{"gname":"University of New South Wales","grp_id":"25","rels":[{"rel_title":"Multimodal Phenotyping of Myofascial Pain Syndrome Using Rotational Shear Wave Elastography and Clinical Network Analysis","rel_doi":"10.64898\/2026.07.23.26358787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358787","rel_abs":"Myofascial pain syndrome (MPS) is characterized by increased muscle stiffness, trigger points, and functional limitations, yet clinical diagnosis remains largely subjective. Shear wave elastography (SWE) provides quantitative assessment of muscle mechanical properties, but its value for identifying biomechanical and clinical phenotypes of MPS is not fully established. This study evaluated whether stiffness parameters derived from multi-angle SWE can reliably characterize upper-trapezius anisotropy, and whether integrating SWE with bioimpedance spectroscopy (BIS), range of motion (ROM), and patient-reported outcomes (PROs) improves differentiation of MPS subgroups. Seventy-one adults completed upper-trapezius SWE, BIS, ROM assessments, and PRO measures. Clinically, 18 were classified as active MPS, 36 as latent, and 17 as normal. Shear wave speed measurements were modeled to estimate longitudinal (uL), transverse (uT), and anisotropy (uE) components. Reliability was examined using intraclass correlation coefficients. Unsupervised clustering and partial-correlation network analysis were applied to biomechanical and clinical variables. uT showed the strongest associations with BIS frequency parameters and ROM measures, indicating sensitivity to fascial composition, and mobility. Multimodal clustering incorporating uT with Fc or ROM identified subgroups with distinct tissue-level and functional characteristics. Network analysis demonstrated a progression in connectivity patterns, shifting from localized mechanical relationships to broader symptom-level coupling involving pain interference, sleep disturbance, emotional distress, and physical function. These findings indicate that SWE-derived stiffness parameters provide reliable, direction-specific quantification of trapezius mechanical properties. Combining SWE with impedance and mobility measures yields physiologically coherent MPS phenotypes that differ in both biomechanical features and clinical network structure, supporting more objective framework for characterizing MPS.","rel_num_authors":13,"rel_authors":[{"author_name":"Matin Jahani Jirsaraei","author_inst":"George Mason University"},{"author_name":"Yu-lin Hsu","author_inst":"George Mason University"},{"author_name":"Reihana Akhwand","author_inst":"George Mason University"},{"author_name":"Abhishek Aher","author_inst":"George Mason University"},{"author_name":"Seiyon Lee","author_inst":"George Mason University"},{"author_name":"Secili DeStefano","author_inst":"Optimal Motion Physical Therapy"},{"author_name":"John Srbely","author_inst":"University of Guelph"},{"author_name":"Jay Shah","author_inst":"National Institutes of Health"},{"author_name":"William Rosenberger","author_inst":"George Mason University"},{"author_name":"Samuel Acuna","author_inst":"George Mason University"},{"author_name":"Yonathan Assefa","author_inst":"National Institutes of Health"},{"author_name":"Lynn H. Gerber","author_inst":"INOVA Health System"},{"author_name":"Siddhartha Sikdar","author_inst":"George Mason University"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Death, Culture, and Conflict: A Qualitative Study on Sociocultural Practices and Their Implications for Maternal and Perinatal Death Surveillance in Eastern Democratic Republic of Congo","rel_doi":"10.64898\/2026.07.22.26358727","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358727","rel_abs":"Background: Death is a social and cultural phenomenon whose meaning shapes how and whether losses are mourned, disclosed, and reported. These dynamics have direct implications for maternal and perinatal death surveillance and response (MPDSR), yet remain understudied, particularly in humanitarian contexts. Methods: This phenomenological qualitative study was conducted in two conflict-affected health zones in Eastern Democratic Republic of Congo. In-depth interviews (n=50) were conducted with bereaved family members of maternal or perinatal deaths, community leaders, and health providers to understand the socio-cultural practices surrounding death and the factors influencing MPDSR. Interviews were transcribed in French and analyzed using inductive thematic content analysis. Results: Four themes characterized the socio-cultural practices surrounding maternal and perinatal deaths: burial practices, mourning and bereavement traditions, rationale for these practices, and the impact of insecurity on customs. Burial and mourning practices differed markedly by type of death, with stillbirths and neonatal deaths accorded significantly less social recognition than maternal deaths. Deaths were commonly attributed to witchcraft or spiritual causality, or blame directed at mothers, husbands, and health providers. Active conflict further disrupted customary practices and eroded community trust. Collectively, these dynamics inhibit disclosure and reporting of deaths, undermining MPDSR case identification. Conclusion: Effective MPDSR in conflict-affected settings requires culturally responsive adaptation, community involvement in case identification, and trust in health sector actors. By documenting specific actors involved in burials, variations in burial and mourning practices, and how conflict changes socio-cultural practices, findings offer actionable entry points for strengthening MPDSR in conflict-affect health zones in Eastern DRC.","rel_num_authors":11,"rel_authors":[{"author_name":"Meighan Mary","author_inst":"University of Maryland School of Medicine"},{"author_name":"Christine Chimanuka Murhima\u2019alika","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Christian Chiribagula Zalinga","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Christian Mugisho Byamungu","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Pacifique Mwene-Batu","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Emilie Grant","author_inst":"Johns Hopkins School of Hygiene and Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Rosine Bigirinama Nshobole","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Gaylord Ngaboyeka","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Salomine Ekambi","author_inst":"Johns Hopkins School of Hygiene and Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Hannah Tappis","author_inst":"Johns Hopkins School of Hygiene and Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Ghislain Bisimwa Balaluka","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Addictive plasmids drive hospital transmission of mupirocin-resistant Staphylococcus aureus","rel_doi":"10.64898\/2026.07.24.26358837","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358837","rel_abs":"Background Mupirocin, a widely used topical agent for decolonization of Staphylococcus aureus, is increasingly compromised by resistance. Although plasmid-mediated mupirocin resistance is a recognized cause of decolonization failure, its role in facilitating hospital-wide transmission is unknown. Methods We conducted genomic surveillance of S. aureus at two interconnected urban hospitals where mupirocin decolonization is routine. Genome sequencing of >10,000 isolates was integrated with patient data to identify transmission and resistance determinants. Bacterial phenotypes and fitness were evaluated in vitro and in murine colonization models. Findings Genome sequencing identified 475 hospital transmission events; none were detected by conventional surveillance. The mupA (ileS2) resistance determinant, carried on conjugative plasmids, was enriched eightfold in methicillin-resistant S. aureus (MRSA) relative to methicillin-susceptible strains. mupA was associated with nearly a threefold greater chance of hospital transmission, especially within endemic healthcare-associated MRSA lineages, and was enriched twofold in hospital-onset infections compared with admission colonizing isolates. Multiple independently evolved inactivating mutations in the essential chromosomal gene ileS1 co-occurred with mupA, creating plasmid addiction in which mupA became indispensable for bacterial survival. Addiction arose most frequently within the dominant community-acquired MRSA lineage, where plasmid carriage reduced colonization fitness in mice. Plasmid-containing strains exhibited stringent-response activation, explaining the fitness costs and collateral tolerance to disinfectants, such as ethanol and peroxide. Although addiction reduced S. aureus fitness, it increased plasmid transfer, and addicted variants spread across hosts, demonstrating adaptation that mitigates these costs. Unexpectedly, we identified a mupirocin-dependent vulnerability to isoleucine limitation, revealing a potential strategy to target mupA-mediated resistance. Interpretation Plasmids promote hospital transmission of mupirocin-resistant S. aureus and create an evolutionary trap in which antibiotic use selects for bacterial dependence on otherwise costly resistance elements. This dependence revealed a collateral bacterial vulnerability that could be exploited to target resistant strains and preserve the effectiveness of mupirocin.","rel_num_authors":19,"rel_authors":[{"author_name":"Magdalena Podkowik","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Ananyaa R Welling","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Somrita Dey","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Alice Tillman","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Gregory Putzel","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Courtney Takats","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Julian McWilliams","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Stacey Bartlett","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Nora Samhadaneh","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Robert J Ulrich","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Kristine B Rabii","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Olufolakemi Olusanya","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Caitlin Otto","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Karl Drlica","author_inst":"Rutgers University"},{"author_name":"Mila  Brum Ortigoza","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Audrey Renson","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Alejandro Pironti","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Sarah Hochman","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Bo Shopsin","author_inst":"NYU Grossman School of Medicine"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Ixodid Tick-Borne Pathogens as Candidate Triggers for Primary Sclerosing Cholangitis: Ecological Evidence","rel_doi":"10.64898\/2026.07.24.26358879","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358879","rel_abs":"Background & Aims. Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown etiology whose prevalence varies >30-fold worldwide, peaking in Northern Europe and the U.S. Upper Midwest. This geographic distribution is not fully explained by recognized risk factors. We examine its correlation with Ixodes tick exposure. Approach & Results. PSC incidence across North America, Europe, and Oceania was compared with Lyme incidence, HLA-DRB1*03 frequency, latitude and other environmental factors. Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) were included as controls. A U.S. analysis (MarketScan, 2018-2022; 110.7 million person-years) correlated age and sex-standardized rates against 24 exposures, including Ixodes density and tick-borne infections, using ancestry-adjusted partial correlations. Cross-country PSC incidence tracked Lyme incidence (Spearman rho = 0.71-0.87); HLA-DRB1*03, AIH, and PBC did not. Alaska Native and Greenlandic populations, high-latitude but without established human exposure to Ixodes-borne pathogens, report no PSC despite high autoimmune liver disease and IBD. In the U.S., PSC was clustered and tracked Ixodes-borne pathogen incidence (ancestry-adjusted partial r, log scale: anaplasmosis +0.50, babesiosis +0.56, Powassan virus disease +0.52; in the Northeast-Midwest block, ancestry- and latitude-adjusted r = +0.72, +0.84, and +0.78, respectively). Non-Ixodes infections (Ehrlichia chaffeensis, spotted fever, tularemia), AIH, and PBC were null-to-negative; rural, agricultural, pollution, and healthcare-access also did not correlate. Conclusions. These ecological analyses are consistent with the hypothesis that Ixodes-borne pathogen exposure may trigger PSC. These ecological data cannot establish causation; they are hypothesis-generating, yielding falsifiable predictions for case control, serologic, and animal-model studies.","rel_num_authors":1,"rel_authors":[{"author_name":"Kevin M. Johnson","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Water Supply Continuity, Frequency, and Health Gains: Ten-Year Evidence from Hubli-Dharwad, India","rel_doi":"10.64898\/2026.07.23.26358804","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358804","rel_abs":"Intermittent water supplies (IWS) serve >1 billion people globally and can transmit waterborne infections. How often and for how long supply is delivered varies between and within IWS systems. The UN Sustainable Development Goals target having water available when needed for >=12 hours\/day or >=4 days\/week but there are scarce data on how supply frequency\/duration within IWS affect health outcomes. We conducted a matched study in Hubli-Dharwad, India, a city served partially by continuous water supply (CWS) since 2007 and partially by IWS. We enrolled 2220 CWS and 2218 IWS households matched on socioeconomics and sanitation. We compared diarrhea prevalence in children <5 years and typhoid fever incidence between households with different water supply characteristics using generalized linear models with robust standard errors and adjusting for socio-demographics and sanitation. Among IWS households, the median supply frequency was every 8 days (interquartile range [IQR]=7-8), and the median supply duration was 4 hours (IQR=3-5). IWS households had 36% higher prevalence of child diarrhea (prevalence ratio [PR]=1.36, 1.00-1.84) and 78% more typhoid fever cases (cumulative incidence ratio [CIR]=1.78, 1.05-3.02) than CWS households. IWS households meeting the UN criterion and those in the top quintiles of supply frequency and duration (receiving water once every 1-6 days or for 7-24 hours per supply cycle) had similar health outcomes as CWS households. IWS households below the UN criterion had higher diarrhea prevalence (PR=1.41, 1.03-1.93) and more typhoid fever cases (CIR=1.93, 1.15-3.22) than CWS households, as well as more typhoid fever cases than IWS households meeting the criterion (CIR=3.66, 1.37-9.79). IWS households in the bottom quintiles of supply frequency and duration (receiving water once every 9-15 days or for <=3 hours per supply cycle) had 45-72% higher child diarrhea prevalence and twice as many typhoid fever cases than CWS households (p-values<0.05). These findings support global efforts to implement CWS. Our results also highlight that increasing supply frequency and duration in IWS systems in the interim can deliver health benefits, and the UN criterion of having water available when needed improves health.","rel_num_authors":6,"rel_authors":[{"author_name":"Ayse Ercumen","author_inst":"North Carolina State University"},{"author_name":"Narayana Billava","author_inst":"Center for Multidisciplinary Development Research"},{"author_name":"Zachary Burt","author_inst":"California Department of Water Resources"},{"author_name":"Sharada Prasad","author_inst":"Infosys"},{"author_name":"Nayanatara Nayak","author_inst":"Center for Multidisciplinary Development Research"},{"author_name":"Emily Kumpel","author_inst":"University of Massachusetts, Amherst"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Discordance Between Biomarker-Confirmed Antiretroviral Therapy and Self-Reported HIV Status Among People Living with HIV in Zambia and South Africa: A Secondary Analysis of HPTN 071 (PopART)","rel_doi":"10.64898\/2026.07.22.26358720","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358720","rel_abs":"Background: Misclassification of HIV status in population-based surveys remains a critical barrier to accurate surveillance and program evaluation. Self-reported HIV status may diverge from objective measures, particularly among individuals receiving antiretroviral therapy (ART). We used biomarker-confirmed antiretroviral (ARV) drug detection to assess the prevalence and correlates of discordance between self-reported HIV status and biologic evidence of HIV treatment among people living with HIV (PLHIV) in Zambia and South Africa. Methods: We conducted a secondary analysis of the HPTN 071 (PopART) cluster-randomized trial. At the 24-month survey visit, participants underwent HIV testing and laboratory assessment for ARV drugs in plasma. We defined discordant self-report (hereafter \"non-disclosure\") as reporting HIV-negative or unknown status among individuals with ARV drugs detected. We estimated the prevalence of non-disclosure, compared prevalence by study arm, and used modified Poisson regression to identify associated factors. We also examined whether non-disclosure was associated with viral suppression (<400 copies\/mL). Results: Among 3,240 PLHIV with ARV drugs detected, 552 (17.0%) did not report an HIV-positive status--indicating that nearly one in six individuals on ART were misclassified by self-report. Non-disclosure did not differ between intervention and control arms (adjusted relative risk [aRR]: 1.03; 95% CI: 0.67-1.58). Non-disclosure was more common among younger individuals (age 18-24 years: aRR 2.30; 95% CI: 1.66-3.19), men (aRR: 1.39; 95% CI: 1.07-1.79), and those in formal employment (aRR: 1.42; 95% CI: 1.06-1.90). Individuals reporting condomless sex at last encounter were also more likely not to disclose (aRR: 1.59; 95% CI: 1.31-1.92). Viral suppression was high overall (93.7%) and did not differ by disclosure status (aRR: 1.06; 95% CI: 0.74-1.52). Conclusion: A substantial proportion of PLHIV receiving ART did not report a known HIV-positive status, highlighting important discordance between biomarker evidence and self-reported data. Despite high levels of viral suppression, these individuals remain \"hidden\" from routine surveillance, with implications for estimating HIV diagnosis and treatment coverage. Strategies that incorporate objective measures alongside self-report, and that address social and structural barriers to disclosure, are essential to improve the accuracy of HIV surveillance and guide effective public health responses.","rel_num_authors":14,"rel_authors":[{"author_name":"Rita Nakalega","author_inst":"MU-JHU Care Limited"},{"author_name":"Daniel Haines","author_inst":"Fred Hutchinson Cancer Research Center Arnold Library: Fred Hutchinson Cancer Center"},{"author_name":"Richard  J Hayes","author_inst":"London School of Hygiene & Tropical Medicine Centre of Global Change and Health: London School of Hygiene & Tropical Medicine"},{"author_name":"Susan  H Eshleman","author_inst":"JHU: Johns Hopkins University"},{"author_name":"Helen Ayles","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Peter Bock","author_inst":"Stellenbosch University"},{"author_name":"Sian Floyd","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Sarah Fidler","author_inst":"Imperial College London"},{"author_name":"William Clarke","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Yaw Agyei","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Autumn Breaud","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Brenda  G Mirembe","author_inst":"MU-JHU Research Collaboration: MU-JHU Care Limited"},{"author_name":"Clemensia Nakabiito","author_inst":"MU-JHU Research Collaboration: MU-JHU Care Limited"},{"author_name":"Deborah Donnell","author_inst":"Fred Hutchinson Cancer Research Center Arnold Library: Fred Hutchinson Cancer Center"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Discordance Between Biomarker-Confirmed Antiretroviral Therapy and Self-Reported HIV Status Among People Living with HIV in Zambia and South Africa: A Secondary Analysis of HPTN 071 (PopART)","rel_doi":"10.64898\/2026.07.22.26358720","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358720","rel_abs":"Background: Misclassification of HIV status in population-based surveys remains a critical barrier to accurate surveillance and program evaluation. Self-reported HIV status may diverge from objective measures, particularly among individuals receiving antiretroviral therapy (ART). We used biomarker-confirmed antiretroviral (ARV) drug detection to assess the prevalence and correlates of discordance between self-reported HIV status and biologic evidence of HIV treatment among people living with HIV (PLHIV) in Zambia and South Africa. Methods: We conducted a secondary analysis of the HPTN 071 (PopART) cluster-randomized trial. At the 24-month survey visit, participants underwent HIV testing and laboratory assessment for ARV drugs in plasma. We defined discordant self-report (hereafter \"non-disclosure\") as reporting HIV-negative or unknown status among individuals with ARV drugs detected. We estimated the prevalence of non-disclosure, compared prevalence by study arm, and used modified Poisson regression to identify associated factors. We also examined whether non-disclosure was associated with viral suppression (<400 copies\/mL). Results: Among 3,240 PLHIV with ARV drugs detected, 552 (17.0%) did not report an HIV-positive status--indicating that nearly one in six individuals on ART were misclassified by self-report. Non-disclosure did not differ between intervention and control arms (adjusted relative risk [aRR]: 1.03; 95% CI: 0.67-1.58). Non-disclosure was more common among younger individuals (age 18-24 years: aRR 2.30; 95% CI: 1.66-3.19), men (aRR: 1.39; 95% CI: 1.07-1.79), and those in formal employment (aRR: 1.42; 95% CI: 1.06-1.90). Individuals reporting condomless sex at last encounter were also more likely not to disclose (aRR: 1.59; 95% CI: 1.31-1.92). Viral suppression was high overall (93.7%) and did not differ by disclosure status (aRR: 1.06; 95% CI: 0.74-1.52). Conclusion: A substantial proportion of PLHIV receiving ART did not report a known HIV-positive status, highlighting important discordance between biomarker evidence and self-reported data. Despite high levels of viral suppression, these individuals remain \"hidden\" from routine surveillance, with implications for estimating HIV diagnosis and treatment coverage. Strategies that incorporate objective measures alongside self-report, and that address social and structural barriers to disclosure, are essential to improve the accuracy of HIV surveillance and guide effective public health responses.","rel_num_authors":14,"rel_authors":[{"author_name":"Rita Nakalega","author_inst":"MU-JHU Care Limited"},{"author_name":"Daniel Haines","author_inst":"Fred Hutchinson Cancer Research Center Arnold Library: Fred Hutchinson Cancer Center"},{"author_name":"Richard  J Hayes","author_inst":"London School of Hygiene & Tropical Medicine Centre of Global Change and Health: London School of Hygiene & Tropical Medicine"},{"author_name":"Susan  H Eshleman","author_inst":"JHU: Johns Hopkins University"},{"author_name":"Helen Ayles","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Peter Bock","author_inst":"Stellenbosch University"},{"author_name":"Sian Floyd","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Sarah Fidler","author_inst":"Imperial College London"},{"author_name":"William Clarke","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Yaw Agyei","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Autumn Breaud","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Brenda  G Mirembe","author_inst":"MU-JHU Research Collaboration: MU-JHU Care Limited"},{"author_name":"Clemensia Nakabiito","author_inst":"MU-JHU Research Collaboration: MU-JHU Care Limited"},{"author_name":"Deborah Donnell","author_inst":"Fred Hutchinson Cancer Research Center Arnold Library: Fred Hutchinson Cancer Center"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"A Pragmatic Trial of a Multilevel Community-Centered Intervention to Reduce Pregnancy Related and Associated Morbidity and Mortality and Disparities: A Study Protocol","rel_doi":"10.64898\/2026.07.23.26358783","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358783","rel_abs":"Introduction: Maternal morbidity and mortality in the US disproportionately affect some women, including the Medicaid-insured, rural, and Black, Hispanic, and Native American populations. The drivers of disparities are complex and there is an urgent need for multilevel interventions focused on pregnancy-related and associated morbidity and mortality (PRAMM). This study will be the first large-scale test of Community Health Worker (CHW) inclusive home visiting and provider\/practice\/system level improvement strategies that support empowered patients, pro-active providers, and integrates community and clinical care designed to reduce PRAMM and disparities among women who are disproportionately affected. Methods and analysis: The primary study outcome will be rates of PRAMM - a composite outcome including pregnancy-associated and pregnancy-related morbidity, severe maternal morbidity, and mortality - and disparities among women disproportionately affected. A quasi-experimental, stepped wedge design will be used. Participants will be Medicaid-insured women in three Michigan counties observed during pregnancy, at birth, and up to one year postpartum, who give birth between 2021-2028 (>101,000 births). Individual health outcomes will be assessed at three steps of the stepped-wedge design. Analyses will use a statewide linked data system including all Medicaid birth and death records, Medicaid claims, and other program data. In the context of Michigan extending pregnancy-related Medicaid, the study will evaluate the impact of the proposed multilevel intervention vs. usual care from early pregnancy through 12 months postpartum. The study was developed with full community engagement and participation including shared leadership with academic and community-based Principal Investigators representing intervention communities. Ethics and dissemination: An Institutional Review Board determined the study exempt from the human subject's regulations, for the following reasons. Two of the three intervention components will not interact with human subjects to collect data - we will only rely on secondary research using data or biospecimens not collected specifically for this study, and the data will be provided without identifiable information by someone without any role in this research study except providing the data. The third intervention component, medical provider surveys, is a benign behavioral intervention where information will be recorded using methods that prevent subjects' identities from being readily ascertained. Results will be published in peer-reviewed journals following EQUATOR guidelines.","rel_num_authors":12,"rel_authors":[{"author_name":"Cristian I Meghea","author_inst":"Michigan State University"},{"author_name":"Hannah Bolder","author_inst":"Michigan State University"},{"author_name":"Xiao Yu","author_inst":"Michigan State University"},{"author_name":"Jennifer  E. Johnson","author_inst":"Michigan State University College of Human Medicine"},{"author_name":"Kimberlydawn Wisdom","author_inst":"Henry Ford Health"},{"author_name":"Jaime Slaughter-Acey","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Margaret Vander Meulen","author_inst":"Strong Beginnings - Healthy Start at Corewell Health"},{"author_name":"Celeste Sanchez Lloyd","author_inst":"Strong Beginnings - Healthy Start at Corewell Health"},{"author_name":"Jennifer Raffo","author_inst":"Michigan State University"},{"author_name":"Hannah Nelson","author_inst":"Michigan State University"},{"author_name":"Ran Meng","author_inst":"Michigan State University"},{"author_name":"Lee Anne Roman","author_inst":"Michigan State University"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Cerebrospinal fluid profile, including \u03b1-Synuclein seeding activity, of p.A53T SNCA mutation carriers: Data from the PPMI Study.","rel_doi":"10.64898\/2026.07.23.26356817","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26356817","rel_abs":"We report here, based on Parkinson's Progression Markers Initiative (PPMI) data, on the Cerebrospinal Fluid (CSF) profile of a group of 12 Parkinson's Disease (PD) subjects with the prototypical p.A53T SNCA mutation, comparing them to 36 matched Healthy Controls (HCs) and 36 idiopathic PD (iPD) cases. We furthermore assessed the CSF profile of 7 asymptomatic carriers of this mutation. There was no significant difference between the 3 groups of A53T-PD, HC and iPD in total alpha synuclein (a-syn) levels, beta-amyloid 1-42, total-Tau and p-Tau, although A53T-PD subjects tended to have slightly lower beta-amyloid 1-42, total-Tau and especially total a-syn levels. All A53T-PD cases had a positive CSF a-syn Seeding Amplification Assay (SAA). Four out of 7 asymptomatic carriers also had a positive SAA, in 3 without motor symptoms or signs and absence of clear prodromal manifestations. Conversion to motoric manifestations has occurred in one out of these 3 subjects, 8 years after SAA positivity, while one other subject only has hyposmia 8 years later. Overall, these results indicate that at least in early stages of PD, CSF Alzheimer's Disease profiles are not significantly different in A53T-PD compared to HCs or iPD, while the CSF a-syn SAA is universally positive in this group. Furthermore, the assay may be positive in asymptomatic carriers at a time with no prodromal manifestations and many years before motor disease onset, opening a window into very early stages of disease pathobiology and opportunities for early therapeutic intervention.","rel_num_authors":11,"rel_authors":[{"author_name":"Athina Maria Simitsi","author_inst":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"},{"author_name":"Nikolaos Papagiannakis","author_inst":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"},{"author_name":"Ioanna Alefanti","author_inst":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"},{"author_name":"Marina Piccilo","author_inst":"1.Centre for Neurodegenerative Diseases (CEMAND), Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\",University of Salerno, Salerno, Ital"},{"author_name":"Paolo Barone","author_inst":"1.Centre for Neurodegenerative Diseases (CEMAND), Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\",University of Salerno, Salerno, Ital"},{"author_name":"David-Erick Lafontant","author_inst":"The University of Iowa, Iowa City, IA, United Statesof America"},{"author_name":"Kenneth Marek","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, United States of America"},{"author_name":"Andrew Siderowf","author_inst":"University of Pennsylvania, Neurology, Philadelphia, AL, United States of America"},{"author_name":"Tanya Simuni","author_inst":"Northwestern University, Parkinson's Disease and Movement Disorders Center, Northwestern University Feinberg School of Medicine, Chicago, USA, Chicago, IL, Unit"},{"author_name":"Christos Koros","author_inst":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"},{"author_name":"Leonidas Stefanis","author_inst":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Study protocol for a multicenter randomized controlled trial comparing standby versus prophylactic extracorporeal membrane oxygenation in high-risk percutaneous coronary intervention (ECMO-READY trial)","rel_doi":"10.64898\/2026.07.24.26358881","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358881","rel_abs":"Background: Although prophylactic veno-arterial extracorporeal membrane oxygenation (VA-ECMO) may provide hemodynamic stability during high-risk percutaneous coronary intervention (PCI), it is also associated with potential complications and may not be necessary in most cases. In this context, we proposed a pre-cannulated standby ECMO strategy and designed the ECMO-READY trial to evaluate the comparative effectiveness of pre-cannulated standby versus prophylactic ECMO strategies in patients undergoing high-risk PCI. Methods: The ECMO-READY trial is a prospective, multicenter, open-label, randomized controlled trial conducted in 8 sites in China. A total of 176 patients scheduled to undergo high-risk PCI will be randomly assigned in a 1:1 ratio to either a pre-cannulated standby ECMO strategy or a prophylactic ECMO strategy. The primary outcome is the 30-day incidence of major adverse events, including death, myocardial, infarction, repeat revascularization, stroke, PCI failure, limb ischemia, major bleeding, vascular injury requiring intervention, and need for renal replacement therapy. Secondary outcomes include post-procedural hemoglobin decline, post-procedural platelet count decline, red blood cell transfusion rate, peak post-procedural interleukin-6 level, use of intra-aortic balloon pump, duration of ECMO support, length of hospital stay, hospitalization cost, and each component of the composite primary outcome. Enrollment began in March 2025 and is anticipated to be completed by December 2026. Discussion: The ECMO-READY trial will provide prospective randomized evidence regarding ECMO support strategies in patients undergoing high-risk PCI and may help inform future clinical practice. Trial registration: ClinicalTrials.gov NCT06274411. Registered on February 23, 2024. Keywords Percutaneous coronary intervention, High-risk, Extracorporeal membrane oxygenation, Ready, Standby, prophylactic, Major adverse events","rel_num_authors":18,"rel_authors":[{"author_name":"Liangshan Wang","author_inst":"Center for Cardiac Critical Care, Beijing An Zhen Hospital of Capital Medical University"},{"author_name":"Yan Wang","author_inst":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing, China."},{"author_name":"Andong Lu","author_inst":"Heart Center, The First Hospital of Lanzhou University, Lanzhou, Gansu, China"},{"author_name":"Kexin Wang","author_inst":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing, China."},{"author_name":"Chenglong Li","author_inst":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing, China."},{"author_name":"Fang Liu","author_inst":"Departments of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China"},{"author_name":"Xiaolin Yu","author_inst":"Department of Cardiology, Cardiac and Pan-Vascular Medicine Center, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, China."},{"author_name":"Dingyu Wang","author_inst":"Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin,Heilongjiang, China"},{"author_name":"Liwen Lyu","author_inst":"Department of Emergency, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China."},{"author_name":"Wenlong Duan","author_inst":"Department of Emergency, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China."},{"author_name":"Xinguang Wei","author_inst":"Department of Cardiopulmonary Bypass,Wuhan Asia Heart Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei , China."},{"author_name":"Eddy Fan","author_inst":"Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada."},{"author_name":"Zhongtao Du","author_inst":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing, China."},{"author_name":"Hong Wang","author_inst":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing, China."},{"author_name":"Yan Liu","author_inst":"Department of Cardiopulmonary Bypass,Wuhan Asia Heart Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei , China."},{"author_name":"Jianchao Li","author_inst":"Department of cardiopulmonary bypass, Fuwai Central-China Cardiovascular Hospital\/Central China Subcenter of National Center for Cardiovascular Diseases, Zhengz"},{"author_name":"Xiaotong Hou","author_inst":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing, China."},{"author_name":"- the ECMO-READY investigators","author_inst":""}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Autoantibodies neutralizing type I interferons underlie a third of cases of Chikungunya virus encephalitis or myelitis","rel_doi":"10.64898\/2026.07.23.26358609","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358609","rel_abs":"Chikungunya virus (CHIKV) infection is typically not life-threatening but may, in rare cases, affect the central nervous system (CNS). In three cohorts of confirmed CHIKV cases from Martinique (French overseas territory) and Brazil (patients aged 0--89 years, n = 245), 20 patients had CNS infection (aged 17--87 years). Autoantibodies neutralizing type I interferons (AAN-I-IFN) were found in 35% of patients (4 male and 3 female, aged 17--87 years) with encephalitis (4\/15), encephalomyelitis (1\/2), or myelitis (2\/3), but were absent in 225 patients without CNS infection. They neutralized high concentrations (10--1,000 ng\/mL) of IFN-2, IFN-8, and IFN-{omega}, and the antibodies of one patient also neutralized IFN-{beta}. All samples also neutralized the other 10 IFN- subtypes (at least 100 pg\/mL). This combination of blood autoantibodies occurs in ~0.02% and 0.6% of healthy individuals under and over 70 years of age, respectively. The presence of AAN-I-IFN before CHIKV infection therefore increased the risk of CNS disease ~850-fold relative to the general population.","rel_num_authors":20,"rel_authors":[{"author_name":"Vu L. Tran","author_inst":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA"},{"author_name":"Adrian Gervais","author_inst":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Sante et de la Recherche Medicale (INSERM) U1163, Necker Hospital fo"},{"author_name":"Marie-Mechtilde Champeaux","author_inst":"Paris Cite University, Imagine Institute, Paris, France"},{"author_name":"Maria Paula de Souza Sampaio","author_inst":"Laboratorio de Investigacao em Saude Global e Doencas Negligenciadas, Instituto Goncalo Moniz, Fiocruz-Bahia, Salvador, Brazil"},{"author_name":"Sylvie L Abel","author_inst":"Caribbean Clinical Investigation Center, Inserm CIC 2504, University Hospital of Martinique, Fort-de-France, France"},{"author_name":"Isabelle Calmont","author_inst":"Caribbean Clinical Investigation Center, Inserm CIC 2504, University Hospital of Martinique, Fort-de-France, France"},{"author_name":"Mateus Santana do Rosario","author_inst":"Laboratorio de Investigacao em Saude Global e Doencas Negligenciadas, Instituto Goncalo Moniz, Fiocruz-Bahia, Salvador, Brazil"},{"author_name":"Laire Schidlowski","author_inst":"Faculdades Pequeno Principe, Av. Iguacu, 333, CEP 80230-020, Reboucas, Curitiba, PR, Brazil"},{"author_name":"Jordan D. Simione","author_inst":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA"},{"author_name":"Pedro Augusto Alves","author_inst":"Laboratorio de Imunologia de Doencas Virais, Instituto Rene Rachou, Fiocruz Minas, Belo Horizonte, Minas Gerais, Brazil"},{"author_name":"Anne Puel","author_inst":"Paris Cite University, Imagine Institute, Paris, France"},{"author_name":"Paul Bastard","author_inst":"Paris Cite University, Imagine Institute, Paris, France"},{"author_name":"Laurent Abel","author_inst":"Paris Cite University, Imagine Institute, Paris, France"},{"author_name":"Carolina Prando","author_inst":"Faculdades Pequeno Principe, Av. Iguacu, 333, CEP 80230-020, Reboucas, Curitiba, PR, Brazil"},{"author_name":"Rafael Freitas de Oliveira Franca","author_inst":"Plataforma de Pesquisa em Medicina Translacional, Fundacao Oswaldo Cruz-Fiocruz Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil"},{"author_name":"Isadora Cristina de Siqueira","author_inst":"Laboratorio de Investigacao em Saude Global e Doencas Negligenciadas, Instituto Goncalo Moniz, Fiocruz-Bahia, Salvador, Brazil"},{"author_name":"Andr\u00e9 Cabi\u00e9","author_inst":"University Hospital of Martinique, Infectious Diseases and Tropical Medicine Unit, F-97200, Martinique; Caribbean Clinical Investigation Center, Inserm CIC 2504"},{"author_name":"Aur\u00e9lie Cobat","author_inst":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Sante et de la Recherche Medicale (INSERM) U1163, Necker Hospital fo"},{"author_name":"Shen-Ying Zhang","author_inst":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA"},{"author_name":"Jean-Laurent Casanova","author_inst":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Making the incomparable comparable: Calibrating patient prioritisation tools for independent surgical procedures onto a common scale","rel_doi":"10.64898\/2026.07.23.26358834","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358834","rel_abs":"Long waiting times for elective surgery remain a persistent challenge in public health systems. Patient prioritisation tools (PPTs) aim to support equitable decision-making by scoring patients based on clinical and non-clinical factors. However, these tools are often developed independently for specific procedures, resulting in non-comparable scores that hinder consistent prioritisation and risk violating the principles of horizontal equity (equal treatment for equal need) and vertical equity (greater need receives higher priority). This study introduces and demonstrates a calibration method to align multiple procedure-specific PPTs onto a unified severity scale. As a proof-of-concept, ten independently developed PPTs from a general surgery unit at a single Australian public hospital were calibrated using an interactive binary search algorithm to identify clinically equivalent patient states across tools, in collaboration with clinicians from the same unit. Each PPT was then aligned to a common reference procedure, and min-max normalisation was applied to standardise scores onto a shared scale. Internal consistency was assessed by comparing calibration outputs against severity rankings from the same clinical team. The calibrated scores demonstrated strong agreement with the team's severity judgements (Kendall's {tau} = -0.734, p < 0.001), indicating that the calibration method preserved the clinicians' intuitive severity rankings. The calibrated scores also preserved the assigned urgency ordering across a cohort of 845 patients. When embedded in an existing dynamic priority formula in simulation, they redistributed waiting time between urgency categories without measurably altering severity concordance. This indicates that the operational effect of the comparable scores depends on the prioritisation formula in which they are embedded, rather than on the calibration itself. These results suggest that the proposed calibration method offers a practical and potentially scalable approach for aligning PPTs across procedures, supporting valid comparisons and enabling more consistent, transparent, and equitable prioritisation. By establishing a common severity scale, this approach addresses a real-world challenge in surgical waiting list management: enabling procedures of inherently different clinical impact to be prioritised fairly and proportionately when competing for shared resources.","rel_num_authors":8,"rel_authors":[{"author_name":"Jack Powers","author_inst":"School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia"},{"author_name":"Franz Ombler","author_inst":"1000minds Ltd, Dunedin, New Zealand"},{"author_name":"Paul Hansen","author_inst":"1000minds Ltd, Dunedin, New Zealand"},{"author_name":"Ratna Aseervatham","author_inst":"Department of General Surgery, Sunshine Coast University Hospital, Queensland, Australia"},{"author_name":"David Grieve","author_inst":"Department of General Surgery, Sunshine Coast University Hospital, Queensland, Australia"},{"author_name":"Suzanne Ryan","author_inst":"Department of General Surgery, Sunshine Coast University Hospital, Queensland, Australia"},{"author_name":"James M. McGree","author_inst":"School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia"},{"author_name":"Paul Corry","author_inst":"School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Impact of Cardiomyopathy and Arrhythmia Genetic Testing on Clinical Management Decisions","rel_doi":"10.64898\/2026.07.22.26358740","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358740","rel_abs":"Genetic testing for cardiomyopathy and arrhythmia (CM\/ARRH) provides diagnostic information and informs screening for at-risk relatives. Clinical guidelines recommend genetic testing for these conditions; however, data on how genetic test results influence clinical management recommendations are limited. Here, we determined the frequency of cardiologist-recommended management changes for patients following CM\/ARRH genetic testing. This was a retrospective cross-sectional study of patients referred for multigene panel testing between April 2016 and April 2024. Genetically-experienced cardiologists at multicenter academic clinical practices were recruited for participation to complete surveys indicating clinical decision making on patients who had genetic testing. Cases for review were randomly selected to have both positive and non-positive results. Among 249 patients (138 positive, 111 non-positive), 136 (54.6%) received clinical management recommendations for their own or their at-risk relatives? care. Of these, 75 (55.1%) received recommendations for the patient?s own care, most frequently additional diagnostic tests\/procedures (n=33). Compared to non-positive results, patients with positive results were more likely to receive recommendations for their own management (66\/138, 47.8% vs 9\/111, 8.1%; P<0.00001). Patients with positive results in arrhythmogenic cardiomyopathy genes had 263% higher odds of recommended management changes compared to those with TTN (OR=3.63, CI:1.40-9.84, P=0.009). The results from CM\/ARRH genetic testing on affected patients influenced cardiologists? medical decision making and management recommendations. Additional research is needed to evaluate how genetic testing for CM\/ARRH impact health outcomes.","rel_num_authors":21,"rel_authors":[{"author_name":"Ana Morales","author_inst":"Geisinger Health"},{"author_name":"Yi-Lee Ting","author_inst":"Laboratory Corporation of America Holdings"},{"author_name":"Brianna Bucknor","author_inst":"Laboratory Corporation of America Holdings"},{"author_name":"Anwar A. Chahal","author_inst":"WellSpan Health"},{"author_name":"Emily Higgs","author_inst":"University of California San Francisco"},{"author_name":"Daniel Judge","author_inst":"Medical University of South Carolina"},{"author_name":"Anjali T. Owens","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Jessica Wang","author_inst":"UCLA Health Internal Medicine"},{"author_name":"Mohamad Alkhayat","author_inst":"WellSpan Health"},{"author_name":"Naomi Barker","author_inst":"Medical University of South Carolina"},{"author_name":"Megan N. Betts","author_inst":"WellSpan Health"},{"author_name":"Jessica Chowns","author_inst":"Hospital of the University of Pennsylvania"},{"author_name":"Rebecca M Eberly","author_inst":"WellSpan Health"},{"author_name":"Edward D Esplin","author_inst":"Invitae"},{"author_name":"Lily Hoffman-Andrews","author_inst":"Perelman School of Medicine at the University of Pennsylvania"},{"author_name":"Ajit Koduri","author_inst":"Baylor College of Medicine Texas Heart Institute"},{"author_name":"Ajith P Nair","author_inst":"Baylor College of Medicine Healthcare"},{"author_name":"Arun Padmanabhan","author_inst":"UCSF School of Medicine"},{"author_name":"Vasanth Vedantham","author_inst":"University of California San Francisco"},{"author_name":"Julianne Wojciak","author_inst":"University of California San Francisco"},{"author_name":"Elizabeth M. McNally","author_inst":"Northwestern University Feinberg School of Medicine"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Development and Psychometric Validation of the Pelvic Dystonia Severity Scale (PDSS)","rel_doi":"10.64898\/2026.07.24.26358500","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358500","rel_abs":"Background. Chronic pelvic pain with involuntary pelvic-floor hypertonicity is common, disabling, and inconsistently measured, and no validated condition-specific severity instrument exists. A refractory subset has been proposed to represent a focal dystonia of the pelvic musculature, termed pelvic dystonia. Purpose. To develop the Pelvic Dystonia Severity Scale (PDSS) and evaluate its measurement properties as a patient-reported measure of pelvic-pain symptom severity and burden, following the COSMIN guidelines. Methods. Cross-sectional study with a test-retest component in 102 adults from an outpatient multidisciplinary pain practice. We assessed data quality, structural validity, internal consistency, test-retest reliability, measurement error, and construct validity against the Global Dystonia Severity Rating Scale (GDS) and Brief Pain Inventory (BPI). Because no validated diagnostic criteria exist, a clinician blinded to PDSS responses rated each participant for clinical signs of pelvic dystonia (present\/possible\/absent) as a provisional reference standard. Results. 100 of 102 participants (98%) returned complete data, with 0% item-level missing data. Factor analysis supported a unidimensional structure (single factor, 68.6% of variance; loadings 0.56-0.93), with high subscale intercorrelations (r = 0.81-0.97). Internal consistency (Cronbach's  0.810-0.924) and test-retest reliability (ICC 0.857-0.953) were strong. Convergent validity was supported by correlations with GDS pelvic-region items (r = 0.56-0.68) and BPI severity (r = 0.44-0.55), and discriminant validity by weak correlations with anatomically remote regions (shoulder\/arm r = 0.03-0.16). PDSS scores rose monotonically across blinded clinical-signs categories (absent 14.9, possible 32.7, present 52.0; Kruskal-Wallis p < 0.001), discriminating signs-present from signs-absent participants with a very large effect (Hedges g = 2.19; ROC AUC = 0.92). Conclusion. The PDSS is a psychometrically robust, unidimensional measure of pelvic-pain symptom severity and burden with strong data quality, reliability, and construct validity. It is suitable for characterizing symptom severity and, pending responsiveness testing, for monitoring treatment. The dystonia interpretation of the underlying phenotype is discussed as a hypothesis for future neurophysiologic and longitudinal study.","rel_num_authors":5,"rel_authors":[{"author_name":"Jason Siefferman","author_inst":"Pain Management, Manhattan Pain Medicine, PLLC, New York, NY, USA"},{"author_name":"Mariia Safroshkina","author_inst":"Pain Management, Manhattan Pain Medicine, PLLC, New York, NY, USA"},{"author_name":"Iuliia Nazarova","author_inst":"Pain Management, Manhattan Pain Medicine, PLLC, New York, NY, USA"},{"author_name":"Andrey Zaznaev","author_inst":"Department of Biomedical Informatics, Columbia University, New York, NY, USA"},{"author_name":"Sameeha Hasan","author_inst":"Pain Management, Manhattan Pain Medicine, PLLC, New York, NY, USA"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Tau isoform imbalance and aggregation are pathological hallmarks of X-linked dystonia-parkinsonism","rel_doi":"10.64898\/2026.07.23.26358614","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358614","rel_abs":"Tauopathies encompass diverse neurodegenerative diseases unified by aberrant patterns of tau deposition in brain. Although most appear sporadic, some are linked to genetic etiologies that offer unique mechanistic insights. Here we report that X-linked Dystonia-Parkinsonism (XDP), caused by a non-coding retrotransposon-associated repeat insertion in TAF1, involves a significant imbalance of tau isoforms and the accumulation of hyperphosphorylated, four-repeat tau in the brain. In striatal tissue, both misfolded tau accumulation, predominantly in astrocytes, and MAPT exon 10 inclusion correlated with repeat length within the causal insertion. Transcriptomic profiling across brain regions revealed dysregulation of known tau-related pathways. Levels of phosphorylated tau181, glial fibrillary acidic protein, and neurofilament light chain were elevated in patient plasma and discriminated XDP from controls. These findings implicate defective tau proteostasis as a key pathogenic mechanism and position XDP as a genetic model for uncovering cellular drivers that may disrupt tau in other more common neurodegenerative diseases.","rel_num_authors":56,"rel_authors":[{"author_name":"Charles Jourdan F Reyes","author_inst":"Massachusetts General Hospital"},{"author_name":"Aloysius Domingo","author_inst":"Massachusetts General Hospital"},{"author_name":"Ellen B Penney","author_inst":"Massachusetts General Hospital"},{"author_name":"Ean Norenberg","author_inst":"Massachusetts General Hospital"},{"author_name":"Justin Han","author_inst":"Massachusetts General Hospital"},{"author_name":"Micaela G Murcar","author_inst":"Massachusetts General Hospital"},{"author_name":"Christine A Vaine","author_inst":"Massachusetts General Hospital"},{"author_name":"Nicolas A Bravo-Vasquez","author_inst":"Massachusetts General Hospital"},{"author_name":"Hoang-Dai Tran","author_inst":"Massachusetts General Hospital"},{"author_name":"Noe Quittot","author_inst":"Massachusetts General Hospital"},{"author_name":"Anastasie Mate de Gerando","author_inst":"Massachusetts General Hospital"},{"author_name":"Nil F Saez-Calveras","author_inst":"UT Southwestern"},{"author_name":"Yogesh Tak","author_inst":"UT Southwestern"},{"author_name":"Rachita Yadav","author_inst":"Massachusetts General Hospital"},{"author_name":"Dadi Gao","author_inst":"Massachusetts General Hospital"},{"author_name":"Siddarth Reed","author_inst":"Massachusetts General Hospital"},{"author_name":"Serkan Erdin","author_inst":"Massachusetts General Hospital"},{"author_name":"Nandini Ramesh","author_inst":"Massachusetts General Hospital"},{"author_name":"Benjamin Wymann","author_inst":"Massachusetts General Hospital"},{"author_name":"Aaron Held","author_inst":"Massachusetts General Hospital"},{"author_name":"Ranee Zara Monsanto","author_inst":"Massachusetts General Hospital"},{"author_name":"Laura Moran","author_inst":"Massachusetts General Hospital"},{"author_name":"Hayden Wheeler","author_inst":"Massachusetts General Hospital"},{"author_name":"Yin Yin Ruan","author_inst":"Massachusetts General Hospital"},{"author_name":"Grant Griesman","author_inst":"Massachusetts General Hospital"},{"author_name":"Grace Anne Field","author_inst":"Massachusetts General Hospital"},{"author_name":"Chao-zong Lee","author_inst":"Massachusetts General Hospital"},{"author_name":"Gelbert Crescencio","author_inst":"Massachusetts General Hospital"},{"author_name":"Matthew Nolan","author_inst":"Massachusetts General Hospital"},{"author_name":"John Lemanski","author_inst":"Massachusetts General Hospital"},{"author_name":"Kathryn OKeefe","author_inst":"Massachusetts General Hospital"},{"author_name":"Bimal Jana","author_inst":"Massachusetts General Hospital"},{"author_name":"Cara Fernandez-Cerado","author_inst":"Sunshine Care Foundation"},{"author_name":"M. Salvie Velasco-Andrada","author_inst":"Sunshine Care Foundation"},{"author_name":"Gierold Paul A Legarda","author_inst":"Sunshine Care Foundation"},{"author_name":"Michelle Sy","author_inst":"Sunshine Care Foundation"},{"author_name":"Madison Hincher","author_inst":"Massachusetts General Hospital"},{"author_name":"Tiziana Petrozziello","author_inst":"Massachusetts General Hospital"},{"author_name":"Pia Kivisakk Webb","author_inst":"Massachusetts General Hospital"},{"author_name":"Ghazaleh Sadri-Vakili","author_inst":"Massachusetts General Hospital"},{"author_name":"Edwin L Munoz","author_inst":"University of the Philippines Manila"},{"author_name":"Mark Angelo C Ang","author_inst":"University of the Philippines Manila"},{"author_name":"Cid Czarina E Diesta","author_inst":"Makati Medical Center"},{"author_name":"Criscely Go","author_inst":"Jose R. Reyes Memorial Medical Center"},{"author_name":"Mark W Albers","author_inst":"Massachusetts General Hospital \/ Harvard Medical School"},{"author_name":"Steven Arnold","author_inst":"Massachusetts General Hospital"},{"author_name":"Brian J Wainger","author_inst":"Massachusetts General Hospital"},{"author_name":"Rachel E Bennett","author_inst":"Massachusetts General Hospital"},{"author_name":"Marc I Diamond","author_inst":"UT Southwestern"},{"author_name":"Jeffrey W Miller","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Bradley T Hyman","author_inst":"Massachusetts General Hospital"},{"author_name":"Nutan Sharma","author_inst":"Massachusetts General Hospital"},{"author_name":"Laurie J Ozelius","author_inst":"Massachusetts General Hospital"},{"author_name":"Michael Talkowski","author_inst":"Massachusetts General Hospital"},{"author_name":"D Cristopher Bragg","author_inst":"Massachusetts General Hospital"},{"author_name":"Clotilde Lagier-Tourenne","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Deep Learning for Individual-Level Classification of Schizophrenia Versus Healthy Controls from Trial-Level Auditory Oddball ERP Waveforms","rel_doi":"10.64898\/2026.07.24.26358816","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358816","rel_abs":"Machine learning approaches may support individual-level classification in psychiatry, but many EEG-based schizophrenia studies have relied on small samples or conventional summary features. We evaluated whether trial-level auditory oddball event-related potential (ERP) waveforms could support schizophrenia versus healthy-control classification using deep learning. The study included 258 patients with schizophrenia and 142 healthy controls. EEG recordings from an auditory duration oddball paradigm were segmented into -100 to 500 ms epochs, and trial-level mismatch waveforms were generated by subtracting each participant's mean standard response from accepted deviant trials. Models were trained using a fixed participant-level training, validation, and test split, with demographic residualization fit only in the training set. Five deep learning architectures were trained on full residualized ERP waveforms and compared with classical machine learning models trained on 18 conventional ERP summary features. Deep learning models achieved higher test set discrimination than classical feature-based models, with AUROC values ranging from 0.797 to 0.857 versus 0.705 to 0.720. Benchmark analyses suggested that performance depended on the combination of waveform-level input and deep learning architecture. These findings support trial-level auditory oddball ERP waveforms as promising classification inputs and candidate electrophysiological biomarkers of schizophrenia-related neural information processing.","rel_num_authors":9,"rel_authors":[{"author_name":"Yi-Han Sheu","author_inst":"Massachusetts General Hospital, Harvard Medical School, Broad Institute of MIT and Harvard"},{"author_name":"Yi-Ting Lin","author_inst":"National Taiwan University Hospital"},{"author_name":"Kristina M. Holton","author_inst":"Harvard University, Broad Institute of MIT and Harvard"},{"author_name":"Chih-Min Liu","author_inst":"National Taiwan University Hospital"},{"author_name":"Yi-Ling Chien","author_inst":"National Taiwan University Hospital"},{"author_name":"Chen-Chung Liu","author_inst":"National Taiwan University Hospital"},{"author_name":"Mei-Hua Hall","author_inst":"McLean Hospital, Harvard Medical School"},{"author_name":"Hai-Gwo Hwu","author_inst":"National Taiwan University Hospital"},{"author_name":"Ming H. Hsieh","author_inst":"National Taiwan University Hospital"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Surrogate Endpoint Evaluation with Causal Mediation: Lessons from the A4 Trial","rel_doi":"10.64898\/2026.07.23.26358810","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358810","rel_abs":"Surrogate endpoints, or measures used in place of the true outcome of interest, have relevance across multiple disease areas. The Prentice Criteria, proposed in 1989, assess surrogacy by evaluating how the treatment's effect on the true outcome operates through the potential surrogate. Using the A4 Study of solanezumab, we evaluate multiple formulations of the Prentice Criteria using causal mediation. We estimated direct and indirect effects of solanezumab on cognitive decline through cerebral amyloid across different, but reasonable, measures of exposure, mediator, outcome, and covariate adjustment. Unsurprisingly given that solanezumab did not show benefit, estimated indirect effects were close to zero. These results provide little evidence of meaningful mediation for memory and global cognition, but precision varied substantially. Confidence interval widths varied by up to a factor of 17 across specifications. Causal mediation analysis of individual-level randomized trial data may contribute to quantitative surrogate endpoint evaluation, but our findings indicate this is only the case when analytic choices are biologically justified, prespecified, and interpreted with attention to uncertainty.","rel_num_authors":8,"rel_authors":[{"author_name":"Evan J. Hoefen","author_inst":"Brown University"},{"author_name":"Michael Flanders","author_inst":"Brown University School of Public Health"},{"author_name":"Jason Gantenberg","author_inst":"Brown University School of Public Health"},{"author_name":"Eleanor Hayes-Larson","author_inst":"University of Southern California"},{"author_name":"Paul  K Crane","author_inst":"University of Washington"},{"author_name":"Seo-Eun Choi","author_inst":"University of Washington"},{"author_name":"Emily H. Trittschuh","author_inst":"University of Washington"},{"author_name":"Sarah Ackley","author_inst":"Brown University School of Public Health"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Developing intrinsic capacity measures for research and practice in an Australian context","rel_doi":"10.64898\/2026.07.23.26358833","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358833","rel_abs":"Introduction: Intrinsic capacity is a key construct for healthy ageing; however, its measurement remains heterogeneous, with insufficient attention to context, data availability, and intended purpose. We operationalised intrinsic capacity to facilitate its assessment in both research and clinical settings. Method: Using data from Concord Health and Ageing in Men Project (CHAMP; 2005-2007; 1,705 Australian men aged [&ge;]70 years), we developed three intrinsic capacity models using confirmatory factor analysis (CFA): literature-based (21 commonly used indicators), minimum-set (10 indicators), and clinically informed (10 indicators selected for clinical feasibility). Convergent validity was assessed using activities of daily living (ADL) and instrumental activities of daily living (IADL) as indicators of functional ability. Predictive validity was examined using 2-year incident ADL and IADL dependency and 10-year mortality follow-up data. Results: All models demonstrated acceptable model fit (robust root mean square error of approximation <0.06). The second-order level of CFA showed significant associations with the cognition, locomotor function, psychological well-being, and vitality domains, but not the sensory domain. Higher intrinsic capacity scores were associated with lower ADL (e.g., ICclinically informed 0.91 [0.90-0.92]) and IADL dependence (e.g., ICclinically informed 0.92 [0.92-0.93]) at baseline, lower incident dependency at follow-up, and lower all-cause mortality (e.g., ICminimum-set 0.96 [0.96-0.97]), demonstrating convergent and predictive validity. Conclusion: This study developed and evaluated three intrinsic capacity models to address measurement challenges and intended use, supporting a validated yet flexible approach to measuring intrinsic capacity in research and practice. Their adoption across diverse research and clinical contexts would facilitate comparability and strengthen the evidence base.","rel_num_authors":9,"rel_authors":[{"author_name":"Jiayue Wang","author_inst":"University of Sydney"},{"author_name":"Philip Clare","author_inst":"University of Sydney"},{"author_name":"Vasi Naganathan","author_inst":"University of Sydney"},{"author_name":"Ding Ding","author_inst":"University of Sydney"},{"author_name":"Matteo Cesari","author_inst":"University of Milan"},{"author_name":"Stephane Cullati","author_inst":"University of Fribourg"},{"author_name":"Julie Byles","author_inst":"University of Newcastle"},{"author_name":"Fiona M. Blyth","author_inst":"University of Sydney"},{"author_name":"Saman Khalatbari-Soltani","author_inst":"University of Sydney"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Comparison of Influenza Vaccine Effectiveness Estimates Using Test-Negative Prospective Enrollment and Electronic Health Record Data, United States, 2024--2025","rel_doi":"10.64898\/2026.07.23.26358258","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358258","rel_abs":"Background: Influenza vaccine effectiveness (VE) is assessed annually through prospective enrollment of patients presenting with acute respiratory symptoms in a test-negative study design. Influenza VE has also been estimated from electronic health record (EHR) databases by linking medical diagnoses, laboratory test results, and patient influenza vaccination. There are limited data on agreement between influenza VE estimates from prospective enrollment versus EHR databases. Methods: The US Influenza Vaccine Effectiveness Network prospectively enrolled outpatients meeting clinical screening criteria and collected respiratory specimens to determine influenza virus infection. Seven study sites also identified EHR databases that included diagnostic codes for outpatient encounters associated with medically attended acute respiratory illness (MAARI), clinical respiratory virus testing, and influenza vaccination status. Effectiveness of influenza vaccination against laboratory-confirmed influenza was estimated from both data sources using logistic regression models including patient age, study site, and month of illness as 100(%) x (1 - adjusted odds ratio), comparing influenza vaccination among laboratory-confirmed influenza-positive patients versus laboratory-confirmed influenza-negative patients. Results: From October 2024--April 2025, 2,016 (30%) of 6,793 prospectively enrolled patients and 75,885 (24%) of 282,444 EHR MAARI encounters had laboratory-confirmed influenza virus infection. Effectiveness of vaccination against laboratory-confirmed influenza was 36% (95% confidence interval [CI]: 26-44) among prospectively enrolled patients and 38% (95% CI: 36-39) among EHR MAARI encounters. Comparing influenza VE estimates from the two data sources, confidence intervals overlapped for all age groups except for adults aged [&ge;]65 years: -3% (95% CI: -53-30) among prospective enrollment versus 35% (95% CI: 32-39) VE from EHR MAARI encounters. Conclusion: Overall, influenza VE estimates from retrospective EHR data were similar to VE estimates using the test-negative design with prospective enrollment. The age group-specific differences in estimated VE observed in US adults aged [&ge;]65 years compared with younger age groups merit further investigation.","rel_num_authors":23,"rel_authors":[{"author_name":"Ashley M Price","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Callie McLean","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Seana Cleary","author_inst":"Influenza Division, US Centers for Disease Control and Prevention, Atlanta, GA, USA; STI Federal, Sault Tribe Incorporated, Sault Ste Marie, Michigan, USA"},{"author_name":"Aleda M Leis","author_inst":"University of Michigan School of Public Health, Ann Arbor, MI, USA"},{"author_name":"Ivana A Vaughn","author_inst":"Henry Ford Health, Detroit, MI, USA"},{"author_name":"Stacey House","author_inst":"Washington University School of Medicine in St. Louis, Department of Emergency Medicine, St. Louis, MO, USA"},{"author_name":"Sam Ellsworth","author_inst":"Washington University School of Medicine in St. Louis, Department of Emergency Medicine, St. Louis, MO, USA"},{"author_name":"Krissy Moehling Geffel","author_inst":"University of Pittsburgh School of Medicine, Department of Family Medicine, Pittsburgh, PA, USA"},{"author_name":"Louise H Taylor","author_inst":"University of Pittsburgh School of Medicine, Department of Family Medicine, Pittsburgh, PA, USA"},{"author_name":"Manjusha Gaglani","author_inst":"Baylor Scott & White Health, Temple, TX, USA; Baylor College of Medicine, Temple, TX, USA"},{"author_name":"Kempapura Murthy","author_inst":"Baylor Scott & White Health, Temple, TX, USA"},{"author_name":"Elie A Saade","author_inst":"University Hospitals of Cleveland, Cleveland, OH, USA"},{"author_name":"Christopher Ladikos","author_inst":"University Hospitals of Cleveland, Cleveland, OH, USA"},{"author_name":"Vel Murugan","author_inst":"Biodesign Center for Personalized Diagnostics and Health Observatory Arizona State University, Tempe, AZ, USA"},{"author_name":"Joanna L Kramer","author_inst":"Phoenix Childrens Hospital, Phoenix, AZ"},{"author_name":"Brian D Williamson","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Erika Kiniry","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Emmanuel B Walter","author_inst":"Duke Human Vaccine Institute, Duke University School of Medicine"},{"author_name":"Natalie AB Bontrager","author_inst":"Duke Human Vaccine Institute, Duke University School of Medicine"},{"author_name":"Sascha Ellington","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Brendan M Flannery","author_inst":"CDC"},{"author_name":"Jessie Chung","author_inst":"US Centers for Disease Control and Prevention"},{"author_name":"- US Flu VE Network Investigators","author_inst":""}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Analytical benchmarking of extraction-free lysis devices for molecular detection of tuberculosis","rel_doi":"10.64898\/2026.07.24.26358841","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358841","rel_abs":"Sample preparation remains a barrier for decentralized, swab-based molecular testing of tuberculosis (TB). Extraction-free workflows offer a simpler alternative, but systematic benchmarking against standard methods is lacking. We evaluated five novel lysis devices, BLINK Shaker Prototype, nPOC-BB, SPS-1, Truelyse, and Thermolyse, against a heat- and bead-beating reference method using contrived M. tuberculosis-spiked tongue and sputum swabs. The primary outcome was lysis efficiency, measured as the relative DNA recovery compared with the reference workflow. Secondary outcomes included nuclease inactivation, biosafety, and usability. In the reference buffer, lysis efficiencies ranged from 51-63% to 95-154% on tongue swabs and 12-54% to 280-644% on sputum swabs across the five devices. In proprietary buffers, performance varied more widely, with lysis efficiencies of 2-4% to 64-80% on tongue swabs and 1% to 94-398% on sputum swabs. Complete biosafety inactivation was achieved by three devices; two showed residual growth (<0.02%). Lysis efficiency of several devices met or exceeded the reference, supporting the feasibility of extraction-free workflows for TB diagnosis, with further optimization of buffer compatibility and biosafety profiles expected to enhance performance.","rel_num_authors":7,"rel_authors":[{"author_name":"Sonal Jain","author_inst":"Heidelberg University Hospital and Faculty of Medicine"},{"author_name":"Alexey Ball","author_inst":"Global Health Labs"},{"author_name":"Caitlin Anderson","author_inst":"Global Health Labs"},{"author_name":"Adithya Cattamanchi","author_inst":"UCSF"},{"author_name":"Claudia Denkinger","author_inst":"University of Heidelberg"},{"author_name":"Amy Steadman","author_inst":"Global Health Labs"},{"author_name":"Seda Yerlikaya","author_inst":"Heidelberg University Hospital and Faculty of Medicine"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"State-Level Variability in Implementation Approaches to SNAP Food Restriction Waivers: A Content Analysis of Bills, Waiver Requests, and Waiver Approvals","rel_doi":"10.64898\/2026.07.23.26358592","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358592","rel_abs":"Background: Since 2025, US states have rapidly adopted waivers to restrict the purchase of \"non-nutritious items\" like soda and candy with Supplemental Nutrition Assistance Program (SNAP) benefits. States have proposed various approaches in terms of food categories restricted and implementation strategies, which may influence the downstream effects of waivers on program participation and participants diets and health. Objective: To examine and describe contextual information related to the adoption and implementation of state-level SNAP food restriction waivers. Design: A content analysis was conducted including publicly available state-level: (1) bills introduced related to SNAP food restriction waivers (2025 to early 2026), (2) waiver requests, and (3) waiver approvals (up to June 2026). Codebooks that captured key elements, such as food and beverage group restrictions and definitions, rationale for restrictions, implementation supports, and evaluation plans, were applied independently by two coders, and discrepancies were resolved through consensus. Participants\/setting: United States Intervention: N\/A Main outcome measures: N\/A Statistical analyses performed: Descriptive statistics were used to summarize the presence of coded elements in documents. Results: Seventy-one bills, 22 waiver requests, and 23 waiver approvals were included. Bills mostly proposed restricting candy (65%) and soft drinks (59%). Of the approved waivers, all restrict the purchase of specific beverage groups with SNAP benefits and 65% restrict the purchase of specific food groups with SNAP benefits. There is a high level of variability in how the same food or beverage groups (e.g., soda) are defined across states. States varied in the implementation supports described in waiver requests, describing strategies like communications plans, nutrition education, and staff training. Conclusions: The current state of SNAP food restriction waivers is highly variable and shifting rapidly. Understanding characteristics of early-adopting states can inform future impact and implementation evaluations of waivers and efforts of additional states that may pursue SNAP food restriction waivers.","rel_num_authors":8,"rel_authors":[{"author_name":"Emily W Duffy","author_inst":"University of North Carolina at Greensboro"},{"author_name":"Miguel Angel Lopez","author_inst":"Center for Nutrition and Health Impact"},{"author_name":"Emily W Dimond","author_inst":"Center for Nutrition and Health Impact"},{"author_name":"Laura E. Balis","author_inst":"Center for Nutition and Health Impact"},{"author_name":"Elizabeth Piekarz-Porter","author_inst":"University of Illinois at Chicago"},{"author_name":"Alyssa J. Moran","author_inst":"University of Pennsylvania"},{"author_name":"Carolina Morales Serrano","author_inst":"Center for Nutrition and Health Impact"},{"author_name":"Elizabeth T. Anderson Steeves","author_inst":"Center for Nutrition and Health Impact"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Treatment Gaps Among Young Medicaid-Enrolled Children with Tooth Decay in Pediatric Primary Care","rel_doi":"10.64898\/2026.07.23.26357672","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26357672","rel_abs":"Objective: To examine whether Medicaid-enrolled preschoolers with untreated decayed teeth received dental treatment within one year of enrollment and identify the factors associated with a treatment gap. Methods: A retrospective cohort analysis of data from a cluster-randomized trial conducted in 18 community-based pediatric primary care practices in Northeastern Ohio (2017-2022). Treatment receipt was determined using Medicaid claims, with treatment gap defined as fewer teeth with treatment claims than teeth found on baseline exam with decay. Multivariable logistic regression assessed the association of treatment gap with child age, sex, race\/ethnicity, caregiver education, and number and location of baseline decayed teeth. Results: Of 766 eligible children, 487 (63.6%) attended the dentist within one year. Among 155\/487 (31.8%) with baseline untreated decay, 90\/155 (58.1%) had a treatment gap. Odontograms visually showed that decay was concentrated on upper anterior and posterior teeth. A treatment gap was associated with a greater number of decayed posterior teeth (OR = 1.90, 95% CI: 1.60-2.30) and decayed anterior teeth (OR = 2.19, 95% CI: 1.51-3.39), both p < 0.001. Other socio-demographic variables were not significantly associated with a treatment gap. Conclusion: More than half of Medicaid-enrolled children attending well-child visits had a dental treatment gap after 1 year. This pattern may reflect dentists' hesitancy to restore primary teeth nearing exfoliation and needing multiple dental visits to complete needed restorative treatment. To address this gap, non-surgical interventions such as silver diamine fluoride can be applied by pediatric primary care providers to control the bacteria and prevent disease progression.","rel_num_authors":5,"rel_authors":[{"author_name":"David Selvaraj","author_inst":"Department of Community Dentistry, Case Western Reserve University School of Dental Medicine, Cleveland OH"},{"author_name":"Sarah D. Ronis","author_inst":"UH Rainbow Center for Child Health & Policy, Cleveland OH; Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland OH"},{"author_name":"Jeffrey M. Albert","author_inst":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland OH"},{"author_name":"Johnie Rose","author_inst":"Center for Community Health Integration, Case Western Reserve University School of Medicine, Cleveland OH"},{"author_name":"Suchitra Nelson","author_inst":"Department of Community Dentistry, Case Western Reserve University School of Dental Medicine, Cleveland OH; Department of Population and Quantitative Health Sci"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Bacterial biosynthetic efficiency is constrained by cell geometry and intracellular diffusion","rel_doi":"10.64898\/2026.07.25.740728","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.25.740728","rel_abs":"Bacterial metabolic strategies are tied to cell size and shape, yet how geometry constrains the efficiency of biomass production is not well understood. Here we develop a coarse-grained whole-cell model of bacterial physiology that couples proteome allocation, metabolic fluxes, and cell geometry to physical limits on surface area and intracellular diffusion. We define the biosynthetic energy efficiency as the fraction of ATP available from imported carbon that is invested in biomass, and find that it is non-monotonic in nutrient availability, peaking precisely at the onset of overflow metabolism. This identifies the metabolic switch as an optimal trade-off between efficient use of imported carbon and rapid growth. Perturbing cell morphology away from the empirical scaling laws shows that increasing surface area at a fixed volume raises both growth rate and efficiency, so the observed size and shape relations sit close to an efficiency optimum rather than being arbitrary. When the empirical growth laws are relaxed and geometry is treated as a free parameter, the model predicts a hard physical limit: the maximum sustainable cell size falls as the target growth rate rises. This ceiling arises from a conflict within the finite proteome budget between the cost of fast growth and the cost of large size, the latter set by the slowing of intracellular diffusion. A few physical rules thus delimit the metabolic strategies and size range available to bacterial life.","rel_num_authors":3,"rel_authors":[{"author_name":"Arianna Cylke","author_inst":"Carnegie Mellon University"},{"author_name":"Indrajit Badvaram","author_inst":"Georgia Institute of Technology"},{"author_name":"Shiladitya Banerjee","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Distribution of luxS and production of autoinducer-2 among gut Bacteroidales","rel_doi":"10.64898\/2026.07.27.740950","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.27.740950","rel_abs":"One of the best studied quorum sensing (QS) molecules, autoinducer-2 (AI-2), regulates processes in numerous bacteria. LuxS is an enzyme of the activated methyl cycle which, along with MtnN, converts S-adenosyl-homocysteine to homocysteine, releasing DPD (4,5-dihydroxy-2,3-pentanedione) which is spontaneously converted to AI-2. Many bacteria do not encode MtnN-LuxS and instead encode SahH, which directly converts S-adenosyl-homocysteine to homocysteine without AI-2 production. The genomes of some gut Bacteroidales were shown to contain luxS, however, these reports, as well as reports of the production of AI-2 by gut Bactereoidales have been inconsistent. We performed a comprehensive analysis of the distribution of luxS and sahH in Bacteroidota with an in-depth exploration of gut Bacteroidales. The data suggest that the ancestral Bacteroidota contained sahH, with numerous independent replacements with mtnN-luxS during diversification. In Bacteroidaceae, Parabacteroides, and many Prevotellaceae, mtnN-luxS or sahH are present in the same genetic region, adjacent to yfhO. Using Bacteroides fragilis, which contains sahH, and Bacteroides uniformis and Phocaeicola vulgatus, whose genomes contain mtnN-luxS, we show that luxS-containing strains produce AI-2. Transcriptomic analyses and gnotobiotic mouse experiments using wild-type strains and mtnN-luxS and sahH genetic swaps showed that Bacteroidaceae species do not respond to AI-2 under the conditions tested. However, analyses of 15 human gut metagenomic datasets show that mtnN-luxS containing Bacteroidales species average between 5.1 - 33% of the total bacteria in these various human gut microbiome datasets, and therefore, likely produce substantial amounts of AI-2 sensed by responsive gut symbionts and pathogens.","rel_num_authors":6,"rel_authors":[{"author_name":"Nolan Warren Kennedy","author_inst":"Northwestern University"},{"author_name":"Rebecca Gellman","author_inst":"The University of Chicago"},{"author_name":"Michael J Coyne","author_inst":"The University of Chicago"},{"author_name":"Jessica Little","author_inst":"The University of Chicago"},{"author_name":"Ashley M Sidebottom","author_inst":"The University of Chicago"},{"author_name":"Laurie Comstock","author_inst":"The University of Chicago"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Remodeled cephalic arch geometry promotes disturbed flow at pre-maturation flow rates in hemodialysis patients","rel_doi":"10.64898\/2026.07.23.740371","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.23.740371","rel_abs":"In the United States, roughly 550,000 people receive routine hemodialysis for end-stage renal disease. This treatment requires an arteriovenous access, most commonly a brachiocephalic fistula. However, these accesses often fail due to stenosis in the cephalic arch (CA), a common complication whose underlying causes remain unclear (Bennet et al., 2015). To characterize the hemodynamic environment in the CA, we employed patient-specific millifluidic models that were perfused with blood-mimicking fluid containing fluorescently labelled beads to visualize flow behaviors. We perfused our models across physiologic (28-45 mL\/min) and elevated (60-423 mL\/min) flow rates and quantified wall shear stress (WSS) and streamline angle as a measure of flow disturbance. Our findings show that the bulk curvature and remodeled wall topography each create regions of persistently low WSS, consistent with prior clinical observations (Hammes et al., 2016). Moreover, remodeled wall topography promotes disturbed flow at elevated flow rates, a hemodynamic profile associated with various vascular pathologies (Chiu & Chien, 2011). Independently performed computational fluid dynamics (CFD) modeling complements these results, showing that remodeled wall topography promotes vortex formation at elevated flow rates, as assessed by Q-criterion. Collectively, our experimental and computational results provide strong evidence for geometry-driven disturbed flow in the CA at elevated flow rates. Notably, we observed disturbed flow at flow rates as low as 81 mL\/min, far below the 600 mL\/min required for hemodialysis. Disturbed flow thus offers a plausible mechanism that relates access flow rates to the vascular pathologies that precede access failure.","rel_num_authors":8,"rel_authors":[{"author_name":"Dylan Cook","author_inst":"University of Chicago"},{"author_name":"Sanjeev Dhara","author_inst":"University of Chicago"},{"author_name":"Maren Klineberg","author_inst":"University of Chicago"},{"author_name":"Nhung Nguyen","author_inst":"University of Chicago"},{"author_name":"Luka Pocivavsek","author_inst":"The University of Chicago"},{"author_name":"Bingqing Xie","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Anindita Basu","author_inst":"University of Chicago"},{"author_name":"Mary Hammes","author_inst":"University of Chicago"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"A Neuroendocrine Circuit That Suppresses Excretion and Pelvic Pain During Activity","rel_doi":"10.64898\/2026.07.23.736864","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.23.736864","rel_abs":"Mate-seeking during peak sexual receptivity is tightly coupled with exploratory movement, a process made more efficient by transient suppression of excretion. Here, we define a functional hypothalamic-hindbrain circuit in mice that promotes locomotion while eliminating urination and defecation for hours. Chemogenetic stimulation of excitatory estrogen-melanocortin-responsive MC4R+ neurons in the ventrolateral ventromedial hypothalamus (VMHvl) effectively silences bladder and colonic visceral reflexes, even at noxious distension pressures, underscoring the potency of this anti-excretion circuit. Pelvic sensations and excretion are restored only after ablating inhibitory GABAergic neurons in the Barrington's nucleus\/locus coeruleus (BAR\/LC) hindbrain region or after antagonizing endogenous endorphin signaling. Our study illustrates how a hormone-responsive brain node prioritizes movement over excretion and blunts pelvic discomfort, thereby optimizing an essential voluntary behavior for evolutionary fitness.","rel_num_authors":10,"rel_authors":[{"author_name":"Lucas E Cabrera-Zapata","author_inst":"University of California, San Francisco"},{"author_name":"Archana Venkataraman","author_inst":"University of California, San Francisco"},{"author_name":"Andrea M Harrington","author_inst":"South Australian Health and Medical Research Institute"},{"author_name":"Jitao Hu","author_inst":"University of California, San Francisco"},{"author_name":"Fernanda Castro-Navarro","author_inst":"University of California, San Francisco"},{"author_name":"Kristina Galatsis","author_inst":"University of California, San Francisco"},{"author_name":"Xin Duan","author_inst":"University of California, San Francisco"},{"author_name":"Stuart M Brierley","author_inst":"South Australian Health and Medical Research Institute"},{"author_name":"Kimberly Keil Stietz","author_inst":"University of Wisconsin-Madison"},{"author_name":"Holly A. Ingraham","author_inst":"University of California, San Francisco"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Nutrient flux governs osteogenic fate commitment through the SLC3A1-cystine Axis","rel_doi":"10.64898\/2026.07.25.740706","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.25.740706","rel_abs":"Skeletal and mesenchymal cells have limited bone-forming potential due to their rarity, tendency for senescence and\/or unstable osteogenic lineage commitment. We previously identified an osteopotent CXCR4 stem cell population with unclear mechanism for its differentiation potential. Here, we found that the cystine transporter SLC3A1 was selectively enriched in CXCR4+ stem cells, uncovering a role for amino acid transport in regulating osteogenic fate commitment. Enforced SLC3A1 expression reprogrammed mesenchymal cells toward a stable osteogenic state while suppressing adipogenic differentiation. Mechanistically, SLC3A1-mediated cystine flux established a glutathione-dependent metabolic program that preserved mitochondrial fitness and restrained stem cell senescence. SLC3A1 also stabilized IGF-1 through suppression of ZMYND8-mediated ubiquitination, uncovering ZMYND8 as a previously unrecognized E3 ligase regulating osteogenic commitment. Cystine supplementation phenocopied the effects of SLC3A1 activation, promoting osteogenic differentiation and skeletal regeneration without genetic manipulation. In vivo, cystine administration accelerated bone regeneration and attenuated ovariectomy-induced bone loss, while analyses of a human osteoporosis cohort, osteoporotic specimens, and single-cell transcriptomic datasets revealed coordinated suppression of the SLC3A1-cystine-IGF-1 pathway in osteoporotic mesenchymal cells. Taken together, these findings establish SLC3A1-mediated cystine transport as a programmable metabolic determinant of osteogenic fate commitment and identify cystine metabolism as a therapeutically targetable axis for skeletal regeneration and osteoporosis.","rel_num_authors":10,"rel_authors":[{"author_name":"Yangshuai Gao","author_inst":"Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China"},{"author_name":"Qixuan Lin","author_inst":"Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China"},{"author_name":"Qing Xu","author_inst":"Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China"},{"author_name":"Shaokang Chen","author_inst":"Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China"},{"author_name":"Lei Jiang","author_inst":"Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China"},{"author_name":"Yiming Hu","author_inst":"Department of Otolaryngology Head and Neck Surgery, Otolaryngological Institute of Shanghai Jiao Tong University, Shanghai Sixth People's Hospital Affiliated to"},{"author_name":"Junrong Cai","author_inst":"Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China"},{"author_name":"Aaron James","author_inst":"Johns Hopkins University"},{"author_name":"Zhongmin Zhang","author_inst":"Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China"},{"author_name":"Jiajia Xu","author_inst":"Southern Medical University"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Spatial modulation of RAF by RAF\/MEK glue enables full-dose combination with pan-RAF inhibitor and potent RAS-mutant tumor-selective MAPK and growth inhibition","rel_doi":"10.64898\/2026.07.24.740654","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.740654","rel_abs":"The clinical benefit of MAPK-targeted therapies depends on greater pathway inhibition in tumors than normal tissues. Although pan-RAF inhibitors are active in RAS-mutant cancers, combining them with MEK inhibitors requires dose reductions due to toxicity, limiting efficacy. We show the toxicity results from MEK inhibitor-mediated feedback relief, which promotes RAF activation and pan-RAF inhibitor engagement in normal cells, narrowing the therapeutic index. We further demonstrate that MEK is exclusively cytosolic, and RAF\/MEK glues overcome this limitation through spatial trapping. By stabilizing cytosolic RAF-MEK complexes, RAF\/MEK glues prevent feedback-driven RAF activation in normal cells while maintaining inhibition of oncogenic RAF signaling in RAS-mutant tumors, where RAF is constitutively activated at the plasma membrane. Consequently, this enables full-dose combination with pan-RAF inhibitors, resulting in deeper MAPK suppression and robust tumor regressions in RAS-mutant models. Thus, by spatially controlling wild-type effectors, drug-induced proximity can be harnessed to increase tumor selectivity of pathway-targeted therapies.","rel_num_authors":17,"rel_authors":[{"author_name":"Poulikos Poulikakos","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Ana Orive-Ramos","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Bijaya Gaire","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Christos Adamopoulos","author_inst":"National and Kapodistrian University of Athens"},{"author_name":"Beau Baars","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Mathieu Desaunay","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Ziyue Kou","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Evangelia Matenoglou","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Silvia Coma","author_inst":"Verastem Oncology"},{"author_name":"Nayeli Gutierrez-Trejo","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Kevin Mohammed","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Stuart A Aaronson","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jian Jin","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Tiphaine Christiane Martin","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Ernesto Guccione","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Evripidis Gavathiotis","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jonathan A Pachter","author_inst":"Verastem Oncology"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"The Mechanical and Biological Evolution of Pressure Ulcer Formation and Healing in Mice","rel_doi":"10.64898\/2026.07.25.740666","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.25.740666","rel_abs":"Pressure ulcers arise from sustained mechanical loading that impairs perfusion and damages skin tissues, yet the coupled mechanical and biological mechanisms of their formation and healing remain poorly characterized. We addressed this gap using a mouse model in which dorsal skin underwent 72 hours of magnet-induced ischemia followed by reperfusion, with tissue collected at 0, 3, 6, and 9 days and compared with baseline controls. From each mouse, we obtained paired samples from pressure ulcer and remote control (non-loaded) sites, mapped thickness by tissue profilometry, and performed equibiaxial testing with full-field digital image correlation and inverse finite element analysis to estimate regional material parameters. In parallel, we quantified CD31+ vasculature, F4\/80+ macrophages, collagen content, and key cytokines. Pressure ulcer sites were compressed and thinner at Day 0, developed ulcers by Day 3, and continued to remodel through Day 9. Mechanical tests revealed heterogeneous strain fields with elevated deformation along ulcer borders, while remote control tissue deformed more homogeneously. These mechanical changes evolved alongside dynamic vessel and macrophage repopulation, increased collagen content at early time points, and cytokine upregulation within pressure ulcer tissue. Collectively, our data define the spatiotemporal co-evolution of tissue geometry, mechanics, collagen remodeling, and inflammation in pressure ulcers and provide a quantitative foundation for predictive mechanobiological models.","rel_num_authors":7,"rel_authors":[{"author_name":"Chien-Yu Lin","author_inst":"The University of Texas at Austin"},{"author_name":"Shreya Sreedhar","author_inst":"The University of Texas at Austin"},{"author_name":"Matthew J. Lohr","author_inst":"The University of Texas at Austin"},{"author_name":"Colton J. Kostelnik","author_inst":"The University of Texas at Austin"},{"author_name":"Alberto Madariaga","author_inst":"The University of Texas at Austin"},{"author_name":"Adrian B. Tepole","author_inst":"Columbia University"},{"author_name":"Manuel K. Rausch","author_inst":"The University of Texas at Austin"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Container-less Acoustic Levitation Expands Plasma Extracellular Vesicle Proteome Coverage by Mitigating Size-Dependent Peptide Loss","rel_doi":"10.64898\/2026.07.25.740687","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.25.740687","rel_abs":"Proteomic profiling of plasma-derived extracellular vesicles (EVs) is limited in part by adsorptive loss of peptides and proteins to container walls during sample preparation. Here we apply an automated, environment-controlled acoustic levitation platform (Levcell) to the tryptic digestion of small EVs (sEVs) isolated from pooled breast cancer patient plasma, and compare it directly with digestion in low-bind microcentrifuge tubes. Across three parallel technical replicates per method, container-less digestion identified 309 +\/- 22 protein groups versus 261 +\/- 6 for tubes (+18.4%; Welch t-test p = 0.053), with equivalent or better quantitative reproducibility (median CV 12.0% vs 14.4%). The gain was strongly asymmetric: 66 protein groups were recovered only under levitation while 10 were recovered only in tubes (exact McNemar p = 3 * 10e-11). Peptides recovered exclusively by levitation were longer and heavier than those exclusive to tubes (median 14 vs 12 residues, 1611 vs 1358 Da; p < 2 * 10e-6; Cliff's delta approx. 0.19-0.20), whereas the total peptide pools were indistinguishable and mean missed-cleavage rates were equivalent (0.276 vs 0.263, p = 0.41), excluding differential digestion efficiency as an explanation. No systematic difference in hydropathy, isoelectric point or hydrophobic residue frequency was detected. The levitation-rescued sub-proteome was enriched for ribosomal, proteasomal, chaperonin and RNA-binding complexes - canonical sEV luminal cargo (MYC targets 16\/19, odds ratio 31.7, q = 5.6 * 10e-8) - and covered 33 of the 100 ExoCarta reference markers versus 22 for tubes, gaining 14 markers while losing three (a single ezrin\/moesin\/radixin protein group; McNemar p = 9.8 * 10e-4). We also report two findings that temper the approach: levitated samples carried an approximately 3.7-fold higher keratin burden, consistent with airborne contamination in an open chamber, and no individual marker showed a significant abundance difference after correction for multiple testing. Container-less processing therefore offers a reproducible gain in sEV proteome coverage attributable to reduced size-dependent peptide loss, provided that contamination control is addressed.","rel_num_authors":4,"rel_authors":[{"author_name":"Edward Huang","author_inst":"University of Illinois Chicago"},{"author_name":"Chang Liu","author_inst":"University of Illinois Chicago"},{"author_name":"Kent Hoskins","author_inst":"University of Illinois Chicago"},{"author_name":"Yu Gao","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Achiral Odd Mechanics in Cell Monolayers","rel_doi":"10.64898\/2026.07.25.740723","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.25.740723","rel_abs":"Cell monolayers are active, orientationally ordered materials whose mechanics can depart from near-equilibrium behavior. Existing continuum theories often inherit assumptions from equilibrium liquid-crystal physics, motivating explicit nonequilibrium formulations. Here, we develop a minimal continuum model of two-dimensional monolayers based on odd mechanics, accounting for broken symmetries and nonequilibrium dynamics. We show that nematic order can support an odd viscous modulus generated by broken time-reversal symmetry and spatial anisotropy, without chirality. The model reproduces half-integer defect motion and stress profiles in Madin--Darby canine kidney (MDCK) monolayers, as well as defect-associated cell accumulation and depletion in neural progenitor and ovarian mesothelium systems. Finally, we estimate the viscous-moduli tensor from measured stress, velocity, and orientation fields in MDCK monolayers and identify a nonzero odd modulus. Our results show that odd mechanics provides a minimal framework for nonequilibrium cell monolayers, complementing conventional active-nematic theories.","rel_num_authors":2,"rel_authors":[{"author_name":"Sreejith Santhosh","author_inst":"University of California San Diego"},{"author_name":"Mattia Serra","author_inst":"UCSD"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Integrative taxonomy reveals cryptic diversity in Chilean Trichomycterinae (Siluriformes, Trichomycteridae)","rel_doi":"10.64898\/2026.07.26.736611","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.26.736611","rel_abs":"Species-level delimitation within the genus Trichomycterus remains one of the main systematic challenges within the Trichomycterinae, particularly in lineages characterised by conservative external morphology, high apparent intraspecific variation, and historical diagnostic criteria based primarily on body proportions, colouration and a few meristic characters. In central Chile, Trichomycterus areolatus has traditionally been interpreted as a widely distributed and morphologically variable species, whilst T. maculatus, originally described from \"Santiago du Chili\", has remained subordinate to this broad conception without a modern phylogenetic reassessment. Here we reassess the specific boundaries of T. areolatus sensu lato using an integrative approach that combines complete mitogenomes, estimates of genetic divergence and comparative morphology of the cephalic laterosensory system associated with the neurocranium. Phylogenetic analyses reveal T. areolatus sensu lato to be non-monophyletic and identify a deeply divergent lineage, geographically coherent and attributable to T. maculatus. This lineage differs from restricted T. areolatus by extensive mitochondrial divergence, comparable to that observed between recognised species of Trichomycterinae, and by discrete characters of the cephalic lateral line system, primarily related to the continuity of the supraorbital canal and the arrangement of the associated pores. The congruence between mitogenomic, nuclear and morphological evidence supports the revalidation of Trichomycterus maculatus Valenciennes, 1846, and calls for a more restricted geographic circumscription of T. areolatus. These results demonstrate that the diversity of Trichomycterinae in central Chile has been underestimated, modify previous interpretation of the distribution of the species involved, and highlight the value of integrating mitogenomics and neurocranial\/laterosensory characters into the taxonomy of morphologically conservative siluriform lineages.","rel_num_authors":2,"rel_authors":[{"author_name":"Claudio Quezada-Romegialli","author_inst":"Universidad de Tarapaca"},{"author_name":"Gloria Arratia","author_inst":"University of Kansas"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"A generalizable speech neuroprosthesis","rel_doi":"10.64898\/2026.07.23.739430","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.23.739430","rel_abs":"Intracortical brain-computer interfaces (BCIs) can restore communication to people with vocal tract paralysis by decoding cortical activity during attempted speech into text. State-of-the-art systems pairing neural-to-phoneme decoders with phoneme-to-word language models have achieved word error rates (WERs) as low as 1%, but only after collecting thousands of sentences of training data. Shortening the data collection process would facilitate scaling this new technology by reducing the time from device implant to high-accuracy communication. Here we introduce a transformer-based decoder model trained jointly across six intracortical speech BCI participants. For every participant - regardless of sex, disease etiology, or attempted speaking strategy - a multi-user model decoded speech more accurately (over 50% lower relative WER on average) than models trained on individual users' data. Notably, the multi-user model could be fine-tuned on fewer than 200 sentences from a held-out user to achieve a WER below 7%. These results reveal how to pool intracortical data across people to yield more accurate, generalizable, and rapidly-deployable decoding models.","rel_num_authors":28,"rel_authors":[{"author_name":"Zachery M. Fogg","author_inst":"University of California, Davis"},{"author_name":"Nicholas S. Card","author_inst":"University of California, Davis"},{"author_name":"Maitreyee Wairagkar","author_inst":"University of California, Davis"},{"author_name":"Aparna Srinivasan","author_inst":"University of California, Davis"},{"author_name":"Tyler Singer-Clark","author_inst":"University of California, Davis"},{"author_name":"Xianda Hou","author_inst":"University of California, Davis"},{"author_name":"Elizaveta Okorokova","author_inst":"University of California, Davis"},{"author_name":"Hamza Peracha","author_inst":"University of California, Davis"},{"author_name":"Carrina Iacobacci","author_inst":"University of California, Davis"},{"author_name":"Tiffany Brailow","author_inst":"University of California, Davis"},{"author_name":"Justin J. Jude","author_inst":"Massachusetts General Hospital"},{"author_name":"Hadar Levi-Aharoni","author_inst":"Massachusetts General Hospital"},{"author_name":"Trung Le","author_inst":"Emory University"},{"author_name":"Domenick Mifsud","author_inst":"Georgia Institute of Technology"},{"author_name":"Pranav Deevi","author_inst":"Emory University"},{"author_name":"Samuel Nason-Tomaszewski","author_inst":"Emory University"},{"author_name":"Anna L. Pritchard","author_inst":"Emory University"},{"author_name":"Yunnuo Zhang","author_inst":"Georgia Institute of Technology"},{"author_name":"Brice Richards","author_inst":"Emory University"},{"author_name":"Payton Bechefsky","author_inst":"Emory University"},{"author_name":"Leigh R. Hochberg","author_inst":"Massachusetts General Hospital"},{"author_name":"Ziv Williams","author_inst":"Massachusetts General Hospital"},{"author_name":"Kiarash Shahlaie","author_inst":"University of California, Davis"},{"author_name":"Nicholas Au Yong","author_inst":"Emory University"},{"author_name":"Daniel Rubin","author_inst":"Massachusetts General Hospital"},{"author_name":"Chethan Pandarinath","author_inst":"Emory University"},{"author_name":"David M. Brandman","author_inst":"University of California, Davis"},{"author_name":"Sergey D. Stavisky","author_inst":"University of California, Davis"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Compact red-shifted near-infrared fluorescent proteins enable deep-tissue SWIR imaging with in vivo optical clearing.","rel_doi":"10.64898\/2026.07.25.740731","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.25.740731","rel_abs":"Compact near-infrared (NIR) fluorescent proteins (FPs) with red-shifted emission are needed for deep-tissue short-wavelength infrared (SWIR) imaging. We engineered a GAF domain from the JSC1 cyanobacteriochrome of thermophilic Leptolyngbya sp. into three monomeric, biliverdin-binding NIR FPs of 19.1 kDa: miRFP729nano, miRFP732nano and miRFP735nano, with excitation\/emission maxima of 714\/729, 716\/732 and 719\/735 nm, respectively. Their off-peak fluorescence beyond 1000 nm was several-fold higher than that of miRFP718nano previously used for SWIR imaging. miRFP732nano functioned as a fusion tag, a component of target-stabilized nanobodies, and a reporter of NF-kappaB and AP-1 transcriptional activities. It enabled single-laser, dual-color three-photon imaging with EGFP to depths of ~950 micrometers in cortex and ~300 micrometers in spinal cord. In mice, miRFP732nano supported SWIR imaging of skeletal muscle, inflammatory signaling and intracellular targets. Combining SWIR detection with biocompatible 4-aminoantipyrine-based in vivo tissue clearing enhanced signal and image sharpness. These red-shifted NIR FPs expand the genetically encoded toolkit for deep-tissue imaging.","rel_num_authors":11,"rel_authors":[{"author_name":"Kyrylo Yu. Manoilov","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Yirui Xu","author_inst":"Duke University"},{"author_name":"Jinhuan Luo","author_inst":"Duke University"},{"author_name":"Olena S. Oliinyk","author_inst":"University of Helsinki"},{"author_name":"Erin Carey","author_inst":"Salk Institute for Biological Studies"},{"author_name":"Kateryna O. Tokarchuk","author_inst":"University of Helsinki"},{"author_name":"Jinghang Zhang","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Guosong Hong","author_inst":"Stanford University"},{"author_name":"Axel Nimmerjahn","author_inst":"Salk Institute for Biological Studies"},{"author_name":"Junjie Yao","author_inst":"Duke University"},{"author_name":"Vladislav V. Verkhusha","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Matrix Stiffness-driven FAK Splicing Tunes Cell Mechanosensing","rel_doi":"10.64898\/2026.07.25.736411","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.25.736411","rel_abs":"The extracellular matrix (ECM) stiffness influences many physiological and pathological processes. Cells can sense mechanical changes within the ECM through mechanosensors, most notably through the focal adhesion kinase (FAK). Using human-derived data and 2D\/3D engineered models, we identified a ubiquitous and uncharacterized FAK isoform lacking exon 4 (FAK{Delta}e4). We demonstrated that FAK{Delta}e4 splicing is regulated by substrate stiffness in a biphasic manner, in which an optimal stiffness is required for a maximal FAK{Delta}e4 expression. We further showed that FAK{Delta}e4 dictates at which stiffness optimal migration speed and invasion occur, impairs focal adhesion dynamics and maturation, and shifts its autophosphorylation and downstream YAP nuclear translocation toward lower stiffness compared to the canonical FAK isoform. Moreover, the FAK{Delta}e4 expression levels to canonical FAK determine at which stiffness cells will converge during durotaxis. Our results reveal how FAK{Delta}e4 acts as a fine-tuning mechanosensing switch and reframe our understanding of mechanotransduction.","rel_num_authors":11,"rel_authors":[{"author_name":"Martial Millet","author_inst":"Universite Laval"},{"author_name":"Juliette Gouhier","author_inst":"Universite Laval"},{"author_name":"Olivier Chancy","author_inst":"Universite Laval"},{"author_name":"Elise Tahon","author_inst":"Universite Laval"},{"author_name":"William David Zakzuk Vivas","author_inst":"Universite Laval"},{"author_name":"Emilie Pic","author_inst":"Centre de recherche du CHU de Quebec - Universite Laval"},{"author_name":"Gabriel Khelifi","author_inst":"Universite Laval"},{"author_name":"Solange Landreville","author_inst":"Universite Laval"},{"author_name":"Samer M.I. Hussein","author_inst":"Universite Laval"},{"author_name":"Dwayne G. Stupack","author_inst":"University of California San Diego"},{"author_name":"Francois Bordeleau","author_inst":"Universite Laval"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Sensory Neuropeptides Dictate Sex-Specific Synovial Immunity and Cartilage Degeneration in Aging Mice","rel_doi":"10.64898\/2026.07.27.740931","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.27.740931","rel_abs":"Sensory neuropeptides, particularly Substance P (SP) and -calcitonin gene-related peptide (CGRP), are implicated in osteoarthritis (OA) pathogenesis. This study elucidates their specific roles in spontaneous, age-related OA. Male and female mice deficient in SP (Tac1-\/-), CGRP (CGRP-\/-), or both (DKO) were evaluated at 6, 12, and 18 months of age. Assessments included histological OARSI scoring for articular cartilage matrix structure, Luminex arrays for systemic serum cytokines, and flow cytometry for local synovial immune cell profiling. Wild type (WT) mice developed early-stage, age-related cartilage degradation, predominantly in the lateral compartment. Conversely, all neuropeptide-deficient strains exhibited significant structural protection against this process. Systemically, SP deficiency distinctly altered cytokine profiles (e.g., decreased IL-23, increased IP-10), whereas CGRP deficiency caused minimal systemic shifts, highlighting a disconnect between circulating markers and local joint preservation. Locally, flow cytometry revealed profound, sexually dimorphic, and age-dependent neuroimmune alterations. In young males, neuropeptide deficiency significantly reduced synovial macrophage counts to levels comparable to those of aged WT mice. Furthermore, male CGRP-\/- mice exhibited an age-related accumulation of CD8+ cytotoxic T cells. In contrast to males, young WT females demonstrated higher baseline CD8+ T cell counts that declined with age, whereas these subpopulations remained persistently low in KO mice. SP and CGRP act as critical modulators of age-related cartilage degradation. Their absence provides robust structural protection mediated through highly localized, sexually dimorphic neuroimmune pathways. These findings emphasize the necessity of targeting the local joint microenvironment for future personalized, sex-specific OA therapies.","rel_num_authors":5,"rel_authors":[{"author_name":"Patrick Pann","author_inst":"University of Regensburg"},{"author_name":"Ravikumar Mayakrishnan","author_inst":"Kiel University"},{"author_name":"Babak Moradi","author_inst":"Kiel University and University Medical Center Schleswig-Holstein"},{"author_name":"Brian Johnstone","author_inst":"Oregon Health & Science University"},{"author_name":"Susanne Graessel","author_inst":"University of Regensburg"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Connectomic analysis reveals the axial circuit for self-righting posture control in Drosophila","rel_doi":"10.64898\/2026.07.25.740718","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.25.740718","rel_abs":"Postural control, the capacity of an animal to detect and correct an inappropriate body orientation, is a widespread and fundamental neurobiological function, yet the neural circuits that implement it remain poorly resolved in most species. The larva of Drosophila melanogaster performs a posture control stereotyped self-righting (SR) manoeuvre when turned upside-down, a behaviour previously shown to depend on a pair of segmentally repeated lateral transverse motor neurons (LT1\/2-MNs) and on the normal expression of several Hox-targeting microRNAs. Here, we use a connectomics and a functional behavioural approach to trace and test the sensory, interneuronal and motor architecture of the SR circuit along the antero-posterior axis. Starting from the LT1\/2-MNs, we identify a set of pre-motor interneurons, their principal upstream partners, and a population of class IV multidendritic sensory neurons as core components of the circuit, and show, through neuron-specific thermogenetic silencing, that inhibiting the great majority of these elements significantly impairs SR performance. We further find substantial overlap between the SR circuit and the previously described nociceptive rolling and touch crawling circuits, converging on shared interneurons including DnB, A02o (Wave-1) and TePn05. Network and axial connectivity analyses reveal a nested, hub-like organisation, a small number of integrator neurons bridging sensory and motor sub-networks, and a consistent decline in synapse number and density towards posterior segments. Together, these data yield the first axial wiring diagram for a postural control circuit in any animal and offer a set of structural principles including: hub organisation, shared sensory-motor structure, and antero-posterior connectivity gradients, which may extend to other segmentally organised nervous systems.","rel_num_authors":5,"rel_authors":[{"author_name":"Joao R. Picao Osorio","author_inst":"cE3c, University of Lisbon"},{"author_name":"William Roseby","author_inst":"University of Sussex"},{"author_name":"Clare E Hancock","author_inst":"University of California at San Francisco (UCSF)"},{"author_name":"Albert Cardona","author_inst":"University of Cambridge"},{"author_name":"Claudio R. Alonso","author_inst":"University of Sussex"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"A surface-intrinsic framework for topology-preserving hippocampal alignment and precision morphometry","rel_doi":"10.64898\/2026.07.22.740127","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740127","rel_abs":"Accurate alignment of hippocampal anatomy across individuals remains challenging due to complex and highly variable folding patterns that are not well captured by conventional volumetric approaches. HippUnfold introduced a surface-based representation of the hippocampus, but key components-including coordinate estimation and inter-subject correspondence-were defined in the volumetric domain, making them susceptible to topological errors and interpolation artifacts. Here, we introduce a surface-intrinsic formulation of hippocampal unfolding in which geometry, intrinsic coordinates, and correspondence are defined directly on subject-specific surface manifolds. Intrinsic anterior-posterior and proximal-distal coordinates are computed by solving Laplace equations on the surface, and correspondence is established through surface-based resampling in unfolded space, replacing inverse volumetric warping. Relative to the original HippUnfold approach, this formulation improves test-retest consistency, subject identifiability, and mesh quality, while better preserving subject-specific gyral and sulcal morphology. Surface representations show reduced distortion between folded and unfolded spaces and eliminate misplaced or outlier vertices associated with volumetric warping. These improvements translate to enhanced sensitivity in a clinical application, improving lateralization of temporal lobe epilepsy. These results demonstrate that a surface-intrinsic formulation provides a principled and robust foundation for hippocampal unfolding, enabling topology-preserving alignment and more accurate characterization of inter-individual variability in health and disease.","rel_num_authors":21,"rel_authors":[{"author_name":"Jordan DeKraker","author_inst":"McGill University"},{"author_name":"Dhananjhay Bansal","author_inst":"Western University"},{"author_name":"Mackenzie Snyder","author_inst":"Western University"},{"author_name":"Bradley G. Karat","author_inst":"Western University; NYU Grossman School of Medicine"},{"author_name":"Nima Talaei Kamalabadi","author_inst":"Western University"},{"author_name":"Mahmoud Yaser Salman","author_inst":"Western University"},{"author_name":"Alexander Ngo","author_inst":"McGill University"},{"author_name":"Judy Chen","author_inst":"McGill University"},{"author_name":"Ella Sahlas","author_inst":"McGill University"},{"author_name":"Jessica Royer","author_inst":"McGill University"},{"author_name":"Donna Gift Cabalo","author_inst":"McGill University"},{"author_name":"Matthew F. Glasser","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Timothy S. Coalson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"John Harwell","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Mastaneh Torkamani-Azar","author_inst":"University of Eastern Finland"},{"author_name":"Yawu Liu","author_inst":"University of Eastern Finland"},{"author_name":"Jussi Tohka","author_inst":"University of Eastern Finland"},{"author_name":"Jonathan C. Lau","author_inst":"Western University"},{"author_name":"Alan C. Evans","author_inst":"McGill University"},{"author_name":"Boris C. Bernhardt","author_inst":"McGill University"},{"author_name":"Ali R. Khan","author_inst":"Western University"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Ms4a4a loss reprograms amyloid-associated microglia and limits dense-core plaque-associated tau spreading","rel_doi":"10.64898\/2026.07.22.740167","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740167","rel_abs":"INTRODUCTION: Microglia regulate amyloid plaque-associated microenvironments that contribute to downstream tau pathology in Alzheimer disease (AD). Variants within the MS4A locus are strongly associated with AD risk and resilience and are linked to microglial biology; however, the functional role of MS4A4A in plaque-associated tau pathology remains poorly understood. METHODS: Single-nucleus RNA sequencing (snRNA-seq) was performed on hippocampi from non-transgenic, Ms4a4a knockout (4A-KO), 5xFAD, and 5xFAD 4A-KO mice at 6 months of age. To assess plaque-associated tau pathology, AD-derived tau aggregates were injected into the hippocampus of 5xFAD and 5xFAD 4A-KO mice at 6 months, and histological analyses were performed 3 months later. RESULTS: Amyloid pathology was the dominant driver of microglial state transitions, while Ms4a4a loss selectively remodeled activated microglial transcriptional programs enriched for interferon, lysosomal, autophagic, and proteostatic pathways. Activated microglia from 5xFAD 4A-KO mice exhibited altered expression of genes linked to immune signaling and protein handling. Following AD-tau inoculation, Ms4a4a loss did not significantly alter overall phospho-tau burden but selectively reduced dense-core plaque-associated neuritic plaque tau (NP-tau), particularly in the contralateral hemisphere. This phenotype was strongest surrounding X-34-positive fibrillar plaques and occurred without major changes in plaque-associated microgliosis. DISCUSSION: These findings identify Ms4a4a as a regulator of plaque-associated microglial programs linked to NP-tau accumulation in the amyloid-bearing brain. More broadly, this work supports a model in which AD resilience-associated microglial pathways selectively shape plaque-associated microenvironments that promote downstream tau pathology.","rel_num_authors":12,"rel_authors":[{"author_name":"Emma P Danhash","author_inst":"Washington University in St Louis"},{"author_name":"Shao-Yu Fang","author_inst":"Washington University in St Louis"},{"author_name":"Jacob A Marsh","author_inst":"Washington University in St Louis"},{"author_name":"Ricardo D'Oliveira Albanus","author_inst":"Washington University in St Louis"},{"author_name":"Anthony C Verbeck","author_inst":"Washington University in St Louis"},{"author_name":"Guangming Huang","author_inst":"Washington University in St Louis"},{"author_name":"Shih Feng You","author_inst":"Washington University in St Louis"},{"author_name":"Erin E Franklin","author_inst":"Washington University in St Louis"},{"author_name":"Richard J Perrin","author_inst":"Washington University in St Louis"},{"author_name":"Wade K Self","author_inst":"Washington University in St Louis"},{"author_name":"David M Holtzman","author_inst":"Washington University in St Louis"},{"author_name":"Celeste M Karch","author_inst":"Washington University in St Louis"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Human decompression in real time: programmable ultrasound imaging during hyperbaric exposure","rel_doi":"10.64898\/2026.07.22.737513","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.737513","rel_abs":"The formation of inert gas bubbles during decompression can lead to decompression sickness (DCS), a major operational risk for divers, compressed-gas workers, astronauts, and high-altitude aviators. In diving, DCS risk is typically inferred from post-dive ultrasound detection of venous gas emboli (VGE), precluding modification of decompression schedules based on real-time physiological feedback. Two-dimensional ultrasound imaging could provide additional insight into decompression-related physiological changes; however, its use in hyperbaric environments has been largely precluded by fire risk associated with elevated oxygen partial pressures (ppO2) in enclosed spaces. Here, we developed a workflow for operating a programmable ultrasound system under hyperbaric conditions and acquiring ultrasound data from the subclavian vein and calf muscle during decompression. A total of 42 dives were conducted by 26 individuals using a previously characterized dive profile to 132 feet seawater (FSW) for 20 min with 9 min of decompression. Three exposure conditions were evaluated: non-exercising, exercising, and a brief pause at 20 FSW during compression. Twelve dives included programmable ultrasound imaging during decompression. Post-dive VGE responses were consistent with prior reports while demonstrating substantial inter-individual variability and sensitivity to modest profile modifications. VGE were detected in the subclavian vein during decompression in two participants and subsequently confirmed by post-dive echocardiography. Calf muscle ultrasound brightness typically increased from pre-dive to decompression measurements, before decreasing below baseline in the 120 min post dive measurement period. These findings demonstrate the feasibility of programmable ultrasound imaging during human decompression and establish a practical framework for ultrasound operation under hyperbaric conditions. This approach may support future physiological studies and development of automated decompression monitoring technologies.","rel_num_authors":11,"rel_authors":[{"author_name":"Joshua Currens","author_inst":"UNC Chapel Hill"},{"author_name":"Michael J. Natoli","author_inst":"Duke University"},{"author_name":"Katherine Eltz","author_inst":"UNC Chapel Hill"},{"author_name":"Gabriela Morales","author_inst":"Duke University"},{"author_name":"Kathlyne J B Bautista","author_inst":"UNC Chapel Hill"},{"author_name":"Paul  A Dayton","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Rachel Lance","author_inst":"Duke University (previous)"},{"author_name":"Omer Oralkan","author_inst":"NCSU"},{"author_name":"Feysel Y Yamaner","author_inst":"Clearsens, Inc."},{"author_name":"Richard E Moon","author_inst":"Duke University"},{"author_name":"Virginie Papadopoulou","author_inst":"UNC Chapel Hill"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"First Order Associations Between Banff Acute Lesions in Kidney Allograft Biopsies and a Urinary Cell Three-Gene Diagnostic Signature","rel_doi":"10.64898\/2026.07.22.740171","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740171","rel_abs":"Banff acute lesion scores underpin histologic classification of kidney allograft biopsies; however, biomarker studies rely on second-order associations with diagnostic categories that introduce confounding. We quantified the first order relationships between Banff acute lesion scores and the validated urinary cell three gene rejection signature. In 354 biopsy- urine pairs, three-gene signature scores computed using a locked regression equation incorporating absolute copy numbers of CD3E mRNA, CXCL10 mRNA, and 18S rRNA in urinary cell RNA-were related to glomerulitis (g), peritubular capillaritis (ptc), interstitial inflammation (i), and tubulitis (t). Signature scores rose monotonically with Banff acute lesion severity, with 1.5 to 1.8-fold higher odds of more severed g, ptc, i, and t (all P<0.0001), and showed good calibration. Associations remained robust for composite microvascular (g+ptc) and tubulointerstitial (i+t) indices and were strongest for severe g and t, supporting this signature as a noninvasive, quantitative readout of acute rejection pathology with immediate diagnostic applicability.","rel_num_authors":10,"rel_authors":[{"author_name":"Carol Li","author_inst":"Weill Cornell Medical College"},{"author_name":"Joesph E Schwartz","author_inst":"Weill Cornell Medical College"},{"author_name":"Thalias Salinas","author_inst":"Weill Cornell Medical College"},{"author_name":"Darshana M Dadhania","author_inst":"Weill Cornell Medical College"},{"author_name":"Alex DeVito","author_inst":"Weill Cornell Medical College"},{"author_name":"William Higgins","author_inst":"Weill Cornell Medical College"},{"author_name":"Steven Salvatore","author_inst":"Weill Cornell Medical College"},{"author_name":"Surya V Seshan","author_inst":"Weill Cornell Medical College"},{"author_name":"Thangamani Muthukumar","author_inst":"Weill Cornell Medical College"},{"author_name":"Manikkam Suthanthiran","author_inst":"Weill Cornell Medical College"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Towards Principled Evaluation of Single-Cell Perturbation Prediction Models","rel_doi":"10.64898\/2026.07.23.740433","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.23.740433","rel_abs":"Single-cell perturbation experiments measure how interventions alter cellular phenotypes. However, the number of possible perturbations and biological contexts far exceeds what can be tested experimentally. Motivated by this constraint, predictive models aim to extrapolate cellular responses to unseen conditions. Despite substantial efforts in model development, benchmark studies have reached inconsistent conclusions about the capabilities of current perturbation-response models. A major challenge is that evaluation protocols vary widely across studies, making results difficult to compare. Furthermore, the lack of consensus on evaluation hampers progress because it is unclear which predictive capabilities new models should prioritize. To help build consensus on evaluation principles, we develop a taxonomy that decomposes evaluation protocols into their representation, metric, score transformation, and reporting strategies. We characterize how these choices determine which aspects of prediction quality a benchmark measures and discuss criteria for selecting and assessing protocols in relation to specific benchmarking goals. We additionally provide scPertEval, a Python package with reference implementations of selected evaluation protocols, and use it to assess protocol behavior across seven publicly available single-cell perturbation datasets. By making evaluation choices and their underlying trade-offs explicit, we aim to stimulate a community discussion about developing more comparable and task-aligned evaluation protocols.","rel_num_authors":6,"rel_authors":[{"author_name":"Philipp Sven Lars Sch\u00e4fer","author_inst":"Heidelberg University Hospital"},{"author_name":"Kendall Reid","author_inst":"Johns Hopkins University"},{"author_name":"Zach Boldyga","author_inst":"Independent Researcher"},{"author_name":"Ekin Deniz Aksu","author_inst":"Max Planck Institute for Molecular Genetics"},{"author_name":"Hugo Hakem","author_inst":"European Bioinformatics Institute"},{"author_name":"Julio Saez-Rodriguez","author_inst":"European Bioinformatics Institute"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Single-cell foundation models identify shared and divergent transcriptomic signatures of aging across invertebrates and mammals","rel_doi":"10.64898\/2026.07.24.740647","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.740647","rel_abs":"Here is the reformatted text with the en-dash replaced with a standard hyphen (`-`): Cross-species aging clocks have so far stayed within mammals. We asked whether a single model can predict age from single cells of fly, worm, mouse, and human, species separated by roughly 800 million years of evolution. We fine-tuned scGPT and Geneformer on 1.3 million such cells, using one parameter set per architecture. Both models classified cells as young, middle, or old, reaching 78.6% and 80.5% accuracy. SHAP attribution then showed where the two architectures agreed and where they diverged. scGPT ranked ribosomal proteins highest in every species, with RPL12 first throughout. Geneformer did the same in mouse and human but favored signaling, chromatin, and ubiquitin-ligase genes in fly and worm. Hiding all 51 ribosomal-protein genes at inference cost 22-28 percentage points of accuracy, against 0.3 points for size-matched random gene sets. Bootstrap resampling, five-fold cross-validation, and comparison with six published aging studies left the rankings largely unchanged. Age-associated signal is therefore accessible to a pooled cross-species model, but which genes carry it depends on how the model encodes expression.","rel_num_authors":3,"rel_authors":[{"author_name":"Mohammad Aman Ullah Al Amin","author_inst":"Old Dominion University"},{"author_name":"Khoi Le","author_inst":"Brown University"},{"author_name":"Hong Qin","author_inst":"Old Dominion University"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Aperiodic EEG activity is a domain-specific marker of attentional aging in neurotypical adults","rel_doi":"10.64898\/2026.07.22.739645","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739645","rel_abs":"Aperiodic neural activity has been reliably shown to be reduced among older adults, and these reductions are associated with age-related cognitive decline. These results suggest that aperiodic activity, as measured by the spectral exponent, might be a viable electrophysiological biomarker for cognitive aging. However, this has not been tested longitudinally, within participants, during normal aging. Here, we used a longitudinal cohort to test whether changes in aperiodic activity between two sessions, approximately 5 years apart, track behavioral change across two domains: sustained attention (Psychomotor Vigilance Test) and executive function (modified Simon task). We found that aperiodic activity declined within individuals after the interval, independent of age at baseline. This within-person change tracked concurrent changes in reaction times during visual attention but was not associated with changes in any Simon task measure. Within a resampling framework, the aperiodic-PVT association was stable across cohort resamples and independently fitted partitions, though it was not confirmed in a small, frozen held-out set. These findings suggest the longitudinal decline in aperiodic activity specifically tracks sustained-attention processing speed rather than general cognitive aging, supporting its potential as a domain-specific biomarker of attentional aging in neurotypical populations.","rel_num_authors":7,"rel_authors":[{"author_name":"Christian Cazares","author_inst":"University of California, San Diego"},{"author_name":"Ali Rigby","author_inst":"University of California, San Diego"},{"author_name":"Leena Kang","author_inst":"University of California, San Diego"},{"author_name":"Stephan Getzmann","author_inst":"Leibniz Research Centre for Working Environment and Human Factors (IfADo)"},{"author_name":"Stefan Arnau","author_inst":"Leibniz Research Centre for Working Environment and Human Factors (IfADo)"},{"author_name":"Edmund Wascher","author_inst":"Leibniz Research Centre for Working Environment and Human Factors (IfADo)"},{"author_name":"Bradley Voytek","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Scaling laws for group-constrained, subject-specific task fMRI analyses","rel_doi":"10.64898\/2026.07.22.740076","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740076","rel_abs":"Functional MRI provides a powerful way to characterize the architecture of the human brain. Yet individual brains often vary in the exact anatomic locations of functionally specific regions; as a result of this variability, traditional random-effects group analyses (RFX) often require unrealistically large sample sizes to converge onto stable results. Here, we explore the scaling patterns for an alternative fMRI analysis framework that accounts for inter-individual topographic variability while still capturing spatial similarities--group-constrained, subject-specific (GcSS) analysis. Using sixteen contrasts from four Human Connectome Project tasks (spanning language, social cognition, motor, and working memory), we first show that the GcSS approach yields much larger effect sizes than traditional RFX analyses. We then investigate the impact of sample size (N=10-450) on the estimation of three key GcSS outputs: (1) group probabilistic maps for the contrast of interest, (2) group-level parcels that serve as anatomical constraints for subsequent functional region of interest (fROI) definitions in individual subjects, and (3) effect sizes of fROI responses to task conditions. For most contrasts, the probabilistic maps show good reliability at N=100 (intraclass correlation, ICC=.75) and excellent reliability at N=200 (ICC=.90). Most group parcels also achieve substantial agreement at N=100 (Dice coefficient, DC=.80). Critically, once robust group parcels are established, the subject-specific portion of the analysis can proceed with much smaller sample sizes: even samples of N=10 participants yield accurate effect size estimates within subject-specific fROIs, detecting 80% of practically meaningful effects (effect size [&ge;] 0.2); with N=20, this increases to 90%. The scaling patterns we observed held not only in the cortex, but also in the cerebellum. Our results challenge the view that fMRI research requires large samples: once the broad region of interest is established (with N=100 or higher), fROI-based analyses can yield generalizable results with small sample sizes (N=10 or N=20).","rel_num_authors":2,"rel_authors":[{"author_name":"Ruimin Gao","author_inst":"Georgia Institute of Technology"},{"author_name":"Anna A. Ivanova","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"The Live Concert of Brains: Performer-Audience Neural Coupling Links Ensemble Coordination to Shared Audience Integration","rel_doi":"10.64898\/2026.07.21.739936","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739936","rel_abs":"Collective social events often require coordinated action by one group to become shared experience in another, yet how this transformation is organized across multiple brains remains unclear. Live music provides a tractable model of this problem because ensemble coordination, performer-audience alignment, and shared audience integration unfold within the same event. Here we tested whether performer-audience neural coupling acts as a cross-role neural interface linking ensemble coordination to shared audience integration. We recorded brain activity from a nine-person live performance system, consisting of a fixed three-performer ensemble and four independent audience groups, using synchronized multi-device functional near-infrared spectroscopy hyperscanning across live trio performance sessions. Inter-brain neural coupling was analyzed across three relational layers: performer-performer (PP), performer-audience (PA), and audience-audience (AA) coupling. Behavioral ratings showed strong affective engagement and shared evaluative alignment. Neural coupling during live performance was not expressed as a diffuse increase across channel pairs, but was organized into task-sensitive relational components with interpretable PC-corr network modules. Crucially, path-based mediation analyses revealed that PA components statistically bridged PP coordination and AA coupling, yielding multiple complete and partial PP->PA->AA pathways. Brain-behavior analyses further suggested that mediation-related PA components were linked to shared performance evaluation and emotional alignment. These findings identify performer-audience coupling as a cross-role neural interface through which coordinated production becomes linked to shared collective reception.","rel_num_authors":10,"rel_authors":[{"author_name":"Yue Ding","author_inst":"Shanghai Mental Health Center"},{"author_name":"Jiameng Liu","author_inst":"Tsinghua University"},{"author_name":"Yifan Xu","author_inst":"Tsinghua University"},{"author_name":"Li Ji","author_inst":"Tsinghua University"},{"author_name":"Yubo Gao","author_inst":"Tsinghua University"},{"author_name":"Zheng Liang","author_inst":"Tsinghua University"},{"author_name":"Yingying Tang","author_inst":"Shanghai Mental Health Center"},{"author_name":"Juan Huang","author_inst":"Johns Hopkins University"},{"author_name":"Xiaoqin Wang","author_inst":"Tsinghua University"},{"author_name":"Dan Zhang","author_inst":"Tsinghua University"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"PWO1 and TRB proteins coordinate chromatin regulation to prevent premature differentiation and ectopic lignin deposition in Arabidopsis","rel_doi":"10.64898\/2026.07.24.740627","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.740627","rel_abs":"The Arabidopsis PWWP-DOMAIN INTERACTOR OF POLYCOMBS1 (PWO1) and Telomere Repeat-Binding Proteins 1-3 (TRB1-3, TRBs) associate with distinct and shared protein complexes involved in epigenetic regulation, yet their cooperative roles in chromatin control and plant development remain largely unexplored. Here, we show that the interaction between PWO1 and TRBs is evolutionarily conserved. Both PWO1 and TRBs associate with plant telomeres, interact at these regions, and are co-enriched at subsets of interspersed telo-box motifs across regulatory regions genome-wide. TRBs facilitate PWO1 binding at shared genomic regions, including telo-box motifs. PWO1 and TRBs share a substantial number of genomic targets and preferentially bind chromatin regions associated with transcriptionally active states, whereas TRBs alone associate with repressive marks at thousands of loci. Genetic analyses show that the pwo1 trb1 trb3 triple mutant displays severe developmental defects, including main stem arrest and early maturation associated with aberrant lignin deposition in interfascicular tissues. In the triple mutant, key enzymes in the lignin biosynthesis pathway are upregulated, indicating that PWO1, TRB1, and TRB3 cooperatively regulate secondary cell wall formation. Together, our findings provide new insights into how PWO1 and TRBs cooperate to regulate chromatin states and orchestrate plant development, highlighting their central role in controlling gene expression programs.","rel_num_authors":14,"rel_authors":[{"author_name":"Ahamed Khan","author_inst":"Institute of Biology, Freie Universitat Berlin, 14195 Berlin, Germany."},{"author_name":"Alzbeta Kusova","author_inst":"National Centre for Biomolecular Research, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic."},{"author_name":"Jan Skalak","author_inst":"Mendel Centre for Plant Genomics and Proteomics, Central European Institute of Technology (CEITEC), Masaryk University, 62500 Brno, Czech Republic."},{"author_name":"Biswajit Ghosh","author_inst":"Institute of Biology, Freie Universitat Berlin, 14195 Berlin, Germany."},{"author_name":"Tingting Yang","author_inst":"State Key Laboratory of Gene Function and Modulation Research, School of Advanced Agricultural Sciences, Peking-Tsinghua Center for Life Sciences, Peking Univer"},{"author_name":"Antonia Lilly Vivien Kelling","author_inst":"Institute of Biology, Freie Universitat Berlin, 14195 Berlin, Germany"},{"author_name":"Laura Hagemann","author_inst":"Institute of Biology, Freie Universitat Berlin, 14195 Berlin, Germany."},{"author_name":"Kishore C S Panigrahi","author_inst":"Plant Biology Laboratory, School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, 752050, India."},{"author_name":"Jan Hejatko","author_inst":"Mendel Centre for Plant Genomics and Proteomics, Central European Institute of Technology (CEITEC), Masaryk University, 62500 Brno, Czech Republic."},{"author_name":"Petra Prochazkova Schrumpfova","author_inst":"National Centre for Biomolecular Research, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic."},{"author_name":"Yue Zhou","author_inst":"State Key Laboratory of Gene Function and Modulation Research, School of Advanced Agricultural Sciences, Peking-Tsinghua Center for Life Sciences, Peking Univer"},{"author_name":"Sara Farrona","author_inst":"School of Biological and Chemical Sciences, National University of Ireland Galway, Galway, H91 TK33, Ireland"},{"author_name":"Iva Mozgova","author_inst":"Institute of Plant Molecular Biology (IPMB), Biology Centre, Czech Academy of Sciences, 37005 Ceske Budejovice, Czech Republic."},{"author_name":"Daniel Schubert","author_inst":"Institute of Biology, Freie Universitat Berlin, 14195 Berlin, Germany."}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Lysyl oxidase drives ccRCC progression by coordinating HIF-2\u03b1 transcription program with tumor microenvironment","rel_doi":"10.64898\/2026.07.24.739825","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.739825","rel_abs":"Clear cell renal cell carcinoma (ccRCC) is driven by persistent HIF-2[alpha]; transcription program initiated by VHL loss, yet molecular mediators sustaining this program are poorly defined. Using single-cell transcriptomics, we identified lysyl oxidase (LOX) as a driver of ccRCC progression, selectively enriched in a hypoxia\/epithelial-mesenchymal transition (EMT) gene program associated with poor outcome. While LOX oxidizes and stabilizes HIF-2[alpha]; by antagonizing HUWE1-mediated ubiquitination and degradation, thereby sustaining HIF-2[alpha];-driven transcription in cancer cells, it also remodels extracellular matrix (ECM) and promotes angiogenesis in the tumor microenvironment (TME). Genetic or pharmacological inhibition of LOX destabilizes HIF-2[alpha];, disrupts ECM, inhibits angiogenesis, and suppresses tumor initiation, growth, and metastasis in vivo. LOX inhibition enhances anti-angiogenic therapy response and remains effective in belzutifan-resistant HIF-2[alpha]; G323E-mutant tumors. Nuclear LOX protein correlates with nuclear HIF-2[alpha]; in high-grade patient tumors. Together, LOX coordinates HIF-2[alpha]; transcription program with TME and is a therapeutic target in ccRCC.","rel_num_authors":23,"rel_authors":[{"author_name":"Burge Ulukan","author_inst":"Medical University of South Carolina"},{"author_name":"Ozge Saatci","author_inst":"Medical University of South Carolina"},{"author_name":"Ariel Madrigal","author_inst":"McGill University"},{"author_name":"Minjun Kim","author_inst":"McGill University"},{"author_name":"Wensheng Tian","author_inst":"University of Ottawa"},{"author_name":"Mustafa Soytas","author_inst":"McGill University"},{"author_name":"Zohreh Mehrjoo","author_inst":"McGill University"},{"author_name":"Ozlem Sener Sahin","author_inst":"Medical University of South Carolina"},{"author_name":"Kukkamadi Sreenivas","author_inst":"University of South Carolina"},{"author_name":"Chintada Nageswara Rao","author_inst":"University of South Carolina"},{"author_name":"Tamiko Nishimura","author_inst":"McGill University"},{"author_name":"Virginie Pillon","author_inst":"McGill University"},{"author_name":"Jean-Sebastian Anoma","author_inst":"Medical University of South Carolina"},{"author_name":"Elizabeth Hill","author_inst":"Medical University of South Carolina"},{"author_name":"Janusz Rak","author_inst":"RIMUHC"},{"author_name":"Campbell McInnes","author_inst":"University of South Carolina"},{"author_name":"Morag Park","author_inst":"McGill University"},{"author_name":"Fadi Brimo","author_inst":"McGill University"},{"author_name":"Simon Tanguay","author_inst":"McGill University"},{"author_name":"Ryan Charles Russell","author_inst":"University of Ottawa"},{"author_name":"Hamed S Najafabadi","author_inst":"McGill University"},{"author_name":"Yasser Riazalhosseini","author_inst":"McGill University"},{"author_name":"Ozgur Sahin","author_inst":"Medical University of South Carolina"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Lysyl oxidase drives ccRCC progression by coordinating HIF-2\u03b1 transcription program with tumor microenvironment","rel_doi":"10.64898\/2026.07.24.739825","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.739825","rel_abs":"Clear cell renal cell carcinoma (ccRCC) is driven by persistent HIF-2[alpha]; transcription program initiated by VHL loss, yet molecular mediators sustaining this program are poorly defined. Using single-cell transcriptomics, we identified lysyl oxidase (LOX) as a driver of ccRCC progression, selectively enriched in a hypoxia\/epithelial-mesenchymal transition (EMT) gene program associated with poor outcome. While LOX oxidizes and stabilizes HIF-2[alpha]; by antagonizing HUWE1-mediated ubiquitination and degradation, thereby sustaining HIF-2[alpha];-driven transcription in cancer cells, it also remodels extracellular matrix (ECM) and promotes angiogenesis in the tumor microenvironment (TME). Genetic or pharmacological inhibition of LOX destabilizes HIF-2[alpha];, disrupts ECM, inhibits angiogenesis, and suppresses tumor initiation, growth, and metastasis in vivo. LOX inhibition enhances anti-angiogenic therapy response and remains effective in belzutifan-resistant HIF-2[alpha]; G323E-mutant tumors. Nuclear LOX protein correlates with nuclear HIF-2[alpha]; in high-grade patient tumors. Together, LOX coordinates HIF-2[alpha]; transcription program with TME and is a therapeutic target in ccRCC.","rel_num_authors":23,"rel_authors":[{"author_name":"Burge Ulukan","author_inst":"Medical University of South Carolina"},{"author_name":"Ozge Saatci","author_inst":"Medical University of South Carolina"},{"author_name":"Ariel Madrigal","author_inst":"McGill University"},{"author_name":"Minjun Kim","author_inst":"McGill University"},{"author_name":"Wensheng Tian","author_inst":"University of Ottawa"},{"author_name":"Mustafa Soytas","author_inst":"McGill University"},{"author_name":"Zohreh Mehrjoo","author_inst":"McGill University"},{"author_name":"Ozlem Sener Sahin","author_inst":"Medical University of South Carolina"},{"author_name":"Kukkamadi Sreenivas","author_inst":"University of South Carolina"},{"author_name":"Chintada Nageswara Rao","author_inst":"University of South Carolina"},{"author_name":"Tamiko Nishimura","author_inst":"McGill University"},{"author_name":"Virginie Pillon","author_inst":"McGill University"},{"author_name":"Jean-Sebastian Anoma","author_inst":"Medical University of South Carolina"},{"author_name":"Elizabeth Hill","author_inst":"Medical University of South Carolina"},{"author_name":"Janusz Rak","author_inst":"RIMUHC"},{"author_name":"Campbell McInnes","author_inst":"University of South Carolina"},{"author_name":"Morag Park","author_inst":"McGill University"},{"author_name":"Fadi Brimo","author_inst":"McGill University"},{"author_name":"Simon Tanguay","author_inst":"McGill University"},{"author_name":"Ryan Charles Russell","author_inst":"University of Ottawa"},{"author_name":"Hamed S Najafabadi","author_inst":"McGill University"},{"author_name":"Yasser Riazalhosseini","author_inst":"McGill University"},{"author_name":"Ozgur Sahin","author_inst":"Medical University of South Carolina"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Integrated Patient-Derived Xenograft and Patient-Derived Cell Models Reveal Therapeutic Vulnerabilities Beyond Standard-of-Care Therapy in Endometrial Cancer","rel_doi":"10.64898\/2026.07.24.740568","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.740568","rel_abs":"Endometrial cancer (EC), the most common gynecologic malignancy in the USA, has seen limited improvement in patient outcomes over recent decades, underscoring the need for relevant preclinical models. To address EC heterogeneity, we established an integrated platform of patient derived xenografts (PDXs) and matched patient derived primary cancer cells (PDCs) for disease modeling and systematic drug sensitivity testing. Fresh tumor specimens (n=103) were collected from EC patients to generate PDXs in immunodeficient mice and corresponding PDCs. Fifty-three PDX models were successfully established (52% engraftment rate), with higher success observed in high grade, recurrent, metastatic tumors (70%), compared with their low-grade counterparts (56%). Histopathologic and immunohistochemical analyses confirmed that PDX tumors faithfully preserved morphology, hormone receptor status, and intertumoral heterogeneity across multiple passages. Using 13 PDC models, we performed an unbiased screening of 179 FDA-approved oncology drugs, revealing marked intertumoral variability in drug response. Almost all PDC models exhibited limited sensitivity to NCCN-recommended therapies, highlighting the need for alternative treatment strategies. In contrast, multiple FDA-approved agents including epigenetic modulators, dual PI3-kinase\/HDAC inhibitors, topoisomerase II inhibitors, and proteasome inhibitors demonstrated potent antitumor activity. Importantly, a low-dose combination of the DNA methyltransferase inhibitor 5-azacytidine and the histone deacetylase inhibitor romidepsin significantly suppressed tumor growth across six independent PDX models. Together, these findings establish a comprehensive PDX and PDC platform as a robust translational resource. By capturing the histopathologic and molecular diversity of EC and identifying clinically actionable therapeutic advantages, including an epigenetic combination regimen, this study offers a translational resource for preclinical drug evaluation.","rel_num_authors":17,"rel_authors":[{"author_name":"Tianyue Li","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242"},{"author_name":"Fang Huang","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242 Present Address: Department of Radiology, The Second Affiliated Hospital of Fujian Medical Uni"},{"author_name":"Xiaohao Huang","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242 Present Address: Nanjing Medical University, Nanjing, China, 210029"},{"author_name":"Ella I Pate","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242 Present Address: Middlebury College, Middlebury, Vermont, 05753"},{"author_name":"Riley Rosenmeyer","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242"},{"author_name":"Mya Messenger","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242"},{"author_name":"Kaylee McSweeney","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242"},{"author_name":"Samuel Robinson","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242"},{"author_name":"Adam Deters","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242"},{"author_name":"Lauren Buchanan","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242"},{"author_name":"Maggie Meehan","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242"},{"author_name":"Nandini Patel","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242"},{"author_name":"Allison Diekema","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242"},{"author_name":"Yiqin Xiong","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242 Present Address: Department of Pathology, Boston University\/Boston Medical Center, Boston, MA,"},{"author_name":"Xiaofang Zhang","author_inst":"University of Iowa Department of Pathology"},{"author_name":"Xiangbing Meng","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242 Department of Pathology, University of Iowa, Iowa City, IA, 52242 Holden Comprehensive Cancer "},{"author_name":"Shujie Yang","author_inst":"Department of Pathology, University of Iowa, Iowa City, IA, 52242 Department of Pathology, University of Iowa, Iowa City, IA, 52242 Holden Comprehensive Cancer "}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"Paralog diversification masks conserved diel regulatory programs during cold acclimation in Brassica rapa","rel_doi":"10.64898\/2026.07.24.740384","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.740384","rel_abs":"Plant stress responses occur within daily cycles of physiology, metabolism, and growth, making timing a critical dimension of acclimation. In Arabidopsis, circadian and diel regulation influence responses to abiotic stress, including cold, but how this temporal regulation is conserved, diversified, or expanded in crop genomes remains unclear. This question is especially challenging in Brassica rapa, which underwent a genome triplication after diverging from Arabidopsis, resulting in multiple retained paralogs that can be grouped by Arabidopsis orthology and ancient homeologous relationships. Here, we generated a B. rapa pangenome spanning six morphotypes and used it to profile diel (24 h) cold acclimation responses across diverse accessions differing in freeze tolerances. Cold altered peak expression time for thousands of genes, which we grouped into distinct phase-change groups. Circadian leaf movement assays revealed accession-specific differences in clock period and temperature compensation under cold, suggesting that altered clock behavior may contribute in part to the diel transcriptome retiming. At the individual gene level, inferred gene regulatory networks (GRNs) were highly accession-specific and lost shared connectivity under cold stress. However, grouping these paralogs by their Arabidopsis orthologs revealed a highly conserved regulatory architecture that was otherwise masked by paralog diversification. Integrating these networks with functional pathways identified key candidate regulators of retimed processes, including modules linked to nighttime phosphorylation and daytime photosynthesis. Finally, analyzing conserved noncoding sequences across the pangenome prioritized specific regulatory targets within cold-retimed groups. Together, these results demonstrate that cold acclimation in B. rapa is shaped by a combination of diel retiming, paralog-specific regulation, and deeply conserved programs.","rel_num_authors":20,"rel_authors":[{"author_name":"Angela M Ricono","author_inst":"Washington University"},{"author_name":"Zachary A. Myers","author_inst":"University of Minnesota"},{"author_name":"Danielle Schoenecker","author_inst":"University of Minnesota"},{"author_name":"Ananda Menon","author_inst":"University of Minnesota"},{"author_name":"Dennis Such","author_inst":"University of Minnesota"},{"author_name":"Adelaide Hazen","author_inst":"University of Minnesota"},{"author_name":"Ava Wise","author_inst":"University of Minnesota"},{"author_name":"Tom\u00e1\u0161 Br\u016fna","author_inst":"US Department of Energy Joint Genome Institute"},{"author_name":"Jerry Jenkins","author_inst":"HudsonAlpha Institute of Biotechnology"},{"author_name":"Christopher Plott","author_inst":"HudsonAlpha Institute for Biotechnology"},{"author_name":"Jenell Webber","author_inst":"HudsonAlpha Institute for Biotechnology"},{"author_name":"LoriBeth Boston","author_inst":"HudsonAlpha Institute for Biotechnology"},{"author_name":"Shengqiang Shu","author_inst":"US Department of Energy joint Genome Institute"},{"author_name":"Yinji Qiu","author_inst":"University of Minnesota"},{"author_name":"Kerry Barry","author_inst":"US Department of Energy Joint Genome Institute"},{"author_name":"Chiemeka K. Nwakama","author_inst":"University of Minnesota"},{"author_name":"Jane Grimwood","author_inst":"HudsonAlpha Institute for Biotechnology"},{"author_name":"Jeremy Schmutz","author_inst":"HudsonAlpha Institute of Biotechnology; US Department of Energy Joint Genome Institute"},{"author_name":"John T. Lovell","author_inst":"HudsonAlpha Institute for Biotechnology; US Department of Energy Joint Genome Institute"},{"author_name":"Kathleen M Greenham","author_inst":"University of Minnesota"}],"rel_date":"2026-07-27","rel_site":"biorxiv"},{"rel_title":"H5N1 influenza binding and cell entry via human class II MHC, and blocking by cross-reactive antibodies","rel_doi":"10.64898\/2026.07.22.739677","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739677","rel_abs":"Highly pathogenic avian influenza H5N1 clade 2.3.4.4b viruses are currently responsible for a multi-species outbreak affecting wild birds, poultry, numerous mammalian species, and humans. Influenza A viruses typically initiate infection through binding to sialic acid, although select bat and human influenza viruses can also exploit class II major histocompatibility complex (MHC-II) molecules for cell entry. Here we show that emerging H5N1 clade 2.3.4.4b viruses, but not historical H5 lineages, bind human MHC-II HLA-DR and mediate sialic acid-independent cell entry. Hemagglutinin binding to primary human immune cells varies with MHC-II expression and is further shaped by HLA-DR allelic variation, identifying host genetic determinants that may influence susceptibility to infection. Mammalian-adaptive substitutions within the hemagglutinin sialic acid receptor-binding domain reduce MHC-II binding, suggesting this interaction is remodeled during clade 2.3.4.4b H5 adaptation to a human host. Lastly, cross-reactive monoclonal antibodies isolated from clade 2.3.4.4b H5-naive humans can block the hemagglutinin-MHC-II interaction. These findings identify a previously unrecognized receptor pathway in contemporary H5N1 viruses and reveal that both human genetic variation and pre-existing humoral immunity can modulate this interaction, with implications for host range, cellular tropism, spillover risk, and therapeutic intervention.","rel_num_authors":25,"rel_authors":[{"author_name":"Taylor Pursell","author_inst":"Stanford University"},{"author_name":"Artem Mikelov","author_inst":"Stanford University"},{"author_name":"Oliver F. Wirz","author_inst":"Stanford University"},{"author_name":"Jordan T Ort","author_inst":"University of Pennsylvania"},{"author_name":"Shuk Hang Li","author_inst":"University of Pennsylvania"},{"author_name":"Reilly K Atkinson","author_inst":"University of Pennsylvania"},{"author_name":"Jiabao Zhong","author_inst":"University of Pennsylvania"},{"author_name":"Jefferson J. S. Santos","author_inst":"University of Pennsylvania"},{"author_name":"Shilpa A Joshi","author_inst":"Stanford University"},{"author_name":"Jumana Afghani","author_inst":"Stanford University"},{"author_name":"Xiaorui Han","author_inst":"Stanford University"},{"author_name":"Emily Haraguchi","author_inst":"Stanford University"},{"author_name":"Ramona A Hoh","author_inst":"Stanford University"},{"author_name":"Ji-Yeun Lee","author_inst":"Stanford University"},{"author_name":"Brandon Lam","author_inst":"Stanford University"},{"author_name":"Alexander Stanford","author_inst":"Stanford University"},{"author_name":"Andrew T DeLaitsch","author_inst":"Stanford University"},{"author_name":"Jackson Schuetz","author_inst":"Stanford University"},{"author_name":"Katharina R\u00f6ltgen","author_inst":"Swiss Tropical and Public Health Institute"},{"author_name":"Sean Van Slyck","author_inst":"Sierra Donor Services"},{"author_name":"Donna Smith","author_inst":"Sierra Donor Services"},{"author_name":"Brian Ha","author_inst":"Sierra Donor Services"},{"author_name":"Claus U. Niemann","author_inst":"University of California, San Francisco"},{"author_name":"Scott E Hensley","author_inst":"University of Pennsylvania"},{"author_name":"Scott D Boyd","author_inst":"Stanford University"}],"rel_date":"2026-07-26","rel_site":"biorxiv"},{"rel_title":"IL-13 Induces a Tuft Cell-Intrinsic CD45 Checkpoint to Limit Intestinal Type 2 Immunity","rel_doi":"10.64898\/2026.07.24.740376","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.740376","rel_abs":"Tuft cells initiate intestinal type 2 immunity, yet the mechanisms that restrain excessive tuft cell activation remain poorly understood. Here, we identify the receptor tyrosine phosphatase CD45 (Ptprc), previously considered a hematopoietic marker, as a regulator of intestinal tuft cell function. CD45 expression is restricted to a subset of tuft cells and is induced by helminth infection and IL-13. Epithelial-specific deletion of Ptprc activated a tuft cell inflammatory program, promoted an epithelial inflammatory state, and increased eosinophil accumulation at homeostasis. During Heligmosomoides polygyrus bakeri infection, CD45 deficiency enhanced ILC2 and Th2 responses and reduced parasite burden, demonstrating that epithelial CD45 limits type 2 immunity in vivo. Accordingly, in intestinal organoids, CD45 was dispensable for IL-13-driven tuft cell differentiation but restrained IL-13-responsive transcriptional programs. Mechanistically, CD45-deficient tuft cells exhibited altered protein abundance of STAT5 and IL17RB, implicated in tuft cell immune regulation. Together, these findings identify CD45 as a tuft cell-intrinsic regulatory checkpoint that restrains intestinal type 2 immunity through an IL-13-induced negative-feedback circuit.","rel_num_authors":20,"rel_authors":[{"author_name":"Carmel Sochen","author_inst":"Weizmann Institute of Science"},{"author_name":"Sacha Lebon","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Aviya Habshush-Menachem","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Avital Sarusi-Portuguez","author_inst":"The Mantoux Bioinformatics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Is"},{"author_name":"Vladyslav Holiar","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Vladislav Rudenko","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Barak Toval","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Jingjing Liu","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Yishai Levin","author_inst":"de Botton Institute for Protein Profiling, Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Isr"},{"author_name":"Ella Vaaknin","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Noa Rosenthal","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Noa Tiferet","author_inst":"Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel"},{"author_name":"Irit Orr","author_inst":"Department of Life Sciences Core Facilities, Faculty of Biochemistry, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Shifra Ben-Dor","author_inst":"Department of Life Sciences Core Facilities, Faculty of Biochemistry, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Rebecca Haffner-Krausz","author_inst":"Department of Veterinary Resources, Faculty of Biochemistry, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Richard Grencis","author_inst":"Lydia Becker Institute of Immunology and Inflammation, Manchester Cell Matrix Centre, Faculty of Biology, Medicine and Health, University of Manchester, Manches"},{"author_name":"Ariel Munitz","author_inst":"Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel"},{"author_name":"Danielle Karo-Atar","author_inst":"Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel"},{"author_name":"Ziv Shulman","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Moshe Biton","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"}],"rel_date":"2026-07-26","rel_site":"biorxiv"},{"rel_title":"IL-13 Induces a Tuft Cell-Intrinsic CD45 Checkpoint to Limit Intestinal Type 2 Immunity","rel_doi":"10.64898\/2026.07.24.740376","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.740376","rel_abs":"Tuft cells initiate intestinal type 2 immunity, yet the mechanisms that restrain excessive tuft cell activation remain poorly understood. Here, we identify the receptor tyrosine phosphatase CD45 (Ptprc), previously considered a hematopoietic marker, as a regulator of intestinal tuft cell function. CD45 expression is restricted to a subset of tuft cells and is induced by helminth infection and IL-13. Epithelial-specific deletion of Ptprc activated a tuft cell inflammatory program, promoted an epithelial inflammatory state, and increased eosinophil accumulation at homeostasis. During Heligmosomoides polygyrus bakeri infection, CD45 deficiency enhanced ILC2 and Th2 responses and reduced parasite burden, demonstrating that epithelial CD45 limits type 2 immunity in vivo. Accordingly, in intestinal organoids, CD45 was dispensable for IL-13-driven tuft cell differentiation but restrained IL-13-responsive transcriptional programs. Mechanistically, CD45-deficient tuft cells exhibited altered protein abundance of STAT5 and IL17RB, implicated in tuft cell immune regulation. Together, these findings identify CD45 as a tuft cell-intrinsic regulatory checkpoint that restrains intestinal type 2 immunity through an IL-13-induced negative-feedback circuit.","rel_num_authors":20,"rel_authors":[{"author_name":"Carmel Sochen","author_inst":"Weizmann Institute of Science"},{"author_name":"Sacha Lebon","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Aviya Habshush-Menachem","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Avital Sarusi-Portuguez","author_inst":"The Mantoux Bioinformatics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Is"},{"author_name":"Vladyslav Holiar","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Vladislav Rudenko","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Barak Toval","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Jingjing Liu","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Yishai Levin","author_inst":"de Botton Institute for Protein Profiling, Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Isr"},{"author_name":"Ella Vaaknin","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Noa Rosenthal","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Noa Tiferet","author_inst":"Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel"},{"author_name":"Irit Orr","author_inst":"Department of Life Sciences Core Facilities, Faculty of Biochemistry, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Shifra Ben-Dor","author_inst":"Department of Life Sciences Core Facilities, Faculty of Biochemistry, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Rebecca Haffner-Krausz","author_inst":"Department of Veterinary Resources, Faculty of Biochemistry, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Richard Grencis","author_inst":"Lydia Becker Institute of Immunology and Inflammation, Manchester Cell Matrix Centre, Faculty of Biology, Medicine and Health, University of Manchester, Manches"},{"author_name":"Ariel Munitz","author_inst":"Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel"},{"author_name":"Danielle Karo-Atar","author_inst":"Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel"},{"author_name":"Ziv Shulman","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Moshe Biton","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"}],"rel_date":"2026-07-26","rel_site":"biorxiv"},{"rel_title":"Optimized cryo-FIB milling strategy to generate thin, minimally damaged biological lamellae","rel_doi":"10.64898\/2026.07.21.739890","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739890","rel_abs":"Focused ion beam (FIB)-milling has been adapted to thin frozen cells for visualization of macromolecular structures in situ with cryogenic electron microscopy. However, only a few large and abundant complexes have been annotated to date. FIB-milling introduces damage which limits the recoverable information from cellular sections. Here, we present Nilas, a low-energy milling strategy optimized to minimize damage and produce thin lamellae. Nilas-milled lamellae show minimal FIB-milling damage, contain areas at or below 50 nm and produce higher resolution in situ 3D reconstructions. Nilas improves the recovery of ribosomal subunits and reduces the predicted minimal detectable molecular mass with two-dimensional template matching (2DTM) to approximately 220 kDa. Consistently, we recover additional non-ribosomal complexes including RNA polymerase III with 2DTM in Nilas-milled lamellae. Nilas is compatible with common milling hardware, making it accessible to diverse users. By extending the size limit for in situ structural biology we bring visual proteomics closer to reality.","rel_num_authors":4,"rel_authors":[{"author_name":"Laina N Hall","author_inst":"UC Berkeley"},{"author_name":"Joshua Paul","author_inst":"UC Berkeley"},{"author_name":"Philip Ngo","author_inst":"UC Berkeley"},{"author_name":"Bronwyn A Lucas","author_inst":"University of California Berkeley"}],"rel_date":"2026-07-25","rel_site":"biorxiv"},{"rel_title":"Developmental tuning of functional manifold dimensionality across the human brain","rel_doi":"10.64898\/2026.07.24.740635","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.740635","rel_abs":"Neural representations vary in their complexity across brain regions and tasks. How this variation emerges over human development remains poorly understood. We estimated intrinsic dimensionality in five naturalistic fMRI datasets (N = 781 unique participants, aged 3 months to 53 years) with T-PHATE -- a nonlinear manifold learning method robust to noisy, autocorrelated signals. In adults, brain regions relevant to a task had higher-dimensional activity than task-irrelevant regions across auditory, visual, and audiovisual stimuli. The modulation of representational complexity by tasks was absent in infants, emerged in early childhood, and strengthened logarithmically through adolescence. It reflected a selective collapse in dimensionality in task irrelevant regions, relative to a resting-state baseline, rather than an expansion of dimensionality in task-relevant regions. Such compression followed a trajectory from global and nonselective in infants to local and precise by adulthood. These results identify selective compression as a developmental engine of functional specialization: rather than adding complexity where it is needed, the brain dynamically pares it away where it is not.","rel_num_authors":2,"rel_authors":[{"author_name":"Erica L. Busch","author_inst":"Yale University"},{"author_name":"Nicholas B Turk-Browne","author_inst":"Yale University"}],"rel_date":"2026-07-25","rel_site":"biorxiv"},{"rel_title":"Understanding attrition: Feasibility and acceptability of a behavioral intervention for dementia care partners","rel_doi":"10.64898\/2026.07.22.26357171","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26357171","rel_abs":"INTRODUCTION: Behavioral intervention studies for family care partners for those with dementia need to be both feasible and acceptable in order implement and complete the investigative work. Our study, Tele-STELLA (Support via Technology: Living and Learning with Advancing dementia), was completed in 2025. While 188 care partners enrolled, the attrition rate was high (44%). Here we describe the feasibility, acceptability, and preliminary efficacy of Tele-STELLA. We further describe our fidelity processes. METHODS: Quantitative measures were used to assess care partner burden, study participation, feasibility and acceptability. Our weekly survey assessed the prevalence of adverse events. Qualitative methods paralleled our quantitative findings, in that care partners generally found the study acceptable, but dementia progression and life demands made participation difficult for some. RESULTS: The total attrition rate was 44%, but was attenuated by increasing the sample size. This adequately-powered study found that the intervention significantly reduced burden. Overall, care partners found the study feasible, but care demands made participation difficult for 28 of the care partners resulting in their withdrawal. In addition, 21 care recipients died, and thus their care partners had to be removed from the study. Qualitive findings mirrored the results. DISCUSSION: Our findings reveal that, even in the later stages of dementia, care partners are willing to participate in intervention research. However, care demands and death can affect the sample size. Our data and recommendations for future studies will inform caregiving scientists in designing behavioral interventions in late-stage dementia.","rel_num_authors":10,"rel_authors":[{"author_name":"Allison Lindauer","author_inst":"OHSU - Oregon Health & Science University"},{"author_name":"Kristin G Cloyes","author_inst":"Oregon Health & Science University"},{"author_name":"Nathan Dieckmann","author_inst":"Oregon Health & Science University"},{"author_name":"Christina Zonker","author_inst":"Oregon Health & Science University"},{"author_name":"Heather Franklin","author_inst":"Oregon Health & Science University"},{"author_name":"Susan Rosenkranz","author_inst":"Oregon Health & Science University"},{"author_name":"Alex Speers","author_inst":"Oregon Health & Science University"},{"author_name":"Michelle Kinsella","author_inst":"Oregon Health & Science University"},{"author_name":"Keely Young","author_inst":"Oregon Health & Science University"},{"author_name":"Aimee Mooney","author_inst":"Oregon Health & Science University"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"Projected economic gains and lives saved under universal healthcare in the United States","rel_doi":"10.64898\/2026.07.22.26358689","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358689","rel_abs":"The US spends more on health care than any other nation, yet tens of millions of Americans are uninsured or underinsured, and coverage retractions enacted in 2025 are widening these gaps. The misalignment between the for-profit insurance architecture and optimal patient care, together with the inefficiencies of a fragmented system, contributes to both unnecessary costs and preventable mortality. We update our previous analyses with the most recent data to project the economic benefits and the number of lives saved that would be achieved by single-payer universal coverage, as proposed in the Medicare for All Act. We estimate that such a system would reduce national health expenditure by $1,041 billion annually. Sources of savings include reductions in administrative overhead, pharmaceutical prices, fraudulent billing, and avoidable emergency care. Combined with the reversal of recent retractions, universal coverage would save over 114,000 lives annually.","rel_num_authors":5,"rel_authors":[{"author_name":"Abhishek Pandey","author_inst":"Yale University"},{"author_name":"Chad R Wells","author_inst":"CIDMA"},{"author_name":"Yang Ye","author_inst":"Yale University"},{"author_name":"Meagan C Fitzpatrick","author_inst":"University of Maryland School of Medicine"},{"author_name":"Alison P Galvani","author_inst":"Yale University"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"Forecasting Trajectories of Physiological Mechanics with Sparse Clinical Data Using a Data Assimilation and Machine Learning Hybrid","rel_doi":"10.64898\/2026.07.22.26358695","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358695","rel_abs":"Clinical decisions for determining optimal patient-specific interventions are complicated prediction tasks that rely on health care professionals' understanding of physiological mechanisms and their dynamics. These decisions are challenged by (a) observational data sparsity and (b) patient heterogeneity. Here, we focus on estimating and forecasting specific physiological properties--that are not explicitly present in clinical observations--to provide additional features using only data available bedside at the time of decision-making. Mechanistic models of physiological system(s), e.g., physiological ordinary differential equation (ODE) models, provide pathways to compensate for data sparsity by synchronizing the model with observations of an individual patient using data assimilation (DA). However, DA used in a standard computational workflow to estimate constant model parameters from presently-known data is less effective at optimizing state forecasts of the model governed by physiological processes that evolve before new observations are available. Stated simply, we cannot forecast the future evolution of the model because we cannot forecast model parameters. To support next-generation clinical decision support, we develop a new DA and machine learning (ML) hybrid pipeline to estimate and forecast individual future physiological processes by forecasting ODE model parameters. This pipeline overcomes model and DA workflow limitations by stacking a DA-estimated posterior empirical distribution of physiological parameters with longitudinal ML forecasting models. We work within the context of glycemic management in an ICU using EHR data to construct and test a use case. We use synthetic data and real-world clinical data to validate the integrated pipeline and quantify uncertainties.","rel_num_authors":7,"rel_authors":[{"author_name":"Yanran Wang","author_inst":"University of Colorado Denver Anschutz Medical Campus"},{"author_name":"J.N. Stroh","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Debashis Ghosh","author_inst":"CU Anschutz: University of Colorado - Anschutz Medical Campus"},{"author_name":"Melike Sirlanci","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"George Hripcsak","author_inst":"Columbia University"},{"author_name":"Tellen D Bennett","author_inst":"University of Colorado School of Medicine"},{"author_name":"David Albers","author_inst":"University of Colorado Anschutz Medical Campus"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"From Recognition to Reimbursement: An Assessment of State Medicaid Coverage Policies for Genetic Counselors and a Path Forward","rel_doi":"10.64898\/2026.07.22.26358669","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358669","rel_abs":"Purpose As genomics permeates all healthcare specialties, genetic counseling in conjunction with genetic testing is broadly recommended. Improving access to genetics professionals is crucial for Americans insured by Medicaid. The purpose of this study was to conduct a comprehensive review of Medicaid policies for genetic counseling performed by Certified Genetic Counselors (CGC(C)). Methods Fee-for-service Medicaid policies across 50 states and Washington DC were reviewed and coded. Four states with exemplary policies were identified, and CGC managers in two of these were surveyed regarding the real-world effects of these policies. Results As of 2024, 20 states (39%) had a published policy for genetic counseling with most (N=16, 80%) expressly covering genetic counseling in connection with any covered genetic test. Of the states without a policy, 12 (24%) mention genetic counseling in the context of scenario-specific policies, and 19 (37%) have no published policy. Twenty states explicitly cover CGC services, while 2 exclude CGCs as service providers. CGC managers in Indiana and Michigan confirmed the policies identified as exemplary successfully led to reimbursement of CGC services. Conclusion There is significant variability in Medicaid coverage for genetic counseling. Comprehensive policies are needed to support patient access to genetics professionals, including CGCs.","rel_num_authors":6,"rel_authors":[{"author_name":"Philip D Connors","author_inst":"Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"},{"author_name":"Yue Guan","author_inst":"Department of Behavioral, Social & Health Education Sciences, Rollins School of Public Health, Emory University, Atlanta, GA"},{"author_name":"Cynthia A James","author_inst":"Johns Hopkins University, School of Medicine"},{"author_name":"Julian Polaris","author_inst":"Manatt, Phelps & Phillips, LLP"},{"author_name":"Blair Cantfil","author_inst":"Manatt, Phelps & Phillips, LLP"},{"author_name":"Colleen A Campbell","author_inst":"University of Iowa"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"From Recognition to Reimbursement: An Assessment of State Medicaid Coverage Policies for Genetic Counselors and a Path Forward","rel_doi":"10.64898\/2026.07.22.26358669","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358669","rel_abs":"Purpose As genomics permeates all healthcare specialties, genetic counseling in conjunction with genetic testing is broadly recommended. Improving access to genetics professionals is crucial for Americans insured by Medicaid. The purpose of this study was to conduct a comprehensive review of Medicaid policies for genetic counseling performed by Certified Genetic Counselors (CGC(C)). Methods Fee-for-service Medicaid policies across 50 states and Washington DC were reviewed and coded. Four states with exemplary policies were identified, and CGC managers in two of these were surveyed regarding the real-world effects of these policies. Results As of 2024, 20 states (39%) had a published policy for genetic counseling with most (N=16, 80%) expressly covering genetic counseling in connection with any covered genetic test. Of the states without a policy, 12 (24%) mention genetic counseling in the context of scenario-specific policies, and 19 (37%) have no published policy. Twenty states explicitly cover CGC services, while 2 exclude CGCs as service providers. CGC managers in Indiana and Michigan confirmed the policies identified as exemplary successfully led to reimbursement of CGC services. Conclusion There is significant variability in Medicaid coverage for genetic counseling. Comprehensive policies are needed to support patient access to genetics professionals, including CGCs.","rel_num_authors":6,"rel_authors":[{"author_name":"Philip D Connors","author_inst":"Department of Obstetrics and Gynecology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"},{"author_name":"Yue Guan","author_inst":"Department of Behavioral, Social & Health Education Sciences, Rollins School of Public Health, Emory University, Atlanta, GA"},{"author_name":"Cynthia A James","author_inst":"Johns Hopkins University, School of Medicine"},{"author_name":"Julian Polaris","author_inst":"Manatt, Phelps & Phillips, LLP"},{"author_name":"Blair Cantfil","author_inst":"Manatt, Phelps & Phillips, LLP"},{"author_name":"Colleen A Campbell","author_inst":"University of Iowa"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"SECISBP2 Deficiency Causes a Lethal Perinatal Cardiomyopathy","rel_doi":"10.64898\/2026.07.22.26358709","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358709","rel_abs":"Selenoproteins are a specialised group of proteins that incorporate selenium, an essential micronutrient, in the form of selenocysteine. The SECIS binding protein 2 (SBP2), encoded by SECISBP2, is a crucial component of the selenocysteine incorporation machinery. SECISBP2 deficiency compromises selenoprotein synthesis, and its knockout causes embryonic lethality in mice. Selenium is critical to cardiac function, and nutritional deficiency causes Keshan disease, a progressive cardiomyopathy. Biallelic variants in SECISBP2 cause pleiotropic phenotypes including abnormal thyroid hormone metabolism, neurodevelopmental disorders and aortic aneurysms. No reported phenotypes to date include cardiomyopathy. We report a consanguineous South Asian family with a history of perinatal deaths due to progressive cardiomyopathy and intractable arrhythmias with a rare homozygous loss-of-function splice site variant in SECISBP2. The SECISBP2 c.1303-2A>G variant was homozygous in four affected offspring and heterozygous in the parents. One child without cardiac disease did not carry this variant. RNA sequencing confirmed that almost all transcripts would undergo nonsense-mediated decay. Further, we observed a pronounced decrease in GPX1 and SELENOH selenoprotein mRNA, as well as a large decrease in SELENOH, GPX1, GPX3 and GPX4 cardiac protein abundance in homozygotes, a molecular hallmark of SECISBP2 deficiency. Notably, we observed a >12-fold decrease in cardiac GPX4, a key selenoprotein that suppresses lipid peroxidation and ferroptosis, suggesting a possible ferroptosis-mediated mechanism for heart failure. Our analysis suggests that c.1303-2A>G is likely the most damaging homozygous variant discovered to date. For the first time, we show that SECISBP2 is essential for human life, with almost complete loss-of-function causing a lethal perinatal cardiomyopathy characterised by pronounced cardiac selenoprotein loss.","rel_num_authors":34,"rel_authors":[{"author_name":"Carlos C. Smith-Diaz","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Natasha Henden","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Natalie Stewart","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Samantha Bryen","author_inst":"Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Centre for Population Genomics, Garvan Institute of Medical R"},{"author_name":"Mark Graham","author_inst":"Biomedical Proteomics, Children's Medical Research Institute, The University of Sydney, Westmead, NSW, Australia."},{"author_name":"Claire Lawley","author_inst":"Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.; The Heart Centre for Children, Sydney Children's Hospitals"},{"author_name":"Alexandra Butters","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Adam T. Piers","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute,"},{"author_name":"Amy Baker","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"David A. Elliott","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute,"},{"author_name":"Ebony Richardson","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Edward Formaini","author_inst":"Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Centre for Population Genomics, Garvan Institute of Medical R"},{"author_name":"Enzo R. Porrello","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute,"},{"author_name":"Helen Doyle","author_inst":"Department of Histopathology, Children's Hospital Westmead, Sydney, NSW, Australia."},{"author_name":"Igor E. Konstantinov","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, Melbourne, VIC, Austr"},{"author_name":"Ingrid King","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia."},{"author_name":"Inuli Subasinghe","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Kathleen Le Marquand","author_inst":"Clinical Genetics Service, Royal Prince Alfred Hospital, Camperdown, NSW, Australia."},{"author_name":"Laura Catto","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Laura Yeates","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Lisa Ewans","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia.; Discipline of Paediatrics and Child Health, Faculty of Medi"},{"author_name":"Rani Sachdev","author_inst":"Centre for Clinical Genetics, Sydney Children's Hospitals Network, Randwick, NSW, Australia.; Specialty of Genomic Medicine, University of Sydney, Sydney, NSW, "},{"author_name":"Rocio Rius","author_inst":"Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Centre for Population Genomics, Garvan Institute of Medical R"},{"author_name":"Samantha Ross","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia.; School of Clinical Medicine, Faculty of Medicine and Health"},{"author_name":"Sui Yu","author_inst":"Genetics and Molecular Pathology, SA Pathology, Adelaide Site, SA, Australia."},{"author_name":"Winnie She","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, Melbourne, VIC, Austr"},{"author_name":"Johan Duflou","author_inst":"Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia."},{"author_name":"Cas Simons","author_inst":"Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Centre for Population Genomics, Garvan Institute of Medical R"},{"author_name":"Daniel G. MacArthur","author_inst":"Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Centre for Population Genomics, Garvan Institute of Medical R"},{"author_name":"Felicity Collins","author_inst":"Clinical Genetics Service, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.; Divisions of Genomic Medicine, Paediatrics and Child Health, University of"},{"author_name":"Ulrich Schweizer","author_inst":"Universitatsklinikum Bonn, Institut fur Biochemie und Molekularbiologie, Universitat Bonn, Bonn, Germany."},{"author_name":"Amali Mallawaarachchi","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia.; Sydney Medical School, Faculty of Medicine and Health, Univ"},{"author_name":"James McNamara","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, Melbourne, VIC, Austr"},{"author_name":"Jodie Ingles","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia.; School of Clinical Medicine, Faculty of Medicine and Health"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"SECISBP2 Deficiency Causes a Lethal Perinatal Cardiomyopathy","rel_doi":"10.64898\/2026.07.22.26358709","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358709","rel_abs":"Selenoproteins are a specialised group of proteins that incorporate selenium, an essential micronutrient, in the form of selenocysteine. The SECIS binding protein 2 (SBP2), encoded by SECISBP2, is a crucial component of the selenocysteine incorporation machinery. SECISBP2 deficiency compromises selenoprotein synthesis, and its knockout causes embryonic lethality in mice. Selenium is critical to cardiac function, and nutritional deficiency causes Keshan disease, a progressive cardiomyopathy. Biallelic variants in SECISBP2 cause pleiotropic phenotypes including abnormal thyroid hormone metabolism, neurodevelopmental disorders and aortic aneurysms. No reported phenotypes to date include cardiomyopathy. We report a consanguineous South Asian family with a history of perinatal deaths due to progressive cardiomyopathy and intractable arrhythmias with a rare homozygous loss-of-function splice site variant in SECISBP2. The SECISBP2 c.1303-2A>G variant was homozygous in four affected offspring and heterozygous in the parents. One child without cardiac disease did not carry this variant. RNA sequencing confirmed that almost all transcripts would undergo nonsense-mediated decay. Further, we observed a pronounced decrease in GPX1 and SELENOH selenoprotein mRNA, as well as a large decrease in SELENOH, GPX1, GPX3 and GPX4 cardiac protein abundance in homozygotes, a molecular hallmark of SECISBP2 deficiency. Notably, we observed a >12-fold decrease in cardiac GPX4, a key selenoprotein that suppresses lipid peroxidation and ferroptosis, suggesting a possible ferroptosis-mediated mechanism for heart failure. Our analysis suggests that c.1303-2A>G is likely the most damaging homozygous variant discovered to date. For the first time, we show that SECISBP2 is essential for human life, with almost complete loss-of-function causing a lethal perinatal cardiomyopathy characterised by pronounced cardiac selenoprotein loss.","rel_num_authors":34,"rel_authors":[{"author_name":"Carlos C. Smith-Diaz","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Natasha Henden","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Natalie Stewart","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Samantha Bryen","author_inst":"Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Centre for Population Genomics, Garvan Institute of Medical R"},{"author_name":"Mark Graham","author_inst":"Biomedical Proteomics, Children's Medical Research Institute, The University of Sydney, Westmead, NSW, Australia."},{"author_name":"Claire Lawley","author_inst":"Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.; The Heart Centre for Children, Sydney Children's Hospitals"},{"author_name":"Alexandra Butters","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Adam T. Piers","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute,"},{"author_name":"Amy Baker","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"David A. Elliott","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute,"},{"author_name":"Ebony Richardson","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Edward Formaini","author_inst":"Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Centre for Population Genomics, Garvan Institute of Medical R"},{"author_name":"Enzo R. Porrello","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute,"},{"author_name":"Helen Doyle","author_inst":"Department of Histopathology, Children's Hospital Westmead, Sydney, NSW, Australia."},{"author_name":"Igor E. Konstantinov","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, Melbourne, VIC, Austr"},{"author_name":"Ingrid King","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia."},{"author_name":"Inuli Subasinghe","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Kathleen Le Marquand","author_inst":"Clinical Genetics Service, Royal Prince Alfred Hospital, Camperdown, NSW, Australia."},{"author_name":"Laura Catto","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Laura Yeates","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia."},{"author_name":"Lisa Ewans","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia.; Discipline of Paediatrics and Child Health, Faculty of Medi"},{"author_name":"Rani Sachdev","author_inst":"Centre for Clinical Genetics, Sydney Children's Hospitals Network, Randwick, NSW, Australia.; Specialty of Genomic Medicine, University of Sydney, Sydney, NSW, "},{"author_name":"Rocio Rius","author_inst":"Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Centre for Population Genomics, Garvan Institute of Medical R"},{"author_name":"Samantha Ross","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia.; School of Clinical Medicine, Faculty of Medicine and Health"},{"author_name":"Sui Yu","author_inst":"Genetics and Molecular Pathology, SA Pathology, Adelaide Site, SA, Australia."},{"author_name":"Winnie She","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, Melbourne, VIC, Austr"},{"author_name":"Johan Duflou","author_inst":"Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia."},{"author_name":"Cas Simons","author_inst":"Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Centre for Population Genomics, Garvan Institute of Medical R"},{"author_name":"Daniel G. MacArthur","author_inst":"Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Centre for Population Genomics, Garvan Institute of Medical R"},{"author_name":"Felicity Collins","author_inst":"Clinical Genetics Service, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.; Divisions of Genomic Medicine, Paediatrics and Child Health, University of"},{"author_name":"Ulrich Schweizer","author_inst":"Universitatsklinikum Bonn, Institut fur Biochemie und Molekularbiologie, Universitat Bonn, Bonn, Germany."},{"author_name":"Amali Mallawaarachchi","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia.; Sydney Medical School, Faculty of Medicine and Health, Univ"},{"author_name":"James McNamara","author_inst":"Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, Melbourne, VIC, Austr"},{"author_name":"Jodie Ingles","author_inst":"Garvan Institute of Medical Research and the University of New South Wales, Sydney, NSW, Australia.; School of Clinical Medicine, Faculty of Medicine and Health"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"Circulating proteins altered in response to the Dietary Approaches to Stop Hypertension (DASH) diet suggest underlying molecular mechanisms and long-term health benefits","rel_doi":"10.64898\/2026.07.22.26358749","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358749","rel_abs":"The Dietary Approaches to Stop Hypertension (DASH) diet reduces blood pressure and cholesterol. However, the mechanisms underlying these effects are unclear, and no randomized studies have evaluated the long-term benefits on health outcomes such as coronary artery disease (CAD) or type 2 diabetes (T2D). We performed a series of Mendelian randomization analyses of 71 serum proteins perturbed by the DASH diet in previous randomized controlled feeding studies to understand their potential mechanistic role on health outcomes. Four proteins (ANGPTL3, INHBC, PCOLCE, PLXNB2) had causal evidence of beneficial effects on risk factors that aligned with diet-induced changes in protein levels. Missense variants in INHBC and PLXNB were associated with lower risks of CAD and T2D respectively, and these effects are directionally concordant with DASH diet-induced changes in protein levels, providing causal evidence that these proteins influence disease risk. Combining molecular phenotyping in randomized interventional studies with human genetics evidence identified molecular regulators of the long-term cardioprotective effects of the DASH diet.","rel_num_authors":9,"rel_authors":[{"author_name":"Hyunju Kim","author_inst":"Department of Epidemiology, University of Washington, Seattle, Washington, USA"},{"author_name":"Jennifer A Brody","author_inst":"Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA"},{"author_name":"Guanghao Qi","author_inst":"Department of Biostatistics, University of Washington, Seattle, Washington, USA"},{"author_name":"Ting Ye","author_inst":"Department of Biostatistics, University of Washington, Seattle, Washington, USA"},{"author_name":"Rizwan Kalani","author_inst":"Department of Neurology, University of Washington, Seattle, WA, USA"},{"author_name":"Lawrence J Appel","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA"},{"author_name":"Casey M Rebholz","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA"},{"author_name":"Neil M Davies","author_inst":"Division of Psychiatry, University College London, London, UK"},{"author_name":"James S Floyd","author_inst":"Department of Epidemiology, University of Washington, Seattle, Washington, USA"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"Under Pressure: The Burden of Hypertension on Armenias Ambulance System","rel_doi":"10.64898\/2026.07.22.26358725","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358725","rel_abs":"Hypertension is a leading cause of premature mortality globally. Armenia, a country located in the South Caucasus, has one of the highest rates of hypertension in the world, with an estimated prevalence of 51% among adults aged 30-79. A previous analysis of ambulance calls from 2016-2022 revealed that high blood pressure was the most common ambulance complaint in Armenia. In the present study, we analyzed a de-identified database of all ambulance calls logged on the Locator software in Armenia from January 1, 2016 to July 31, 2022. Among all adults who reported at least one chief complaint, 28.8% listed high blood pressure as their sole complaint. Within this cohort, 61.0% of patients were over 60 years old, and 70.1% of patients were women. The rate of transfer to the hospital was 9.2%. Call volume fluctuated by season, with higher frequencies in the winter and spring and lower frequencies in the summer and fall. Results indicate that a significant proportion of ambulance calls are for non-emergency cases of high blood pressure with no additional reported medical complaints, indicating that Armenias elevated prevalence of hypertension places a significant burden on its ambulance system. Policymakers should prioritize hypertension as a national issue, and consider multi-modal policy interventions aimed at reducing ambulance utilization for high blood pressure.","rel_num_authors":5,"rel_authors":[{"author_name":"Ani Arzoumanian","author_inst":"UMass Chan Medical School TH Chan School of Medicine: University of Massachusetts Chan Medical School TH Chan School of Medicine"},{"author_name":"Anya Agopian","author_inst":"American University of Armenia"},{"author_name":"Marine Hovhannisyan","author_inst":"Yerevan State Medical University Named after Mkhitar Heratsi"},{"author_name":"Aline Baghdassarian","author_inst":"University of Virginia School of Medicine"},{"author_name":"Sharon Chekijian","author_inst":"Yale School of Medicine: Yale University School of Medicine"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"Under Pressure: The Burden of Hypertension on Armenias Ambulance System","rel_doi":"10.64898\/2026.07.22.26358725","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358725","rel_abs":"Hypertension is a leading cause of premature mortality globally. Armenia, a country located in the South Caucasus, has one of the highest rates of hypertension in the world, with an estimated prevalence of 51% among adults aged 30-79. A previous analysis of ambulance calls from 2016-2022 revealed that high blood pressure was the most common ambulance complaint in Armenia. In the present study, we analyzed a de-identified database of all ambulance calls logged on the Locator software in Armenia from January 1, 2016 to July 31, 2022. Among all adults who reported at least one chief complaint, 28.8% listed high blood pressure as their sole complaint. Within this cohort, 61.0% of patients were over 60 years old, and 70.1% of patients were women. The rate of transfer to the hospital was 9.2%. Call volume fluctuated by season, with higher frequencies in the winter and spring and lower frequencies in the summer and fall. Results indicate that a significant proportion of ambulance calls are for non-emergency cases of high blood pressure with no additional reported medical complaints, indicating that Armenias elevated prevalence of hypertension places a significant burden on its ambulance system. Policymakers should prioritize hypertension as a national issue, and consider multi-modal policy interventions aimed at reducing ambulance utilization for high blood pressure.","rel_num_authors":5,"rel_authors":[{"author_name":"Ani Arzoumanian","author_inst":"UMass Chan Medical School TH Chan School of Medicine: University of Massachusetts Chan Medical School TH Chan School of Medicine"},{"author_name":"Anya Agopian","author_inst":"American University of Armenia"},{"author_name":"Marine Hovhannisyan","author_inst":"Yerevan State Medical University Named after Mkhitar Heratsi"},{"author_name":"Aline Baghdassarian","author_inst":"University of Virginia School of Medicine"},{"author_name":"Sharon Chekijian","author_inst":"Yale School of Medicine: Yale University School of Medicine"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"Prevalence and determinants of Skilled Birth Attendance Among Women Who Delivered in the Past 12 Months in Sene East District, Ghana: A Community-Based Cross-Sectional Study","rel_doi":"10.64898\/2026.07.22.26358729","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358729","rel_abs":"Background Skilled birth attendance is essential to reduce maternal and neonatal mortality. However, the use of skilled delivery services is still low in many rural areas of Ghana including the Sene East District. This study investigated the level and determinants of skilled birth attendance among women who delivered in the district in the last 12 months. Methods A community-based cross-sectional study was conducted among 430 women who delivered within the last 12 months. The respondents were selected from Child Welfare Clinics by simple random sampling. Data was collected using a structured questionnaire and analysed using logistic regression. Variables with p-values <0.05 at the bivariate level were included in the multivariable logistic regression model. Statistical significance was p < 0.05. Results The prevalence of skilled birth attendance among respondents was 64.9%. In a multivariable logistic regression model, women who had a previous delivery at home were less likely to deliver with skilled birth attendants during the most recent pregnancy than first-time mothers (AOR = 0.1, 95% CI: 0.02-0.41). Women who had delivered at a traditional birth attendant's (TBA) place during their previous delivery had significantly lower odds of skilled birth attendance (AOR = 0.1, 95% CI: 0.01-0.44). On the other hand, women who had previously delivered in a health facility were six times more likely to use skilled birth attendants than first-time mothers (AOR = 6.3, 95% CI: 1.32-30.7). Also, mothers living more than 10 km from the nearest health facility were 70% less likely to use skilled birth attendance than mothers living within 5 km of a health facility (AOR = 0.3, 95% CI: 0.14-0.80). Conclusion The uptake of skilled birth attendance in Sene East District is suboptimal. Enhancing access to health facilities, strengthening antenatal care services and addressing barriers to skilled delivery may improve maternal health service utilization in the district.","rel_num_authors":5,"rel_authors":[{"author_name":"Maxwell  Adjiabadek Akesem","author_inst":"Ghana Health Service"},{"author_name":"Daniel Ankomah","author_inst":"Ghana Health Service"},{"author_name":"Joseph  Kubi Appiah","author_inst":"Ghana Health Service"},{"author_name":"Elijah  Wamale Nlamba","author_inst":"Ghana Health Service"},{"author_name":"Cyprian  Issahaku Dorgbetor","author_inst":"The Chinese University of Hong Kong"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"Delay distributions limit the identifiability of rapid variations in epidemics","rel_doi":"10.64898\/2026.07.23.26358599","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358599","rel_abs":"Public-health surveillance systems rely on downstream indicators to infer latent infection incidence, but delays and observation noise provide only an indirect and temporally distorted view of the underlying epidemic process. Reconstructing upstream epidemic trajectories from these observations is therefore an ill-posed inverse problem, in which different reconstruction assumptions may produce different trajectories that remain consistent with the observed data. Here, we develop a general spectral framework that quantifies the statistical distinguishability of candidate upstream trajectories under delayed and noisy observations. We show that epidemiological delay distributions impose a frequency-dependent temporal resolution limit on epidemic surveillance, fundamentally constraining the distinguishability of rapid upstream variation. This limitation propagates to epidemiological inference, making some quantities substantially more sensitive to reconstruction assumptions than others and rendering distinct event-impact profiles difficult to distinguish from downstream observations.","rel_num_authors":3,"rel_authors":[{"author_name":"Jingjing Tang","author_inst":"Carnegie Mellon University"},{"author_name":"Bryan Wilder","author_inst":"Carnegie Mellon University"},{"author_name":"Roni Rosenfeld","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"Combined sleep, domain-specific physical activity, and nutrition in relation to all-cause mortality among US adults","rel_doi":"10.64898\/2026.07.23.26358753","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358753","rel_abs":"Background Sleep duration, physical activity, and nutrition (SPAN) are each associated with mortality risk, yet they are usually examined individually or in pairs, with limited attention to their combined associations and differences across physical activity domains. We examined combined SPAN behaviours in relation to all-cause mortality across different physical activity domains (occupational physical activity (OPA), leisure-time physical activity (LTPA) and transportational physical activity (TPA)). Methods We included adults aged 18 years or older from the National Health and Nutrition Examination Survey 2007-2018. Sleep duration was self-reported in hours\/day. Physical activity, including moderate-to-vigorous physical activity (MVPA) across domains, was assessed using the Global Physical Activity Questionnaire. Diet quality was estimated from 24-hour dietary recalls using the Healthy Eating Index-2020 (HEI-2020). We created 27 mutually exclusive joint categories using tertiles of physical activity and HEI-2020, and guideline-based sleep-duration groups (<7, 7-8, and >8 h\/day), with the lowest combination as the reference. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs for all-cause mortality. To estimate the minimum combined variations associated with lower mortality risk, we used the 5th percentile of each behaviour as the reference. Results Among 31,875 participants (median age 48.0 years; 51.4% female), 2,623 deaths occurred over a median follow-up of 6.75 years. In joint categorical analyses, a combination of optimal sleep (7-8 h\/day), high diet quality (HEI-2020: >56.0), and high LTPA (>35.4 min\/day) or high TPA (>25.7 min\/day) was associated with the lowest all-cause mortality risk (HR = 0.44, 95%CI: 0.29-0.65; HR = 0.54, 95%CI: 0.37-0.77). The lowest HR for OPA was observed for sleep duration (3.-6.5 h\/day), moderate OPA (1.4-114.0 min\/day), and high diet quality (HR = 0.53, 95%CI: 0.37-0.75). Relative to the reference values (sleep: 5 h\/day, MVPA\/PA domains: 0 min\/day and HEI-2020: 32.29), a combined minimum increment of 15 min\/day of sleep, 5 HEI-2020 points, in combination with either 10.8 min\/day of total MVPA, 24.0 min\/day of OPA, or 5.2 min\/day of LTPA, were associated with 10% lower all-cause mortality. For TPA, the 10% lower risk corresponded to 30 additional min\/day of sleep, 5 HEI-2020 points, and 5.5 min\/day of transport PA. Conclusions Modest combined increments in SPAN were associated with lower all-cause mortality among US adults across physical activity domains, with combinations including higher amounts of LTPA showing the most favourable profile.","rel_num_authors":13,"rel_authors":[{"author_name":"Qingyang Lu","author_inst":"Monash University"},{"author_name":"Nicholas A. Koemel","author_inst":"Monash University"},{"author_name":"Raaj Kishore Biswas","author_inst":"University of Sydney"},{"author_name":"Wenxin Bian","author_inst":"University of Sydney"},{"author_name":"Joshua F. Wiley","author_inst":"Monash University"},{"author_name":"Matthew P Pase","author_inst":"Monash University"},{"author_name":"Sean P.A. Drummond","author_inst":"Monash University"},{"author_name":"Patrick Oliver","author_inst":"Monash University"},{"author_name":"Margaret Allman Farinelli","author_inst":"University of Sydney"},{"author_name":"Peter A. Cistulli","author_inst":"University of Sydney"},{"author_name":"Stephen J. Simpson","author_inst":"University of Sydney"},{"author_name":"Matthew N Ahmadi","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"},{"author_name":"Emmanuel Stamatakis","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"Digital phenotyping of aortic stenosis-related remodeling reveals complementary structural, electrical, and hemodynamic signatures","rel_doi":"10.64898\/2026.07.22.26358600","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358600","rel_abs":"Aortic stenosis (AS) is a heterogeneous disease of aging characterized by valvular calcification and distinct structural, electrical, and hemodynamic remodeling that are incompletely captured by any single diagnostic measure. Here we show that three AI-derived digital biomarkers resolve AS-related remodeling into complementary structural (cine-CMR Digital AS Severity Index, DASSi), electrical (AI-ECG), and hemodynamic (phase-contrast CMR peak aortic velocity) axes. Among 68,714 UK Biobank participants, all three biomarkers were independently associated with prevalent AS and prospectively predicted aortic valve replacement. Genetic and transcriptomic analyses of the digital phenotypes revealed partially distinct, heritable architectures: peak aortic velocity aligned closely with clinical AS genetics, whereas DASSi and AI-ECG defined a shared myocardial-remodeling axis largely independent of clinical AS susceptibility. These findings support AS as a multidimensional remodeling syndrome and establish a novel digital phenotyping framework for dissecting complex cardiovascular disease into complementary, biologically informative axes.","rel_num_authors":7,"rel_authors":[{"author_name":"Wenjing Luo","author_inst":"Yale School of Medicine"},{"author_name":"Ryan B. Choi","author_inst":"Yale School of Medicine"},{"author_name":"Doris Yang","author_inst":"Yale School of Medicine"},{"author_name":"Lovedeep Singh Dhingra","author_inst":"Yale School of Medicine"},{"author_name":"Philip M. Croon","author_inst":"Yale School of Medcine"},{"author_name":"Rohan Khera","author_inst":"Yale School of Medicine"},{"author_name":"Evangelos K. Oikonomou","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"A unified 12-lead ECG-language model for interpretation and clinical-endpoint prediction","rel_doi":"10.64898\/2026.07.22.26358591","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358591","rel_abs":"Automated electrocardiogram (ECG) interpretation has advanced, yet most systems remain narrow classifiers that emit fixed labels rather than the narratives or endpoint-specific answers clinicians need. Generative approaches could instead produce rich narratives, but are constrained by the gap between continuous biosignals and discrete language tokens. Here we present DeepECG-Tok, which reframes ECG interpretation as a unified instruction-following problem. A residual vector-quantization tokenizer (QINCo) maps 12-lead waveforms to language-model-compatible tokens. Its frozen embeddings achieved a macro-averaged area under the receiver operating characteristic curve (AUROC) of 0.96 for 77-condition classification, outperforming supervised and self-supervised baselines. Aligned with a large language model, a single instruction-tuned model performed ECG interpretation, structured reporting and clinical endpoint prediction, including left ventricular ejection fraction, structural heart disease and atrial fibrillation risk, using 7.27 million question answer pairs. Endpoint classifiers using the frozen tokenizer transferred without retraining to four external cohorts, retaining AUROCs of 0.88--0.90. Evaluated end to end using an ontology-grounded large language model as a judge, which achieved a mean agreement (Cohen's K) of 0.82 against two cardiologists, the unified instruction-tuned model scored 0.71 internally and 0.50--0.53 in the same external cohorts. In a blinded reader study, board-certified cardiologists and residents rated its free-text reports comparably to reference clinician reports, with a paired win-tie-loss distribution of 32:35:33 and a forced-choice preference of 0.53 among decided cases, with no significant difference between the model and reference reports in either comparison. These findings establish discrete ECG tokenization as a foundation for general-purpose models that generate clinically useful interpretations and answer diverse questions directly from cardiac waveforms.","rel_num_authors":14,"rel_authors":[{"author_name":"Rohan Banerjee","author_inst":"Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, QC, H1T 1C8 Canada; HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada"},{"author_name":"Juliette Beaulieu","author_inst":"Universite de Montreal, Montreal, Quebec, Canada"},{"author_name":"Nicolas Dostie","author_inst":"HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada; Universit\u00e9 de Montr\u00e9al, Montreal, Quebec, Canada"},{"author_name":"Blandine Mond\u00e9sert","author_inst":"Montreal Heart Institute, Karen and Murray Dalfen arrhythmia center, Adult Congenital Heart Disease Center; Universit\u00e9 de Montr\u00e9al"},{"author_name":"Ram Ahuja","author_inst":"HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada; Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Rd, Ottawa, ON K1H 8"},{"author_name":"Alexis Nolin-Lapalme","author_inst":"HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada; Mila - Qu\u00e9bec AI Institute, Montreal, Quebec, Canada H2S 3H1; Universit\u00e9 de Montr\u00e9al, Montrea"},{"author_name":"Gilbert Jabbour","author_inst":"Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, QC, H1T 1C8 Canada; HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada"},{"author_name":"Shreya Shree Srikanth","author_inst":"Department of Computer Science, University of Toronto, 27 King's College Cir, Toronto, ON, M5S 1A1 Canada; HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1"},{"author_name":"Guillaume Marquis-Gravel","author_inst":"Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, QC, H1T 1C8 Canada; Universite de Montreal, Montreal, Quebec, Canada"},{"author_name":"Olivier Tastet","author_inst":"Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, QC, H1T 1C8 Canada; HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada"},{"author_name":"Achille Sowa","author_inst":"HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada"},{"author_name":"Julia Cadrin-Tourigny","author_inst":"Montreal Heart Institute, Karen and Murray Dalfen arrhythmia center, Cardiovascular genetics center"},{"author_name":"Jacques Delfrate","author_inst":"Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, QC, H1T 1C8 Canada; HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada"},{"author_name":"Robert Avram","author_inst":"Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, QC, H1T 1C8 Canada, HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"A unified 12-lead ECG-language model for interpretation and clinical-endpoint prediction","rel_doi":"10.64898\/2026.07.22.26358591","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358591","rel_abs":"Automated electrocardiogram (ECG) interpretation has advanced, yet most systems remain narrow classifiers that emit fixed labels rather than the narratives or endpoint-specific answers clinicians need. Generative approaches could instead produce rich narratives, but are constrained by the gap between continuous biosignals and discrete language tokens. Here we present DeepECG-Tok, which reframes ECG interpretation as a unified instruction-following problem. A residual vector-quantization tokenizer (QINCo) maps 12-lead waveforms to language-model-compatible tokens. Its frozen embeddings achieved a macro-averaged area under the receiver operating characteristic curve (AUROC) of 0.96 for 77-condition classification, outperforming supervised and self-supervised baselines. Aligned with a large language model, a single instruction-tuned model performed ECG interpretation, structured reporting and clinical endpoint prediction, including left ventricular ejection fraction, structural heart disease and atrial fibrillation risk, using 7.27 million question answer pairs. Endpoint classifiers using the frozen tokenizer transferred without retraining to four external cohorts, retaining AUROCs of 0.88--0.90. Evaluated end to end using an ontology-grounded large language model as a judge, which achieved a mean agreement (Cohen's K) of 0.82 against two cardiologists, the unified instruction-tuned model scored 0.71 internally and 0.50--0.53 in the same external cohorts. In a blinded reader study, board-certified cardiologists and residents rated its free-text reports comparably to reference clinician reports, with a paired win-tie-loss distribution of 32:35:33 and a forced-choice preference of 0.53 among decided cases, with no significant difference between the model and reference reports in either comparison. These findings establish discrete ECG tokenization as a foundation for general-purpose models that generate clinically useful interpretations and answer diverse questions directly from cardiac waveforms.","rel_num_authors":14,"rel_authors":[{"author_name":"Rohan Banerjee","author_inst":"Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, QC, H1T 1C8 Canada; HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada"},{"author_name":"Juliette Beaulieu","author_inst":"Universite de Montreal, Montreal, Quebec, Canada"},{"author_name":"Nicolas Dostie","author_inst":"HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada; Universit\u00e9 de Montr\u00e9al, Montreal, Quebec, Canada"},{"author_name":"Blandine Mond\u00e9sert","author_inst":"Montreal Heart Institute, Karen and Murray Dalfen arrhythmia center, Adult Congenital Heart Disease Center; Universit\u00e9 de Montr\u00e9al"},{"author_name":"Ram Ahuja","author_inst":"HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada; Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Rd, Ottawa, ON K1H 8"},{"author_name":"Alexis Nolin-Lapalme","author_inst":"HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada; Mila - Qu\u00e9bec AI Institute, Montreal, Quebec, Canada H2S 3H1; Universit\u00e9 de Montr\u00e9al, Montrea"},{"author_name":"Gilbert Jabbour","author_inst":"Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, QC, H1T 1C8 Canada; HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada"},{"author_name":"Shreya Shree Srikanth","author_inst":"Department of Computer Science, University of Toronto, 27 King's College Cir, Toronto, ON, M5S 1A1 Canada; HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1"},{"author_name":"Guillaume Marquis-Gravel","author_inst":"Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, QC, H1T 1C8 Canada; Universite de Montreal, Montreal, Quebec, Canada"},{"author_name":"Olivier Tastet","author_inst":"Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, QC, H1T 1C8 Canada; HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada"},{"author_name":"Achille Sowa","author_inst":"HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada"},{"author_name":"Julia Cadrin-Tourigny","author_inst":"Montreal Heart Institute, Karen and Murray Dalfen arrhythmia center, Cardiovascular genetics center"},{"author_name":"Jacques Delfrate","author_inst":"Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, QC, H1T 1C8 Canada; HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada"},{"author_name":"Robert Avram","author_inst":"Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, QC, H1T 1C8 Canada, HeartWise.ai Laboratory, 5000 Belanger Street, QC, H1T 1C8 Canada"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"AI-Enabled Echocardiography Identifies an Adverse Epicardial Adiposity Phenotype Associated with Cardiometabolic Dysfunction","rel_doi":"10.64898\/2026.07.22.26358690","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358690","rel_abs":"Background: Excess epicardial adipose tissue (EAT) is associated with cardiovascular-kidney-metabolic (CKM) dysfunction, but its assessment has traditionally required advanced imaging. We tested whether AI-enhanced echocardiography could enable scalable phenotyping of adverse epicardial adiposity and identify individuals at increased cardiometabolic risk. Methods: We developed PanAdipo, a video-based deep learning model in 1,114,441 videos from 28,797 studies across the Yale-New Haven Health System (YNHHS; 2016-2022), using expert reader annotations of prominent EAT (2.5% of studies). PanAdipo was evaluated in four cohorts: a temporally distinct YNHHS TTE set (n=4,588), an emergency department point-of-care ultrasound cohort across YNHHS (n=10,957), the geographically distinct MIMIC-IV cohort (n=4,549), and the community-based Multi-Ethnic Study of Atherosclerosis (MESA Exam 6, n=2,740). Analyses examined (i) discrimination of prominent EAT; (ii) independence from conventional echocardiographic outputs; (iii) spatial explainability using gradient-weighted class activation mapping; (iv) correspondence with paired cardiac CT-derived body composition phenotypes (n=5,594); and (v) age-, sex-, and BMI-independent associations with cardiometabolic biomarkers and incident metabolic disease. Results: In the held-out health system test set, PanAdipo discriminated prominent EAT with an AUROC of 0.91 (95% CI, 0.88-0.94), exceeding conventional measures of cardiac function and structure. In explainability analyses, the model's attention localized to the epicardial area across views and throughout the cardiac cycle. On paired cardiac CT imaging, the PanAdipo score correlated most strongly with epicardial adiposity (Spearman's rho=0.75; P<0.001) with weaker correlations with other adipose and non-adipose compartments and only modest correlations with BMI across cohorts (rho=0.19-0.40). In MESA, greater PanAdipo scores were independently associated with higher HOMA-IR and triglycerides, associations that persisted among normoglycemic participants. Higher PanAdipo scores were also associated with newly documented metabolic disease, including MASLD\/MASH, after adjustment for BMI (HRpooled 1.25 [1.08-1.44] per 1-SD increment in log[PanAdipo]). Conclusions: AI-enabled echocardiography provides a scalable, view-agnostic biomarker that characterizes adverse epicardial adiposity and is associated with cardiometabolic dysfunction, highlighting a novel role for echocardiography in CKM risk stratification.","rel_num_authors":8,"rel_authors":[{"author_name":"Arya Aminorroaya","author_inst":"Yale School of Medicine"},{"author_name":"Andreas Coppi","author_inst":"Yale School of Medcine"},{"author_name":"Robert L. McNamara","author_inst":"Yale School of Medcine"},{"author_name":"Joao A.C. Lima","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Harlan M. Krumholz","author_inst":"Yale University"},{"author_name":"Charalambos Antoniades","author_inst":"University of Oxford"},{"author_name":"Rohan Khera","author_inst":"Yale School of Medicine"},{"author_name":"Evangelos K. Oikonomou","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"AI-Enabled Echocardiography Identifies an Adverse Epicardial Adiposity Phenotype Associated with Cardiometabolic Dysfunction","rel_doi":"10.64898\/2026.07.22.26358690","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358690","rel_abs":"Background: Excess epicardial adipose tissue (EAT) is associated with cardiovascular-kidney-metabolic (CKM) dysfunction, but its assessment has traditionally required advanced imaging. We tested whether AI-enhanced echocardiography could enable scalable phenotyping of adverse epicardial adiposity and identify individuals at increased cardiometabolic risk. Methods: We developed PanAdipo, a video-based deep learning model in 1,114,441 videos from 28,797 studies across the Yale-New Haven Health System (YNHHS; 2016-2022), using expert reader annotations of prominent EAT (2.5% of studies). PanAdipo was evaluated in four cohorts: a temporally distinct YNHHS TTE set (n=4,588), an emergency department point-of-care ultrasound cohort across YNHHS (n=10,957), the geographically distinct MIMIC-IV cohort (n=4,549), and the community-based Multi-Ethnic Study of Atherosclerosis (MESA Exam 6, n=2,740). Analyses examined (i) discrimination of prominent EAT; (ii) independence from conventional echocardiographic outputs; (iii) spatial explainability using gradient-weighted class activation mapping; (iv) correspondence with paired cardiac CT-derived body composition phenotypes (n=5,594); and (v) age-, sex-, and BMI-independent associations with cardiometabolic biomarkers and incident metabolic disease. Results: In the held-out health system test set, PanAdipo discriminated prominent EAT with an AUROC of 0.91 (95% CI, 0.88-0.94), exceeding conventional measures of cardiac function and structure. In explainability analyses, the model's attention localized to the epicardial area across views and throughout the cardiac cycle. On paired cardiac CT imaging, the PanAdipo score correlated most strongly with epicardial adiposity (Spearman's rho=0.75; P<0.001) with weaker correlations with other adipose and non-adipose compartments and only modest correlations with BMI across cohorts (rho=0.19-0.40). In MESA, greater PanAdipo scores were independently associated with higher HOMA-IR and triglycerides, associations that persisted among normoglycemic participants. Higher PanAdipo scores were also associated with newly documented metabolic disease, including MASLD\/MASH, after adjustment for BMI (HRpooled 1.25 [1.08-1.44] per 1-SD increment in log[PanAdipo]). Conclusions: AI-enabled echocardiography provides a scalable, view-agnostic biomarker that characterizes adverse epicardial adiposity and is associated with cardiometabolic dysfunction, highlighting a novel role for echocardiography in CKM risk stratification.","rel_num_authors":8,"rel_authors":[{"author_name":"Arya Aminorroaya","author_inst":"Yale School of Medicine"},{"author_name":"Andreas Coppi","author_inst":"Yale School of Medcine"},{"author_name":"Robert L. McNamara","author_inst":"Yale School of Medcine"},{"author_name":"Joao A.C. Lima","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Harlan M. Krumholz","author_inst":"Yale University"},{"author_name":"Charalambos Antoniades","author_inst":"University of Oxford"},{"author_name":"Rohan Khera","author_inst":"Yale School of Medicine"},{"author_name":"Evangelos K. Oikonomou","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-24","rel_site":"medrxiv"},{"rel_title":"EXCAVATE-HT: A Bioinformatic Pipeline to Identify Targetable Genomic Variants for Allele-Specific Editing","rel_doi":"10.64898\/2026.07.23.739930","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.23.739930","rel_abs":"Allele-specific CRISPR\/Cas editing is a powerful tool with great potential for treating genetic diseases and for uncovering the effects of allelic diversity. By targeting commonly inherited single nucleotide polymorphisms (SNPs), a small number of gRNAs can treat many more individuals than targeting rare disease mutations. However, current tools for identifying common targetable variants and generating CRISPR guide RNAs (gRNA) have fundamental conceptual and technical limitations. Here, we introduce EXCAVATE-HT (EXtracting Common Allelic VAriants for Targeted Editing in High-Throughput) a bioinformatic tool that mines population variant data to generate CRISPR libraries targeting genomic loci for allele-specific editing. Users define their loci of interest, Cas species, and SNP frequency, then EXCAVATE-HT outputs an annotated list of allele-specific gRNAs. EXCAVATE-HT can also generate libraries of gRNA pairs to enable excision. We illustrate the use of EXCAVATE-HT to design and characterize multiple gRNA libraries for allele-specific targeting of the disease gene, Cone-Rod Homeobox (CRX). EXCAVATE-HT revealed multiple excisions that could treat >30-fold more patients than targeting a single CRX disease mutation.","rel_num_authors":5,"rel_authors":[{"author_name":"Akshita G Saxena","author_inst":"University of California, San Francisco"},{"author_name":"Grace D Ramey","author_inst":"University of California, San Francisco"},{"author_name":"John A Capra","author_inst":"University of California, San Francisco"},{"author_name":"Bruce R Conklin","author_inst":"Gladstone Institutes"},{"author_name":"Bria L Macklin","author_inst":"Gladstone Institutes"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"The Barcode Inference Pipeline (BIP): From Sequencer Output to DNA Barcodes","rel_doi":"10.64898\/2026.07.21.739876","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739876","rel_abs":"DNA barcoding involves the recovery of a DNA sequence for a target gene region from its source specimen. This process gains complexity when multiple sequences are recovered from a specimen, as is often the case when data are generated by high-throughput sequencers. This diversity can reflect both methodological artifacts (e.g., chimeras, PCR errors, sequencing errors, tag jumps) and real template diversity in the DNA extract (e.g., contamination, endosymbionts, NUMTs, parasites). To support analysis of the sequence data from three million specimens annually, the Centre for Biodiversity Genomics (CBG) has developed BIP, the Barcode Inference Pipeline. Compatible with all sequencing platforms, BIP processes .fastq files and returns both target DNA barcodes and non-target sequences. To generate results, BIP implements quality and size filtration, demultiplexing, primer trimming, chimera scanning, sequence error correction, OTU delineation, and sequence identification. When analysis targets the cytochrome c oxidase 1 (COI) barcode region, BIP also assigns each OTU to a known BIN or identifies its nearest neighbour BIN. As final output, BIP returns summary files ready for upload to BOLD or for other downstream analyses. They include a taxonomic assignment for each OTU, generated by comparison with a DNA barcode reference library. We describe BIP's flexibility and structure, then demonstrate its functionality by analyzing COI sequence data from 100K specimens. Because of its capacity to disentangle target and non-target sequences, BIP outperforms an alternative software package, ONTbarcoder, in several important ways. To ease access, installation, and functionality, BIP is provided as a Docker container (github.com\/cbg-innov\/BIP).","rel_num_authors":6,"rel_authors":[{"author_name":"Sean WJ Prosser","author_inst":"Centre for Biodiversity Genomics, University of Guelph"},{"author_name":"Ken A Thompson","author_inst":"Centre for Biodiversity Genomics, University of Guelph"},{"author_name":"Nicholas W Bard","author_inst":"Centre for Biodiversity Genomics, University of Guelph"},{"author_name":"Robin A Floyd","author_inst":"Centre for Biodiversity Genomics, University of Guelph"},{"author_name":"Emine Ozsahin","author_inst":"Centre for Biodiversity Genomics, University of Guelph"},{"author_name":"Paul D. N. Hebert","author_inst":"Centre for Biodiversity Genomics, University of Guelph"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"Pathogenic MAPK8IP3 variants drive distinct motor and behavioral phenotypes in humans and mice","rel_doi":"10.64898\/2026.07.20.739682","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739682","rel_abs":"Pathogenic variants in MAPK8IP3 (JIP3) cause Neurodevelopmental Disorder with or without variable Brain Abnormalities (NEDBA), characterized by cognitive impairment, global developmental delay, motor dysfunction, abnormal muscle tone, behavioral dysregulation including autism and attention deficit hyperactivity disorder (ADHD), seizures, and structural brain abnormalities. While more than 30 largely de novo MAPK8IP3 variants have been reported, the functional impact of variants across JIP3 protein structural domains is poorly defined. To address this knowledge gap, we compare clinical features of individuals with a truncating (p.E27X) or one of two missense (p.R578C and p.R1146C) variants from distinct JIP3 functional protein domains to corresponding knock-in mouse models. Our findings showed that all individuals, regardless of variant type, exhibited delays in language and gross motor function, but individual variants were associated with distinct motor, cognitive, and psychiatric symptoms. Corresponding homozygous p.E27X and p.R1147C variant mice resulted in embryonic lethality, consistent with essential roles for JIP3 in early neurodevelopment. Behavioral characterization of viable heterozygous mice revealed variant-specific locomotor, motor coordination, and hindlimb clasping defects that closely recapitulate clinical observations. Heterozygous p.R579C mice exhibited reduced locomotion, impaired motor performance, and hypertonia-like clasping, mirroring human motor deficits. In contrast, p.R1147C mice displayed hyperactivity, hindlimb clasping, and decreased brain weight, paralleling human clinical features. Together, our findings demonstrate that while distinct MAPK8IP3 variants lead to some shared phenotypes, they are also associated with distinct phenotypes that could reveal domain-specific aspects of JIP3 function. This work establishes the first domain-resolved in vivo rodent models of NEDBA and provides a validated translational platform for mechanistic investigation and preclinical therapeutic testing.","rel_num_authors":12,"rel_authors":[{"author_name":"Camerron M Crowder","author_inst":"University of Alabama at Birmingham"},{"author_name":"Lyndsay R Watkins","author_inst":"Mayo Clinic"},{"author_name":"Alexa Geltzeiler","author_inst":"Boston Children's Hospital and Harvard Medical School"},{"author_name":"Priya Patel","author_inst":"University of Illinois at Chicago"},{"author_name":"Judit Ortiz-Perez","author_inst":"Mayo Clinic"},{"author_name":"Danielle Schmidt","author_inst":"Mayo Clinic"},{"author_name":"Christopher Schmitz","author_inst":"Mayo Clinic"},{"author_name":"Jalen Aguilar","author_inst":"University of Illinois at Chicago"},{"author_name":"Shraddha Ghanta","author_inst":"University of Illinois at Chicago"},{"author_name":"Swetha Gowrishankar","author_inst":"University of Illinois at Chicago"},{"author_name":"Wendy K Chung","author_inst":"Boston Children's Hospital and Harvard Medical School"},{"author_name":"Laura Lambert","author_inst":"Mayo Clinic"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"Sub-endothelial platelet activation amplifies neutrophil transmigration within venular walls","rel_doi":"10.64898\/2026.07.21.739803","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739803","rel_abs":"Neutrophil recruitment into inflamed tissues requires coordinated transmigration across the multilayered venular wall, yet how this process is regulated beyond the endothelium remains poorly understood. Here, we identify a previously unrecognized platelet-neutrophil circuit that controls this post-endothelial phase. Intravital microscopy of inflamed cremasteric venules showed that pioneer neutrophil transmigration enabled platelet entry into the sub-endothelial compartment of venular walls. There, platelets became activated and released CXCL7 in a GPVI- and GPIb-dependent manner, generating spatially confined chemokine microdomains. These platelet-derived cues directed follower neutrophil migration and promoted their exit across the pericyte layer into the interstitial tissue. Collectively, these findings identify extraluminal platelets as spatial organizers of neutrophil trafficking and uncover a localized intramural feedback mechanism in which neutrophils amplify their own recruitment within venular walls.\n\nGraphical summary\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC=\"FIGDIR\/small\/739803v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (24K):\norg.highwire.dtl.DTLVardef@18c4d82org.highwire.dtl.DTLVardef@349cdborg.highwire.dtl.DTLVardef@260590org.highwire.dtl.DTLVardef@373103_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":11,"rel_authors":[{"author_name":"Tugce Cimen","author_inst":"Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"},{"author_name":"Marilia Fernandes Manchope","author_inst":"Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"},{"author_name":"Luisa Klinkenberg","author_inst":"Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"},{"author_name":"Vanessa Goeb","author_inst":"Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"},{"author_name":"Beatriz Hoffmann Salles Bianchini","author_inst":"Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"},{"author_name":"Natalia Reglero-Real","author_inst":"Universidad Autonoma de Madrid, Madrid, Spain"},{"author_name":"Wolfgang Kastenmueller","author_inst":"Institute of Systems Immunology, Julius-Maximilians-University of Wuerzburg, Wuerzburg, Germany"},{"author_name":"Ronen Alon","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Bernhard Nieswandt","author_inst":"Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"},{"author_name":"David Stegner","author_inst":"Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"},{"author_name":"Tamara Girbl-Huemer","author_inst":"Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"Intergenerational epigenetic signatures of prenatal adversity and their role in emerging child psychopathology","rel_doi":"10.64898\/2026.07.20.739628","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739628","rel_abs":"Background: Adversity during pregnancy is associated with alterations in offspring brain development. DNA methylation (DNAm) is a type of epigenetic modification is a putative mechanism for the intergenerational transfer of prenatal adversity on developmental outcomes. We examined the effects of prenatal social disadvantage (PSD) and prenatal psychosocial stress (PSS) on offspring epigenome-wide DNAm at four time points from infancy to age 4, and tested whether persistent DNAm signals mediated associations between PSD, PSS, and child psychopathology at ages 4-6. Methods: Longitudinal DNAm data (birth, Y1, Y2, Y3) was derived from salivary tissue of 281 infants (43.7% female) in the eLABE study. We examined epigenome-wide associations between DNAm and PSD and PSS. Linear models were adjusted for age, child sex, child race, maternal tobacco smoking, cell type composition, and batch effects. Mediation analyses tested whether birth DNAm mediated associations between prenatal exposures and internalizing and externalizing symptoms at ages 4-6. Results: PSD was associated with 47 FDR-significant CpGs at birth and 3 at year 1. PSS was associated with 3 FDR-significant CpGs at birth. Thirteen CpGs showed PSD-associated significance across all four timepoints, including two CpGs associated with genes involved with neuronal maturation (BCL11B) and one CpG associated with a gene implicated in brain vascular health (ZNF474). Exploratory mediation analyses revealed an indirect effect of methylation at ZNF474 (cg19980369; p=0.028; pFDR=0.360) on the association between PSD and year 4-6 externalizing symptoms. Conclusions: PSD was associated with epigenetic signatures at birth, with a subset of associations persisting across early childhood and converging on cellular stress response biology. PSS showed minimal epigenetic associations, suggesting differential biological embedding of structural versus psychological dimensions of adversity.","rel_num_authors":11,"rel_authors":[{"author_name":"Anna Constantino-Pettit","author_inst":"Washington University in St. Louis"},{"author_name":"Alexandre Lussier","author_inst":"Massachusetts General Hospital"},{"author_name":"Mia Ruppel","author_inst":"Washington University in St. Louis"},{"author_name":"Erin Dunn","author_inst":"Purdue University"},{"author_name":"Darina Czamara","author_inst":"Max-Planck-Institute of Psychiatry"},{"author_name":"Tara Smyser","author_inst":"Washington University in St. Louis"},{"author_name":"Ryan Bogdan","author_inst":"Washington University in St. Louis"},{"author_name":"Barbara Warner","author_inst":"Washington University in St. Louis"},{"author_name":"Christopher Smyser","author_inst":"Washington University in St. Louis"},{"author_name":"Cynthia Rogers","author_inst":"Washington University in St. Louis"},{"author_name":"Joan Luby","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"Beyond Expression Prediction: Benchmarking Differential Expression Classification in Single-Cell Perturbation Models","rel_doi":"10.64898\/2026.07.20.739620","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739620","rel_abs":"Accurate predictions of transcriptomic responses to genetic perturbations could unlock our understanding of gene functions and regulatory networks. While a growing number of methods and benchmarks target this task, existing evaluations focus on mean expression accuracy alone. This overlooks differential expression (DE), which captures both mean and variance and forms the basis for biological interpretation and experimental follow-up. Here, we systematically evaluate a diverse set of deep learning and non-deep-learning methods for their ability to predict DE outcomes under two generalization regimes: unseen perturbations within the same cell line, and unseen cellular contexts across cell lines. We find that simple baselines, such as embedding-based nearest neighbors, are competitive and often outperform specialized deep learning models for DE classification across datasets and evaluation metrics. We further show that sparsity calibration, motivated by the structure of single-cell data, substantially improves DE classification for deep learning models that do not explicitly account for sparsity. Together, our findings establish practical baselines and evaluation principles for benchmarking perturbation models on DE prediction.","rel_num_authors":4,"rel_authors":[{"author_name":"Junwei Sun","author_inst":"Johns Hopkins University"},{"author_name":"Yuxun He","author_inst":"Johns Hopkins University"},{"author_name":"Ouyang Zhu","author_inst":"University of Notre Dame"},{"author_name":"Yiqun T. Chen","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"BioGeoSyn: a graphical software for reproducible biogeographic analyses and cross-clade synthesis of biogeographic events","rel_doi":"10.64898\/2026.07.21.739740","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739740","rel_abs":"1. Historical biogeography increasingly looks beyond one clade at a time, pooling range-evolution and speciation events from lineages that share a region to ask whether the same geological and climatic events shaped them together. Despite the momentum behind this cross-clade synthesis, it still has no dedicated software. 2. We present BioGeoSyn, an open-source graphical application (with an equivalent scripting interface) that makes a complete, reproducible BioGeoBEARS analysis point-and-click: guided data upload and validation, model fitting and comparison, biogeographic stochastic mapping (BSM), and standardized tables, publication figures and a report. 3. Its one novel capability is cross-clade synthesis. Once every clade's events carry the same seven process labels and sit on a common time axis, BioGeoSyn integrates event rates through time, overall and region-resolved, across independently analysed clades, each carrying a 95% interval propagated from the stochastic maps, to reveal shared biogeographic pulses. 4. BioGeoSyn lowers the barrier to reproducible historical biogeography for non-programmers and provides a ready-to-use route to multi-clade biogeographic-event synthesis.","rel_num_authors":2,"rel_authors":[{"author_name":"Wei Xu Sr.","author_inst":"Tel Aviv University"},{"author_name":"Yun-He Wu Sr.","author_inst":"Nanjing Normal University"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"Age-Related Changes in the Neural Dynamics of Speech Production Following Noninvasive Brain Stimulation","rel_doi":"10.64898\/2026.07.20.739631","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739631","rel_abs":"Non-nvasive brain stimulation is a promising technique to restore neural function in older adults by enhancing cortical excitability. In the present study, we examined the behavioral and neural effects of three stimulation protocols over the supplementary motor area on speech production in older adults. These protocols included fixed-frequency and personalized high-definition transcranial alternating current stimulation (HDtACS) and high-definition transcranial random noise stimulation (HDtRNS). We also compared the effects of personalized HDtACS and tRNS between younger and older adults. Two groups, older adults (mean age: 69 y) and younger adults (mean age: 19.87), participated in this study. Older adults attended a four-session experiment including sham, fixed-frequency beta-HD-tACS (17 Hz), personalized beta-HDtACS, and HDtRNS. Younger participants also followed a similar study design but without fixed-frequency beta-HD-tACS. Following 25 minutes of stimulation, participants were asked to complete a speech production task while their EEG activity was recorded. Both personalized tACS and tRNS significantly reduced reaction times compared to sham in younger and older adults. In older adults, personalized tACS and tRNS both effectively modulated speech motor network but exhibited distinct spatial profile. While personalized tACS produced more focal modulation, tRNS elicited broader modulation across distributed neural networks and engaged multiple oscillatory frequencies. Broadband and personalized stimulation approaches (personalized tACS and tRNS) were more effective than fixed-frequency beta-tACS in modulating behavioral and neural responses measured throughout a distributed speech-motor network in older adults.","rel_num_authors":3,"rel_authors":[{"author_name":"Fatemeh Tabari","author_inst":"Louisiana State University"},{"author_name":"Joel I Berger","author_inst":"University of Iowa"},{"author_name":"Karim Johari","author_inst":"Louisiana State University"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"CNVeil resolves haplotype-specific copy number and uncovers subclonal architecture hidden from total copy number profiling in single-cell cancergenomes","rel_doi":"10.64898\/2026.07.20.739667","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739667","rel_abs":"Single-cell DNA sequencing (scDNA-seq) resolves copy number variation (CNV) at single-cell resolution, revealing tumor heterogeneity and subclonal structure. Most existing methods, however, infer only total copy number. Haplotype-resolved copy number, which captures allelic imbalance and clonal evolution, remains far less developed, largely because low coverage, allelic dropout, and technical noise in scDNA-seq make phased allelic inference substantially harder than total copy number estimation. We present CNVeil, a haplotype-aware framework that infers total, allele-specific, and chromosome-scale haplotype-resolved copy number from scDNA-seq data. CNVeil first builds robust total copy number profiles through highly variable bin selection, hierarchical clustering, subclone-aware ploidy estimation, and cross-cell consensus segmentation. Using this profile as a stable scaffold, it infers allele-specific copy number with an expectation-maximization algorithm applied to heterozygous SNP allele counts, then reconstructs haplotype-specific copy number by enforcing coherent haplotype orientation across adjacent segments via dynamic programming. We benchmarked CNVeil against 12 state-of-the-art methods, including eight total copy number callers, two allele-specific callers, and two haplotype-resolved callers, across 20 simulated and real datasets spanning six experimental settings, including high-multiplexed single-nucleus sequencing, Acoustic Cell Tagmentation (ACT), and 10x Chromium. This constitutes the largest comparative evaluation of single-cell copy number inference methods to date. CNVeil consistently outperformed existing tools in segmentation accuracy, ploidy inference, subclone identification, and allele-specific copy number estimation. In a breast cancer multi-omics (wellDR-seq) cohort, CNVeil uncovered haplotype-specific subclonal diversification invisible to total copy number analysis alone and linked allele-specific copy number states to transcriptional variation. By transforming sparse single-cell allelic signals into chromosome-scale haplotype-resolved profiles, CNVeil closes a major methodological gap and provides a scalable framework for studying tumor evolution and functional genomic heterogeneity at single-cell resolution.","rel_num_authors":8,"rel_authors":[{"author_name":"Weiman Yuan","author_inst":"Department of Biomedical Engineering, Vanderbilt University"},{"author_name":"Can Luo","author_inst":"Department of Biomedical Engineering, Vanderbilt University"},{"author_name":"Yunfei Hu","author_inst":"Department of Computer Science, Vanderbilt University"},{"author_name":"Liting Zhang","author_inst":"Department of Computer Science, Florida State University"},{"author_name":"Zihang Wen","author_inst":"Carnegie Mellon University"},{"author_name":"Yichen Henry Liu","author_inst":"Department of Computer Science, Vanderbilt University"},{"author_name":"Xian Mallory Fan","author_inst":"Department of Computer Science, Florida State University"},{"author_name":"Xin Maizie Zhou","author_inst":"Vanderbilt university"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"CNVeil resolves haplotype-specific copy number and uncovers subclonal architecture hidden from total copy number profiling in single-cell cancergenomes","rel_doi":"10.64898\/2026.07.20.739667","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739667","rel_abs":"Single-cell DNA sequencing (scDNA-seq) resolves copy number variation (CNV) at single-cell resolution, revealing tumor heterogeneity and subclonal structure. Most existing methods, however, infer only total copy number. Haplotype-resolved copy number, which captures allelic imbalance and clonal evolution, remains far less developed, largely because low coverage, allelic dropout, and technical noise in scDNA-seq make phased allelic inference substantially harder than total copy number estimation. We present CNVeil, a haplotype-aware framework that infers total, allele-specific, and chromosome-scale haplotype-resolved copy number from scDNA-seq data. CNVeil first builds robust total copy number profiles through highly variable bin selection, hierarchical clustering, subclone-aware ploidy estimation, and cross-cell consensus segmentation. Using this profile as a stable scaffold, it infers allele-specific copy number with an expectation-maximization algorithm applied to heterozygous SNP allele counts, then reconstructs haplotype-specific copy number by enforcing coherent haplotype orientation across adjacent segments via dynamic programming. We benchmarked CNVeil against 12 state-of-the-art methods, including eight total copy number callers, two allele-specific callers, and two haplotype-resolved callers, across 20 simulated and real datasets spanning six experimental settings, including high-multiplexed single-nucleus sequencing, Acoustic Cell Tagmentation (ACT), and 10x Chromium. This constitutes the largest comparative evaluation of single-cell copy number inference methods to date. CNVeil consistently outperformed existing tools in segmentation accuracy, ploidy inference, subclone identification, and allele-specific copy number estimation. In a breast cancer multi-omics (wellDR-seq) cohort, CNVeil uncovered haplotype-specific subclonal diversification invisible to total copy number analysis alone and linked allele-specific copy number states to transcriptional variation. By transforming sparse single-cell allelic signals into chromosome-scale haplotype-resolved profiles, CNVeil closes a major methodological gap and provides a scalable framework for studying tumor evolution and functional genomic heterogeneity at single-cell resolution.","rel_num_authors":8,"rel_authors":[{"author_name":"Weiman Yuan","author_inst":"Department of Biomedical Engineering, Vanderbilt University"},{"author_name":"Can Luo","author_inst":"Department of Biomedical Engineering, Vanderbilt University"},{"author_name":"Yunfei Hu","author_inst":"Department of Computer Science, Vanderbilt University"},{"author_name":"Liting Zhang","author_inst":"Department of Computer Science, Florida State University"},{"author_name":"Zihang Wen","author_inst":"Carnegie Mellon University"},{"author_name":"Yichen Henry Liu","author_inst":"Department of Computer Science, Vanderbilt University"},{"author_name":"Xian Mallory Fan","author_inst":"Department of Computer Science, Florida State University"},{"author_name":"Xin Maizie Zhou","author_inst":"Vanderbilt university"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"Wrong but useful: Bombyx silkworm W chromosome assemblies are flawed but still capture strongly reduced diversity of repetitive DNA","rel_doi":"10.64898\/2026.07.21.739781","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739781","rel_abs":"Degenerate sex chromosomes (e.g., the Y or W) remain among the most difficult regions of eukaryotic genomes to assemble because they are highly repetitive and structurally complex. While many recent lepidopteran genome assemblies contain W chromosome scaffolds, the accuracy and consistency of these assemblies remain uncertain, due to lack of replication within species. However, the silkworm moth Bombyx mori is an exception, with numerous independent W chromosome assemblies currently available. We compared six independent long-read W chromosome assemblies, which proved to be highly inconsistent in structure, even among nominally identical genotypes. In contrast, autosomes and the Z chromosome were highly concordant among these assemblies, indicating that current assemblies remain unreliable for resolving W chromosome structure. Additionally, we analyzed repetitive DNA content across the genome. First, we combined assembly- and read-based repeat-discovery methods to generate a comprehensive and curated Bombyx repeat library, which we make publicly available. Assessing repeat content and diversity, we find that the W chromosome is comprised almost entirely of repetitive DNA but that the richness and divergence of W repeats are substantially reduced compared to the remainder of the genome. This reduced diversity, initially inferred from assemblies, is confirmed by direct analysis of PacBio HiFi sequencing reads partitioned by chromosome. We also demonstrate that the B. mori p50ma genome assembly (the current NCBI RefSeq assembly) carries a W chromosome and mitochondrial genome introgressed from B. mandarina. This discovery provided an opportunity to investigate patterns of divergence between closely related W haplotypes, revealing substantially more rapid turnover of repeat content on the W than elsewhere in the genome. Together, our results show that current W chromosome assemblies, although structurally flawed, nevertheless capture robust biological patterns of repeat diversity and support the hypothesis that rapid repeat turnover, rather than frequent chromosome replacement, may underlie the apparent lack of W chromosome homology across Lepidoptera.","rel_num_authors":2,"rel_authors":[{"author_name":"Martina Dalikova","author_inst":"University of South Bohemia Faculty of Science: Jihoceska Univerzita v Ceskych Budejovicich Prirodovedecka Fakulta"},{"author_name":"James Richmond Walters","author_inst":"University of Kansas"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"Surface architecture of the bacterial envelope determines phage adsorption route in pathogenic Escherichia coli O157:H7","rel_doi":"10.64898\/2026.07.23.740414","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.23.740414","rel_abs":"The outermost surface layers of Gram-negative bacteria determine phage access to terminal receptors, yet their genetic basis has been mapped almost exclusively in laboratory strains that lack them. Here we apply genome-wide RB-TnSeq fitness profiling to four Escherichia coli O157:H7 strains from distinct phylogenetic clades sharing the O157 O-antigen, using 38 phages with terminal receptors previously mapped in E. coli K-12 strain. RB-TnSeq fitness landscapes across all four pathogenic backgrounds were mostly similar, and dominated by surface-associated loci, including the gfc-etk group 4 capsule operon, O-antigen biosynthesis genes, LPS core assembly genes and outer membrane proteins. Disruption of gfc-etk abolished infection in 11 genetically diverse myoviruses, establishing the O-antigen capsule as a widespread required primary recognition substrate. O-antigen loci generated two classes of fitness score patterns. For 10 phages, disruption increased infectivity, indicating it is a barrier to receptor access; for 3 others, disruption abolished infectivity, demonstrating it can also be a primary recognition substrate. Outer membrane protein receptor identity was conserved across laboratory and pathogenic backgrounds, with the same proteins recognized in both K-12 and O157:H7, while glycan layer state determines whether these receptors are reached. These results demonstrate that outer surface glycan layers can act as primary and optional recognition substrates for phage infection, or as physical barriers preventing terminal receptor access. Extending the ability to probe phage-targeted receptors beyond outer membrane proteins provides a framework for incorporating glycan layer state into predictive models of phage-host interactions.","rel_num_authors":12,"rel_authors":[{"author_name":"Edwin Omar Rivera-Lopez","author_inst":"Department of Food Science, The Pennsylvania State University, University Park, Pennsylvania, USA"},{"author_name":"Lucas Moriniere","author_inst":"University of California Berkeley"},{"author_name":"Alexey Kazakov","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Denish Piya","author_inst":"Lawrence Berkeley National Lab, Berkeley, CA, USA"},{"author_name":"Melina Pena","author_inst":"California Institute for Quantitative Biosciences, University of California Berkeley, CA, USA"},{"author_name":"Benjamin Weinberg","author_inst":"Lawrence Berkeley National Lab, Berkeley, CA, USA"},{"author_name":"Jie Feng","author_inst":"Department of Food Science, The Pennsylvania State University, University Park, Pennsylvania, USA"},{"author_name":"Avery J.C. Noonan","author_inst":"Environmental Genomics & Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA"},{"author_name":"Adam Deutschbauer","author_inst":"Environmental Genomics & Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA"},{"author_name":"Adam P. Arkin","author_inst":"California Institute for Quantitative Biosciences, University of California Berkeley, CA, USA"},{"author_name":"Vivek K Mutalik","author_inst":"Environmental Genomics & Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA"},{"author_name":"Edward G. Dudley","author_inst":"E. coli Reference Center, The Pennsylvania State University, University Park, Pennsylvania, USA"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"SIRT1 remodels astrocyte metabolism and promotes viral replication during neurotropic orthoflavivirus infection","rel_doi":"10.64898\/2026.07.23.740149","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.23.740149","rel_abs":"Orthoflaviviruses depend on host metabolic resources to replicate, but how distinct cell types in the central nervous system (CNS) alter their metabolism in response to infection remains incompletely understood. Here, we examined whether the NAD+-dependent deacetylase SIRT1 is engaged during Zika virus (ZIKV) and West Nile virus (WNV) infection and whether its activity influences infection outcomes. SIRT1 activity increased in astrocytes isolated from infected mouse brains and in infected primary human astrocytes, but not in neurons or CNS myeloid cells. In astrocytes, infection induced transcriptomic, metabolomic, and functional changes consistent with SIRT1 activation, enhanced NAD+ salvage, and enhanced oxidative metabolism. Pharmacologic inhibition of SIRT1 or NAD+ salvage reduced ZIKV replication in astrocytes, whereas SIRT1 activation or supplementation with an NAD+ precursor increased replication. In mice, SIRT1 inhibition or nicotinamide (NAM) treatment reduced viral burden and mortality following ZIKV and WNV infection, while SIRT1 activation worsened disease. Together, these findings identify NAD+\/SIRT1 as key regulators of cellular metabolism in infected astrocytes and support a role for this pathway in promoting orthoflavivirus replication and pathogenesis.","rel_num_authors":5,"rel_authors":[{"author_name":"Juan P Angel","author_inst":"Rutgers University"},{"author_name":"Diego Alzate","author_inst":"Rutgers University"},{"author_name":"Marissa Lindman","author_inst":"Rutgers University"},{"author_name":"Colm Atkins","author_inst":"Rutgers University"},{"author_name":"Brian P Daniels","author_inst":"Rutgers University"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"Histological assessment of integrated human cortical organoid grafts after controlled cortical impact","rel_doi":"10.64898\/2026.07.20.739683","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739683","rel_abs":"Rodent models are a mainstay of traumatic brain injury (TBI) research, including investigations into the pathophysiology and treatment of this condition. However, there are fundamental molecular and cellular differences between rodent and human neurons, as well as other cells of the brain. Brain organoids derived from human pluripotent stem cells recapitulate key features of the human brain and have been used to model a variety of neurological disorders. Here, we developed a novel in vivo model of human TBI based on controlled cortical impact (CCI) injuries of human organoid grafts transplanted into the brains of young adult rats. Cortical organoids derived from human induced pluripotent stem cells (iPSCs) were grown for 50-60 days in vitro before transplantation into rat visual cortex. Injures were performed 2 months later, and histological outcomes were examined at 7 or 30 days after injury. Injury cavities in the integrated grafts were identified at both endpoints with a progression toward larger cavities sizes with time. The injured human tissue exhibited evidence of neuroinflammation with elevated numbers of IBA1+ cells and axonal injury with APP+ cells. There was evidence of increased cell proliferation in the injured grafts acutely after injury that decreased with time. The injured grafts also showed evidence of phosphorylated tau aggregates and accumulation of PNAG, a polysaccharide associated with microbial pathogens. These results support the feasibility of using human organoid grafts in rats as a model of TBI, potentially including the study of long-term neurodegeneration and microbial penetration of the brain after injury.","rel_num_authors":14,"rel_authors":[{"author_name":"Caitlyn Smith","author_inst":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Sarah Hamimi","author_inst":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Mackenzie Castellanos","author_inst":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Emma S Noel","author_inst":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Ana Paulina Serrano","author_inst":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Said Inaltekin","author_inst":"The University of Texas at Dallas, 800 W. Campbell Road, Richardson, TX 75080-3021"},{"author_name":"Nirvaa Shah","author_inst":"Bryn Mawr College, Department of Biology, 101 N Merion Ave, Bryn Mawr, PA 19010"},{"author_name":"William A Perez","author_inst":"Vanderbilt University, 2201 West End Ave, Nashville, TN 37235"},{"author_name":"Frank J Rauscher","author_inst":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Jaeha Kim","author_inst":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Hailong Song","author_inst":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Victoria E Johnson","author_inst":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Han-Chiao Isaac Chen","author_inst":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Dennis Jgamadze","author_inst":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"Graph in Graph (GiG): A novel graph AI framework for integrating and interpreting whole-person healthmedical and omics data","rel_doi":"10.64898\/2026.07.20.739657","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739657","rel_abs":"Medical records and omics data are rapidly becoming standard in healthcare settings, which characterize the whole-person from dysfunctional molecules to phenotypes, and thus offer potential for precise disease diagnosis and target discovery. Whereas, it remains an open problem to systematically integrate and interprete medical record and omics data of individual patients. In this study, for the first time, we propose a novel graph AI model framework, Graph in Graph (GiG), to integrate and interpret the whole-person medical and omic datasets. Specifically, the medical record data is modeled using a person-phenotype graph, followed by omics signaling graphs of invidival patients, which enables the integration of information learned from omic-signaling graph and medical phenotype features to characterize individual patients and to prioritize important omic biomarkers and phenotypes. As an exploratory study, we applied and evaluated the GiG model to study the type 2 diabetes (T2D) and pre-T2D vs healthy using the Long Life Family Study (LLFS) cohort, which enrolls families with exceptional longevity to uncover biological mechanisms of healthy aging with medical and omics data. The evaluation results showed that GiG not only achieve a high prediction but also can interpret the prediction by ranking the essential clinical and omic biomarkers. The GiG framework can be applied to other studies by effectively integrating and interpreting medical and omic datasets for disease diagnosis and pathogenesis discovery.","rel_num_authors":10,"rel_authors":[{"author_name":"Heming Zhang","author_inst":"Institute for Informatics, Data Science and Biostatistics (I2DB), Washington University in St Louis"},{"author_name":"Yifei Lu","author_inst":"Institute for Informatics, Data Science and Biostatistics (I2DB), Washington University in St Louis"},{"author_name":"Kaiwen Fang","author_inst":"Institute for Informatics, Data Science and Biostatistics (I2DB), Washington University in St Louis"},{"author_name":"ZIXI XU","author_inst":"Institute for Informatics, Data Science and Biostatistics (I2DB), Washington University in St Louis"},{"author_name":"Vaha Akbary Moghaddam","author_inst":"Division of Statistical Genomics, Department of Genetics, Washington University in St. Louis"},{"author_name":"Ping An","author_inst":"Division of Statistical Genomics, Department of Genetics, Washington University in St. Louis"},{"author_name":"Shiow Jin","author_inst":"Division of Statistical Genomics, Department of Genetics, Washington University in St. Louis"},{"author_name":"Mary Wojczynski","author_inst":"Division of Statistical Genomics, Department of Genetics, Washington University in St. Louis"},{"author_name":"Michael Province","author_inst":"Division of Statistical Genomics, Department of Genetics, Washington University in St. Louis"},{"author_name":"Fuhai Li","author_inst":"Institute for Informatics, Data Science and Biostatistics (I2DB), Washington University in St Louis"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"FusedFCR: A Fused Forward Continuation-Ratio model for marker selection along cell-fate trajectories","rel_doi":"10.64898\/2026.07.20.739649","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739649","rel_abs":"Time-course single-cell RNA sequencing (scRNA-seq) data collected across ordered stages provide population-level snapshots of differentiation, disease progression, and aging. Supervised pseudotime methods use observed stage labels to reconstruct continuous progression but generally do not identify marker genes associated with changes from one stage to the next. Unsupervised pseudotime-based marker selection methods infer latent trajectories directly from expression data and identify trajectory-associated genes, but do not explicitly link these associations to the observed stages. We propose FusedFCR, a regularized forward continuation-ratio model that represents cellular progression through a sequence of conditional transitions across ordered stages. FusedFCR combines a lasso penalty for gene selection with a fusion penalty that encourages similar effects across adjacent transitions while allowing transient and direction-changing associations. The resulting transition-specific coefficients support interpretable gene selection and a continuous pseudotime-like projection anchored to the observed developmental stages. In simulations, FusedFCR accurately recovered gene-effect trajectories and improved predictive performance relative to alternative methods. Applied to mouse pancreatic beta-cell differentiation across seven time points and human extravillous trophoblast differentiation across four time points, FusedFCR identified biologically interpretable genes associated with distinct developmental transitions. Gene set enrichment analysis further revealed stage-specific pathway activity consistent with known developmental biology, while held-out stage-classification accuracy was competitive or superior across both datasets. Together, these results show that FusedFCR complements pseudotemporal ordering by identifying which molecular programs change and when those changes emerge along the developmental trajectory. An accompanying R package is available on GitHub.","rel_num_authors":9,"rel_authors":[{"author_name":"Chloe Mattila","author_inst":"Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Anirban Chakraborty","author_inst":"Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Peggi Angel","author_inst":"Department of Pharmacology and Immunology, Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Sha Cao","author_inst":"Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Kalyani Sonawane","author_inst":"Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA"},{"author_name":"Elizabeth Hill","author_inst":"Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA"},{"author_name":"Dongjun Chung","author_inst":"Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA"},{"author_name":"Brian Neelon","author_inst":"Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Souvik Seal","author_inst":"Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA"}],"rel_date":"2026-07-24","rel_site":"biorxiv"},{"rel_title":"The \"Weekend Warrior\" Physical Activity Pattern and Cardiometabolic Health: A Pooled Harmonized Individual Participant Analysis of the ProPASS Consortium","rel_doi":"10.64898\/2026.07.21.26358626","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358626","rel_abs":"BackgroundWhile \"weekend warrior\" (WW) physical activity (PA) pattern has been associated with cardiovascular benefits, most existing evidence is based on self-reported PA. Evidence using harmonized, thigh-worn accelerometry to examine associations between the weekend warrior phenotype and comprehensive cardiometabolic profiles remains limited.\n\nMethodsWe pooled harmonized individual-participant data from six cohorts in the Prospective Physical Activity, Sitting and Sleep (ProPASS) Consortium. In this cross-sectional analysis, participants were classified as inactive (<150 min\/week MVPA), weekend warriors ([&ge;]150 min\/week with [&ge;]50% accumulated on 1-2 days), or regularly active [&ge;]150 min\/week but not meeting the WW criterion). A composite cardiometabolic score averaged eight standardized indicators: triglycerides, HDL cholesterol, total cholesterol, HbA1c, body mass index, waist circumference, systolic blood pressure, and diastolic blood pressure. Generalized linear models were used to estimate associations between PA patterns and both composite and individual cardiometabolic outcomes, adjusted for age, sex, smoking, alcohol intake, self-rated health, CVD history, medication use, blood biomarker fasting status, and cohort.\n\nResultsAmong 13,904 adults (mean age 54.3{+\/-}9.5 years; 54.7% women), 61.8% were inactive, 24.5% weekend warriors, and 13.7% regularly active. Compared with inactivity, both active patterns were associated with more favorable composite cardiometabolic scores (WW: {beta} = -0.118 (95% CI: -0.142, -0.095); regularly active: {beta} = -0.111 (95% CI: -0.141, -0.081)), with negative values indicating better cardiometabolic health. Weekend warriors and regularly active adults showed broadly similar associations across individual markers, including lower adiposity (BMI and waist circumference) and more favorable metabolic biomarkers (higher HDL cholesterol; lower triglycerides and HbA1c), with no meaningful differences between the two active patterns for the composite score or any individual outcome. Associations with total cholesterol and blood pressure were small.\n\nConclusionsBoth active patterns were associated with more favorable cardiometabolic profiles than inactivity, and profiles were broadly comparable whether MVPA was concentrated on 1-2 most active days (weekend warrior) or accumulated more regularly across the week.","rel_num_authors":28,"rel_authors":[{"author_name":"Shan Jiang","author_inst":"The Education University of Hong Kong"},{"author_name":"- The ProPASS Collaborators","author_inst":"-"},{"author_name":"Matthew N Ahmadi","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"},{"author_name":"Nicholas A. Koemel","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"},{"author_name":"Amy S. Ha","author_inst":"The Education University of Hong Kong"},{"author_name":"Raaj Kishore Biswas","author_inst":"University of Sydney"},{"author_name":"Joanna M Blodgett","author_inst":"Institute of Sport Exercise and Health"},{"author_name":"John Mitchell","author_inst":"UCL Queen Square Institute of Neurology"},{"author_name":"Borja del Pozo Cruz","author_inst":"Universidad Europea de Madrid SLU"},{"author_name":"Richard Pulsford","author_inst":"University of Exeter Faculty of Health and Life Sciences"},{"author_name":"Kristin Suorsa","author_inst":"Department of Public Health, University of Turku and Turku University Hospital, Turku, Finland; 2 Centre for Population Health Research, University of Turku and"},{"author_name":"Dick H.J. Thijssen","author_inst":"Radboud University Medical Centre"},{"author_name":"Esm\u00e9e A. Bakker","author_inst":"Radboud universitair medisch centrum"},{"author_name":"Carlos A. Celis-Morales","author_inst":"University of Glasgow Library"},{"author_name":"Peter J Johansson","author_inst":"Occupational and Environmental Medicine, Department of Medical Sciences, Uppsala University"},{"author_name":"Pasan Hettiarachchi","author_inst":"Department of Medical Sciences, Uppsala University"},{"author_name":"Sari Stenholm","author_inst":"Department of Public Health, University of Turku and Turku University Hospital"},{"author_name":"Gita D. Mishra","author_inst":"The University of Queensland"},{"author_name":"Sarah Keadle","author_inst":"California Polytechnic State University"},{"author_name":"Vegar Rangul","author_inst":"HUNT Research Centre, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU)"},{"author_name":"Nidhi Gupta","author_inst":"National Research Centre for the Working Environment"},{"author_name":"Stavros Kyriakidis","author_inst":"The National Research Centre for the Working Environment"},{"author_name":"Marvin Y. Chong","author_inst":"Universiteit Maastricht"},{"author_name":"Annemarie Koster","author_inst":"Maastricht University"},{"author_name":"Andrew Atkin","author_inst":"School of Health Sciences and Norwich Epidemiology Centre, University of East Anglia"},{"author_name":"I-Min Lee","author_inst":"Harvard Medical School"},{"author_name":"Mark Hamer","author_inst":"University College London"},{"author_name":"Emmanuel Stamatakis","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"The \"Weekend Warrior\" Physical Activity Pattern and Cardiometabolic Health: A Pooled Harmonized Individual Participant Analysis of the ProPASS Consortium","rel_doi":"10.64898\/2026.07.21.26358626","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358626","rel_abs":"BackgroundWhile \"weekend warrior\" (WW) physical activity (PA) pattern has been associated with cardiovascular benefits, most existing evidence is based on self-reported PA. Evidence using harmonized, thigh-worn accelerometry to examine associations between the weekend warrior phenotype and comprehensive cardiometabolic profiles remains limited.\n\nMethodsWe pooled harmonized individual-participant data from six cohorts in the Prospective Physical Activity, Sitting and Sleep (ProPASS) Consortium. In this cross-sectional analysis, participants were classified as inactive (<150 min\/week MVPA), weekend warriors ([&ge;]150 min\/week with [&ge;]50% accumulated on 1-2 days), or regularly active [&ge;]150 min\/week but not meeting the WW criterion). A composite cardiometabolic score averaged eight standardized indicators: triglycerides, HDL cholesterol, total cholesterol, HbA1c, body mass index, waist circumference, systolic blood pressure, and diastolic blood pressure. Generalized linear models were used to estimate associations between PA patterns and both composite and individual cardiometabolic outcomes, adjusted for age, sex, smoking, alcohol intake, self-rated health, CVD history, medication use, blood biomarker fasting status, and cohort.\n\nResultsAmong 13,904 adults (mean age 54.3{+\/-}9.5 years; 54.7% women), 61.8% were inactive, 24.5% weekend warriors, and 13.7% regularly active. Compared with inactivity, both active patterns were associated with more favorable composite cardiometabolic scores (WW: {beta} = -0.118 (95% CI: -0.142, -0.095); regularly active: {beta} = -0.111 (95% CI: -0.141, -0.081)), with negative values indicating better cardiometabolic health. Weekend warriors and regularly active adults showed broadly similar associations across individual markers, including lower adiposity (BMI and waist circumference) and more favorable metabolic biomarkers (higher HDL cholesterol; lower triglycerides and HbA1c), with no meaningful differences between the two active patterns for the composite score or any individual outcome. Associations with total cholesterol and blood pressure were small.\n\nConclusionsBoth active patterns were associated with more favorable cardiometabolic profiles than inactivity, and profiles were broadly comparable whether MVPA was concentrated on 1-2 most active days (weekend warrior) or accumulated more regularly across the week.","rel_num_authors":28,"rel_authors":[{"author_name":"Shan Jiang","author_inst":"The Education University of Hong Kong"},{"author_name":"- The ProPASS Collaborators","author_inst":"-"},{"author_name":"Matthew N Ahmadi","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"},{"author_name":"Nicholas A. Koemel","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"},{"author_name":"Amy S. Ha","author_inst":"The Education University of Hong Kong"},{"author_name":"Raaj Kishore Biswas","author_inst":"University of Sydney"},{"author_name":"Joanna M Blodgett","author_inst":"Institute of Sport Exercise and Health"},{"author_name":"John Mitchell","author_inst":"UCL Queen Square Institute of Neurology"},{"author_name":"Borja del Pozo Cruz","author_inst":"Universidad Europea de Madrid SLU"},{"author_name":"Richard Pulsford","author_inst":"University of Exeter Faculty of Health and Life Sciences"},{"author_name":"Kristin Suorsa","author_inst":"Department of Public Health, University of Turku and Turku University Hospital, Turku, Finland; 2 Centre for Population Health Research, University of Turku and"},{"author_name":"Dick H.J. Thijssen","author_inst":"Radboud University Medical Centre"},{"author_name":"Esm\u00e9e A. Bakker","author_inst":"Radboud universitair medisch centrum"},{"author_name":"Carlos A. Celis-Morales","author_inst":"University of Glasgow Library"},{"author_name":"Peter J Johansson","author_inst":"Occupational and Environmental Medicine, Department of Medical Sciences, Uppsala University"},{"author_name":"Pasan Hettiarachchi","author_inst":"Department of Medical Sciences, Uppsala University"},{"author_name":"Sari Stenholm","author_inst":"Department of Public Health, University of Turku and Turku University Hospital"},{"author_name":"Gita D. Mishra","author_inst":"The University of Queensland"},{"author_name":"Sarah Keadle","author_inst":"California Polytechnic State University"},{"author_name":"Vegar Rangul","author_inst":"HUNT Research Centre, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU)"},{"author_name":"Nidhi Gupta","author_inst":"National Research Centre for the Working Environment"},{"author_name":"Stavros Kyriakidis","author_inst":"The National Research Centre for the Working Environment"},{"author_name":"Marvin Y. Chong","author_inst":"Universiteit Maastricht"},{"author_name":"Annemarie Koster","author_inst":"Maastricht University"},{"author_name":"Andrew Atkin","author_inst":"School of Health Sciences and Norwich Epidemiology Centre, University of East Anglia"},{"author_name":"I-Min Lee","author_inst":"Harvard Medical School"},{"author_name":"Mark Hamer","author_inst":"University College London"},{"author_name":"Emmanuel Stamatakis","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Village-level surveillance of neonatal disease with integrated real-time dashboards and quality-control in Uganda","rel_doi":"10.64898\/2026.07.21.26358401","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358401","rel_abs":"IntroductionNeonatal mortality remains disproportionately high in sub-Saharan Africa, where an estimated 27 neonatal deaths per 1,000 live births occur annually. Infections, including sepsis and meningitis, account for a substantial proportion of these deaths, while neural tube defects (NTDs) contribute significantly to both neonatal mortality and long-term disability. Existing surveillance systems in the region are predominantly facility-based, missing the substantial proportion of births and deaths that occur in the community. Population-based surveillance platforms that capture community-level data are urgently needed to generate accurate incidence estimates, identify modifiable risk factors, and guide evidence-based interventions.\n\nCohort DescriptionThe Consortium to Reduce Infant Mortality (CONRIM) is a multi-institutional partnership among Ugandan physicians and scientists, Yale University, Penn State University, Boston Childrens Hospital\/Harvard Medical School, and Ugandas National Planning Authority. CONRIM conducts prospective, community-based neonatal surveillance within the Busoga Kingdom in eastern Uganda. A network of 813 trained Village Health Team members conducts household-level visits using a structured Open Data Kit (ODK)-based mobile questionnaire to capture every birth, assess for danger signs of possible serious bacterial infection (pSBI), screen for NTDs, and record maternal nutrition and folic acid use, water, sanitation and hygiene (WASH) conditions, and health care utilization.\n\nFindings to DateSince surveillance began in June 2025, the platform has registered approximately 22,200 household submissions and over 5,700 newborn encounters across the Jinja District (population 660,000). Early data have identified higher than expected rates of infants with NTDs including encephalocele and spina bifida; documented folic acid non-use in before and during most pregnancies; characterized WASH conditions in birthplaces; and mapped geospatial hotspots of neonatal infection risk in northeastern rural subcounties. Prospective 28-day follow-up of all live births has demonstrated a neonatal mortality rate of 21.5 per 1000 live births. A real-time data quality monitoring system with 21 automated quality control flags maintains a 99% clean-record rate.\n\nFuture PlansOngoing and planned activities include laboratory-based confirmation of neonatal sepsis via blood culture and cerebrospinal fluid analysis with polymerase chain reaction capacity, portable neuroimaging for NTDs, environmental sampling, genomic studies of folate metabolism pathway genes, linkage with facility-based records at Jinja Regional Referral Hospital and Mulago National Referral Hospital, and community-level interventions informed by surveillance findings.\n\nKey MessagesO_ST_ABSWhat is already known on this topicC_ST_ABSNeonatal mortality remains disproportionately high in sub-Saharan Africa, with sepsis and neural tube defects (NTDs) among the leading preventable causes. Existing surveillance systems are predominantly facility-based and fail to capture births, deaths, and environmental exposures occurring at the community level. Emerging approaches in digital health, geospatial analytics, and pathogen genomics have demonstrated potential to enhance infectious disease surveillance, but these have rarely been integrated into population-based neonatal monitoring systems in low-resource settings.\n\nWhat this study addsThe Consortium to Reduce Infant Mortality (CONRIM) is a multidisciplinary initiative designed to develop scalable, population-based systems for understanding and reducing neonatal mortality through integrated epidemiologic, environmental, and biologic data.\n\nThis paper describes one implementation of the CONRIM framework in the Busoga Kingdom of eastern Uganda, where a network of 813 trained Village Health Team members conducts longitudinal, community-based surveillance of births, neonatal outcomes, NTDs, maternal nutrition (including folic acid use), water, sanitation and hygiene (WASH) conditions, and care-seeking behaviour.\n\nThis implementation integrates: O_LIreal-time digital data capture with automated quality control,\nC_LIO_LIgeospatial information systems (GIS) and remote sensing to characterize environmental risk factors,\nC_LIO_LIpopulation-level genomic and metagenomic sampling to investigate host and pathogen factors, and\nC_LIO_LIa One Health framework linking human, animal, and environmental exposures.\nC_LI\n\nEarly findings highlight high data completeness, geospatial clustering of neonatal infection risk, low preconception folic acid use, and identification of NTD cases not captured by facility-based systems.\n\nHow this study might affect research, practice, or policyThis study demonstrates the feasibility of implementing a community-based, real-time neonatal surveillance system within an existing community health worker network in a low-resource setting. By integrating geospatial, genomic, and environmental data within a unified platform, the CONRIM framework enables more precise identification of drivers of neonatal morbidity and mortality.\n\nThe approach supports targeted public health interventions, including geographically informed infection control strategies, improved referral pathways, and evidence generation for folic acid fortification policies. More broadly, CONRIM provides a scalable infrastructure for future interventional studies and precision public health strategies aimed at reducing neonatal mortality.","rel_num_authors":41,"rel_authors":[{"author_name":"Joseph N. Paulson","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA"},{"author_name":"Andrew J. Whalen","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA"},{"author_name":"Starlin Tindimwebwa","author_inst":"Busoga Kingdom Health Department \/ CONRIM Uganda Field Team, Jinja, Uganda"},{"author_name":"Justice Hansen","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA"},{"author_name":"Davis Natukwatsa","author_inst":"Busoga Kingdom Health Department \/ CONRIM Uganda Field Team, Jinja, Uganda"},{"author_name":"Steven Kalifuba","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Moses Ochora","author_inst":"Department of Paediatrics and Child Health, Soroti University, Soroti, Uganda; National Planning Authority, Kampala, Uganda"},{"author_name":"Ronnie Mulondo","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA"},{"author_name":"Edith Mbabazi-Kabachelor","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA"},{"author_name":"Kamron Ramelmeier","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Brian Kaaya Nsubuga","author_inst":"Busoga Kingdom Health Department \/ CONRIM Uganda Field Team, Jinja, Uganda"},{"author_name":"Philip O. Omadi","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Joshua Magombe","author_inst":"Department of Neurosurgery, Mulago National Referral Hospital, Kampala, Uganda"},{"author_name":"Carmit Cohen","author_inst":"BGU-FOR (Food Systems, One Health & Resilience) Research Center, Ben Gurion University of the Negev, Beer Sheba, Israel"},{"author_name":"Norbert Muzahura","author_inst":"Department of Neurosurgery, Mulago National Referral Hospital, Kampala, Uganda"},{"author_name":"Justin Onen","author_inst":"Department of Neurosurgery, Mulago National Referral Hospital, Kampala, Uganda"},{"author_name":"Peter Ssenyonga","author_inst":"Department of Neurosurgery, Mulago National Referral Hospital, Kampala, Uganda"},{"author_name":"James R. Broach","author_inst":"Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, USA"},{"author_name":"Sarah U. Morton","author_inst":"Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA, USA"},{"author_name":"Marwan Osman","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA"},{"author_name":"Moses Joloba","author_inst":"Makerere University Biomedical Research Center, Kampala, Uganda"},{"author_name":"Edgar Kigozi","author_inst":"Makerere University Biomedical Research Center, Kampala, Uganda"},{"author_name":"Andrew Katabalwa","author_inst":"Makerere University Biomedical Research Center, Kampala, Uganda"},{"author_name":"Julian Apako","author_inst":"Makerere University Biomedical Research Center, Kampala, Uganda"},{"author_name":"Hilda Amutuhaire","author_inst":"Department of Agricultural Production, College of Agricultural and Environmental Sciences, Makerere University, P.O. Box, 7062, Kampala, Uganda"},{"author_name":"John Baptist Tumuhairwe","author_inst":"Department of Agricultural Production, College of Agricultural and Environmental Sciences, Makerere University, P.O. Box, 7062, Kampala, Uganda"},{"author_name":"Agatha Kayemba","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Josephine Namyalo","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Henry Masengere","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Harriet Nambuya","author_inst":"Regional Referral Hospital of Jinja, Jinja, Uganda"},{"author_name":"Agatha Namutosi","author_inst":"Regional Referral Hospital of Jinja, Jinja, Uganda"},{"author_name":"Sophia Kasuswa","author_inst":"Regional Referral Hospital of Jinja, Jinja, Uganda"},{"author_name":"Emma Omo","author_inst":"Regional Referral Hospital of Jinja, Jinja, Uganda"},{"author_name":"Ivan Tibenkana","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Alfred Yayi","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Joseph Muvawala","author_inst":"Busoga Kingdom Health Department \/ CONRIM Uganda Field Team, Jinja, Uganda; National Planning Authority, Kampala, Uganda"},{"author_name":"William Nadiope IV","author_inst":"Kingdom of Busoga, Bugembe, Uganda"},{"author_name":"Abraham Muwanguzi","author_inst":"Busoga Kingdom Health Department \/ CONRIM Uganda Field Team, Jinja, Uganda; National Planning Authority, Kampala, Uganda"},{"author_name":"Elias Kumbakumba","author_inst":"Department of Pediatrics, Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Jessica E. Ericson","author_inst":"Division of Pediatric Infectious Disease, Pennsylvania State University College of Medicine, Hershey, PA, USA"},{"author_name":"Steven J. Schiff","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA; Department of Epidemiology of Microbial Diseases, Yale University School of"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Community leaders as vaccine champions and the lessons from the COVID-19 pandemic in Papua New Guinea","rel_doi":"10.64898\/2026.07.21.26358216","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358216","rel_abs":"The lessons learned from the COVID-19 pandemic are essential for implementing substantive changes and present a significant opportunity to strengthen the resilience of health systems on both national and global scales in responding to future public health crises. It is widely acknowledged that COVID-19 vaccination represents one of the most effective strategies to contain the pandemic. Nonetheless, vaccine hesitancy continues to evoke fear and uncertainty, particularly in contexts such as Papua New Guinea (PNG), a nation characterised by one of the lowest COVID-19 vaccination rates worldwide. Insights from previous public health interventions in PNG emphasise the critical role that community leaders play in ensuring the success of such initiatives. This publication reports on a study investigating the influence of community leaders on COVID-19 vaccine uptake in PNG.\n\nQualitative research was carried out across seven provinces between July and November 2021, involving interviews with 131 participants, including healthcare professionals, key informants, community leaders, and primary health service clients. There was considerable support for community-led strategies, with participants advocating for awareness programs to be delivered by community leaders. The advantages of locally driven approaches include the trust communities place in their leaders and shared lived experiences, which enable them to address their specific needs effectively while respecting and building upon local beliefs and customs. The effectiveness of place-based vaccine champions was also endorsed, recognising the importance of collaborations between health systems, governments, and community leaders to promote COVID-19 vaccination.\n\nThese findings underscore the importance of sustained support and  bottom-up strategies to empower community leaders in fostering community ownership of health promotion initiatives and building resilient health systems, not only for COVID-19 vaccine distribution but also for future health interventions.","rel_num_authors":11,"rel_authors":[{"author_name":"Katrina Shen","author_inst":"UNSW Medicne Kirby Institute: The Kirby Institute"},{"author_name":"Jamee Newland","author_inst":"UNSW Medicne Kirby Institute: The Kirby Institute"},{"author_name":"Nalisa Neuendorf","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Ruthy Boli-Neo","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Lisa  Michelle Vallely","author_inst":"UNSW Medicne Kirby Institute: The Kirby Institute"},{"author_name":"Agnes Mek","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Anna Maalsen","author_inst":"World Health Organization"},{"author_name":"Leanne  J. Robinson","author_inst":"Burnet Institute"},{"author_name":"William Pomat","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Moses Laman","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Angela Kelly-Hanku","author_inst":"UNSW Medicne Kirby Institute: The Kirby Institute"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Pembrolizumab in advanced acral lentiginous melanoma: final results of a single-centre, open-label, phase II trial in an East Asian population","rel_doi":"10.64898\/2026.07.22.26358641","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358641","rel_abs":"BackgroundAcral lentiginous melanoma (ALM) is the predominant melanoma subtype in East Asian populations, accounting for roughly 50-58% of cases, compared with 2-3% in populations of European ancestry. ALM is genomically and biologically distinct from sun-exposed cutaneous melanoma, and East Asian and acral patients were markedly under-represented in the pivotal anti-PD-1 registration trials. At the time this study was designed, no prospective trial had evaluated a checkpoint inhibitor specifically in ALM. We conducted a phase II trial to estimate the activity of pembrolizumab in this population.\n\nMethodsIn this single-centre, single-arm, open-label phase II trial, adults with metastatic or locoregionally advanced inoperable ALM who were naive to anti-PD-1\/PD-L1 therapy received pembrolizumab 200 mg intravenously every 3 weeks until progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints included duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety (CTCAE v4.0). A Simon minimax two-stage design (P0=0.10, P1=0.30, =0.05, power=80%) planned enrolment of up to 28 patients.\n\nResultsBetween February 2017 and June 2019, 9 patients were enrolled before recruitment was halted for slow accrual, the interval availability of reimbursed pembrolizumab, and a low observed response signal. Median age was 72 years (range 48-78); 6 (67%) were male; all had ECOG performance status 0 and metastatic disease; 7 (78%) had received prior therapy. One patient achieved a partial response (ORR 11.1%, 95% CI 0.0-31.6%), with a DoR of 19 months; 3 had stable disease and 4 progressed. CBR (response or stable disease [&ge;]12 weeks) was 44.4% (95% CI 12.0-76.9). At a median follow-up of 7.6 months, median PFS was 3.4 months (95% CI 1.4-21.3) and median OS was 7.6 months (95% CI 2.0- 34.3). Two grade 3 adverse events occurred, both assessed as unrelated to study drug; no treatment-related grade [&ge;]3 events were recorded. In an exploratory analysis, an LDH-to-upper-limit-of-normal ratio >1.5 was associated with worse OS (median 4.3 vs 26.5 months; HR 4.58, 95% CI 0.82-25.7; log-rank p=0.06).\n\nConclusionsRecruitment was constrained by disease rarity and a shifting reimbursement landscape, and the trial closed before completing stage I. Within these limitations, single-agent pembrolizumab showed only modest activity in advanced ALM, consistent with the limited efficacy subsequently reported in larger contemporary acral melanoma cohorts. The exploratory association between elevated LDH ratio and poorer survival warrants prospective evaluation.\n\nWhat is already known \/ what this study addsO_LIALM is the commonest melanoma subtype in East Asia but was almost absent from the trials that established PD-1 blockade; no prospective checkpoint-inhibitor trial in pure ALM existed when this study was designed.\nC_LIO_LIIn this prospective phase II trial, single-agent pembrolizumab produced an ORR of 11.1% with modest survival, consistent with limited activity later reported in larger acral cohorts.\nC_LIO_LIAn exploratory signal linking elevated LDH ratio to poorer survival supports its prognostic relevance and the need for collaborative, biomarker-driven trials dedicated to ALM.\nC_LI","rel_num_authors":12,"rel_authors":[{"author_name":"Herbert H Loong","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Winnie Yeo","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Candy Yuen","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Frankie Mo","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Tung Ching Chan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Kirsty W C Lee","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Chiu Yan Chan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Ashley C Y Wong","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Kenneth W C Wong","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Daisy C M Lam","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Joanna Tong","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Carlos Wong","author_inst":"University of Hong Kong"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Resolving the classification rates and molecular architecture of early-onset chronic kidney disease with NephVar","rel_doi":"10.64898\/2026.07.22.26358680","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358680","rel_abs":"The genetic architecture of early-onset chronic kidney disease (CKD) is caused by more than 200 monogenic genes, where their common diagnostic classes include congenital anomalies of the kidney and urinary tract, steroid-resistant nephrotic syndrome, nephronophthisis-related ciliopathies, chronic glomerulonephritis, and urinary stone disease. While advancements in whole-exome and whole-genome sequencing have enabled identification of disease-causing variants, their rates of classification have remained unknown. Likewise, the molecular effects of these pathogenic variants remain unresolved, which is essential for improving personalized treatment approaches. In this study, we collected clinical and biophysical data from 117,373 genetic variants across 129 monogenic genes causing early-onset CKD. This data established the NephVar registry, which aims to be a molecular dictionary for nephrologists to classify variants and resolve their unique molecular effects. Through NephVar, we estimated 1-15% of alleles are reclassified and the time to reclassification per variant is 2-12 years in early-onset CKD. Furthermore, NephVar identified the molecular effects of all variant types, emphasizing missense variants. Our analyses indicate that intrinsically disordered regions of proteins are protective against disease-causing missense alleles across most diagnostic classes, but often occur through a buried loss-of-function (LoF) mechanism. Additionally, we show that the mode of inheritance for these monogenic genes influences clustering patterns of genetic variants, where autosomal dominant (AD) genes are more clustered than those of autosomal recessive (AR) genes. This data accurately predicted the non-LoF effects in INF2, PAX2, GATA3, ACTN4, and LMX1B causing inherited nephrotic syndromes. We demonstrate that variant effect prediction is effective for downgrading variants of unknown significance and classifying AR genes, but challenging for pathogenic alleles in AD genes. Lastly, we propose standards and guidelines for determining non-LoF effects, including gain-of-function and dominant negative, in inherited nephrotic syndrome. Overall, the NephVar renal registry has important implications for defining the molecular architecture and estimating the progress of molecular diagnostics for early-onset CKD.","rel_num_authors":2,"rel_authors":[{"author_name":"Joshua P Pillai","author_inst":"University of California, San Diego"},{"author_name":"John A Sayer","author_inst":"Newcastle University"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Changes in disability status and oral healthcare affordability among working-age Australians","rel_doi":"10.64898\/2026.07.21.26358621","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358621","rel_abs":"ImportanceOral healthcare is often financed outside universal medical coverage, leaving working-age adults exposed to out-of-pocket costs. People with long-term disability may face added financial, physical, and service barriers to care, but longitudinal evidence on disability and oral healthcare unaffordability is limited.\n\nObjectiveTo estimate the effect of time-varying long-term disability on oral healthcare unaffordability among working-age adults in Australia.\n\nDesignLongitudinal cohort study using Household, Income and Labour Dynamics in Australia survey data from waves 18 to 22 (2018-2022), analysed with targeted maximum likelihood estimation for longitudinal modified treatment policies.\n\nSettingNationally representative household panel survey in Australia.\n\nParticipantsAdults aged 25 to 65 years at wave 18 who could validly contribute to the longitudinal analysis (identified using HILDA longitudinal weights) and had complete baseline covariate data.\n\nExposureTime-varying self-reported disability at waves 18 to 21 (2018-2022), defined as any long-term health condition, impairment, or disability restricting everyday activities and lasting, or likely to last, for at least 6 months. Hypothetical interventions comprised 50% and 25% reductions in the odds of disability at each wave, and deterministic sustained disability and no disability regimes.\n\nMain Outcome and MeasureSelf-reported avoidance of dental treatment because of cost at wave 22 (2022).\n\nResultsThe analytic sample included 9635 adults; 4901 (50.9%) were female, mean age was 44 (SD=12) years, and 2419 (25.1%) reported disability at baseline. A total of 399 participants (4.1%) reported oral healthcare unaffordable at wave 22 follow-up. Compared with the natural course, sustained disability increased the risk of unaffordability (risk ratio [RR], 1.60; 95% CI, 1.15-2.22). No disability at any time point reduced the risk (RR, 0.59; 95% CI, 0.45-0.77). Reducing the odds of disability by 50% and 25% also reduced the risk of oral healthcare unaffordability by 28% (RR, 0.72; 95% CI, 0.65-0.81) and 17% (RR, 0.83; 95% CI, 0.78-0.89), respectively.\n\nConclusions and RelevanceUnder the study assumptions, long-term disability was estimated to increase experienced unaffordability of oral healthcare among working-age Australians. Population level policy responses should address both the upstream conditions that shape disability trajectories and the downstream exclusion of adult dental care from routine financial protection.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat is the estimated effect of time-varying disability status on oral healthcare affordability among working-age adults in Australia?\n\nFindingsIn this longitudinal cohort analysis of 9635 working-age adults, reducing the odds of disability by 50% or 25% was associated with lower risk of finding oral healthcare unaffordable at follow-up, while sustained disability was associated with higher risk.\n\nMeaningThe findings support paired policy attention to disability prevention and oral healthcare financing protections for working-age adults with disability.","rel_num_authors":7,"rel_authors":[{"author_name":"Upul Cooray","author_inst":"The University of Sydney"},{"author_name":"Gagandeep Kaur","author_inst":"The University of Sydney"},{"author_name":"Saman Khalatbari-Soltani","author_inst":"The University of Sydney"},{"author_name":"Barbara Janssens","author_inst":"Ghent University"},{"author_name":"George Disney","author_inst":"University of Melbourne"},{"author_name":"Ruby Cole","author_inst":"The University of Sydney"},{"author_name":"Ankur Singh","author_inst":"The University of Sydney"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Palliative Care among People with Advanced Heart Failure: Between Hospital Variation in the US Veterans Administration","rel_doi":"10.64898\/2026.07.22.26358645","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358645","rel_abs":"BackgroundPalliative care is recommended by clinical practice guidelines for patients with advanced heart failure (aHF), yet specialty palliative care (SPC) remains substantially underutilized in this population. We sought to quantify between-facility variation in SPC receipt among people with aHF and determine how much variation is explained by patient case mix and facility structural characteristics versus residual unmeasured factors.\n\nMethodsThis retrospective cohort study included 23,991 Veterans with prevalent aHF identified through administrative data across 133 VA Medical Centers (VAMCs) with [&ge;]20 aHF cases, from January 2022 to December 2023. Variation was assessed using multilevel logistic regression with facility random intercepts, the intraclass correlation coefficient (ICC), and the adjusted median odds ratio (aMOR). Facility-specific risk-standardized SPC rates were used to estimate SPC encounters attributable to facility performance better or worse than the national rate.\n\nResultsOf the sample, the mean patient age was 72.3 years (SD = 10.0), and 97.6% were male. The national observed rate of SPC was 17.5%, with risk-adjusted rates varying approximately 14-fold across facilities (3.3% to 45.6%). The adjusted ICC was 11.5%, and aMOR was 1.87 (95% Confidence Intervals 1.70-2.06). Measured patient case-mix and facility structural characteristics explained only 18.9% of between-facility variation (proportional reduction in the ICC, fully adjusted vs. null model). Facilities performing better than the national rate delivered 791 more SPC encounters than expected (17.8%), while those performing worse than the national rate delivered 480 fewer encounters than expected (10.8%).\n\nConclusionsIn the context of a national mean rate of SPC that reflects substantial underuse, delivery varied 14-fold across VAMCs, with most variation unexplained by patient complexity or measured facility resources. These findings suggest that potentially modifiable organizational factors, beyond patient preferences or facility structures alone, may contribute to current utilization gaps and represent actionable targets for quality improvement.\n\nClinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSIn this national cohort of 23,991 people with advanced heart failure cared for at 133 VA Medical Centers, risk-adjusted rates of specialist palliative care delivery varied 14-fold across facilities (median odds ratio 1.87). Measured patient case-mix and facility structural characteristics explained only 18.9% of the between-facility variation.\n\nClinical implications?Substantial variation in palliative care delivery across VAMCs is not accounted for by differences in patient complexity or facility resources, suggesting that institutional processes and referral practices are key drivers and represent actionable targets for quality improvement.","rel_num_authors":14,"rel_authors":[{"author_name":"Shelli Feder","author_inst":"Yale University"},{"author_name":"Na Ouyang","author_inst":"Yale"},{"author_name":"Ling Han","author_inst":"Yale"},{"author_name":"Erica Abel","author_inst":"VA"},{"author_name":"Eric DeRycke","author_inst":"VA"},{"author_name":"Daniel Kinder","author_inst":"VA"},{"author_name":"Nancy Redeker","author_inst":"University of Connecticut"},{"author_name":"Leslie A. Curry","author_inst":"Yale School of Public Health and Yale Global Health Leadership Institute"},{"author_name":"Carol Lurhs","author_inst":"VA"},{"author_name":"Cari Levy","author_inst":"VA"},{"author_name":"Jennifer Ibarra","author_inst":"VA"},{"author_name":"Dio Kavalieratos","author_inst":"Emory University"},{"author_name":"Kathleen Akgun","author_inst":"VA"},{"author_name":"Larry A Allen","author_inst":"University of Colorado School of Medicine, Aurora, CO"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Circulating protein profiling identifies prognostic biomarkers in amyotrophic lateral Sclerosis","rel_doi":"10.64898\/2026.07.20.26354798","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26354798","rel_abs":"In the pathologically and clinically heterogeneous neurodegenerative disorder amyotrophic lateral sclerosis (ALS), objective biochemical predictors of survival are essential to handle complexity in clinical trials, enrich clinical decision-making and interrogate the biology of disease progression. In this longitudinal study, we performed high-depth proximity extension assay proteomics using 1,095 samples of serum (N=851) and CSF (N=244) from 426 people with ALS, with orthogonal replication in an external cohort of 349 people with ALS. Age- and sex-adjusted Cox analysis identified 57 proteins in serum, including neurofilament light chain (NEFL) and peripherin, as well as five proteins in CSF, including tropomyosin 3 (TPM3) that were associated with survival (FDR-adjusted p<0.05). Penalised Cox regression identified a panel of 9 serum proteins - including NEFL, peripherin, TNF receptor superfamily member 27 (EDA2R) and calcitonin - that reflect the extent of disease as well as the progression rate, improving survival prediction compared with models using clinical parameters and NEFL. Joint modelling identified associations between the longitudinal trajectories of serum EDA2R and calcitonin with survival, highlighting their potential role in measuring disease progression. This work indicates the utility of multiple proteins reflecting diverse biological pathways in refining survival stratification and highlights systemic factors in ALS progression.","rel_num_authors":23,"rel_authors":[{"author_name":"Hadar Klimovski","author_inst":"Weizmann Institute of Science"},{"author_name":"Marcel Weinreich","author_inst":"University of Sheffield"},{"author_name":"Andrew Strange","author_inst":"University of Sheffield"},{"author_name":"Iddo Magen","author_inst":"Weizmann Institute of Science"},{"author_name":"Nancy - Sarah Yacovzada","author_inst":"Weizmann Institute Of Science"},{"author_name":"Yahel Cohen","author_inst":"Weizmann Institute of Science"},{"author_name":"Dganit Melamed-Kadosh","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"David G Lester","author_inst":"University of Oxford"},{"author_name":"Avigail Taylor","author_inst":"University of Oxford"},{"author_name":"Yuhan Zhou","author_inst":"University of Oxford"},{"author_name":"Tamar Ziv","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Beatrice Abramovich","author_inst":"Sourasky Medical Center"},{"author_name":"Anand G Subramaniam","author_inst":"Tel Aviv University"},{"author_name":"Eran Perlson","author_inst":"Tel Aviv University"},{"author_name":"Vivian Drory","author_inst":"Tel-Aviv University"},{"author_name":"Arie Admon","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Pamela J Shaw","author_inst":"University of Sheffield"},{"author_name":"Andrea Malaspina","author_inst":"University College London"},{"author_name":"Martin R Turner","author_inst":"University of Oxford"},{"author_name":"Kevin Talbot","author_inst":"University of Oxford"},{"author_name":"Alexander G Thompson","author_inst":"University of Oxford"},{"author_name":"Johnathan Cooper-Knock","author_inst":"University of Sheffield"},{"author_name":"Eran Hornstein","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Circulating protein profiling identifies prognostic biomarkers in amyotrophic lateral Sclerosis","rel_doi":"10.64898\/2026.07.20.26354798","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26354798","rel_abs":"In the pathologically and clinically heterogeneous neurodegenerative disorder amyotrophic lateral sclerosis (ALS), objective biochemical predictors of survival are essential to handle complexity in clinical trials, enrich clinical decision-making and interrogate the biology of disease progression. In this longitudinal study, we performed high-depth proximity extension assay proteomics using 1,095 samples of serum (N=851) and CSF (N=244) from 426 people with ALS, with orthogonal replication in an external cohort of 349 people with ALS. Age- and sex-adjusted Cox analysis identified 57 proteins in serum, including neurofilament light chain (NEFL) and peripherin, as well as five proteins in CSF, including tropomyosin 3 (TPM3) that were associated with survival (FDR-adjusted p<0.05). Penalised Cox regression identified a panel of 9 serum proteins - including NEFL, peripherin, TNF receptor superfamily member 27 (EDA2R) and calcitonin - that reflect the extent of disease as well as the progression rate, improving survival prediction compared with models using clinical parameters and NEFL. Joint modelling identified associations between the longitudinal trajectories of serum EDA2R and calcitonin with survival, highlighting their potential role in measuring disease progression. This work indicates the utility of multiple proteins reflecting diverse biological pathways in refining survival stratification and highlights systemic factors in ALS progression.","rel_num_authors":23,"rel_authors":[{"author_name":"Hadar Klimovski","author_inst":"Weizmann Institute of Science"},{"author_name":"Marcel Weinreich","author_inst":"University of Sheffield"},{"author_name":"Andrew Strange","author_inst":"University of Sheffield"},{"author_name":"Iddo Magen","author_inst":"Weizmann Institute of Science"},{"author_name":"Nancy - Sarah Yacovzada","author_inst":"Weizmann Institute Of Science"},{"author_name":"Yahel Cohen","author_inst":"Weizmann Institute of Science"},{"author_name":"Dganit Melamed-Kadosh","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"David G Lester","author_inst":"University of Oxford"},{"author_name":"Avigail Taylor","author_inst":"University of Oxford"},{"author_name":"Yuhan Zhou","author_inst":"University of Oxford"},{"author_name":"Tamar Ziv","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Beatrice Abramovich","author_inst":"Sourasky Medical Center"},{"author_name":"Anand G Subramaniam","author_inst":"Tel Aviv University"},{"author_name":"Eran Perlson","author_inst":"Tel Aviv University"},{"author_name":"Vivian Drory","author_inst":"Tel-Aviv University"},{"author_name":"Arie Admon","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Pamela J Shaw","author_inst":"University of Sheffield"},{"author_name":"Andrea Malaspina","author_inst":"University College London"},{"author_name":"Martin R Turner","author_inst":"University of Oxford"},{"author_name":"Kevin Talbot","author_inst":"University of Oxford"},{"author_name":"Alexander G Thompson","author_inst":"University of Oxford"},{"author_name":"Johnathan Cooper-Knock","author_inst":"University of Sheffield"},{"author_name":"Eran Hornstein","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-07-23","rel_site":"medrxiv"}]}