant from the stimulating contacts. We apply ACM to stimulate deep regions of the spinal cord, distant from dorsal root entry zones which are preferentially activated during low frequency stimulation (LFS). ACM applies multipolar, biphasic rectangular pulses to exceed activation thresholds in deeper neuronal populations, with reduced surface activation, potentially due to high-frequency suppression of neural activity. In epidural spinal cord stimulation in rats, ACM achieved single-muscle selectivity among fourteen monitored muscles with minimal co-activation of other muscles. Using simultaneous, high spatiotemporal resolution, 2,112-channel brain-spine recordings, we characterized the response latencies and pathways consistent with focal recruitment at depth. We observed chronic stability of the electrode and ACM in freely behaving animals over 68 days post-implantation. By enabling focal activation with epidural surface electrodes, ACM may expand the reach and precision of neuromodulation and neural interfaces.","rel_num_authors":22,"rel_authors":[{"author_name":"Ritwik Vatsyayan","author_inst":"University of California San Diego"},{"author_name":"Fadi Khoury","author_inst":"University of California San Diego"},{"author_name":"Tara S Porter","author_inst":"University of California San Diego"},{"author_name":"Eleni Sinopoulou","author_inst":"University of California San Diego"},{"author_name":"Hadi Day","author_inst":"University of California San Diego"},{"author_name":"Samantha Russman","author_inst":"University of California San Diego"},{"author_name":"Rhea Montgomery-Walsh","author_inst":"University of California San Diego"},{"author_name":"Kaushik Shukla","author_inst":"University of California San Diego"},{"author_name":"Helen Saad","author_inst":"University of California San Diego"},{"author_name":"Andrew M Bourhis","author_inst":"University of California San Diego"},{"author_name":"Jihwan Lee","author_inst":"University of California San Diego"},{"author_name":"Karen J Tonsfeldt","author_inst":"Oregon Health and Sciences University"},{"author_name":"Akira Nagamori","author_inst":"Salk Institute of Biological Sciences"},{"author_name":"Hoi Sang U","author_inst":"University of California San Diego"},{"author_name":"David M Roth","author_inst":"University of California San Diego"},{"author_name":"Drew Hall","author_inst":"UCSD"},{"author_name":"Sharona Ben-Haim","author_inst":"University of California San Diego"},{"author_name":"Eiman Azim","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Tony L. Yaksh","author_inst":"University of California, San Diego"},{"author_name":"Alexander Khalessi","author_inst":"University of California San Diego"},{"author_name":"Mark Tuszynski","author_inst":"University of California San Diego"},{"author_name":"Shadi A. Dayeh","author_inst":"University of California San Diego"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Adaptive Charge Modulation Enables Focal, Selective Spinal Cord Stimulation","rel_doi":"10.64898\/2026.06.16.732691","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732691","rel_abs":"Clinical neuromodulation primarily employs near-field low frequency electrical stimulation to activate neurons in the immediate vicinity of the electrode. We introduce Adaptive Charge Modulation (ACM), a spatiotemporal, charge-balanced stimulation strategy that focuses activation at deep tissue sites distant from the stimulating contacts. We apply ACM to stimulate deep regions of the spinal cord, distant from dorsal root entry zones which are preferentially activated during low frequency stimulation (LFS). ACM applies multipolar, biphasic rectangular pulses to exceed activation thresholds in deeper neuronal populations, with reduced surface activation, potentially due to high-frequency suppression of neural activity. In epidural spinal cord stimulation in rats, ACM achieved single-muscle selectivity among fourteen monitored muscles with minimal co-activation of other muscles. Using simultaneous, high spatiotemporal resolution, 2,112-channel brain-spine recordings, we characterized the response latencies and pathways consistent with focal recruitment at depth. We observed chronic stability of the electrode and ACM in freely behaving animals over 68 days post-implantation. By enabling focal activation with epidural surface electrodes, ACM may expand the reach and precision of neuromodulation and neural interfaces.","rel_num_authors":22,"rel_authors":[{"author_name":"Ritwik Vatsyayan","author_inst":"University of California San Diego"},{"author_name":"Fadi Khoury","author_inst":"University of California San Diego"},{"author_name":"Tara S Porter","author_inst":"University of California San Diego"},{"author_name":"Eleni Sinopoulou","author_inst":"University of California San Diego"},{"author_name":"Hadi Day","author_inst":"University of California San Diego"},{"author_name":"Samantha Russman","author_inst":"University of California San Diego"},{"author_name":"Rhea Montgomery-Walsh","author_inst":"University of California San Diego"},{"author_name":"Kaushik Shukla","author_inst":"University of California San Diego"},{"author_name":"Helen Saad","author_inst":"University of California San Diego"},{"author_name":"Andrew M Bourhis","author_inst":"University of California San Diego"},{"author_name":"Jihwan Lee","author_inst":"University of California San Diego"},{"author_name":"Karen J Tonsfeldt","author_inst":"Oregon Health and Sciences University"},{"author_name":"Akira Nagamori","author_inst":"Salk Institute of Biological Sciences"},{"author_name":"Hoi Sang U","author_inst":"University of California San Diego"},{"author_name":"David M Roth","author_inst":"University of California San Diego"},{"author_name":"Drew Hall","author_inst":"UCSD"},{"author_name":"Sharona Ben-Haim","author_inst":"University of California San Diego"},{"author_name":"Eiman Azim","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Tony L. Yaksh","author_inst":"University of California, San Diego"},{"author_name":"Alexander Khalessi","author_inst":"University of California San Diego"},{"author_name":"Mark Tuszynski","author_inst":"University of California San Diego"},{"author_name":"Shadi A. Dayeh","author_inst":"University of California San Diego"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Systemic degradation of repressive transcription factors gates gene expression and cell fate specification","rel_doi":"10.64898\/2026.06.16.732780","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732780","rel_abs":"While proteasomes are best known for eliminating defective proteins or turning off signaling pathways, they also enable crucial cellular activities. Critical among these, proteasomes allow cells to initiate gene expression, but underlying targets and regulatory mechanisms remain poorly understood. Here, we report that proteasomes drive the systemic degradation of repressive transcription factors to eject TLE\/Groucho-family co-repressors from chromatin and thereby constantly free transcription start sites for activator binding. This circuitry requires the E3 ligase SCF-FBXL14, which modifies its targets dependent on presentation by TLEs, but independently of their identity. The continuous cycling of co-repressors off chromatin, as achieved by systemic turnover of a protein family, is essential for stem cells to translate developmental cues into lineage-specific gene expression, and it is disrupted by cancer mutations in TLE1 that impair SCFFBXL14-recruitment. We conclude that systemic degradation of repressive transcription factors establishes co-repressor dynamics required for genes expression and cell fate specification.","rel_num_authors":7,"rel_authors":[{"author_name":"Predrag Jevtic","author_inst":"University of California, Berkeley"},{"author_name":"Samuel R Witus","author_inst":"UC Berkeley"},{"author_name":"Devlon M McCloud","author_inst":"UC Berkeley"},{"author_name":"Zhi Yang","author_inst":"UC Berkeley"},{"author_name":"Ana Milunevic Jevtic","author_inst":"UC Berkeley"},{"author_name":"Heegwang Roh","author_inst":"UC Berkeley"},{"author_name":"Michael Rape","author_inst":"UC Berkeley"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"The optical origin of the human skin color 'banana' in CIELAB space","rel_doi":"10.64898\/2026.06.16.732713","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732713","rel_abs":"Human skin colors occupy a characteristic banana-shaped region in CIE L*a*b* space, but why skin color coordinates are restricted to this region and how they relate to melanin and blood remain incompletely understood. We developed a physics-based framework linking skin chromophore content to colorimeter-derived skin color coordinates using two complementary three-layer light transport models. Across physiologic ranges of epidermal melanosome volume fraction and dermal blood volume fraction, simulated reflectance spectra were converted to CIE L*a*b* coordinates and compared with human skin color measurements from the International Skin Spectra Archive. Physiologic variation in melanin and blood reproduced the observed banana-shaped locus and revealed distinct chromophore-specific trajectories. Iso-melanin trajectories became progressively more linear as melanin increased, whereas iso-blood trajectories retained the curvature of the skin color locus. As melanin increased, perceptible color differences from blood volume changes were reduced, providing a mechanistic explanation for reduced erythema visibility in highly pigmented skin. These relationships were stable across plausible variations in layer thickness and tissue oxygenation and agreed with external validation data. The framework also identified when the Individual Typology Angle is confounded by blood or distorted by dermal melanin. Together, these findings establish a mechanistic optical basis for interpreting colorimeter-derived skin color coordinates.","rel_num_authors":7,"rel_authors":[{"author_name":"Maysoon Harunani","author_inst":"Washington University in St. Louis"},{"author_name":"Ye Jin Han","author_inst":"Washington University in St. Louis"},{"author_name":"Mutian Shen","author_inst":"Washington University in St. Louis"},{"author_name":"Blake Sparkman","author_inst":"Washington University in St. Louis"},{"author_name":"David Chen","author_inst":"Washington University School of Medicine"},{"author_name":"Zohar Nussinov","author_inst":"Washington University in St. Louis"},{"author_name":"Leonid Shmuylovich","author_inst":"Washington University in Saint Louis"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Microstructural and Biomechanical Determinants of Biological Aging","rel_doi":"10.64898\/2026.06.16.732769","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732769","rel_abs":"The pulmonary artery undergoes measurable structural and mechanical deterioration with age, but whether these changes can be integrated into a quantitative normative aging prediction model has not been demonstrated. Using two-photon imaging and paired vascular mechanical measurements from C57BL6 mice spanning 6 to 24 months, we developed a multimodal support vector regression (SVR) model integrating collagen fiber orientation, straightness, and hemodynamic mechanical parameters to predict normative age. Fiber orientation was encoded via the von Mises probability density function referenced to the circumferential and axial vessel wall axes providing a principled circular-variable encoding of both mean direction and concentration. The microstructure-only model achieved leave-one-out (LOO) R{superscript 2} = 0.596, Mean Absolute Error (MAE) = 3.43 months. Adding vascular mechanical parameters (PWV) raised a combined LOO R{superscript 2} to 0.834 (MAE = 2.26 months), a 40.1% improvement. Because pulmonary vascular and parenchymal aging are mechanistically coupled, lung mechanics were included as a complementary readout to assess whether airway mechanics contribute independent predictive signal beyond vascular microstructure alone. A sex dimorphism was observed, where females drove the majority of the collagen-based predictive signal (female-only R{superscript 2} = 0.960 vs. male-only R{superscript 2} = 0.658). These results establish a multimodal framework for vascular biological age quantification that integrates structural and mechanical aging signatures.","rel_num_authors":8,"rel_authors":[{"author_name":"Pramath Doddaballapur","author_inst":"University California, Santa Barbara"},{"author_name":"Jack Di Palo","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine"},{"author_name":"Dongnan Liu","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine"},{"author_name":"Liqin Lin","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine"},{"author_name":"Cristina CAVINATO","author_inst":"Univ. Montpellier, CNRS"},{"author_name":"Abhay B Ramachandra","author_inst":"Department of Mechanical Engineering, Iowa State University"},{"author_name":"Xiting Yan","author_inst":"Yale University School of Medicine"},{"author_name":"Edward P Manning","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Microstructural and Biomechanical Determinants of Biological Aging","rel_doi":"10.64898\/2026.06.16.732769","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732769","rel_abs":"The pulmonary artery undergoes measurable structural and mechanical deterioration with age, but whether these changes can be integrated into a quantitative normative aging prediction model has not been demonstrated. Using two-photon imaging and paired vascular mechanical measurements from C57BL6 mice spanning 6 to 24 months, we developed a multimodal support vector regression (SVR) model integrating collagen fiber orientation, straightness, and hemodynamic mechanical parameters to predict normative age. Fiber orientation was encoded via the von Mises probability density function referenced to the circumferential and axial vessel wall axes providing a principled circular-variable encoding of both mean direction and concentration. The microstructure-only model achieved leave-one-out (LOO) R{superscript 2} = 0.596, Mean Absolute Error (MAE) = 3.43 months. Adding vascular mechanical parameters (PWV) raised a combined LOO R{superscript 2} to 0.834 (MAE = 2.26 months), a 40.1% improvement. Because pulmonary vascular and parenchymal aging are mechanistically coupled, lung mechanics were included as a complementary readout to assess whether airway mechanics contribute independent predictive signal beyond vascular microstructure alone. A sex dimorphism was observed, where females drove the majority of the collagen-based predictive signal (female-only R{superscript 2} = 0.960 vs. male-only R{superscript 2} = 0.658). These results establish a multimodal framework for vascular biological age quantification that integrates structural and mechanical aging signatures.","rel_num_authors":8,"rel_authors":[{"author_name":"Pramath Doddaballapur","author_inst":"University California, Santa Barbara"},{"author_name":"Jack Di Palo","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine"},{"author_name":"Dongnan Liu","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine"},{"author_name":"Liqin Lin","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine"},{"author_name":"Cristina CAVINATO","author_inst":"Univ. Montpellier, CNRS"},{"author_name":"Abhay B Ramachandra","author_inst":"Department of Mechanical Engineering, Iowa State University"},{"author_name":"Xiting Yan","author_inst":"Yale University School of Medicine"},{"author_name":"Edward P Manning","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"RNA 3D Motif Dynamics Guide Assembly of the Replication Initiation Complex in Flaviviruses","rel_doi":"10.64898\/2026.06.16.732768","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732768","rel_abs":"Viral genomes encode dynamic RNA structures that are specifically recognized by proteins to regulate critical steps of the viral life cycle. Although these RNAs exist as multi-state conformational ensembles, structural studies have largely captured single conformations, limiting our mechanistic understanding of RNA-protein recognition and function. Here, using single-particle cryo-electron microscopy (cryo-EM), single-molecule Forster resonance energy transfer, and biochemical assays, we show how flaviviral genomes use structural dynamics encoded in their stem-loop A (SLA) to guide a conserved, multi-step mechanism of negative-strand synthesis initiation by non-structural protein 5 (NS5). Cryo-EM ensembles of SLAs from dengue, Zika, West Nile, and yellow fever viruses reveal a conserved conformational landscape dictated by alternative stacking configurations of a central three-way junction (3WJ). Cryo-EM structures of SLA-NS5 complexes from dengue and Zika show that NS5 engages a specific state within SLA 3D ensemble, one in which the 3WJ adopts a GRR\/A tetraloop-like motif that we identify across diverse structural RNAs. Strikingly, mutations that substantially destabilize this state impair negative-strand synthesis without affecting NS5 binding, decoupling binding from function and ruling out a simple conformational-capture mechanism. Instead, the SLA's intrinsic structural dynamics direct a post-binding conformational search that converts an initial, conformationally heterogeneous encounter complex into a productive replication-initiation complex. These results demonstrate a mechanism of RNA-protein recognition in which the 3D conformational ensemble of an RNA guides formation of the functional state downstream of binding, and identify a ubiquitous, intrinsically dynamic 3D motif within the SLA's 3WJ as a critical determinant of flavivirus negative-strand synthesis.","rel_num_authors":8,"rel_authors":[{"author_name":"Lorena V Streit","author_inst":"The Rockefeller University"},{"author_name":"Takashi Onikubo","author_inst":"The Rockefeller University"},{"author_name":"Miro A Astore","author_inst":"The Rockefeller University"},{"author_name":"Emily A Cioppa","author_inst":"The Rockefeller University"},{"author_name":"Paul Dominic B Olinares","author_inst":"The Rockefeller University"},{"author_name":"Linas Urnavicius","author_inst":"The Rockefeller University"},{"author_name":"Danny Incarnato","author_inst":"University of Groningen"},{"author_name":"Steve L Bonilla","author_inst":"The Rockefeller University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Preserved Medial Temporal Lobe Flexibility Predicts Memory Generalization Only in the Context of Good Sleep Quality among Older African Americans","rel_doi":"10.64898\/2026.06.15.26355704","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355704","rel_abs":"Objectives: Poor sleep quality is a risk factor for Alzheimer's disease (AD). Older African Americans experience disproportionately high rates of sleep disturbance and AD. Medial temporal lobe (MTL) flexibility reflects dynamic neural reorganization and may be a marker of generalization performance. This study examined whether sleep quality moderates the association between MTL flexibility and memory generalization. Methods: Fifty older African Americans (MeanAge=69.7{+\/-}6.21 years; 80% women) underwent rs-fMRI to quantify MTL flexibility, Rutgers Acquired Equivalence Task for memory generalization, and Pittsburgh Sleep Quality Index for sleep quality. Results: Greater MTL flexibility was associated with better generalization (r=0.367, p=.017). Good sleepers showed higher MTL flexibility (F(1,44)=8.11, p2=.156, p=.007) and superior generalization (F(1,46)= 12.33, p2=.211, p=.001). Sleep quality significantly moderated the MTL flexibility and generalization relationship ({beta}=-1.519, p=.012). Conclusions: Preserved MTL flexibility may confer generalization only in good sleepers, suggesting that sleep disturbance may disrupt the MTL neural resilience among older African Americans.","rel_num_authors":5,"rel_authors":[{"author_name":"Payton G White","author_inst":"Rutgers University- Newark"},{"author_name":"Miray Budak","author_inst":"Rutgers University- Newark"},{"author_name":"Soodeh Moallemian","author_inst":"Rutgers University-Newark"},{"author_name":"Bernadette Fausto","author_inst":"Thomas Jefferson University"},{"author_name":"Mark Gluck","author_inst":"Rutgers University-Newark"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Reverse engineering of motor unit discharge in multiple sclerosis reveals heterogeneity of voluntary motor commands","rel_doi":"10.64898\/2026.06.15.26355613","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355613","rel_abs":"Central nervous system injury causes motor deficits through derangement of excitatory, inhibitory, and\/or neuromodulatory inputs to motoneurons, the three fundamental components of motor commands. Typically, study of pathologic neural control in humans is restricted to only one of the three. Chardon et al. (2024) presented a fundamentally new approach to comprehensively study all components by reverse engineering motor unit firing patterns. We apply their framework to motor unit firing patterns from 89 people with multiple sclerosis (MS) and 34 controls to study excitatory, inhibitory, and neuromodulatory contributions to pathologic motor output. Disruptions to all components are plausible in MS, a disease hallmarked by heterogeneity in nearly all aspects. Accordingly, we found abnormalities in MS for all three components. Notably, neuromodulation included both high and low extremes. Our results suggest that pathophysiology of motor commands in MS varies among patients, a finding fundamentally different from other studied populations showing relative consistency.","rel_num_authors":8,"rel_authors":[{"author_name":"Laura M. McPherson","author_inst":"Washington University School of Medicine"},{"author_name":"Keith Lohse","author_inst":"Washington University School of Medicine"},{"author_name":"Skyler M. Simon","author_inst":"Washington University School of Medicine"},{"author_name":"Daniel B. Free","author_inst":"Washington University School of Medicine"},{"author_name":"James Andrew Beauchamp","author_inst":"Carnegie Mellon University"},{"author_name":"Francesco Negro","author_inst":"University of Brescia"},{"author_name":"Robert T. Naismith","author_inst":"Washington University School of Medicine"},{"author_name":"Anne H. Cross","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Reverse engineering of motor unit discharge in multiple sclerosis reveals heterogeneity of voluntary motor commands","rel_doi":"10.64898\/2026.06.15.26355613","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355613","rel_abs":"Central nervous system injury causes motor deficits through derangement of excitatory, inhibitory, and\/or neuromodulatory inputs to motoneurons, the three fundamental components of motor commands. Typically, study of pathologic neural control in humans is restricted to only one of the three. Chardon et al. (2024) presented a fundamentally new approach to comprehensively study all components by reverse engineering motor unit firing patterns. We apply their framework to motor unit firing patterns from 89 people with multiple sclerosis (MS) and 34 controls to study excitatory, inhibitory, and neuromodulatory contributions to pathologic motor output. Disruptions to all components are plausible in MS, a disease hallmarked by heterogeneity in nearly all aspects. Accordingly, we found abnormalities in MS for all three components. Notably, neuromodulation included both high and low extremes. Our results suggest that pathophysiology of motor commands in MS varies among patients, a finding fundamentally different from other studied populations showing relative consistency.","rel_num_authors":8,"rel_authors":[{"author_name":"Laura M. McPherson","author_inst":"Washington University School of Medicine"},{"author_name":"Keith Lohse","author_inst":"Washington University School of Medicine"},{"author_name":"Skyler M. Simon","author_inst":"Washington University School of Medicine"},{"author_name":"Daniel B. Free","author_inst":"Washington University School of Medicine"},{"author_name":"James Andrew Beauchamp","author_inst":"Carnegie Mellon University"},{"author_name":"Francesco Negro","author_inst":"University of Brescia"},{"author_name":"Robert T. Naismith","author_inst":"Washington University School of Medicine"},{"author_name":"Anne H. Cross","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"A multistate model of frailty progression after severe infections in adults >=65 years in England: a matched-cohort study","rel_doi":"10.64898\/2026.06.16.26355787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355787","rel_abs":"Background Evidence on frailty progression following severe infections is limited. We compared rates of transition to greater frailty or death between adults with and without severe infection in England. Methods We conducted a matched-cohort study among adults aged [&ge;]65 years (1,452,117: median age 76 years, 45% male) in Clinical Practice Research Datalink Aurum (2006-2019). Adults with severe infection (hospitalised primarily due to infection) were matched on calendar time to individuals without severe infection on age, sex, and primary care practice. The admission date was used as index date and same was assigned to matched unexposed adults. We measured frailty using Electronic Frailty Index, a proportion of 36 health deficits in validated categories (Fit 0-0.12, Mild >0.12-0.24, Moderate >0.24-0.36, Severe >0.36). In a time-varying Markov multistate model, we focused on forward transitions from baseline or intermediate frailty states to higher states or death. For each transition, we used Cox regression to estimate cause-specific transition hazard ratios (HR) with 95% confidence intervals (CIs), comparing adults with and without severe infection. We adjusted for baseline frailty score, age, sex, deprivation, harmful alcohol use, smoking, and primary care infection history 5 years before index date. We estimated state occupancy probabilities, and expected length of stay (ELOS) in each state at year five among adults with and without severe infection. We explored effect modification by infection type. Results Across all transitions, severe infection was associated with higher adjusted hazards of transitioning to worsening frailty or death, HR, 95% CI: (fit to: mild[1.56, 1.54-1.58], moderate[2.51, 1.79-3.51], death[4.57, 4.50-4.65]; mild to: moderate[1.52, 1.50-1.53], severe[1.90, 1.43-2.52], death[2.67, 2.64-2.70]; moderate to: severe[1.40, 1.38-1.42], death[1.87, 1.85-1.90]; severe to death[1.48, 1.46-1.50]). Transition hazard ratios were strongest for lower respiratory tract infections, followed by sepsis, urinary tract infections, meningitis\/encephalitis, gastroenteritis, and skin and soft tissue infections. At five years, adults with severe infection had higher probabilities of transitioning to greater frailty or death across all transitions and lower ELOS in each frailty state than those without severe infection. Interpretation Severe infections may accelerate frailty deterioration in older age. Prevention through vaccination, early detection, and prompt management may help mitigate this decline.","rel_num_authors":10,"rel_authors":[{"author_name":"Kwabena Asare","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine"},{"author_name":"Kate E. Mansfield","author_inst":"School of Health and Care Sciences, University of Lincoln, Lincoln, United Kingdom."},{"author_name":"Georgia R. Gore-Langton","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom."},{"author_name":"Eleanor Barry","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom."},{"author_name":"Ruth Keogh","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom."},{"author_name":"Vincent Lo Re III","author_inst":"Center for Pharmacoepidemiology and Treatment Science, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, NJ, Unite"},{"author_name":"Maria C. Rodriguez-Barradas","author_inst":"Michael E. DeBakey VA Medical Center, Houston, TX, United States."},{"author_name":"Amy c. Justice","author_inst":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States."},{"author_name":"Christopher T. Rentsch","author_inst":"US Department of Veterans Affairs, London School of Hygiene and Tropical Medicine"},{"author_name":"Charlotte Warren-Gash","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom."}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Identifying anaphylaxis using weakly-supervised prediction models and natural language processing","rel_doi":"10.64898\/2026.06.09.26355005","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355005","rel_abs":"Objectives Scalable computable phenotyping algorithms are critical for conducting high-throughput disease-outcome research in large, distributed-data electronic health record (EHR) and claims data settings. We developed and evaluated a claims- and EHR-based computable phenotyping algorithm for anaphylaxis, a rare acute condition that is challenging to accurately identify using claims data alone. Materials and Methods Potential anaphylaxis events came from two healthcare systems (Kaiser Permanente Washington [KPWA] and Vanderbilt University Medical Center [VUMC]). We engineered features from clinical text using automated natural language processing (NLP) methods. We then developed a phenotyping algorithm using four NLP- and diagnosis code-based silver labels (proxies for the gold-standard labels). Gold-standard abstracted outcomes were used to evaluate algorithm performance. Results The largest area under the receiver operating characteristic curve (AUC) was 0.931 for an NLP-based silver-label model at KPWA. Depending on the model and healthcare system site, positive predictive value (PPV) and sensitivity at the threshold of predicted probability that maximized F1 score ranged from 0.52 to 0.77 (PPV) and 0.78 to 1 (sensitivity). Discussion NLP-based silver-label models had large AUC at KPWA but not at VUMC. This may be because clinical text at KPWA is only available for outpatient encounters and secure messaging. High sensitivity for identifying anaphylaxis can be obtained using our best-performing models. Conclusion The best-performing models had better PPV and sensitivity tradeoffs than prior bespoke anaphylaxis models with costly, manually curated features. The simplicity of the approach compared to traditional phenotyping methods allows it to be deployed easily at multiple health care systems.","rel_num_authors":19,"rel_authors":[{"author_name":"Brian D Williamson","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"David J Cronkite","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Onchee Yu","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Arvind Ramaprasan","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Sharon Fuller","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Jennifer Covey","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Erika Kiniry","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Daniel Park","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Robert Winter","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jill Whitaker","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Michael F McLemore","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Saranrat Wittayanukorn","author_inst":"US Food and Drug Administration"},{"author_name":"Danijela Stojanovic","author_inst":"US Food and Drug Administration"},{"author_name":"Yueqin Zhao","author_inst":"US Food and Drug Administration"},{"author_name":"Sarah Dutcher","author_inst":"US Food and Drug Administration"},{"author_name":"David S Carrell","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Lisa A Jackson","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Jennifer C Nelson","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Joshua C Smith","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Diagnostic Concordance of Immediate Versus 1-Hour Technetium-99m Hydroxydiphosphonate Scintigraphy in Suspected Transthyretin Amyloid Cardiomyopathy","rel_doi":"10.64898\/2026.06.16.26355752","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355752","rel_abs":"Background Bone-avid tracer myocardial scintigraphy for the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) has traditionally employed imaging at one or 3-hour intervals. Technetium-99m hydroxydiphosphonate (99mTc-HDP) has unique characteristics that may enable earlier imaging. We investigated the diagnostic concordance of immediate versus 1-hour acquisitions. Methods Consecutive patients with suspected ATTR-CM underwent planar imaging and SPECT\/CT immediately and at 1-hour following the administration of 99mTc-HDP. Perugini grades and heart to contralateral lung (H\/CL) ratios were assessed. Target-to-background ratios (TBRs) were calculated on the SPECT\/CT acquisitions using the left ventricular (LV) septum and three background regions: aorta, LV blood-pool, and vertebrae. We assessed diagnostic concordance using Cohen's Kappa ({kappa}), temporal stability using paired t-tests, and correlation between timepoints using Pearson's coefficient (r). The 1-hour SPECT\/CT interpretation served as the protocol reference standard. Results Forty-eight patients (83% male; median age, 80 [73-85] years) were evaluated. One-hour SPECT\/CT identified 19 positive and 29 negative cases. Immediate SPECT\/CT demonstrated 100% diagnostic concordance with the 1-hour reference standard ({kappa} = 1.000; 95% CI: 1.00 to 1.00; p < 0.001). The LV septum\/LV Blood-Pool TBR showed the highest correlation (r = 0.956; 95% CI: 0.922 to 0.975; p < 0.001). The LV Septum\/Aorta TBR demonstrated high correlation (r = 0.918; 95% CI: 0.857 to 0.953; p < 0.001) and remained stable in the ATTR-negative cohort (-0.02; 95% CI: -0.08 to 0.04; p = 0.54). Significant decrease in the LV Septum\/Vertebrae TBR in the ATTR-negative (-0.55; 95% CI: -0.64 to -0.47; p < 0.001) and ATTR-positive cohorts (-1.14; 95% CI: -1.39 to -0.89; p < 0.001) was observed. Conclusions Immediate 99mTc-HDP SPECT\/CT is diagnostically concordant with standard 1-hour protocols. By leveraging SPECT\/CT and the favorable kinetics of 99mTc-HDP, immediate-phase imaging can accurately reproduce 1-hour acquisitions in cases of suspected ATTR-CM. This expedited approach may improve nuclear laboratory throughput and patient satisfaction.","rel_num_authors":12,"rel_authors":[{"author_name":"Andrew Costa","author_inst":"Oregon Health and Science University"},{"author_name":"Austen Suits","author_inst":"Oregon Health and Science University"},{"author_name":"Jack Miller","author_inst":"Oregon Health and Science University"},{"author_name":"Maros Ferencik","author_inst":"Oregon Health and Science University"},{"author_name":"David M. German","author_inst":"Oregon Health and Science University"},{"author_name":"Evan F. Shalen","author_inst":"Oregon Health and Science University"},{"author_name":"Gagandeep Choudhary","author_inst":"Oregon Health and Science University"},{"author_name":"Laszlo Szidonya","author_inst":"Oregon Health and Science University"},{"author_name":"Mike Nguyen","author_inst":"Oregon Health and Science University"},{"author_name":"Nadine Mallak","author_inst":"Oregon Health and Science University"},{"author_name":"Sebastan Obrzut","author_inst":"Oregon Health and Science University"},{"author_name":"Ahmad Masri","author_inst":"Oregon Health and Science University"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Proteomics Uncovers Cryptic JPH2 Loss in Paediatric Dilated Cardiomyopathy","rel_doi":"10.64898\/2026.06.16.26355718","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355718","rel_abs":"Despite recent advances in next-generation sequencing, genetic diagnostic rates for dilated cardiomyopathy (DCM) remain low. Among paediatric DCM, causes are often heritable, with a greater frequency of de novo, recessive and syndromic causes of disease. Novel diagnostic methods are therefore required to solve monogenic cases. To assess the value of proteomics as a diagnostic tool for paediatric DCM, we obtained left ventricle myocardial samples from paediatric patients undergoing heart transplantation at the Royal Children's Hospital, Melbourne. We performed genome sequencing and proteomics and leveraged this multi-omics dataset to uncover the molecular cause of disease in a gene elusive proband. The proband carried a heterozygous JPH2 frameshift variant identified on clinical exome sequencing. However, proteomic analysis showed a pronounced downregulation of JPH2, suggestive of biallelic loss-of-function. Closer inspection of the genomic data revealed a large inversion (~8.34 Mb) with a breakpoint falling within intron 5 of JPH2 that displaces the 3'UTR from the coding transcript. The two variants were confirmed to be in trans using long read DNA sequencing, consistent with a diagnosis of JPH2 autosomal recessive DCM. Finally, we applied RNA sequencing with total RNA library preparation to show that transcripts containing a 3'UTR were reduced to ~10% relative to controls. As a proof-of-principle, we present the first reported use of proteomics from explanted cardiac tissue to provide a genetic diagnosis. Our methodology has broad relevance to patients with genetically unsolved Mendelian diseases, who might undergo organ transplantation as part of clinical management.","rel_num_authors":29,"rel_authors":[{"author_name":"Carlos C Smith-Diaz","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Valerii Iaprintsev","author_inst":"The Royal Children's Hospital Melbourne; University of Melbourne; Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine"},{"author_name":"Hannah Huckstep","author_inst":"Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine"},{"author_name":"Ivan Macciocca","author_inst":"Victorian Clinical Genetics Services; University of Melbourne; Murdoch Children's Research Institute"},{"author_name":"Adam T Piers","author_inst":"Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine; Centre for Population Genomics"},{"author_name":"Natasha Henden","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Samantha Bryen","author_inst":"Centre for Population Genomics"},{"author_name":"Natalie Stewart","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Alexandra Butters","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Amy Baker","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Laura Catto","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Leah Kemp","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Ingrid King","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Lina H H Le","author_inst":"Murdoch Children's Research Institute"},{"author_name":"David A Elliott","author_inst":"University of Melbourne; Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine; Melbourne Centre for Cardiovascular Genom"},{"author_name":"Kevin I Watt","author_inst":"Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine; The University of Melbourne"},{"author_name":"Jacob Mathew","author_inst":"Murdoch Children's Research Institute; The Royal Children's Hospital Melbourne"},{"author_name":"Robert Justo","author_inst":"Queensland Childrens Hospital"},{"author_name":"Ebony Richardson","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Cas Simons","author_inst":"Centre for Population Genomics"},{"author_name":"Andrew P Landstrom","author_inst":"The Children's Hospital of Philadelphia; University of Pennsylvania"},{"author_name":"Christina V Theodoris","author_inst":"Gladstone Institute of Cardiovascular Disease; Gladstone Institute of Data Science and Biotechnology; University of California, San Francisco"},{"author_name":"Ira W Deveson","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Daniel G MacArthur","author_inst":"Centre for Population Genomics"},{"author_name":"Igor Konstantinov","author_inst":"The Royal Children's Hospital, Melbourne; University of Melbourne; Murdoch Children's Research Institute; Melbourne Centre for Cardiovascular Genomics and Regen"},{"author_name":"Robert Weintraub","author_inst":"Murdoch Children's Research Institute; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine; The Royal Children's Hospital, Melbourne"},{"author_name":"Enzo R Porrello","author_inst":"University of Melbourne; Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine; Melbourne Centre for Cardiovascular Genom"},{"author_name":"Sean J Humphrey","author_inst":"Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine"},{"author_name":"Jodie Ingles","author_inst":"Garvan Institute of Medical Research"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Characterizing the genetic basis of Cardio-Renal-Metabolic multimorbidity using multivariate genomic modelling","rel_doi":"10.64898\/2026.06.16.26355643","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355643","rel_abs":"Cardio-renal-metabolic multimorbidity (CRMM) encompasses interrelated conditions affecting the heart, kidneys, and metabolic systems. Although the genetics of individual components are well studied, their shared architecture remains unclear. Here, we performed the largest multi-ancestry multivariate GWAS of CRMM across seven biobanks, including individuals of European (EUR; neff = 353,130), African (AFR; neff = 75,436), and East Asian (EAS; neff = 164,373) ancestry. We identified 287 lead loci in EUR, 30 in AFR, and 202 in EAS. Cross-ancestry analyses revealed ancestry-specific signals and 24 shared loci mapping to FTO and TCF7L2. Drug-repurposing highlighted candidates used for type 2 diabetes and hypertension. Mendelian randomization supported causal links with diverse diseases, while polygenic risk scores showed improved prediction across ancestries. Collectively, these findings advance understanding of CRMM genetics and inform precision medicine.","rel_num_authors":4,"rel_authors":[{"author_name":"Abhiram D. B.","author_inst":"Institute for Biomedicine and Glycomics, Griffith University, Brisbane, Australia"},{"author_name":"Vignesh Arunachalam","author_inst":"Department of Dermatology, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Rodney A Lea","author_inst":"Centre for Genomics and Personalised Health, School of Biomedical Science, Queensland"},{"author_name":"Shivashankar H. Nagaraj","author_inst":"Institute for Biomedicine and Glycomics, Griffith University, Brisbane, Australia"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Azacytidine restores T cell function in AML by modulating DNA methylation","rel_doi":"10.64898\/2026.06.14.732148","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732148","rel_abs":"AML is an aggressive blood cancer associated with poor clinical outcomes. Chemotherapy remains the standard of treatment, but unfortunately relapse is very common, highlighting the need for alternative therapies. T cell dysfunction and exhaustion are prominent in AML and may represent a barrier to effective immunotherapy yet remains poorly studied in AML. DNA methylation is a major driver of T cell exhaustion and inhibition of de novo methylation can block exhaustion and restore T cell function in chronic viral infections and other cancers but is understudied in AML. Here, we investigated the impact of azacytidine (Aza), an FDA-approved hypomethylating agent, on T cell exhaustion in AML. Using a spontaneous AML mouse model and samples from patients with AML, we found that Aza treatment modulates T cell function. In vivo Aza-treatment of AML-bearing mice decreased tumor burden and reshaped CD8+ T cell states, with increases in frequencies of memory subsets and decreases in regulatory T cells (Tregs). Functionally, Aza treatment overcame the impaired proliferation displayed by both CD4 and CD8+ T cells in our model. DNA methylation sequencing of T cells after Aza treatment revealed hypomethylation and increased expression of stem-like precursor gene TCF7 and E2F2, a regulator of cell cycle progression and proliferation. Similar changes in phenotypes were observed in cultures of AML patient samples treated with Aza. Collectively, we show that Aza remodels epigenetic and functional states in AML and has the potential to reverse T cell exhaustion, with enhanced memory and proliferation capacity. Our work generates a mechanistic framework that provides rationale of combining hypomethylating agents with T cell-based immunotherapies in this lethal disease.\n\nData Sharing StatementRRBS data is available in GEO under the accession number GSE328721. For original data please contact Dr. Evan F. Lind.\n\nKey PointsAzacytidine mediated epigenetic modulation can alleviate T cell exhaustion in AML\n\nTranslational RelevanceImmune therapy has shown limited efficacy in AML, despite increasing evidence of T cell dysfunction in this malignancy. Azacytidine (Aza) is an FDA approved drug for AML, but patients develop therapy resistance and relapse. Studies have mainly focused on Azas tumor intrinsic effects. In this study, we investigated the impact of Aza on immune function, especially T cell exhaustion in AML, since exhaustion is a major mechanism of disease resistance. We demonstrated that Aza can modulate T cell phenotype and restore T cell proliferation. Mechanistically, Aza induces epigenetic reprogramming in T cells and increases the expression of a stem-like precursor marker, TCF7. By shifting the focus on T cell biology, our study provides a rationale for combining Aza with other immunotherapies that can enhance durable immune responses in this malignancy.","rel_num_authors":7,"rel_authors":[{"author_name":"Ravina Pandita","author_inst":"Oregon Health & Science University"},{"author_name":"Yoko Kosaka","author_inst":"Oregon Health & Science University"},{"author_name":"Jessica S Mulkey","author_inst":"Oregon Health & Science University"},{"author_name":"Cora E Layman","author_inst":"Oregon Health & Science University"},{"author_name":"Brett E Davis","author_inst":"Oregon Health & Science University"},{"author_name":"Lucia Carbone","author_inst":"Oregon health & science university"},{"author_name":"Evan F Lind","author_inst":"Oregon Health & Science University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"FALCON: Closed-Loop Multi-Objective Optimization of Lipid Nanoparticles for Cell-Selective mRNA Delivery","rel_doi":"10.64898\/2026.06.13.731774","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.731774","rel_abs":"Efficient, cell type-selective delivery of genetic payloads remains a central challenge in the development of gene and cell therapies. Lipid nanoparticles (LNPs) offer a versatile delivery platform, but their optimization is hindered by reliance on brute-force screening methods that are laborious, resource-intensive, and focus on single targets. Here, we present FALCON (Framework for Active Learning-driven Compositional Optimization of Nanoparticles), a closed-loop pipeline that leverages iterative screening, surrogate modeling, and multi-objective optimization to accelerate LNP compositional design. In B cell-targeted validation experiments, FALCON-optimized LNPs achieved a 1.8-fold increase in splenic B cell transfection in vivo compared with reference compositions. When optimized for selectivity, FALCON LNPs displayed an 84-fold improvement in selective transfection of splenic B cells over off-target liver populations and enabled spleen-tropic behavior across factorial panels of varying ionizable and helper lipid chemistries. In vaccine studies, these LNPs induced higher IgG2c antibody titers and a more Th1-biased immune profile. FALCON was also deployed to optimize LNPs for myeloid cell-selective delivery, achieving enhanced in vivo selectivity following systemic administration both across and within spleen and liver compartments. Our results establish FALCON as a useful tool for data-driven design of LNP compositions for precision gene delivery.","rel_num_authors":28,"rel_authors":[{"author_name":"Wu Han Toh","author_inst":"Johns Hopkins University"},{"author_name":"Leonardo Cheng","author_inst":"Johns Hopkins University"},{"author_name":"Brandon Chang","author_inst":"Johns Hopkins University"},{"author_name":"Di Yu","author_inst":"Johns Hopkins University"},{"author_name":"Jingyao Ma","author_inst":"Johns Hopkins University"},{"author_name":"Xiuchun Huang","author_inst":"Johns Hopkins University"},{"author_name":"Gene Weng","author_inst":"Johns Hopkins University"},{"author_name":"Yining Zhu","author_inst":"Johns Hopkins University"},{"author_name":"Xiaoya Lu","author_inst":"Johns Hopkins University"},{"author_name":"Jinghan Lin","author_inst":"Johns Hopkins University"},{"author_name":"Jin Liu","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Joseph Choy","author_inst":"Johns Hopkins University"},{"author_name":"Autumn Greco","author_inst":"Johns Hopkins University"},{"author_name":"Manav Jain","author_inst":"Johns Hopkins University"},{"author_name":"Joanna Yang","author_inst":"Johns Hopkins University"},{"author_name":"Milan Patel","author_inst":"Johns Hopkins University"},{"author_name":"Grace Shoemaker","author_inst":"Johns Hopkins University"},{"author_name":"Isabella Cozzone","author_inst":"Johns Hopkins University"},{"author_name":"Daniel Antov","author_inst":"Johns Hopkins University"},{"author_name":"Kevin Zhang","author_inst":"Johns Hopkins University"},{"author_name":"Sarp Kayabas","author_inst":"Johns Hopkins University"},{"author_name":"Charles Shin","author_inst":"Johns Hopkins University"},{"author_name":"Ataes Aggarwal","author_inst":"Johns Hopkins University"},{"author_name":"Jordan Green","author_inst":"Johns Hopkins University"},{"author_name":"Stephany Tzeng","author_inst":"Johns Hopkins University"},{"author_name":"Ramya Kumar","author_inst":"Colorado School of Mines"},{"author_name":"Maximilian F Konig","author_inst":"Johns Hopkins University"},{"author_name":"Hai-Quan Mao","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Colorful connections: pigment-based plumage and breeding condition are associated with gut microbiome variation in the Common Yellowthroat","rel_doi":"10.64898\/2026.06.16.732689","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732689","rel_abs":"Carotenoid- and melanin-based plumage coloration traits are key signals in avian communication and sexual selection as they are often thought to provide \"honest\" information about individual condition and fitness. These traits arise through distinct but interconnected physiological and genetic pathways. Recent work suggests that there may be a link between host-associated gut microbiota and the functional pathways leading to pigment-based plumage coloration, but this remains largely unexplored in wild populations. To address this gap, we tested whether variation in plumage coloration, as well as breeding condition, is associated with gut microbiome variation in wild populations of male Common Yellowthroats (Parulidae: Geothlypis trichas). We quantified multiple plumage coloration traits and characterized gut microbiome bacterial diversity using 16S rRNA metabarcoding. Through a comprehensive modeling framework, we found that individuals with brighter, more orange-tinted breast feathers and smaller cloacal protuberances (a proxy for breeding condition) exhibited higher gut microbiome diversity. At the taxonomic level, Methylobacterium-Methylorubrum, a carotenoid-producing bacteria, showed strong associations with multiple plumage traits, including mask area, breast feather hue, and saturation. Our results demonstrate that gut microbiome diversity is associated with variation in carotenoid-based coloration traits and breeding condition in Common Yellowthroats. More broadly, these results highlight the potential for host-microbiome interactions to shape phenotypic variation through physiological pathways in wild animal populations.","rel_num_authors":7,"rel_authors":[{"author_name":"Alix E Matthews","author_inst":"University at Buffalo"},{"author_name":"Maxima Gomez-Palmer","author_inst":"Department of Biology, Carleton College, Northfield, MN 55057, USA"},{"author_name":"Sebastian Gallego","author_inst":"Department of Biological Sciences, University at Buffalo (SUNY), Buffalo, NY 14260, USA"},{"author_name":"Mads Moore","author_inst":"Department of Ecology, Evolutionary Biology, and Environmental Sciences, Columbia University, New York, NY 10027, USA"},{"author_name":"Lan-Nhi Phung","author_inst":"Center for Innovation in Health Sciences, VinUniversity, Hanoi, Vietnam 10000"},{"author_name":"Daniel T Baldassarre","author_inst":"SUNY Oswego"},{"author_name":"Marcella D Baiz","author_inst":"Department of Biological Sciences, University at Buffalo (SUNY), Buffalo, NY 14260, USA"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Stability and Compressibility of Tear Film Lipid Layer: Impact of Benzalkonium Chloride Presence","rel_doi":"10.64898\/2026.06.13.731656","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.731656","rel_abs":"PURPOSE.: Benzalkonium chloride (BAK), a common preservative in eye drops, has a major side effect of dry eye. The mechanisms are typically attributed to BAK cytotoxicity. However, due to its surfactant properties, BAK can disrupt the tear film lipid layer (TFLL), leading to dry eye. This study examined the stability and compressibility of the TFLL and the impact of the presence of BAK. METHODS.: Meibomian gland secretion (meibum, source of the TFLL) was collected from sacrificed cows ' eyelids. Lipids were extracted by dissolving meibum in chloroform to a final concentration of 1 mg\/mL, with one solution additionally containing 0.1 mg\/mL BAK. Each solution was overlaid on a water subphase in a Langmuir Trough-Blodgett trough. The changes of surface pressure ({pi}) with area (A) for the lipid film upon compression were monitored, and the corresponding compression modulus (Cs-1) at each data point was determined. RESULTS.: The {pi}-A isotherms for meibum lipid monolayers exhibited near-reversible behavior with a smooth profile with a maximum {pi} of approximately 32 mN\/m. The Cs-1-{pi} isotherms of the meibum lipid monolayer show that the films are gel-like with a constant compressive modulus of 24-32 mN\/m within the surface pressure range of 8-30 mN\/m. In contrast, adding BAK dramatically decreased the maximum surface pressure to only 10 mN\/m and the compressive modulus to only 2-10 mN\/m. CONCLUSIONS.: This study demonstrated that BAK disrupts the meibum lipid layer by forming a monolayer with decreased stability and reduced compressive resistance, a mechanism that may underlie its dry-eye side effect yet has largely been neglected.","rel_num_authors":4,"rel_authors":[{"author_name":"Jianzhong Chen","author_inst":"Medical College of Georgia, Augusta University"},{"author_name":"Yiming Zhang","author_inst":"School of Materials Science and Engineering, Georgia Institute of Technology"},{"author_name":"Thai Minh Han Nguyen","author_inst":"Medical College of Georgia, Augusta University"},{"author_name":"Vladimir V Tsukruk","author_inst":"School of Materials Science and Engineering, Georgia Institute of Technology"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Correcting spatial transcriptomics data affected by a prevalent transcript leakage problem across platforms, species, and tissues","rel_doi":"10.64898\/2026.06.13.732076","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.732076","rel_abs":"Spatial transcriptomics has been widely applied to study the spatial distribution of cell types, cell states, and specific gene expression in tissue samples. However, we show that there is a prevalent transcript leakage problem in spatial transcriptomics data, where transcripts expressed by a cell diffuse to its neighborhood and are recurrently detected in the nearby cells. By analyzing published data sets, we show that this problem is general across data produced from different tissues and different species using different imaging-based and sequencing-based spatial transcriptomics platforms. It affects both upstream tasks such as expression quantification as well as downstream tasks such as cell-type annotation and detection of spatially-dependent gene expression. To tackle the transcript leakage problem, we propose a reference-free Bayesian model-based method, DeLeakage, which cleans up the data much more effectively than existing denoising methods. DeLeakage also improves cell-type annotation and avoids false detection of spatially dependent expression.","rel_num_authors":14,"rel_authors":[{"author_name":"Christina Huan Shi","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Yibo Zhai","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Savio Ho-Chit Chow","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Liangbang Li","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Chase M Carver","author_inst":"Mayo Clinic"},{"author_name":"Marcos Garcia Teneche","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Jesus Flores","author_inst":"University of California San Diego"},{"author_name":"Colin Kern","author_inst":"University of California San Diego"},{"author_name":"Peter D Adams","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Bing Ren","author_inst":"New York Genome Center"},{"author_name":"Marissa J Schafer","author_inst":"Mayo Clinic"},{"author_name":"Quan Zhu","author_inst":"University of California San Diego"},{"author_name":"Yingying Wei","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Kevin Y. Yip","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Correcting spatial transcriptomics data affected by a prevalent transcript leakage problem across platforms, species, and tissues","rel_doi":"10.64898\/2026.06.13.732076","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.732076","rel_abs":"Spatial transcriptomics has been widely applied to study the spatial distribution of cell types, cell states, and specific gene expression in tissue samples. However, we show that there is a prevalent transcript leakage problem in spatial transcriptomics data, where transcripts expressed by a cell diffuse to its neighborhood and are recurrently detected in the nearby cells. By analyzing published data sets, we show that this problem is general across data produced from different tissues and different species using different imaging-based and sequencing-based spatial transcriptomics platforms. It affects both upstream tasks such as expression quantification as well as downstream tasks such as cell-type annotation and detection of spatially-dependent gene expression. To tackle the transcript leakage problem, we propose a reference-free Bayesian model-based method, DeLeakage, which cleans up the data much more effectively than existing denoising methods. DeLeakage also improves cell-type annotation and avoids false detection of spatially dependent expression.","rel_num_authors":14,"rel_authors":[{"author_name":"Christina Huan Shi","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Yibo Zhai","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Savio Ho-Chit Chow","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Liangbang Li","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Chase M Carver","author_inst":"Mayo Clinic"},{"author_name":"Marcos Garcia Teneche","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Jesus Flores","author_inst":"University of California San Diego"},{"author_name":"Colin Kern","author_inst":"University of California San Diego"},{"author_name":"Peter D Adams","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Bing Ren","author_inst":"New York Genome Center"},{"author_name":"Marissa J Schafer","author_inst":"Mayo Clinic"},{"author_name":"Quan Zhu","author_inst":"University of California San Diego"},{"author_name":"Yingying Wei","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Kevin Y. Yip","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Simultaneous regeneration of skin and bone in full-thickness cranial composite defects","rel_doi":"10.64898\/2026.06.16.732662","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732662","rel_abs":"Traumatic cranial defects often involve concurrent loss of soft and hard tissues and can progress to chronic defects due to delayed healing associated with infection or other co-morbidities. Despite autologous reconstruction remaining the clinical standard, it requires staged procedures using heterogeneous tissues, increasing operative time, costs, and surgical risks. Moreover, current tissue engineering approaches focus on single tissues or acute tissue defect models, limiting their clinical applications. Herein, we describe an acellular, material-driven 3D-printed composite scaffold designed to regenerate both bone and skin within composite cranial defects. The scaffold integrates controlled copper ion release from both organic and inorganic components with 3D-printed citrate polymer and citrate polymer-ceramic composites. Integrated thermoresponsive citrate-based hydrogels further enable spatially defined dermoconductive and osteoconductive properties, supporting a one-step surgical approach. At 12 weeks post-implantation, our scaffold enhanced keratinocyte organization, collagen deposition, and defect coverage with mature bone, achieving histological outcomes comparable to autografts. Furthermore, the system suppressed bacterial burden. Thus, this acellular platform represents a clinically promising synchronized strategy to address the complex demands of traumatic craniofacial composite defects.","rel_num_authors":9,"rel_authors":[{"author_name":"Mirae Kim","author_inst":"Northwestern University"},{"author_name":"Yi Zhu","author_inst":"The University of Chicago"},{"author_name":"Shivakalyani Adepu","author_inst":"Northwestern University"},{"author_name":"Caralyn Paige Collins","author_inst":"Northwestern University"},{"author_name":"Maria Mendez-Santos","author_inst":"Northwestern University"},{"author_name":"Cheng Sun","author_inst":"Northwestern University"},{"author_name":"Tong-Chuan He","author_inst":"The University of Chicago"},{"author_name":"Russell Reid","author_inst":"The University of Chicago"},{"author_name":"Guillermo Antonio Ameer","author_inst":"Northwestern University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Label-Free All-Electrical Tracking of Individual and Collective Cell Migration on a Megapixel CMOS Capacitance Sensor","rel_doi":"10.64898\/2026.06.16.731623","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.731623","rel_abs":"Label-free tracking of adherent cell migration could enable important insights into biological processes such as tissue repair, inflammatory response, or cancer progression. Nevertheless, visualizing unlabeled animal cells using optical microscopy remains challenging due to low contrast as well as frequent changes in cell shape and number. A promising alternative uses electrical capacitance measurements, which are sensitive to cell adhesion to electrode surfaces. However, prior examples often utilized electrodes with areas larger than single cells, resulting in averaged readouts over multiple cells. Here, we demonstrate label-free, live-cell tracking using a capacitance sensor array with more than 1 million pixels on a 10 micron pitch across an area larger than 1 square centimeter. We show that single cell morphology can be clearly segmented, and then used to reconstruct migration and proliferation dynamics using optical flow. We further track the spreading of multicellular spheroids, revealing fast-moving peripheral regions led by a collective leader cell \"front.\" Finally, we demonstrate label-free imaging of millimeter-scale honeycomb-shaped tissues without the multi-image stitching often required for conventional microscopy. We utilize mutual capacitance measurements with electrically-programmable electrode spacing to reconstruct topographical features of these engineered tissues. Overall, CMOS capacitance imaging arrays enables label-free imaging spanning from single cells to large tissues, in a portable and scalable format for settings where optical microscopy may be difficult to access.","rel_num_authors":7,"rel_authors":[{"author_name":"Hyuntae Jeong","author_inst":"Brown University"},{"author_name":"Pushkaraj S Joshi","author_inst":"Brown University"},{"author_name":"Yinshi Hu","author_inst":"Brown University"},{"author_name":"Jiwon Kim","author_inst":"Brown University"},{"author_name":"Anh Hoang Vu","author_inst":"Brown University"},{"author_name":"Jacob K Rosenstein","author_inst":"Brown University"},{"author_name":"Ian Y Wong","author_inst":"Brown University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"HyenaSET: Hyena Sound Event Transcripts and benchmark animal2vec performance for parsing animal communication","rel_doi":"10.64898\/2026.06.14.732108","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732108","rel_abs":"Here, we present HyenaSET, a large (~1640 hours) bioacoustic dataset derived from collar-mounted audio recorders deployed on 19 spotted hyenas in the Maasai Mara National Reserve, Kenya. Within this dataset, 243 hours have been strongly labeled by identifying the onset and offset of all vocalizations as well as their types, and the labels have been validated by experts on hyena vocalizations and behavior. Within the strongly labeled data, the total amount of time hyenas were vocalizing was 9.5 hours (3.9%). Furthermore, each vocalization has been manually identified as \"focal\" (emitted by the hyena wearing the collar) or \"non-focal\" (emitted by a nearby conspecific), making use of information from collar-mounted accelerometers that picked up vibrations of the animal's throat when it produced vocalizations. In addition to the labeled data, we also provide a large corpus of unlabeled data from the same recordings, which can be used for un- or self-supervised machine learning tasks. To ensure reproducibility of this dataset as a benchmark in machine learning studies, we present it alongside five stratified cross-validation train\/test splits to enable accurate comparisons, and we also provide a train\/test split in which specific individuals are left out of the training set to assess generalizability across individuals. Finally, as a performance benchmark, we present baseline results for this dataset using animal2vec, a recently developed transformer-based model optimized for bioacoustic data.","rel_num_authors":11,"rel_authors":[{"author_name":"Jana Maria Woerner","author_inst":"Michigan State University"},{"author_name":"C\u00e9line Angonin","author_inst":"Tilburg University"},{"author_name":"Andrew S. Gersick","author_inst":"Princeton University"},{"author_name":"Kay E. Holekamp","author_inst":"Michigan State University"},{"author_name":"Frants Havmand Jensen","author_inst":"Aarhus University"},{"author_name":"Mark P. Johnson","author_inst":"Aarhus University"},{"author_name":"Marsden H. M. Onsare","author_inst":"Mara Hyena Project"},{"author_name":"Malit O. Pioon","author_inst":"Mara Hyena Project"},{"author_name":"Julian Sch\u00e4fer-Zimmermann","author_inst":"Max Planck Institute of Animal Behavior"},{"author_name":"Ariana Strandburg-Peshkin","author_inst":"Max Planck Institute of Animal Behavior"},{"author_name":"Eli D. Strauss","author_inst":"Michigan State University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Emergent feasibility in random ecological systems with higher-order interactions","rel_doi":"10.64898\/2026.06.11.728491","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.728491","rel_abs":"A recurring lesson from random ecological models is that coexistence is hard to come by: in the Generalized Lotka-Volterra (GLV) model with pairwise interactions, the probability that randomly sampled parameters admit a positive (feasible) equilibrium - a necessary condition for coexistence - is exactly 1\/2n in n species, vanishing rapidly with diversity. This rarity is often read as evidence that coexistence demands specific ecological mechanisms. Real interactions, however, are rarely strictly pairwise: any nonlinear dependence of one species growth rate on anothers abundance, Taylor-expanded, generates higher-order interactions (HOIs) of increasing degree. Treating the interaction order d as a knob that indexes this nonlinearity, we map the random GLV with HOIs onto the Kostlan-Shub-Smale class of random polynomial systems and approximate the probability of feasibility (Pf ) analytically. We find a phase transition at d = 4: below this threshold, Pf decays with diversity as in the pairwise case; above it, the exponential proliferation of equilibria outpaces the probability that any given equilibrium is feasible, and the probability of feasibility increases with n, approaching one. The transition appears to be universal across symmetric coefficient distributions, but vanishes when sign symmetry of the parameter distribution is broken. This work uncovers a route by which feasibility emerges from nonlinearity alone, with no fine-tuning of parameters and no appeal to specific ecological mechanisms.","rel_num_authors":4,"rel_authors":[{"author_name":"Pablo Lechon-Alonso","author_inst":"University of Chicago"},{"author_name":"Alexander Strang","author_inst":"University of California Berkeley"},{"author_name":"Paul Breiding","author_inst":"OsnabrukUniversity"},{"author_name":"Stefano Allesina","author_inst":"University of Chicago"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Emergent feasibility in random ecological systems with higher-order interactions","rel_doi":"10.64898\/2026.06.11.728491","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.728491","rel_abs":"A recurring lesson from random ecological models is that coexistence is hard to come by: in the Generalized Lotka-Volterra (GLV) model with pairwise interactions, the probability that randomly sampled parameters admit a positive (feasible) equilibrium - a necessary condition for coexistence - is exactly 1\/2n in n species, vanishing rapidly with diversity. This rarity is often read as evidence that coexistence demands specific ecological mechanisms. Real interactions, however, are rarely strictly pairwise: any nonlinear dependence of one species growth rate on anothers abundance, Taylor-expanded, generates higher-order interactions (HOIs) of increasing degree. Treating the interaction order d as a knob that indexes this nonlinearity, we map the random GLV with HOIs onto the Kostlan-Shub-Smale class of random polynomial systems and approximate the probability of feasibility (Pf ) analytically. We find a phase transition at d = 4: below this threshold, Pf decays with diversity as in the pairwise case; above it, the exponential proliferation of equilibria outpaces the probability that any given equilibrium is feasible, and the probability of feasibility increases with n, approaching one. The transition appears to be universal across symmetric coefficient distributions, but vanishes when sign symmetry of the parameter distribution is broken. This work uncovers a route by which feasibility emerges from nonlinearity alone, with no fine-tuning of parameters and no appeal to specific ecological mechanisms.","rel_num_authors":4,"rel_authors":[{"author_name":"Pablo Lechon-Alonso","author_inst":"University of Chicago"},{"author_name":"Alexander Strang","author_inst":"University of California Berkeley"},{"author_name":"Paul Breiding","author_inst":"OsnabrukUniversity"},{"author_name":"Stefano Allesina","author_inst":"University of Chicago"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Experimental landscape connectivity decreases temporal variability in communities over 24 years of assembly","rel_doi":"10.64898\/2026.06.16.732628","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732628","rel_abs":"Landscape connectivity is a key regulator of dispersal, which is an important process in community assembly. Theory predicts that connectivity may influence spatial and temporal patterns of community assembly; however, empirically evaluating the role of connectivity is nearly impossible due to the need to isolate its influence over long time frames and large spatial extents. We overcome these challenges through a large-scale, long-term connectivity experiment to test how connectivity affects plant community turnover and directionality of change over 24 years of assembly. Plant communities within connected patches had lower temporal variability in composition compared to plant communities within unconnected patches. Differences in composition between patches and the directionality of compositional changes were driven more by the amount of edge habitat in a patch and the time since the start of assembly. All community responses to connectivity were stronger for species with wind or unassisted dispersal compared to those with seeds dispersed by animals. Connectivitys role in regulating local community dynamics is critical for understanding community assembly and increasingly relevant in an era of anthropogenic land-use change.\n\nSignificance StatementConnectivity between habitat patches facilitates dispersal to localities, yet the impact of connectivity on local species assemblages is exceptionally challenging to isolate from other spatial changes over time. In a 24-year experiment, we found that connectivity stabilized local community composition as a higher number of species persisted across years within patches connected by corridors. Independent of connectivity, edge effects were more important for driving compositional differences between patches. Importantly, these patterns would not have been captured with short-term data or without controlling for confounding spatial changes. Our findings have broad conservation relevance. Anthropogenic landscape changes that result in a loss of connectivity or increased edge effects may disrupt local community assembly over time.","rel_num_authors":6,"rel_authors":[{"author_name":"Katherine A Hulting","author_inst":"Michigan State University"},{"author_name":"Lars A Brudvig","author_inst":"Michigan State University"},{"author_name":"Melissa A Burt","author_inst":"Tusculum University"},{"author_name":"Christopher R Warneke","author_inst":"University of Wisconsin-Madison"},{"author_name":"Ellen I Damschen","author_inst":"University of Wisconsin-Madison"},{"author_name":"Nick M Haddad","author_inst":"Michigan State University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"NKG2C+CD27- Defines Human CD8+ Regulatory T Cells","rel_doi":"10.64898\/2026.06.15.732401","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732401","rel_abs":"Here we identify NKG2C+CD27- as a novel surface marker unifying multiple previously reported CD8+ regulatory T cell (Treg) populations. This population displays high clonality and divides into CD226- (Treg1) and CD226+ (Treg2) subsets, with Treg2 exhibiting stronger suppressive activities. Up to 35% of CD8+ TEMRA cells are Tregs, whereas approximately 85% of CD8+ Tregs are TEMRA cells, which increase with aging. These findings establish a unified and novel cell surface marker for CD8+ Tregs and their subsets, which resolves prior heterogeneity in the field, and show that CD8+ TEMRA cells are a heterogeneous population that includes T cells with regulatory function. Our findings provide a critical framework for the isolation and in-depth functional characterization of CD8+ Tregs in health, aging, and disease.","rel_num_authors":7,"rel_authors":[{"author_name":"Xuyang Li","author_inst":"Johns Hopkins University"},{"author_name":"Somen K. Mistri","author_inst":"Mass General Brigham, Boston"},{"author_name":"Tian Cao","author_inst":"Mass General Brigham"},{"author_name":"Rajesh K. Krishnan","author_inst":"Mass General Brigham"},{"author_name":"Martin Hemberg","author_inst":"Mass General Brigham"},{"author_name":"Howard L. Weiner","author_inst":"Mass General Brigham"},{"author_name":"Dan Hu","author_inst":"Mass General Brigham"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Characterizing the Effects of Chronic Cannabis Vapour Exposure and Withdrawal on Cannabinoid Triad, Somatic Signs and Behavioural Network Reorganization Adult Male Rats","rel_doi":"10.64898\/2026.06.12.731896","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731896","rel_abs":"Rationale: Cannabis withdrawal contributes to relapse in individuals with cannabis use disorder, yet preclinical studies have largely focused on withdrawal induced by injected cannabinoids rather than inhaled cannabis, which remains the most common route in humans. The behavioural effects of chronic exposure to vapourized cannabis flower and resulting withdrawal after cessation of exposure remain poorly characterized. Objectives: To determine the behavioural effects of chronic vapourized high-THC cannabis flower exposure on cannabinoid tetrad, somatic withdrawal and behavioural transition networks in rats following both chronic vapour exposure and administration of the cannabinoid receptor 1 (CB1) receptor antagonist SR141716A (rimonabant). Methods: Two studies were conducted using adult male Sprague Dawley rats. The first study (N = 16) exposed rats to either air or vapourized high-THC cannabis flower three times a day for seven days using a Volcano vapourizer, followed by intraperitoneal administration of the CB1 antagonist SR141716A (3 mg\/kg). The second study (N = 24) included two air controls and two cannabis groups, with one of each receiving either saline or SR141716A. Behavioural assessments included triad measurements to confirm the cannabis effect, along with withdrawal assessment via a sucrose preference test and somatic signs 30 minutes following rimonabant administration. Results: Repeated cannabis vapour exposure produced reduced locomotor activity, hypothermia, and increased tail-flick latency. Rimonabant administration precipitated withdrawal characterized by increased total withdrawal scores and somatic signs, including blinking, body shakes\/tremors, and grooming-related behaviours. Behavioural network analyses revealed substantial reorganization of behavioural transition structure during both chronic cannabis exposure and withdrawal. Chronic cannabis exposure was associated with reduced network modularity, a condensed behavioural repertoire, and altered behavioural centrality measures. At the same time, precipitated withdrawal further increased the influence of exploratory behaviours, particularly sniffing, and reduced the network prominence of locomotor-associated behaviours, such as walking, beyond that detected using conventional behavioural measures alone. Conclusion: Chronic exposure to vapourized cannabis flower followed by CB1 receptor antagonism produces reliable withdrawal symptoms in rats. Behavioural network analyses further reveal that cannabis exposure and withdrawal are both associated with widespread reorganization of behavioural dynamics, suggesting that withdrawal alters not only individual behaviours but also the structure of behavioural transitions. These findings establish a translational model of cannabis withdrawal using inhaled cannabis flower vapour and identify behavioural network analysis as a sensitive approach for characterizing withdrawal-related behavioural states.","rel_num_authors":11,"rel_authors":[{"author_name":"Abdalla M Albeely","author_inst":"Western University"},{"author_name":"Hakan Kayir","author_inst":"Western University"},{"author_name":"Richard Quansah Amissah","author_inst":"Western University"},{"author_name":"Bahar Zali","author_inst":"Western University"},{"author_name":"Selim Karahan","author_inst":"Western University"},{"author_name":"Jaiden Smith","author_inst":"University of Guelph"},{"author_name":"Asim A Ibrahim","author_inst":"Western University"},{"author_name":"Ahmad Hassan","author_inst":"University of Guelph"},{"author_name":"Sara Hussein","author_inst":"University of Guelph"},{"author_name":"Jude A Frie","author_inst":"Western University"},{"author_name":"Jibran Khokhar","author_inst":"Western University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Incorporation of single-neuron projectome-based connectivity motifs enhances the cortex-specific performance of artificial neural networks","rel_doi":"10.64898\/2026.06.12.732007","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.732007","rel_abs":"The organizational principles of natural neural networks could inspire the new architecture design of artificial neural networks (ANNs). Analysis of single-neuron connectomes of mouse brains revealed distinct profiles of three-node connectivity motifs in various cortical areas and hippocampal formation. A connectome-informed neural network algorithm (\"CINA\") was developed to incorporate natural connectivity motifs into ANN algorithms represented by recurrent neural network (RNN) and transformer-based large language model (LLM). We found that incorporation of the average profile of cortical motifs improved the RNN's performance in noise-resistant categorization and motor learning benchmark tasks, as compared with RNNs with random connectivity. Notably, incorporating cortex-specific motifs further elevated the RNN's performance in tasks related to the cortical function, and this effect was enhanced by artificially increasing the bias in the motif profile. Similar experimental results were verified on an LLM using Motif-Transformer for natural language question answering and brain-signal decoding tasks. Graph-theoretic analyses showed that incorporating natural motifs drove the emergence of modular and small-world properties in ANNs. Together, we demonstrated not only connectome-inspired optimization of ANN architecture but also functional significance of specific motif profiles in various cortices.","rel_num_authors":16,"rel_authors":[{"author_name":"Yue Sun","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Wangzi Yao","author_inst":"Institute of Automation, Chinese Academy of Sciences"},{"author_name":"Jian Zhang","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Wei Song","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Xuanle Zhao","author_inst":"Institute of Automation, Chinese Academy of Sciences"},{"author_name":"Chonghe Hao","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Xinyu Chen","author_inst":"School of Artificial Intelligence, China University of Mining and Technology-Beijing"},{"author_name":"Shuxin Zeng","author_inst":"School of Artificial Intelligence, University of Chinese Academy of Sciences"},{"author_name":"Shuncheng Jia","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Yun Yang","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Xu Chen","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Xiong Xiao","author_inst":"Center for Excellence in Brain Science and Intelligence Technology"},{"author_name":"Mu-ming Poo","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Yangang Sun","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"},{"author_name":"Bo Xu","author_inst":"Institute of Automation, Chinese Academy of Sciences"},{"author_name":"Tielin Zhang","author_inst":"Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Institut"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Experiment-free learning of exoskeleton assistance is not an unsolved problem","rel_doi":"10.64898\/2026.06.16.731058","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.731058","rel_abs":"We present three quantitative methods: 1) estimation of exoskeleton mechanical power and energy ratio from published data, 2) a systematic review of the exoskeleton literature on reported energy ratios, and 3) timing correction analysis of the replication experiment, to address concerns raised by Collins et al. (2026) about Luo et al. (2024). Together, these analyses support the reported metabolic reductions and the validity of exoskeleton control via learning in simulation. The critique rests on an unsupported premise: that exoskeleton energy ratios above 4 are physiologically implausible. This premise of Collins et al. (2026) is not supported by the cited evidence, and the error originates in their own cited source. Sawicki and Ferris (2009), the paper they invoke as authority for the limit of 4, state explicitly that \"reported values of the muscular efficiency range from 0.10 to 0.34, with many sources assuming an average of ~0.25.\" The value of 4 corresponds to this average, it is not a physiological ceiling. Treating an average as a physiological upper limit is a fundamental error. The published exoskeleton literature further contradicts the claim, including work by the authors of the critique themselves (Collins et al., 2015: 4.3; Young et al., 2017: 5.0) and independent work (Malcolm et al., 2013: 4.8; Seo et al., 2017: 6.7). In contrast, our walking energy ratio is 2.4, calculated directly from Fig. 4 of our paper. Our device delivers higher peak torque (14.1 Nm vs. 10.9 Nm, Lim et al., 2019) and achieves a slightly larger metabolic reduction (24.3% vs. 21%). Independent groups have since demonstrated meaningful metabolic reductions using learning-in-simulation frameworks, including Barati et al. (2026, 15.2% mean and 22.5% maximum) and Zhou et al. (2025, ~20% during running). The claim of Collins et al. (2026) that this problem \"remains unsolved\" is directly contradicted by these independent results.","rel_num_authors":10,"rel_authors":[{"author_name":"Shuzhen Luo","author_inst":"Mechanical Engineering, Embry-Riddle Aeronautical University"},{"author_name":"Menghan Jiang","author_inst":"Mechanical & Aerospace Engineering, North Carolina State University"},{"author_name":"Sainan Zhang","author_inst":"Mechanical Engineering, Kennesaw State University"},{"author_name":"Junxi Zhu","author_inst":"Siemens"},{"author_name":"Shuangyue Yu","author_inst":"Beijing University of Technology"},{"author_name":"Israel Dominguez Silva","author_inst":"Amazon Robotics"},{"author_name":"Bolei Zhou","author_inst":"Computer Science, University of California, Los Angeles"},{"author_name":"Hyunwoo Yuk","author_inst":"Mechanical Engineering, Korea Advanced Institute of Science and Technology"},{"author_name":"Xianlian Zhou","author_inst":"Biomedical Engineering, New Jersey Institute of Technology"},{"author_name":"Hao Su","author_inst":"Biomedical Engineering, Computer Science, New York University"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Towards Passive Dietary Monitoring: Dilated CNN-Based Meal Detection Using Ambulatory High-Resolution Electrogastrography","rel_doi":"10.64898\/2026.06.13.731982","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.731982","rel_abs":"Background: Objective tools for longitudinal dietary monitoring, despite its importance in the health triad of diet, sleep, and exercise, remain limited. Widely available ambulatory options include continuous glucose monitoring, which is a delayed response, and manual logging, which is rife with human error. Clinical tools such as gastric emptying scintigraphy are impractical for everyday use. High-resolution electrogastrography (HR-EGG) offers an alternative by treating gastric myoelectric activity as a biomarker of digestive state. However, its utility for ambulatory meal detection remains unclear. We hypothesize that HR-EGG and accelerometry together encode distinct postprandial gastric signatures to enable automated meal detection, and that postural context represents a relevant source of variation in signal detectability. Methods: HR-EGG and accelerometry data were collected from seven healthy adults across sixteen 150-minute meal sessions under IRB-approved protocol. Each session included a 30-minute fasted baseline, consumption of a standardized meal, and 90-minute postprandial period of sitting, walking, and lying in a randomized order. Features of the gastric slow wave, including raw and normalized bandpower, phase gradient directionality (PGD), wave direction, and wave speed, were extracted alongside triaxial accelerometer magnitude. A dilated one-dimensional convolutional network (1D CNN) was trained to classify meal consumption at five-minute resolution using leave-one-subject-out cross-validation. Postural effects on gastric myoelectric metrics were assessed using the Friedman test. Results: The model achieved a mean AUROC of 0.925 (95% CI: [0.857, 0.993]) and mean AUPRC of 0.824 (95% CI: [0.668, 0.980]; null model: 0.20). Feature ablation showed PGD as the most informative input ({Delta}AUPRC = -0.188), with wave propagation speed the least informative ({Delta}AUPRC = - 0.105). Walking produced the highest signal-to-noise ratio (9.94 dB), lying had the most stable gastric rhythm (89.1% normogastric), and sitting demonstrated the greatest frequency instability (dominant frequency standard deviation = 0.825 cpm). Conclusion: A dilated 1D CNN applied to spatiotemporal HR-EGG features enables temporally aware passive meal detection across ambulatory contexts. This study framework addresses a gap between clinical need for objective dietary monitoring and the limitations of current detection methods.","rel_num_authors":2,"rel_authors":[{"author_name":"Belinda Chen","author_inst":"University of California, San Francisco"},{"author_name":"Sandya Subramanian","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Towards Passive Dietary Monitoring: Dilated CNN-Based Meal Detection Using Ambulatory High-Resolution Electrogastrography","rel_doi":"10.64898\/2026.06.13.731982","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.731982","rel_abs":"Background: Objective tools for longitudinal dietary monitoring, despite its importance in the health triad of diet, sleep, and exercise, remain limited. Widely available ambulatory options include continuous glucose monitoring, which is a delayed response, and manual logging, which is rife with human error. Clinical tools such as gastric emptying scintigraphy are impractical for everyday use. High-resolution electrogastrography (HR-EGG) offers an alternative by treating gastric myoelectric activity as a biomarker of digestive state. However, its utility for ambulatory meal detection remains unclear. We hypothesize that HR-EGG and accelerometry together encode distinct postprandial gastric signatures to enable automated meal detection, and that postural context represents a relevant source of variation in signal detectability. Methods: HR-EGG and accelerometry data were collected from seven healthy adults across sixteen 150-minute meal sessions under IRB-approved protocol. Each session included a 30-minute fasted baseline, consumption of a standardized meal, and 90-minute postprandial period of sitting, walking, and lying in a randomized order. Features of the gastric slow wave, including raw and normalized bandpower, phase gradient directionality (PGD), wave direction, and wave speed, were extracted alongside triaxial accelerometer magnitude. A dilated one-dimensional convolutional network (1D CNN) was trained to classify meal consumption at five-minute resolution using leave-one-subject-out cross-validation. Postural effects on gastric myoelectric metrics were assessed using the Friedman test. Results: The model achieved a mean AUROC of 0.925 (95% CI: [0.857, 0.993]) and mean AUPRC of 0.824 (95% CI: [0.668, 0.980]; null model: 0.20). Feature ablation showed PGD as the most informative input ({Delta}AUPRC = -0.188), with wave propagation speed the least informative ({Delta}AUPRC = - 0.105). Walking produced the highest signal-to-noise ratio (9.94 dB), lying had the most stable gastric rhythm (89.1% normogastric), and sitting demonstrated the greatest frequency instability (dominant frequency standard deviation = 0.825 cpm). Conclusion: A dilated 1D CNN applied to spatiotemporal HR-EGG features enables temporally aware passive meal detection across ambulatory contexts. This study framework addresses a gap between clinical need for objective dietary monitoring and the limitations of current detection methods.","rel_num_authors":2,"rel_authors":[{"author_name":"Belinda Chen","author_inst":"University of California, San Francisco"},{"author_name":"Sandya Subramanian","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-17","rel_site":"biorxiv"},{"rel_title":"Enteral docosahexaenoic and arachidonic acid supplementation and retinopathy of prematurity: a re-analysis of randomized controlled trials in preterm infants","rel_doi":"10.64898\/2026.06.12.26355524","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355524","rel_abs":"BackgroundA recent meta-analysis by Dang et al. [1] concluded that enteral supplementation with docosahexaenoic acid (DHA), with or without arachidonic acid (ARA) did not significantly affect retinopathy of prematurity (ROP) outcomes in preterm infants. Of four eligible trials that supplemented both DHA and ARA, only two contributed to each ROP outcome analyzed, and severe ROP was not assessed.\n\nMethodsWe replicated the eligibility criteria and search strategy of Dang et al., restricted to trials that supplemented both DHA and ARA, and reanalyzed three ROP endpoints (any ROP, ROP requiring treatment, and severe ROP [stage 3 and\/or treated]) using complete outcome records from all eligible trials. Crude risk ratios (RR) were pooled by Mantel-Haenszel fixed-effect meta-analysis. Gestational age-adjusted odds ratios (adjOR) were pooled on the log scale by inverse-variance random-effects meta-analysis with restricted maximum likelihood (REML) estimation of between-study variance and Hartung-Knapp confidence intervals.\n\nResultsFive trials were included; one trial was identified in our replicated search but was excluded by Dang et al. without a stated rationale. The pooled estimate for any ROP was consistent with Dang et al. (RR 0.87 [95% CI 0.71-1.08]; adjOR 0.70 [0.46-1.08]). For ROP requiring treatment, the crude RR suggested a lower risk but did not reach statistical significance (RR 0.60 [0.35-1.04]), whereas the gestational age-adjusted estimate indicated lower odds (adjOR 0.47 [0.23-0.94]). For severe ROP, DHA+ARA supplementation produced a significant protective effect in both unadjusted and adjusted models (RR 0.56 [0.36-0.86]; adjOR 0.42 [0.19-0.96]).\n\nConclusionsWhen all eligible trials contribute to each endpoint and severe ROP is included as an outcome, enteral DHA+ARA supplementation reduces severe ROP and is associated with lower odds of ROP requiring treatment after adjustment for gestational age. These findings differ from the conclusions of Dang et al. and support reconsideration of DHA+ARA supplementation as a strategy to reduce sight-threatening ROP in preterm infants.","rel_num_authors":9,"rel_authors":[{"author_name":"Ulrika Sjoebom","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"author_name":"Aldina Pivodic","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"author_name":"Pia Lundgren","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"author_name":"Sissel J Moltu","author_inst":"Department of Neonatal Intensive Care, Oslo University Hospital, Norway."},{"author_name":"Brandy Frost","author_inst":"Department of Pediatrics, Division of Neonatology, Endeavor Health, Evanston, IL; Pritzker School of Medicine, University of Chicago, Chicago, IL, USA."},{"author_name":"Daniel T Robinson","author_inst":"Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Christine Henriksen","author_inst":"Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Norway."},{"author_name":"Ann Hellstroem","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"author_name":"Anders K Nilsson","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Adverse Childhood Experiences and Growth Outcomes in Childhood: A Longitudinal EHR-Based Study","rel_doi":"10.64898\/2026.06.15.26355527","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355527","rel_abs":"Adverse childhood experiences (ACEs) are among the strongest risk factors for long-term mental and physical health complications, yet their impact on childhood biological development remains incompletely understood. In this study, we leverage longitudinal electronic health record (EHR) data from over 400,000 pediatric patients to examine the relationship between clinical ACE documentation identified from a Natural Language Processing (NLP) algorithm and growth trajectories across childhood and adolescence. In this cohort, ACE documentation was associated with consistently lower height Z-scores, reduced final attained height, and earlier timing of peak growth velocity. Differences in height became significant approximately two years before ACE documentation, suggesting that growth disruption precedes formal clinical recognition. Importantly, the magnitude of growth disruption depended on the child's age at ACE documentation, with earlier ACE associated with the largest alterations in height and growth timing. These findings support a model in which early stress impacts childhood growth during sensitive periods and may represents a clinically accessible biomarker of the negative health consequences of ACEs.","rel_num_authors":9,"rel_authors":[{"author_name":"Samuel Palmer","author_inst":"Vanderbilt University"},{"author_name":"Cathy Shyr","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Theodore J Morley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"John Shelley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Lide Han","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jill H Simmons","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Cosmin Bejan","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Colin Walsh","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Douglas M Ruderfer","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Validating an Early Pregnancy HbA1c as the Screening Test for Gestational Diabetes Mellitus: Findings from PRISMA Pakistan Cohort","rel_doi":"10.64898\/2026.06.08.26355138","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355138","rel_abs":"BackgroundEarly identification of gestational diabetes mellitus (GDM) is critical to improving maternal and neonatal outcomes, particularly in resource-constrained settings where universal oral glucose tolerance testing (OGTT) is burdensome. We assessed whether early-pregnancy HbA1c alone or combined with common risk factors can predict GDM and reduce the burden of OGTT requirements in a peri-urban cohort in Karachi, Pakistan.\n\nMethodsWe conducted a secondary analysis of the Pregnancy Risk Infant Surveillance and Measurement Alliance (PRISMA) Pakistan cohort. Women enrolled before 20 weeks gestation with available early-pregnancy HbA1c and a 2-hour 75g OGTT at 24-28 weeks were included. We externally validated GDM prediction models originally developed in the STRiDE-India cohort. Model performance was evaluated using receiver operating characteristic (ROC) curves and area under the curve (AUC). We assessed four models: HbA1c alone (Model 1a); age, BMI, and family history of diabetes mellitus (FH DM) (Model 1b); HbA1c combined with age, BMI, and FH DM (Model 2); and an extended model, i.e., Model 2 combined with socioeconomic status, gestational age, parity, systolic and diastolic blood pressure (Model 3). A dual-threshold approach was applied to assess rule-in and rule-out performance.\n\nResultsAmong 2,489 women, GDM incidence was 7.5% (n=186). Models with a broader set of predictors demonstrated higher AUC values, with Model 2 achieving an AUC of 0.61 (95% CI: 0.57-0.66). Including additional factors (Model 3) did not further improve predictive ability (AUC: 0.62; 95% CI: 0.58-0.66). In addition, at predefined thresholds, Model 2 achieved sensitivity of 73.7% (rule-out) and specificity of 83.5% (rule-in), with potential to reduce OGTT requirements (58.5%).\n\nConclusionsEarly-pregnancy risk stratification using HbA1c combined with simple clinical predictors offers a pragmatic approach to streamline GDM screening among high-risk pregnant women. A dual-threshold strategy using Model 2 could reduce reliance on universal OGTT while prioritizing high-risk women for confirmatory testing.\n\nWhat is already known on this topicStudies have indicated that HbA1c may be an acceptable biomarker for identifying high-risk pregnant women with GDM and hence reducing the unnecessary burden of OGTT in resource-constrained settings. However, its ability to predict Pakistani women at high risk of GDM is unclear.\n\nWhat this study addsEarly pregnancy HbA1c, together with age, BMI, and family history of diabetes achieved an AUC of 0.61 (95% CI: 0.57-0.66), with 58.5% of OGTTs could be avoided using this method.\n\nHow this study might affect research, practice or policyEarly pregnancy HbA1c-based prediction model is best positioned as pragmatic triage strategies to prioritize women for OGTT rather than replacing it. Such approaches may optimize resource use, particularly in settings where access to diagnostic testing is limited.","rel_num_authors":9,"rel_authors":[{"author_name":"Sabahat Naz","author_inst":"Aga Khan University"},{"author_name":"Nida Yazdani","author_inst":"Aga Khan University"},{"author_name":"Zahra Hoodbhoy","author_inst":"The Aga Khan University"},{"author_name":"Yonas Ghebremihael-Weldeselassie","author_inst":"University of Warwick"},{"author_name":"Azqa Mazhar","author_inst":"The Aga Khan University"},{"author_name":"Aneeta Hotwani","author_inst":"Aga Khan University"},{"author_name":"Fyezah Jehan","author_inst":"Aga Khan University"},{"author_name":"Muhammad Imran Nisar","author_inst":"Aga Khan University"},{"author_name":"Romaina Iqbal","author_inst":"Aga Khan University"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Development of an automated, imaging-based preoperative screening model for early identification of malnutrition in an abdominal surgery cohort","rel_doi":"10.64898\/2026.06.08.26355187","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355187","rel_abs":"BackgroundClinical malnutrition affects one in five abdominal surgery patients and increases postoperative complications and mortality. Current screening occurs after admission, closing the window for preoperative nutritional intervention. No objective, scalable preoperative screening tool exists.\n\nObjectiveTo determine whether automated volumetric CT-based body composition analysis improves preoperative identification of surgical patients at risk for clinical malnutrition compared to clinical variables or single-slice imaging alone.\n\nMethodsRetrospective cohort study of adults undergoing elective abdominal surgery at a quaternary academic medical center (2018-2021) with a preoperative CT scan within 90 days and complete nutrition assessment. Clinical malnutrition was diagnosed by a registered dietitian using ASPEN\/AND criteria. Three sex-stratified Elastic Net models were compared: (1) base clinical variables; (2) base plus L3 single-slice skeletal muscle index and attenuation; and (3) base plus comprehensive 3D volumetric quantification of five muscle groups and two fat depots. Discrimination (AUROC), calibration (Brier score), and clinical utility (decision curve analysis) were assessed via 10-fold cross-validation.\n\nResultsAmong 1,143 patients (52.4% female; mean age 60.5 years), 231 (20.2%) were diagnosed with malnutrition. Malnourished patients had significantly higher complication rates (36.4% vs. 15.4%, p<0.001) and prolonged length of stay (45.9% vs. 16.4%, p<0.001). Critically, 27.2% of malnourished patients were not flagged as at-risk by the standard Malnutrition Screening Tool. The volumetric model (Model 3) achieved the highest discrimination (males: AUROC 0.808; females: 0.794) and best calibration (males: Brier 0.129; females: 0.124), significantly outperforming both the base model (males: p=0.004; females: p<0.001) and L3 model (males: p=0.019; females: p<0.001). L3 features modestly improved discrimination but paradoxically worsened calibration -- an effect corrected by volumetric features. Sex-specific risk profiles differed markedly, with ASA classification dominating female models and demographic factors dominating male models.\n\nConclusionsAutomated volumetric CT body composition analysis significantly improves preoperative malnutrition risk identification, with sex-stratified models revealing distinct risk profiles. Leveraging imaging already obtained for surgical planning, this approach opens a preoperative window for nutritional intervention that current practice fails to utilize.","rel_num_authors":14,"rel_authors":[{"author_name":"Victoria M Gershuni","author_inst":"University of Pennsylvania"},{"author_name":"Raheema A Damani","author_inst":"University of Pennsylvania"},{"author_name":"Shubha Vasisht","author_inst":"University of Pennsylvania"},{"author_name":"Rakesh Sharma","author_inst":"University of Pennsylvania"},{"author_name":"James Rowe","author_inst":"University of Pennsylvania"},{"author_name":"Charlene Compher","author_inst":"University of Pennsylvania"},{"author_name":"Jeffrey Duda","author_inst":"University of Pennsylvania"},{"author_name":"Hersh Sagreiya","author_inst":"University of Pennsylvania"},{"author_name":"Rachel Kelz","author_inst":"University of Pennsylvania"},{"author_name":"Hongzhe Lee","author_inst":"University of Pennsylvania"},{"author_name":"Gregory Tasian","author_inst":"University of Pennsylvania"},{"author_name":"Scott M. Damrauer","author_inst":"University of Pennsylvania"},{"author_name":"Gary D. Wu","author_inst":"University of Pennsylvania"},{"author_name":"Walter R Witschey","author_inst":"University of Pennsylvania"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"MRMU: A New Paradigm for Mendelian Randomization by Accounting for Measured Covariates and Unmeasured Confounders","rel_doi":"10.64898\/2026.06.15.26355649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355649","rel_abs":"Mendelian randomization (MR) is a powerful approach for causal inference, however, its reliability is frequently compromised by unadjusted covariates and unmeasured confounders, such as unmeasured pleiotropy and sample structure. To address these challenges, we introduce MRMU, a novel paradigm for the MR framework. Unlike traditional single-variable or multivariable MR methods, MRMU selects instrumental variables only from the exposure of interest and estimates one exposure effect at a time, while jointly accounting for measured covariates and unmeasured confounders. This design improves the reliability of MR analyses. In simulations and real data, MRMU achieved better type I error control, higher statistical power, and more accurate effect estimation than existing MR methods. Applying to coronary artery disease (CAD), MRMU identified robust cardiometabolic risk factors, including LDL-C, APOB, systolic blood pressure, body mass index, and smoking initiation, with consistent evidence across multiple CAD datasets. In contrast, traits such as HDL-C, height, and educational attainment, which were found to be significant by existing MR methods, were no longer supported by MRMU. MRMU further supported blood pressure-related traits, rather than lipid traits, as the more relevant pathway linking urate to CAD. Finally, by integrating large-scale plasma proteomics data, MRMU identified candidate CAD drug targets beyond established HMGCR- and PCSK9-related pathways, highlighting its utility for therapeutic target prioritization.","rel_num_authors":6,"rel_authors":[{"author_name":"Xianghong Hu","author_inst":"Shenzhen University"},{"author_name":"Jiashun Xiao","author_inst":"Sun Yat-sen University"},{"author_name":"Xinrui Huang","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Zhiwei Wang","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Hongyu Zhao","author_inst":"Yale School of Public Health"},{"author_name":"Can Yang","author_inst":"The Hong Kong University of Science and Technology"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Investigating naming error patterns after non-invasive brain stimulation and language treatment in persons with aphasia","rel_doi":"10.64898\/2026.06.08.26354856","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26354856","rel_abs":"BackgroundTranscranial direct current stimulation (tDCS) paired with behavioral language therapy can improve naming in persons with aphasia (PWA), yet naming errors persist. Little is known about how naming error patterns change after non-invasive brain stimulation is combined with language treatment.\n\nAimsTo examine whether right cerebellar tDCS plus computerized aphasia therapy changes the types of naming errors in people with chronic aphasia across timepoints, and to determine whether effects differ by cerebellar tDCS polarity (anode vs. cathode).\n\nMethods and ProceduresIn a randomized, double-blind, sham-controlled, within-subject crossover study, we retrospectively analyzed behavioral data from 24 individuals with post-stroke aphasia. Each participant completed two 15-session intervention periods (3-5 sessions\/week) with active cerebellar tDCS + computerized aphasia therapy and sham + computerized aphasia therapy, separated by a two-month washout. General linear models (GLMs) assessed longitudinal changes in six error types (semantic, phonological real word, phonological nonword, no response, mixed, unrelated) on an untrained picture naming task (Philadelphia Naming Test; PNT) and a trained task (Naming 80; N80). Additional GLMs evaluated polarity effects with 2 (Group: anode vs. cathode) x 2 (Treatment) interactions, and treatment-order effects with 2 (Group: tDCS-first vs. sham-first) x 2 (Treatment) interactions.\n\nOutcomes and ResultsActive cerebellar tDCS did not significantly change error types for trained items (N80). For untrained items (PNT), active tDCS reduced several error types relative to sham, with the clearest and most durable reduction in phonological nonword errors; more moderate reductions occurred for phonological real word and unrelated errors. Mixed errors showed a marginally opposite pattern, tending to increase after tDCS and decrease after sham.\n\nPolarity analyses indicated broadly similar effects across anodal and cathodal stimulation overall, but only the anode group showed a reliable treatment effect for phonological nonword errors on the PNT. Treatment-order analyses revealed no significant order effects.\n\nConclusionsOur results indicate a shift in naming error types, particularly after tDCS treatment for the untrained naming task (PNT). These findings may help guide the course of treatment approaches of those with aphasia and what error naming pattern types may show changes post stroke when combining non-invasive brain stimulation and computerized aphasia therapy.\n\nClinical Trial RegistrationCerebellar Transcranial Direct Current Stimulation and Aphasia Treatment [NCT02901574]","rel_num_authors":6,"rel_authors":[{"author_name":"Myra J. Sydnor","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Micah Alan Johnson","author_inst":"Johns Hopkins University Department of Biostatistics, Bloomberg School of Public Health"},{"author_name":"Becky Lammers","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Jamie L. Murter","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Martin Lindquist","author_inst":"Johns Hopkins University Department of Biostatistics, Bloomberg School of Public Health"},{"author_name":"Rajani Sebastian","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Adherence to Red Reflex and Vision Screening Recommendations: A Deep Dive into Primary Care Implementation Gaps","rel_doi":"10.64898\/2026.06.08.26355190","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355190","rel_abs":"AbstractO_ST_ABSIntroductionC_ST_ABSEarly childhood vision screening is critical for detecting amblyopia and other vision-threatening conditions. Despite screening recommendations during well-child visits, rates remain low. Red reflex assessment is recommended to identify serious ocular pathology, yet its use in primary care is not well described. We examined rates and drivers of vision screening in pediatric primary care.\n\nMethodsWe conducted a retrospective review of electronic health records for children 3-5 years attending well-child visits in 2022 in one of three representative primary care clinics within a university health system. Outcomes were documented red reflex and functional vision tests. We evaluated associations with patient demographics and clinic site using multivariable logistic regression\n\nResultsAmong 1,003 visits, 21.1% (n=212) had a documented red reflex assessment, and 60.8% (n=610) a functional vision test. Younger children (ages 3 and 4 vs. 5 years) had higher odds of red reflex assessment [adjusted odds ratio (aOR) 9.00 and 8.64], and lower odds of a functional vision (aOR 0.47 and 0.59) test. Females had higher odds of red reflex assessment (aOR 1.53). Other\/Multiracial children had lower odds of red reflex assessment than Non-Hispanic White children (aOR 0.48). Screening rates varied significantly by clinic site\n\nConclusionsVisual function and red reflex assessment are inconsistently performed in pediatric primary care, with particularly low rates of red reflex documentation. Screening rates varied between clinics and were affected by age. These findings highlight missed opportunities for early detection of vision-threatening conditions and identify targets for improving adherence to pediatric vision screening recommendations.","rel_num_authors":13,"rel_authors":[{"author_name":"Afua O Asare","author_inst":"University of Utah Health John A Moran Eye Center"},{"author_name":"Giovani Robles","author_inst":"The University of Utah Spencer Fox Eccles School of Medicine"},{"author_name":"E Eugenie Hartmann","author_inst":"Akron Childrens Hospital"},{"author_name":"Carole Stipelman","author_inst":"Department of Pediatrics, University of Utah Health"},{"author_name":"Dallen Calder","author_inst":"The University of Utah Spencer Fox Eccles School of Medicine"},{"author_name":"Olaoluwa Omotowa","author_inst":"The University of Utah Spencer Fox Eccles School of Medicine"},{"author_name":"Jessie Montgomery","author_inst":"The University of Utah Spencer Fox Eccles School of Medicine"},{"author_name":"Bryce T Baugh","author_inst":"John A. Moran Eye Center, University of Utah Health"},{"author_name":"Brian Stagg","author_inst":"University of Utah Health John A Moran Eye Center"},{"author_name":"Guilherme Del Fiol","author_inst":"Department of Biomedical Informatics, University of Utah"},{"author_name":"Melissa  H. Watt","author_inst":"Department of Population Health Sciences, The University of Utah"},{"author_name":"Michelle R Hribar","author_inst":"University of Illinois Chicago"},{"author_name":"JD Smith","author_inst":"Department of Population Health Sciences, University of Utah"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Prevalence and Correlates of Ideal Cardiovascular Health among Ugandan Adolescents: A Cross-Sectional Study","rel_doi":"10.64898\/2026.06.13.26355572","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355572","rel_abs":"IntroductionCardiovascular disease (CVD) risk factors often emerge during adolescence and track into adulthood, yet data on cardiovascular health (CVH) in sub-Saharan Africa remain limited. We assessed the prevalence and correlates of ideal CVH among Ugandan adolescents.\n\nMethodsWe analysed baseline data of adolescents enrolled in a cluster-randomised controlled trial being conducted in urban (Kampala) and rural (Jinja) districts of Uganda. In this study, Ideal CVH was defined as meeting \"ideal\" status of 5-7 of the American Heart Associations Lifes Simple 7 metrics. Random-effects logistic regression was used to identify factors associated with ideal CVH, accounting for village-level clustering.\n\nResultsWe recruited 1316 participants with a mean age of 13.2 years, of whom 58.1% were female. Overall, the prevalence of ideal CVH was 66.8% (95% CI: 64.2% - 69.3%). The prevalence was higher in Jinja (74.4%, 95%CI: 70.9% - 77.7%) than Kampala (59.6%, 95%CI: 55.8%-63.2%) and the difference was evident (p<0.001). Male adolescents had higher odds of ideal CVH than females in both rural (aOR=1.55, 95%CI: 1.05-2.29) and urban (aOR=1.90, 95%CI: 1.38-2.63) settings. Increasing age and higher education level were associated with lower odds of ideal CVH in both settings, likely reflecting age-related behavioural changes.\n\nConclusionMore than half of Ugandan adolescents have ideal CVH, with disparities by sex, age, and urbanisation. These findings suggest that cardiovascular health declines during adolescence and highlight the need for early, targeted interventions, particularly among female and urban adolescents.","rel_num_authors":24,"rel_authors":[{"author_name":"Levicatus Mugenyi","author_inst":"MRC\/UVRI Uganda Research Unit On AIDS: MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Simple Ouma","author_inst":"TASO: AIDS Support Organisation"},{"author_name":"Ivan Namakoola","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Arthur Namara","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Isaac  Samuel Kintu","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Francis  Xavier Namugera","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Sumayiya Nalubega","author_inst":"TASO: AIDS Support Organisation"},{"author_name":"Sanula Nanozi","author_inst":"TASO: AIDS Support Organisation"},{"author_name":"Faith Tumuhairwe","author_inst":"TASO: AIDS Support Organisation"},{"author_name":"Dorothy Mirembe","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Charles Ssekyanzi","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Costella Tindyebwa","author_inst":"Roundoff Synergy"},{"author_name":"Martin Muddu","author_inst":"Infectious Diseases Research Collaboration"},{"author_name":"Flavia Zalwango","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Mathias Akugizibwe","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Moreen  Chaka Namulundu","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Perez  Nicholas Ochanda","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Eleanor Namusoke","author_inst":"Republic of Uganda Ministry of Health"},{"author_name":"Mina Nakawuka","author_inst":"Republic of Uganda Ministry of Health"},{"author_name":"Gerald Mutungi","author_inst":"Republic of Uganda Ministry of Health"},{"author_name":"Rachel King","author_inst":"University of California San Francisco"},{"author_name":"Moffat Nyirenda","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"David Moore","author_inst":"The University of British Columbia"},{"author_name":"Josephine Birungi","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Nocturnal Respiratory Rate and Variability Predict Long-term Mortality in Stable Outpatients with Cardiovascular Disease","rel_doi":"10.64898\/2026.06.12.26355214","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355214","rel_abs":"BackgroundRespiratory rate (RR) predicts short-term mortality in acute care settings, yet its prognostic significance in clinically stable outpatients remains poorly defined.\n\nObjectivesTo determine whether the median and variability of nocturnal respiratory rate (NRR) are independently associated with long-term cardiovascular and all-cause mortality in outpatients with cardiovascular disease.\n\nMethodsWe analyzed overnight chest belt waveforms from elective polysomnography in 5,679 older adults with cardiovascular disease enrolled in the Sleep Heart Health Study (SHHS). NRR was quantified at 30-second resolution, and per-subject median NRR and within-night variability (standard deviation) were derived. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate associations with cardiovascular and all-cause mortality over 3-year and 15-year follow-up periods, adjusting for demographic characteristics, cardiopulmonary comorbidities, and sleep apnea severity.\n\nResultsHigher median NRR and greater NRR variability were each associated with increased cardiovascular and all-cause mortality. Combining these metrics identified a high-risk group characterized by high median and high variability of NRR, with nearly five-fold higher 3-year all-cause mortality compared with a low-risk group (unadjusted HR: 2.61; 95% CI: 1.65, 4.14; p<0.001; adjusted HR: 2.15; 95% CI: 1.30, 3.55; p=0.003).\n\nConclusionsBoth the baseline level and variability of NRR independently predict morttality in clinically stable outpatients with cardiovascular disease. Densely profiled NRR represents a promising, underutilized biomarker for long-term risk stratification.\n\nCondensed AbstractNocturnal respiratory rate (NRR) is an underutilized biomarker whose prognostic significance in stable cardiovascular outpatients is unknown. In 5,679 participants from the Sleep Heart Health Study, median NRR and within-night variability derived from overnight polysomnography independently predicted cardiovascular and all-cause mortality. Stratification based on these metrics identified a high-risk group with nearly five-fold higher 3-year mortality compared with a low-risk group (adjusted HR: 2.15; 95% CI: 1.30-3.55; p=0.003).","rel_num_authors":8,"rel_authors":[{"author_name":"Raimon Pedros-Valls","author_inst":"University of California San Diego"},{"author_name":"Keshav S Gupta","author_inst":"University of California San Diego"},{"author_name":"Nicholas Harrington","author_inst":"Nightingale Labs"},{"author_name":"Justin D Yu","author_inst":"University of California San Diego"},{"author_name":"Jeremy Orr","author_inst":"University of California San Diego"},{"author_name":"Robert L Owens","author_inst":"University of California San Diego"},{"author_name":"David Torres Barba","author_inst":"University of California San Diego"},{"author_name":"Kevin R King","author_inst":"University of California San Diego"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"RationaleFibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.\n\nObjectivesTo identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.\n\nMethodsWe performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.\n\nResultsTwo molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.\n\nConclusionMulti-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"RationaleFibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.\n\nObjectivesTo identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.\n\nMethodsWe performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.\n\nResultsTwo molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.\n\nConclusionMulti-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"RationaleFibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.\n\nObjectivesTo identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.\n\nMethodsWe performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.\n\nResultsTwo molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.\n\nConclusionMulti-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"RationaleFibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.\n\nObjectivesTo identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.\n\nMethodsWe performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.\n\nResultsTwo molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.\n\nConclusionMulti-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Non-invasive intracranial pressure waveform reconstruction with deep learning","rel_doi":"10.64898\/2026.06.07.26354958","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354958","rel_abs":"Continuous intracranial pressure (ICP) monitoring requires invasive instrumentation and reaches only a subset of the critically ill patients who might need it. We tested whether deep learning models trained on routinely acquired extracranial signals can reconstruct continuous ICP waveforms at clinically relevant accuracy. Using data from adults admitted to the intensive care unit at a single quaternary health system, five deep learning architectures were trained on high-frequency arterial blood pressure, photoplethysmography, and electrocardiography waveforms, using invasive intraparenchymal ICP as ground truth; two fusion strategies and three training objectives were evaluated, and models were externally validated on a held-out independent dataset (the MIMIC-III Waveform Database). Performance was assessed by mean absolute error (MAE) and waveform similarity by Pearson correlation (r). Across 158 critically ill adults ([~]5,322 hours) from two institutions (Johns Hopkins Hospital, Baltimore; Beth Israel Deaconess Medical Center, Boston), external-validation MAE ranged from 4.276 to 4.946 mmHg and Pearson r from 0.599 to 0.722, with the multiscale encoder-decoder model showing the most favorable MAE-correlation tradeoff. These findings provide the first demonstration that continuous ICP waveform reconstruction from bedside signals generalizes across institutions at clinically relevant accuracy, establishing a foundation for non-invasive ICP monitoring and motivating validation across broader populations and ICP ranges.","rel_num_authors":4,"rel_authors":[{"author_name":"Ansh Goyal","author_inst":"Johns Hopkins University"},{"author_name":"Veet Zaveri","author_inst":"Johns Hopkins University"},{"author_name":"Carl W Harris","author_inst":"Johns Hopkins University"},{"author_name":"Robert David Stevens","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Multi-domain AD risk burden and plasma biomarkers in cognitively unimpaired adults","rel_doi":"10.64898\/2026.06.11.26355499","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355499","rel_abs":"IntroductionAlzheimers disease (AD) pathology accumulates decades before symptom onset, yet how the cumulative effect of genetic, familial, and modifiable lifestyle risk burden jointly affects plasma biomarker levels and trajectories in cognitively unimpaired older adults remains unknown.\n\nMethodsWe analyzed data from 261 participants in the PREVENT-AD cohort. A composite risk score integrating APOE {varepsilon}4 status, polygenic score, family history, and modifiable\/lifestyle risk was examined against six plasma biomarkers using linear regression and linear mixed-effects models.\n\nResultsAPOE {varepsilon}4 was the strongest predictor of plasma biomarker levels. Higher composite risk burden was associated with elevated ptau181, ptau217, ptau217\/A{beta}42, and GFAP levels, and lower A{beta}42\/40 levels. A higher risk burden was predictive of accelerated ptau181 accumulation.\n\nDiscussionCumulative AD risk burden is broadly associated with plasma biomarker levels and specifically predicts accelerated ptau181 accumulation in cognitively unimpaired older adults, supporting structured composite risk profiling as a framework for AD risk stratification.","rel_num_authors":5,"rel_authors":[{"author_name":"Michelle Y Li","author_inst":"University of California, San Francisco"},{"author_name":"Paulina Tolosa-Tort","author_inst":"University of California, San Francisco"},{"author_name":"Margo B Heston","author_inst":"University of California, San Francisco"},{"author_name":"Philip Insel","author_inst":"University of California, San Francisco"},{"author_name":"Shea J Andrews","author_inst":"University of California San Francisco"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Fanconi Anemia as a Window into Premalignant Field Cancerization of the Oral Mucosa","rel_doi":"10.64898\/2026.06.13.26354719","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26354719","rel_abs":"Head and neck squamous cell carcinoma (HNSCC) evolves through stepwise clonal expansion within genetically altered mucosa fields, yet actionable biomarkers remain undefined. Leveraging Fanconi anemia (FA), a cancer predisposition syndrome with extreme HNSCC risk due to defective DNA interstrand crosslink repair, we profiled premalignant changes in the oral cavity using noninvasive brush biopsies. Consistent with our prior demonstration of genomic instability in FA-associated SCCs, we detected pathogenic TP53 variants in 26% and copy number alterations in 60.5% in clinically normal-appearing oral mucosa of individuals with FA. These subclinical clonal expansions define candidate biomarkers of early clonal evolution amenable to serial sampling for risk stratification and prevention studies. Since FA-associated SCCs share genomic features with sporadic HNSCC, these findings may extend to the broader population. We also identify somatic reversion of a pathogenic FANCB variant, providing evidence of genomic self-correction and suggesting a potential avenue for gene-based cancer prevention in FA.\n\nStatement of significanceOral mucosa of individuals with Fanconi anemia contains frequent abnormal clones creating a premalignant field that increases cancer risk. The noninvasive brush sampling approach allows repeated measurements, ongoing surveillance, and assessment of prophylactic strategies that may be useful in the prevention of cancers in people with FA and in the general population. Somatic reversion of a pathogenic FANC variant may protect the oral mucosa from DNA repair deficiency and premalignant clonal evolution.","rel_num_authors":24,"rel_authors":[{"author_name":"Tamar Berger","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Frank X. Donovan","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Yu-Chien Lin","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Shivatheja Soma","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Francis May","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Kinjal Bhadresha","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Christine Krieg","author_inst":"Fanconi-Anamie Hilfe e.V, Eschau, Germany"},{"author_name":"Neelam Giri","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Lisa J McReynolds","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Armando Filie","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Zohreh Khavandgar","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Denise M Laronde","author_inst":"University of British Columbia, Vancouver, BC, Canada"},{"author_name":"Martial Guillaud","author_inst":"British Columbia Cancer Research Centre, Vancouver, BC, Canada"},{"author_name":"Sharon A Savage","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"David I. Kutler","author_inst":"Weill Cornell Medical College, New York, NY, USA"},{"author_name":"Wayne Crismani","author_inst":"The University of Melbourne, Parkville, Victoria, Australia"},{"author_name":"Eunike Velleuer","author_inst":"University of Dusseldorf, Germany"},{"author_name":"Rachel Uppgaard","author_inst":"University of Minnesota, Minneapolis, USA"},{"author_name":"Ursula L. Harper","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"K. Olivia Alston","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"James W. Thomas","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Arleen D. Auerbach","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Settara C. Chandrasekharappa","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Agata Smogorzewska","author_inst":"The Rockefeller University, New York, NY, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Using wastewater surveillance to explore community-level dietary intake in sewered and non-sewered sanitation systems in Malawi, Africa","rel_doi":"10.64898\/2026.06.07.26354900","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354900","rel_abs":"Wastewater can be used to measure biomarkers that reflect population-level dietary intake and diversity; however, how this approach may apply in a low-income country remains a knowledge gap. This study aims to evaluate whether select dietary-related metabolites can be detected in wastewater and environmental surveillance (WES) samples from both sewered and non-sewered sanitation systems in Malawi, Africa. Fourteen WES samples were collected and analyzed from two university campuses in Mzuzu and Thyolo, Malawi. Four targets were analyzed: N-methyl-2-pyridone-5-carboxamide (2PY; a biomarker of vitamin B3), 4-pyridoxic acid (4-PA; a biomarker of vitamin B6), as well as enterodiol and enterolactone (biomarkers of dietary fiber and polyphenol consumption). An 18-question survey, paired spatiotemporally with the WES measurements, assessed self-reported daily dietary intake, food insecurity, and nutrient deficiency symptoms among 500 respondents. Among the 14 WES samples, 2PY, 4-PA, and enterolactone were detected, while enterodiol was not detected above the method limit (<0.3 mg\/kg). Most respondents (79%; 397\/500) reported consuming foods associated with the 2PY biomarker. Many respondents (62%; 311\/500) also reported consuming foods linked to the 4-PA biomarker. Fewer respondents (36%; 181\/500) reported consuming foods associated with enterodiol or enterolactone, such as whole grains (e.g., millet) and other fiber-rich plant foods (e.g., beans, chickpeas, or pigeon peas). This study demonstrates the potential feasibility of monitoring dietary-related metabolites in both sewered and non-sewered sanitation systems in a low-income country to augment community-level nutrition data. 2PY, 4-PA, and enterolactone were detectable in WES samples, supporting the advancement of this emerging field in nutrition and food security research.","rel_num_authors":10,"rel_authors":[{"author_name":"Rochelle H Holm","author_inst":"University of Louisville"},{"author_name":"Petros Chigwechokha","author_inst":"Malawi University of Science and Technology"},{"author_name":"Chisomo Kaponda","author_inst":"Malawi University of Science and Technology"},{"author_name":"Makayla Stephens","author_inst":"University of Louisville"},{"author_name":"Hannah Limbong","author_inst":"University of Louisville"},{"author_name":"Ayse Ercumen","author_inst":"North Carolina State University"},{"author_name":"Joy Hart","author_inst":"University of Louisville"},{"author_name":"Cassandra  L Workman","author_inst":"University of North Carolina at Greensboro"},{"author_name":"Francis  L. de los Reyes","author_inst":"North Carolina State University"},{"author_name":"Brighton  Austin Chunga","author_inst":"Mzuzu University"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Instrumental Activities of Daily Living in Older Adults with Epilepsy: A Cross-Sectional and Longitudinal Multicenter Study","rel_doi":"10.64898\/2026.06.13.26355582","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355582","rel_abs":"ObjectiveInstrumental activities of daily living (IADLs) represent a critical but understudied measure of day-to-day function in persons with epilepsy(PWE). In the multicenter Brain Aging and Cognition in Epilepsy (BrACE) study of PWE aged [&ge;]55 years, we examined the proportion, clinical correlates, epilepsy-related predictors, and longitudinal trajectory of IADL impairment.\n\nMethodsIADLs were assessed using the Functional Activities Questionnaire(FAQ; range=0-30; higher=more impaired); FAQ[&ge;]2 defines MCI-level impairment and FAQ[&ge;]5 dementia-level functional impairment. Multivariable logistic regression identified predictors of baseline function. Global cognition (Montreal Cognitive Assessment [MoCA]), individual cognitive measures, and quality of life (QOL) were compared between the impaired and unimpaired groups. Linear regression evaluated predictors of longitudinal functional decline.\n\nResultsOf 57 participants(mean age=66.6{+\/-}7.2 years; female=52.6%), 38.6%(n=22) had MCI-level functional impairment and 17.5%(n=10) had dementia-level functional impairment. In univariate analyses, worse FAQ scores were associated with lower education, higher area deprivation index, early-onset epilepsy (EOE < 60 years), antiseizure medication polytherapy, and epilepsy localization (all p < 0.05). In multivariable analysis, temporal lobe epilepsy (OR=4.46, 95%-CI=1.09-21.83,p=0.047), EOE(OR=7.14,95%-CI=1.16-59.97,p=0.046), and lower education(OR=0.70,95%-CI=0.49-0.93,p=0.025) remained independently associated with baseline MCI-level functional-impairment. Lower education (OR=0.55,95%-CI=0.29-0.84, p=0.021) was the only factor associated with dementia-level IADL-impairment. IADL-impaired participants demonstrated lower verbal memory scores(adjusted-p=0.041) and MoCA(adjusted-p<0.001), particularly in visuospatial\/executive function, attention, and memory subscores, and worse QOL(adjusted-p=0.041). IADL-impairment was greatest in financially-mediated and memory-dependent tasks.\n\nLongitudinally, EOE({beta}=7.51,95%-CI=1.92-13.10,p=0.017) and older age({beta}=0.38,95%-CI=0.12-0.65,p=0.012) predicted greater functional decline. Nearly one-third progressed to significantly worse function over a two-year period, with 15.4% progressing from MCI-level to dementia-level impairment and 15.4% from normal function to MCI-level IADL-impairment.\n\nConclusionsFunctional impairment affects [~]40% of older PWE, with [~]1-in-6 experiencing functional impairment comparable to overt dementias. Temporal lobe localization, EOE, lower education, and poorer cognition are important determinants of baseline functional status. EOE and older age predict accelerated functional decline, suggesting that cumulative disease burden and aging-related processes may drive functional deterioration. These findings provide one of the first epilepsy-specific longitudinal characterizations of IADL impairment and support routine functional assessment in PWE.\n\nKey Points- Functional impairment is common in older PWE, affecting[~] 40%, with 1 in 6 showing dementia-level functional impairment.\n- Temporal lobe epilepsy localization, early-onset epilepsy, and lower education are independently associated with baseline MCI-level functional impairment.\n- Lower education was the only independent predictor of dementia-level IADL impairment.\n- IADL impairment was associated with worse verbal memory, global cognition, and quality of life.\n- Over two years, early-onset epilepsy and older age predicted greater functional decline, with nearly one-third progressing to worse functional status.","rel_num_authors":17,"rel_authors":[{"author_name":"Ifrah Zawar","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Anny Reyes","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Kayela Arrotta","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Bruce P. Hermann","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Robyn M. Busch","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Mark Quigg","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Jaideep Kapur","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Aaron F. Struck","author_inst":"Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"},{"author_name":"Vineet Punia","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Alena Stasenko","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"McKenna E. Williams","author_inst":"Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Katherine J. Bangen","author_inst":"Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Irene Wang","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jerry J. Shih","author_inst":"Department of Neurology, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Lisa Ferguson","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jana E. Jones","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Carrie R. McDonald","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA | Department of Psychiatry, University of Californ"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Instrumental Activities of Daily Living in Older Adults with Epilepsy: A Cross-Sectional and Longitudinal Multicenter Study","rel_doi":"10.64898\/2026.06.13.26355582","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355582","rel_abs":"ObjectiveInstrumental activities of daily living (IADLs) represent a critical but understudied measure of day-to-day function in persons with epilepsy(PWE). In the multicenter Brain Aging and Cognition in Epilepsy (BrACE) study of PWE aged [&ge;]55 years, we examined the proportion, clinical correlates, epilepsy-related predictors, and longitudinal trajectory of IADL impairment.\n\nMethodsIADLs were assessed using the Functional Activities Questionnaire(FAQ; range=0-30; higher=more impaired); FAQ[&ge;]2 defines MCI-level impairment and FAQ[&ge;]5 dementia-level functional impairment. Multivariable logistic regression identified predictors of baseline function. Global cognition (Montreal Cognitive Assessment [MoCA]), individual cognitive measures, and quality of life (QOL) were compared between the impaired and unimpaired groups. Linear regression evaluated predictors of longitudinal functional decline.\n\nResultsOf 57 participants(mean age=66.6{+\/-}7.2 years; female=52.6%), 38.6%(n=22) had MCI-level functional impairment and 17.5%(n=10) had dementia-level functional impairment. In univariate analyses, worse FAQ scores were associated with lower education, higher area deprivation index, early-onset epilepsy (EOE < 60 years), antiseizure medication polytherapy, and epilepsy localization (all p < 0.05). In multivariable analysis, temporal lobe epilepsy (OR=4.46, 95%-CI=1.09-21.83,p=0.047), EOE(OR=7.14,95%-CI=1.16-59.97,p=0.046), and lower education(OR=0.70,95%-CI=0.49-0.93,p=0.025) remained independently associated with baseline MCI-level functional-impairment. Lower education (OR=0.55,95%-CI=0.29-0.84, p=0.021) was the only factor associated with dementia-level IADL-impairment. IADL-impaired participants demonstrated lower verbal memory scores(adjusted-p=0.041) and MoCA(adjusted-p<0.001), particularly in visuospatial\/executive function, attention, and memory subscores, and worse QOL(adjusted-p=0.041). IADL-impairment was greatest in financially-mediated and memory-dependent tasks.\n\nLongitudinally, EOE({beta}=7.51,95%-CI=1.92-13.10,p=0.017) and older age({beta}=0.38,95%-CI=0.12-0.65,p=0.012) predicted greater functional decline. Nearly one-third progressed to significantly worse function over a two-year period, with 15.4% progressing from MCI-level to dementia-level impairment and 15.4% from normal function to MCI-level IADL-impairment.\n\nConclusionsFunctional impairment affects [~]40% of older PWE, with [~]1-in-6 experiencing functional impairment comparable to overt dementias. Temporal lobe localization, EOE, lower education, and poorer cognition are important determinants of baseline functional status. EOE and older age predict accelerated functional decline, suggesting that cumulative disease burden and aging-related processes may drive functional deterioration. These findings provide one of the first epilepsy-specific longitudinal characterizations of IADL impairment and support routine functional assessment in PWE.\n\nKey Points- Functional impairment is common in older PWE, affecting[~] 40%, with 1 in 6 showing dementia-level functional impairment.\n- Temporal lobe epilepsy localization, early-onset epilepsy, and lower education are independently associated with baseline MCI-level functional impairment.\n- Lower education was the only independent predictor of dementia-level IADL impairment.\n- IADL impairment was associated with worse verbal memory, global cognition, and quality of life.\n- Over two years, early-onset epilepsy and older age predicted greater functional decline, with nearly one-third progressing to worse functional status.","rel_num_authors":17,"rel_authors":[{"author_name":"Ifrah Zawar","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Anny Reyes","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Kayela Arrotta","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Bruce P. Hermann","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Robyn M. Busch","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Mark Quigg","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Jaideep Kapur","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Aaron F. Struck","author_inst":"Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"},{"author_name":"Vineet Punia","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Alena Stasenko","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"McKenna E. Williams","author_inst":"Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Katherine J. Bangen","author_inst":"Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Irene Wang","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jerry J. Shih","author_inst":"Department of Neurology, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Lisa Ferguson","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jana E. Jones","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Carrie R. McDonald","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA | Department of Psychiatry, University of Californ"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Pulmonary extracellular vesicles drive alveolar macrophage dysfunction via microRNA transfer in Acute Respiratory Distress Syndrome","rel_doi":"10.64898\/2026.06.13.26355564","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355564","rel_abs":"BackgroundAlveolar macrophage (AM) dysfunction contributes to Acute Respiratory Distress Syndrome (ARDS) pathogenesis. We investigated the role of extracellular vesicles (EVs) in mediating this dysfunction.\n\nMethodsPulmonary EVs were isolated from broncho-alveolar lavage and non-directed bronchial lavage samples of ventilated sepsis patients with and without ARDS, and post-operative control patients via ultracentrifugation. AMs were isolated from lung tissue resections of lobectomy patients. AMs were treated with pooled EVs for 24 hours prior to functional, metabolic and autophagy profiling. EV cargo was profiled via small RNA transcriptomics and proteomics. Mechanistic role of EV microRNAs was assessed via mimic \/ antagomir transfection.\n\nResultsPulmonary EVs from sepsis patients with ARDS impaired AM efferocytosis, and control EVs had no effect. ARDS EV treatment enhanced AM mitochondrial-linked respiration, but not glycolysis. ARDS EV treatment impaired LC3B-II and LAMP1 expression, indicating dysregulated AM autophagy-lysosomal machinery. Proteomics revealed downregulation of innate immune pathways in ARDS EVs. Transcriptomics revealed enrichment of 24 microRNAs in ARDS EVs; miR-652-3p was the most enriched, validated by RT-qPCR. EV miR-652-3p was associated with 90-day mortality (9.20 vs 0.59 RQ, p=0.0295) and inversely correlated with oxygenation (PaO2\/FiO2). AM transfection with miR-652-3p mimic induced similar dysregulation of function and autophagy as ARDS EVs. Transfection of ARDS EVs with antagomirs to miR-652-3p prior to AM treatment partially rescued efferocytosis and autophagy.\n\nConclusionsTargeting EV miR-652-3p may restore alveolar macrophage function and reduce excessive inflammation, thus offering a novel therapeutic strategy for patients with ARDS.","rel_num_authors":16,"rel_authors":[{"author_name":"Katie L. Spencer","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Charlie Mafham","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Joshua Price","author_inst":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, U"},{"author_name":"Ellen Jenkins","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Celine H. Chen","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Samuel Quarton","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Louise E. Crowley","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Xiaohong Jiang","author_inst":"Department of Geriatric Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China"},{"author_name":"Jose R. Hombrebueno","author_inst":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, U"},{"author_name":"Michael A. Matthay","author_inst":"Cardiovascular Research Institute, Department of Medicine, and Department of Anaesthesia, University of California San Francisco, San Francisco, California, U.S"},{"author_name":"Mark Lindsay","author_inst":"Department of Life Sciences, University of Bath, Bath, UK"},{"author_name":"Babu Naidu","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"David R Thickett","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Dhruv Parekh","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Aaron Scott","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Rahul Y Mahida","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Based Detection of Airway Mucus Plugs on CT and Associations With Clinical Outcomes in COPDGene","rel_doi":"10.64898\/2026.06.10.26355393","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355393","rel_abs":"RATIONALEAirway mucus plugging is a clinically relevant manifestation of airway pathology in chronic obstructive pulmonary disease (COPD) and is associated with increased mortality even in early disease; however, visual computed tomography (CT) assessment is subjective and labor intensive.\n\nOBJECTIVESTo develop an AI-based quantitative CT method for automated detection of airway mucus plugging and evaluate associations with physiologic impairment and clinical outcomes.\n\nMETHODSInspiratory CT scans from 8,971 COPDGene Phase 1 (GOLD 0-4 and PRISm) participants were analyzed. An AI-based framework combining 3D airway segmentation discontinuities and convolutional neural network classification identified mucus plug obstructions, yielding mucus plug burden (total plug count). Associations with outcomes were evaluated using covariate-adjusted models.\n\nMEASUREMENTS AND MAIN RESULTSHigher mucus plug burden was associated with lower post-bronchodilator FEV % predicted ({rho} = -0.41; P < 0.001), greater air trapping (LAA < -856 HU; {rho} = 0.33; P < 0.001), worse health status (SGRQ; {rho} = 0.31; P < 0.001), and shorter 6-minute walk distance ({rho} = -0.26; P < 0.001). Among GOLD 1-4 participants, mucus plug presence was independently associated with increased all-cause mortality (adjusted hazard ratio, 1.28; P < 0.005) and exacerbation frequency (adjusted incidence rate ratio, 1.32; P < 0.005). Plug presence was also associated with increased respiratory mortality across GOLD categories and cardiovascular mortality in GOLD 1-2.\n\nCONCLUSIONSAI-based quantitative CT assessment of airway mucus plugging provides a scalable, reproducible measure associated with physiologic impairment and adverse outcomes in COPD, supporting its role in risk stratification and future therapeutic studies.","rel_num_authors":11,"rel_authors":[{"author_name":"John Oyer","author_inst":"University of Michigan"},{"author_name":"Ali Namvar","author_inst":"University of Michigan"},{"author_name":"Benjamin A Hoff","author_inst":"University of Michigan"},{"author_name":"Christopher Bosma","author_inst":"University of Michigan"},{"author_name":"Wassim L Labaki","author_inst":"University of Michigan"},{"author_name":"Ella A Kazerooni","author_inst":"University of Michigan"},{"author_name":"Fernando J Martinez","author_inst":"University of Massachusetts, Worcester"},{"author_name":"Charles R Hatt","author_inst":"4D Medical Inc."},{"author_name":"Meilan K Han","author_inst":"University of Michigan"},{"author_name":"Craig J Galban","author_inst":"University of Michigan"},{"author_name":"Sundaresh Ram","author_inst":"Emory University & Georgia Institute of Technology"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Based Detection of Airway Mucus Plugs on CT and Associations With Clinical Outcomes in COPDGene","rel_doi":"10.64898\/2026.06.10.26355393","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355393","rel_abs":"RATIONALEAirway mucus plugging is a clinically relevant manifestation of airway pathology in chronic obstructive pulmonary disease (COPD) and is associated with increased mortality even in early disease; however, visual computed tomography (CT) assessment is subjective and labor intensive.\n\nOBJECTIVESTo develop an AI-based quantitative CT method for automated detection of airway mucus plugging and evaluate associations with physiologic impairment and clinical outcomes.\n\nMETHODSInspiratory CT scans from 8,971 COPDGene Phase 1 (GOLD 0-4 and PRISm) participants were analyzed. An AI-based framework combining 3D airway segmentation discontinuities and convolutional neural network classification identified mucus plug obstructions, yielding mucus plug burden (total plug count). Associations with outcomes were evaluated using covariate-adjusted models.\n\nMEASUREMENTS AND MAIN RESULTSHigher mucus plug burden was associated with lower post-bronchodilator FEV % predicted ({rho} = -0.41; P < 0.001), greater air trapping (LAA < -856 HU; {rho} = 0.33; P < 0.001), worse health status (SGRQ; {rho} = 0.31; P < 0.001), and shorter 6-minute walk distance ({rho} = -0.26; P < 0.001). Among GOLD 1-4 participants, mucus plug presence was independently associated with increased all-cause mortality (adjusted hazard ratio, 1.28; P < 0.005) and exacerbation frequency (adjusted incidence rate ratio, 1.32; P < 0.005). Plug presence was also associated with increased respiratory mortality across GOLD categories and cardiovascular mortality in GOLD 1-2.\n\nCONCLUSIONSAI-based quantitative CT assessment of airway mucus plugging provides a scalable, reproducible measure associated with physiologic impairment and adverse outcomes in COPD, supporting its role in risk stratification and future therapeutic studies.","rel_num_authors":11,"rel_authors":[{"author_name":"John Oyer","author_inst":"University of Michigan"},{"author_name":"Ali Namvar","author_inst":"University of Michigan"},{"author_name":"Benjamin A Hoff","author_inst":"University of Michigan"},{"author_name":"Christopher Bosma","author_inst":"University of Michigan"},{"author_name":"Wassim L Labaki","author_inst":"University of Michigan"},{"author_name":"Ella A Kazerooni","author_inst":"University of Michigan"},{"author_name":"Fernando J Martinez","author_inst":"University of Massachusetts, Worcester"},{"author_name":"Charles R Hatt","author_inst":"4D Medical Inc."},{"author_name":"Meilan K Han","author_inst":"University of Michigan"},{"author_name":"Craig J Galban","author_inst":"University of Michigan"},{"author_name":"Sundaresh Ram","author_inst":"Emory University & Georgia Institute of Technology"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Challenges and opportunities of gap score methods for studying psychopathology resilience and vulnerability","rel_doi":"10.64898\/2026.06.13.26355592","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355592","rel_abs":"BackgroundThe widespread prevalence of psychopathology, which affects approximately 50% of the global population, often manifests during adolescence. Understanding why some individuals remain resilient while others experience mental health challenges despite similar environmental risks is essential for developing early interventions. However, past efforts have faced challenges with the retrospective definition of resilience. Here, we aim to address these challenges by quantifying resilience to psychopathology at the individual level.\n\nMethodsIn the Adolescent Brain and Cognitive Development (ABCD) Study(R) (N = 11,868), we utilized gradient-boosted tree regression to predict 2-year follow-up psychopathology from 208 Social Determinants of Health features. We used the \"gap score\" method--the difference between model-predicted and reported psychopathology--to quantify individual differences in psychopathology resilience and susceptibility, defined as the Resilience-Susceptibility Gap (RS-Gap). We validated the RS-Gap against independent 3-year follow-up clinical and quality-of-life outcomes.\n\nResultsCollinearity between gap scores and reported symptoms was high (r=-0.84), requiring further correction. Four bias-correction techniques were implemented and compared. After appropriate bias-correction, greater RS-Gap scores were associated with a higher likelihood of poor academic and social outcomes one year later, suggesting that early adaptation to adversity may carry a latent long-term cost.\n\nConclusions\n\nDependency between RS-Gap and psychopathology scores is a statistical challenge for gap score resilience methods. Our comparisons demonstrate that correction is mandatory to separate resilience signal from shared variance with psychopathology scores. Findings converged across different bias correction methods, providing a validated framework for using gap scores to identify high-risk developmental trajectories in youth.","rel_num_authors":7,"rel_authors":[{"author_name":"Hailey Modi","author_inst":"Washington University in St. Louis"},{"author_name":"David AA Baranger","author_inst":"Medical College of Wisconsin"},{"author_name":"Jared V Balbona","author_inst":"Virginia Commonwealth University"},{"author_name":"Samuel Naranjo Rinc\u00f3n","author_inst":"Washington University in St. Louis"},{"author_name":"Aaron John Gorelik","author_inst":"Washington University in St. Louis"},{"author_name":"Ryan Bogdan","author_inst":"Washington University in St. Louis"},{"author_name":"Janine D Bijsterbosch","author_inst":"Washington University in St Louis"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Latent tuberculosis infection workflows in four primary healthcare systems in the United States","rel_doi":"10.64898\/2026.06.12.26355200","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355200","rel_abs":"BackgroundLatent tuberculosis - infection (LTBI) reactivation accounts for most tuberculosis (TB) cases in the United States (U.S.). Expanding primary care LTBI services can improve detection and treatment, but real-world implementation is not well described.\n\nObjectiveDescribe how LTBI screening and treatment workflows are operationalized into practice in diverse U.S. primary care health systems.\n\nDesignDescriptive, multi-site study.\n\nSettingFour U.S. primary care health systems participating in the U.S. Centers for Disease Control and Prevention (CDC) Tuberculosis Epidemiologic Studies Consortium III (TBESC-III, 2020-2022).\n\nPatientsPatients visiting any study site (N = 3,522,077).\n\nMeasurementsElectronic medical record (EMR) data on patient demographics, TB test type, and results. Using narrative reporting and study documentation, LTBI care workflows were summarized by site into six domains: patient registration, TB testing evaluation, TB testing, TB disease assessment, LTBI diagnosis, and LTBI treatment.\n\nResultsSites implemented recommended practices for testing and treatment: interferon-gamma release assays were the predominant test, and short-course rifamycin-based regimens were the primary treatment. Follow-up care practices and documentation of treatment outcomes varied. Country of birth was not consistently recorded at all sites, limiting TB screening capability based on nativity. Physician training, EMR decision-support tools, and patient education resources differed in scope and availability.\n\nLimitationsDescriptive design using self-reported workflows; may not generalize to all primary care settings or reflect physician-level variations.\n\nConclusionWe provide a descriptive snapshot showing how LTBI care workflows varied in approach and consistency at four primary care systems with integrated LTBI services. These real-world examples may serve as templates for U.S. primary care systems seeking to expand TB testing and treatment.\n\nPrimary Funding SourceU.S. Centers for Disease Control and Prevention (TBESC-III).","rel_num_authors":10,"rel_authors":[{"author_name":"Julie Espey","author_inst":"Centers for Disease Control and Prevention, Atlanta"},{"author_name":"Julie Venci","author_inst":"Denver Health and Hospital Authority"},{"author_name":"Paul Y Wada","author_inst":"Kaiser Permanente Northern California, Oakland"},{"author_name":"Yoseph Sorri","author_inst":"Public Health-Seattle and King County, Seattle"},{"author_name":"Amy Tang","author_inst":"North East Medical Services, San Francisco"},{"author_name":"Beatrice Francis","author_inst":"Public Health Institute at Denver Health, Denver"},{"author_name":"Jacek Skarbinski","author_inst":"Kaiser Permanente Northern California, Oakland"},{"author_name":"Masahiro Narita","author_inst":"Public Health-Seattle and King County, Seattle"},{"author_name":"Priya B Shete","author_inst":"University of California San Franciso Medical Center Neurosurgery Clinic"},{"author_name":"Winglee Kathryn","author_inst":"Centers for Disease Control and Prevention, Atlanta"}],"rel_date":"2026-06-15","rel_site":"medrxiv"}]}