{"gname":"University of Iowa","grp_id":"24","rels":[{"rel_title":"Evaluation of Large Language Models for Post-Cystectomy Sexual Health Counseling in Women: A Pilot Study","rel_doi":"10.64898\/2026.06.25.26356154","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356154","rel_abs":"Abstract Objective To evaluate the adherence to guidelines and readability of large language model-generated sexual health information related to female sexual dysfunction following cystectomy, and to determine whether adherence differs across models and prompt formats. A secondary objective was to introduce an analytic strategy using principal component analysis to examine the dimensions of readability metrics. Methods Three large language models (LLMs), ChatGPT, Gemini, and Perplexity were prompted with six clinical questions related to sexual function after cystectomy. Questions were phrased in long-form and short-form language. Responses were independently graded by two reviewers, derived from guideline recommendations. Linear mixed-effects models predicted adherence as functions of LLM, prompt, and reviewer, with clinical questions as a random intercept. Readability was assessed using five metrics, and principal component analysis (PCA) was used to determine latent structure. Results ChatGPT demonstrated the highest (estimated marginal mean [emm] = 0.769), outperforming Gemini (0.499) and Perplexity (0.457). Shorter, less complex prompts elicited higher adherence than more complex, clinical prompts. All models produced content that exceeded recommended reading levels. PCA demonstrated that a single dominant component accounted for 76.7% of variance across readability indices, indicating a shared underlying construct. Conclusion ChatGPT produced the most guideline-concordant information overall. High linguistic complexity was seen across models, highlighting a barrier to patient comprehension. These findings characterize large language models as variable medical information systems whose outputs rely heavily on prompt structure and model type.","rel_num_authors":7,"rel_authors":[{"author_name":"Faheed Shafau","author_inst":"Michigan State University College of Human Medicine"},{"author_name":"Aakash A Dave","author_inst":"Michigan State University"},{"author_name":"Ibukunoluwa Omole","author_inst":"Michigan State University College of Human Medicine"},{"author_name":"Taeris Guzman","author_inst":"Northeast Ohio Medical University"},{"author_name":"Najibha Rehman","author_inst":"Henry Ford Health System"},{"author_name":"Ekene Enemchukwu","author_inst":"Stanford University School of Medicine"},{"author_name":"Larissa Bresler","author_inst":"Northwestern University Feinberg School of Medicine"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Artificially sweetened beverage intake and risk of liver-related adverse events in individuals with MASLD: A prospective UK Biobank cohort study","rel_doi":"10.64898\/2026.07.04.26357265","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357265","rel_abs":"Purpose Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease and liver-related morbidity worldwide. Although dietary factors may influence MASLD progression, the long-term liver-specific implications of artificially sweetened beverage (ASB) intake remain unclear. We aimed to examine the association between ASB intake and the risk of liver-related adverse events and liver-related death among individuals with MASLD. Methods This prospective cohort study included 50,562 participants with MASLD from the UK Biobank. ASB intake was assessed using 24-hour dietary recalls and categorized as 0, >0-1, and >1 serving\/day. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for liver-related adverse events and liver-related death. Restricted cubic spline models were used to assess dose-response patterns, and competing-risk analyses were performed by treating liver-related death as a competing event for liver-related adverse events. Additional substitution, subgroup and sensitivity analyses were conducted to evaluate the robustness of the findings. Results During a median follow-up of 12.8 years, 292 liver-related adverse events and 91 liver-related deaths occurred. Compared with participants reporting no ASB intake, those consuming >1 serving\/day had a higher risk of liver-related adverse events in the fully adjusted model (HR 1.40, 95% CI 1.02-1.93; P = 0.039), whereas the association for >0-1 serving\/day was not statistically significant (HR 1.26, 95% CI 0.92-1.71; P = 0.149). The risk of liver-related adverse events increased across ASB intake categories (P for trend = 0.023). Restricted cubic spline analysis indicated a positive linear association between ASB intake and liver-related adverse events (P-overall <0.001; P-nonlinearity = 0.72). In competing-risk analysis, the association for >1 serving\/day remained consistent after accounting for liver-related death as a competing event (sub-HR 1.40, 95% CI 1.02-1.93; P = 0.038; Gray test P = 0.006). The association was robust in sensitivity analyses. ASB intake was not significantly associated with liver-related death, and beverage substitution analyses showed no significant associations. Conclusion Among individuals with MASLD, high ASB intake, particularly >1 serving\/day, was associated with an increased risk of liver-related adverse events, but not liver-related death. This association was consistent across dose-response, competing-risk, and sensitivity analyses, suggesting that high ASB intake may represent a potential dietary risk marker for adverse liver outcomes in MASLD.","rel_num_authors":7,"rel_authors":[{"author_name":"ning xu","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Jiaxi Lin","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Lihe Liu","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Shiqi Zhu","author_inst":"Soochow University Affiliated No 1 People\\'s Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Rui Li","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Jinzhou Zhu","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Chunfang Xu","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Exploring the Application of the Observational Medical Outcomes Partnership Common Data Model to Multi-site Stroke Rehabilitation Research Data","rel_doi":"10.64898\/2026.06.28.26356618","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.28.26356618","rel_abs":"Background: Emerging artificial intelligence and machine learning (AI\/ML) tools can help generate robust knowledge to support precision rehabilitation approaches for varied patient populations. There is a large amount of research-generated and clinical rehabilitation data available for this purpose; however, a pronounced lack of interoperability prevents large-scale data aggregation. Common data models (CDMs) such as Observational Medical Outcomes Partnership (OMOP) have improved data interoperability across healthcare settings, and more recently, for clinical rehabilitation data, specifically. However, the application of these CDMs to research-generated data has not yet been explored. Therefore, as a foundational step, our study evaluated the breadth and depth of OMOP CDM coverage for data in a multi-site repository of harmonized rehabilitation research data: the Enhancing NeuroImaging Genetics through Meta-Analysis Stroke Recovery (ENIGMA-SR) database. Methods: Two raters independently mapped data elements representing 46 demographics and medical history (DMH) ENIGMA-SR variables and 95 distinct ENIGMA-SR rehabilitation assessments to OMOP standard concepts. Initial rater agreement was assessed for data element inclusion in OMOP and for specific OMOP concepts used (primary metric: Gwet's agreement coefficient [AC]). Mapping differences were reconciled, and final mappings were descriptively analyzed to examine (1) overall OMOP inclusion, (2) inclusion of more granular levels (subscales, items) of complex assessments, and (3) mapped OMOP concept characteristics. Results: Initial rater agreement was good\/very good for overall OMOP inclusion of DMH and assessment data elements and for OMOP concepts mapped across almost all assessment data elements (Gwet's AC: 0.79-0.89). Initial OMOP concept agreement was more variable for DMH data elements; however, all mapping differences were successfully reconciled to 100%. Overall, DMH data elements had higher OMOP inclusion than rehabilitation assessments: 84.8% (39\/46) vs. 58.9% (56\/95). OMOP coverage was particularly limited for complex assessment subscale- and item-level data elements (9.4% [3\/32]; 19.2% [14\/73]) and did not match the granularity level represented in ENIGMA-SR data for 56.2% (41\/73) of complex assessments. DMH and top-level assessment data elements were frequently mapped to multiple OMOP concepts (median: 6, 2; range: 1-23, 1-8), and for > 50% of these data elements the concepts spanned 2-3 different OMOP domains. Conclusion: For ENIGMA-SR, the OMOP CDM has good coverage of DMH data, moderate top-level coverage of rehabilitation assessments, and very limited coverage of assessment subscales and items. This uneven coverage, combined with variability in OMOP concepts and domains mapped to equivalent data points, presents challenges for aggregating clinical and research-generated rehabilitation data into AI\/ML-ready datasets. Moreover, software tools currently available to facilitate the mapping process do not effectively accommodate content- and structure-related features inherent to research-generated data. Going forward, the utility of the OMOP CDM to aggregate multi-source rehabilitation data may be improved by expanding the catalogue of OMOP rehabilitation-related concepts, building cross-walks to research-oriented data standards, and adapting emerging computational tools to streamline the mapping process.","rel_num_authors":7,"rel_authors":[{"author_name":"Katherine J. Loomis","author_inst":"University of Southern California"},{"author_name":"Amisha Kumar","author_inst":"University of Southern California"},{"author_name":"Octavio Marin-Pardo","author_inst":"University of Southern California"},{"author_name":"Grace C. Bellinger","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Margaret A. French","author_inst":"University of Utah"},{"author_name":"Ryan T. Roemmich","author_inst":"Kennedy Krieger Institute\/Johns Hopkins University School of Medicine"},{"author_name":"Sook-Lei Liew","author_inst":"University of Southern California"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Genomic Evidence Links Inflammation to Residual Pulmonary Vascular Obstruction and Risk of Pulmonary Embolism Recurrence","rel_doi":"10.64898\/2026.06.26.26356642","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356642","rel_abs":"Background and Aims: Residual pulmonary vascular obstruction (RPVO) defined as the persistence of thrombotic material within the pulmonary arteries several months after an acute pulmonary embolism (PE) is associated with an increased risk of severe complications, including recurrent events and chronic pulmonary hypertension. However, the genomic architecture underlying RPVO in unprovoked PE remains poorly understood, and this study aims to address this gap. Method: By leveraging genetic and imaging RPVO data from three independent cohorts totaling 586 unprovoked PE patients, we conducted a meta-analysis of genome wide association study (GWAS) of RPVO using a dedicated statistical method to handle the semi-continuous distribution of RPVO. The meta-GWAS was complemented by haplotype association analyses and transcriptome wide association studies as well as Mendelian Randomization (MR) approaches based on plasma metabolites and proteins. Results: Through meta-GWAS, we identified one locus, OSTN, associated with RPVO (lead variant rs59109356 associated with a ~2-fold increase of RPVO, p=3.92x10-8). A second locus, CCN4, previously reported to associate with pulmonary fibrosis, was also identified, with evidence of association approaching genome-wide significance (p=6.7x10-8). We also identified a common haplotype spanning over AHSG\/HRG\/KNG1 associated with a ~3-fold increase of RPVO (p=2.96x10-8). Using plasma protein-based MR, we demonstrated that one unit increase in genetically determined plasma levels of IL-1 R AcP encoding IL1RAP was associated with a 28% (p=1.32x10-6) reduction in RPVO. We also observed statistical evidence that the CCN4 (p=0.06) and IL1RAP (p=0.02) loci associate with the risk of PE recurrence in a sample of 1,617 unprovoked PE patients. Conclusions: By identifying novel molecular determinants of RPVO that map to loci involved in inflammatory pathways and vascular remodeling, our study provides evidence that inflammation is the predominant, and likely the key mechanism underlying RPVO, whereas impaired fibrinolysis appears to play a more limited role.","rel_num_authors":22,"rel_authors":[{"author_name":"Floriane Samaria","author_inst":"Universite de Bordeaux"},{"author_name":"Gaelle Munsch","author_inst":"Universite de Brest"},{"author_name":"Ohanna C. L Bezerra","author_inst":"University of Toronto"},{"author_name":"Kerri L Wiggins","author_inst":"University of Washington"},{"author_name":"Lenaick Gourhant","author_inst":"Centre Hospitalier Univeristaire de Brest"},{"author_name":"Astrid van Hylckama Vlieg","author_inst":"Leids Universitair Medisch Centrum"},{"author_name":"Marine Germain","author_inst":"Universite de Bordeaux"},{"author_name":"Robert Olaso","author_inst":"Universite Paris-Saclay"},{"author_name":"Ilana Caro","author_inst":"Universite de Bordeaux"},{"author_name":"Noemie Saut","author_inst":"Aix-Marseille University"},{"author_name":"Delphine Bacq","author_inst":"Universite Paris-Saclay"},{"author_name":"Catherine A. Lemarie","author_inst":"Universite de Brest"},{"author_name":"Stephanie Debette","author_inst":"Universite de Bordeaux"},{"author_name":"Nicholas L. Smith","author_inst":"University of Washington"},{"author_name":"Frits Richard Rosendaal","author_inst":"Leiden Universitair Medisch Centrum"},{"author_name":"Pierre-Emmanuel Morange","author_inst":"Aix-Marseille University"},{"author_name":"Gregoire Le Gal","author_inst":"University of Ottawa"},{"author_name":"Jean-Fran\u00e7ois Deleuze","author_inst":"Universite Paris-Saclay"},{"author_name":"France Gagnon","author_inst":"University of Toronto Mississauga"},{"author_name":"Marc A. Rodger","author_inst":"McGill University"},{"author_name":"Francis Couturaud","author_inst":"Centre Hospitalier Universitaire de Brest"},{"author_name":"David-Alexandre Tregouet","author_inst":"Universite de Bordeaux"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Genomic Evidence Links Inflammation to Residual Pulmonary Vascular Obstruction and Risk of Pulmonary Embolism Recurrence","rel_doi":"10.64898\/2026.06.26.26356642","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356642","rel_abs":"Background and Aims: Residual pulmonary vascular obstruction (RPVO) defined as the persistence of thrombotic material within the pulmonary arteries several months after an acute pulmonary embolism (PE) is associated with an increased risk of severe complications, including recurrent events and chronic pulmonary hypertension. However, the genomic architecture underlying RPVO in unprovoked PE remains poorly understood, and this study aims to address this gap. Method: By leveraging genetic and imaging RPVO data from three independent cohorts totaling 586 unprovoked PE patients, we conducted a meta-analysis of genome wide association study (GWAS) of RPVO using a dedicated statistical method to handle the semi-continuous distribution of RPVO. The meta-GWAS was complemented by haplotype association analyses and transcriptome wide association studies as well as Mendelian Randomization (MR) approaches based on plasma metabolites and proteins. Results: Through meta-GWAS, we identified one locus, OSTN, associated with RPVO (lead variant rs59109356 associated with a ~2-fold increase of RPVO, p=3.92x10-8). A second locus, CCN4, previously reported to associate with pulmonary fibrosis, was also identified, with evidence of association approaching genome-wide significance (p=6.7x10-8). We also identified a common haplotype spanning over AHSG\/HRG\/KNG1 associated with a ~3-fold increase of RPVO (p=2.96x10-8). Using plasma protein-based MR, we demonstrated that one unit increase in genetically determined plasma levels of IL-1 R AcP encoding IL1RAP was associated with a 28% (p=1.32x10-6) reduction in RPVO. We also observed statistical evidence that the CCN4 (p=0.06) and IL1RAP (p=0.02) loci associate with the risk of PE recurrence in a sample of 1,617 unprovoked PE patients. Conclusions: By identifying novel molecular determinants of RPVO that map to loci involved in inflammatory pathways and vascular remodeling, our study provides evidence that inflammation is the predominant, and likely the key mechanism underlying RPVO, whereas impaired fibrinolysis appears to play a more limited role.","rel_num_authors":22,"rel_authors":[{"author_name":"Floriane Samaria","author_inst":"Universite de Bordeaux"},{"author_name":"Gaelle Munsch","author_inst":"Universite de Brest"},{"author_name":"Ohanna C. L Bezerra","author_inst":"University of Toronto"},{"author_name":"Kerri L Wiggins","author_inst":"University of Washington"},{"author_name":"Lenaick Gourhant","author_inst":"Centre Hospitalier Univeristaire de Brest"},{"author_name":"Astrid van Hylckama Vlieg","author_inst":"Leids Universitair Medisch Centrum"},{"author_name":"Marine Germain","author_inst":"Universite de Bordeaux"},{"author_name":"Robert Olaso","author_inst":"Universite Paris-Saclay"},{"author_name":"Ilana Caro","author_inst":"Universite de Bordeaux"},{"author_name":"Noemie Saut","author_inst":"Aix-Marseille University"},{"author_name":"Delphine Bacq","author_inst":"Universite Paris-Saclay"},{"author_name":"Catherine A. Lemarie","author_inst":"Universite de Brest"},{"author_name":"Stephanie Debette","author_inst":"Universite de Bordeaux"},{"author_name":"Nicholas L. Smith","author_inst":"University of Washington"},{"author_name":"Frits Richard Rosendaal","author_inst":"Leiden Universitair Medisch Centrum"},{"author_name":"Pierre-Emmanuel Morange","author_inst":"Aix-Marseille University"},{"author_name":"Gregoire Le Gal","author_inst":"University of Ottawa"},{"author_name":"Jean-Fran\u00e7ois Deleuze","author_inst":"Universite Paris-Saclay"},{"author_name":"France Gagnon","author_inst":"University of Toronto Mississauga"},{"author_name":"Marc A. Rodger","author_inst":"McGill University"},{"author_name":"Francis Couturaud","author_inst":"Centre Hospitalier Universitaire de Brest"},{"author_name":"David-Alexandre Tregouet","author_inst":"Universite de Bordeaux"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Effect of initiating an ARB- versus ACEI-based regimen on dementia risk, a target trial emulation of 2.5 million US Veterans","rel_doi":"10.64898\/2026.07.05.26357173","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357173","rel_abs":"Background: Hypertension is a modifiable risk factor for dementia, yet the comparative effectiveness of angiotensin receptor blockers (ARBs) versus angiotensin converting enzyme inhibitors (ACEIs) on dementia risk remains uncertain. Objective: To compare the risk of dementia and dementia-free death of ARB versus ACEI initiation among US Veterans with incident hypertension. Methods: We conducted a retrospective target trial emulation using a new-user, active-comparator design among Veterans with incident hypertension. We analyzed longitudinal electronic health records from 2,577,000 individuals who initiated ARBs or ACEIs between 1\/1\/2000-12\/31\/2017, with up to five years of follow-up. The exposure was initiation of an ARB-based versus ACEI-based antihypertensive regimen. Co-primary outcomes were dementia, identified using natural language processing of clinical notes, and dementia-free death. We used inverse probability of treatment weights based on 66 pretreatment covariates to estimate the cumulative incidence of the outcomes for each treatment group. Weighted risk ratios and absolute risk differences through five years were computed with bootstrapped 95% CIs. Secondary outcomes included all-cause death and a composite of dementia or death, evaluated using a weighted Kaplan-Meier approach. Results: Among 2,577,000 Veterans (mean age, 63 years; 4.5% female; 65% White; 15% Black), 10% initiated ARBs and 90% initiated ACEIs. Over five years of follow up, 6% developed dementia, 12% died without dementia, and 13% died overall. ARB initiation yielded consistently lower risk of dementia (risk ratio, 0.88; 95% CI, 0.83-0.93 at 6 months to 0.92; 95% CI, 0.90-0.94 at 5 years) and dementia-free death (risk ratio, 0.90; 95% CI, 0.86-0.96 at 6 months to 1.00; 95% CI, 0.98-1.01 at 5 years) than ACEI initiation. Effects on secondary outcomes were similar to those for primary outcomes. Greater protective dementia effects were observed in older and male Veterans and non-statin users, with similar effects on dementia-free death. Discussion: Among US Veterans with incident treated hypertension, initiation of ARB versus ACEI antihypertensive regimen conveyed a modestly lower risk of dementia. Given the high prevalence of hypertension, these modest effects may confer meaningful population-level benefits on brain health. Future research estimating per-protocol effects using a more generalizable population is needed to confirm our findings. Key words: antihypertensive medication, dementia, natural language processing, target trial emulation, Veteran","rel_num_authors":14,"rel_authors":[{"author_name":"Yizhe Xu","author_inst":"University of Utah"},{"author_name":"Jianlin Shi","author_inst":"University of Utah"},{"author_name":"Ryan Andrews","author_inst":"Columbia University"},{"author_name":"Catherine G. Derington","author_inst":"University of Utah School of Medicine"},{"author_name":"Tom Greene","author_inst":"University of Utah"},{"author_name":"Daniel Scharfstein","author_inst":"University of Utah"},{"author_name":"Ransmond Berchie","author_inst":"University of Utah"},{"author_name":"Mark Supiano","author_inst":"University of Utah"},{"author_name":"Jeff Williamson","author_inst":"Wake Forest University"},{"author_name":"Nicholas Pajewski","author_inst":"Wake Forest University"},{"author_name":"Jeremy Pruzin","author_inst":"Banner Alzheimer's Institute"},{"author_name":"Jaejin An","author_inst":"Kaiser Permanente Southern California"},{"author_name":"Jordana Cohen","author_inst":"University of Pennsylvania"},{"author_name":"Adam P. Bress","author_inst":"University of Utah, School of Medicine"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Enabled Detection of Vascular Perfusion Defects on Ventilation\/Perfusion (V\/Q) Scintigraphy for Pulmonary Embolism","rel_doi":"10.64898\/2026.06.25.26356599","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356599","rel_abs":"Accurate interpretation of planar ventilation-perfusion (V\/Q) scintigraphy, used for diagnosing pulmonary embolism (PE) based on PIOPED\/EANM guidelines, requires objective assessment of mismatched V\/Q defects. Manual delineation of V\/Q defects is time-consuming, subject to interobserver variability, and rarely performed in practice, limiting standardized reporting and quantification of disease burden. To address these challenges, we evaluated four modern AI models for automated segmentation of vascular perfusion defects in planar V\/Q scans and compared their performance to human annotators. We retrospectively identified 2,118 patients who underwent planar V\/Q scans at The Ottawa Hospital (June 2019-February 2023). Six standard projections (ANT, POST, LAO, RAO, LPO, RPO) were included. Four 2D neural networks (U-Net, nnU-Net, Swin UNETR, and a Bottleneck Transformer U-Net [BTU-Net]) were trained on 1,313 patients (7,878 projections) and validated on 329 (1,974 projections) using physician-annotated defects. A hold-out test set of 46 high probability patients was used to evaluate segmentation quality, and defect detection accuracy using free-response receiver operating characteristic (FROC) analysis, where BTU-Net was the only model performing on par with human readers, showing robust sensitivity across the entire range of segmentation probabilities. At 1.5 false positives per projection rate (FPPR), BTU-Net outperformed other models with a sensitivity of 0.529 {+\/-} 0.026, On a separate hold-out set of low likelihood of disease patients (n=430), the lowest FPPR was 0.08 {+\/-} 0.01 for BTU-Net (P<0.0001). BTU-Net enables rapid, consistent, and accurate interpretation of planar V\/Q scans. Such tools may enhance diagnostic efficiency, standardize reporting, and support non-expert readers in evaluating PE.","rel_num_authors":16,"rel_authors":[{"author_name":"Amir Jabbarpour","author_inst":"Caleton University"},{"author_name":"Eric Moulton","author_inst":"Jubilant DraxImage"},{"author_name":"Sanaz Kaviani","author_inst":"The Ottawa Hospital"},{"author_name":"Wanzhen Zeng","author_inst":"The Ottawa Hospital"},{"author_name":"Siraj Ghassel","author_inst":"University of Ottawa"},{"author_name":"Ramin Akbarian","author_inst":"The Ottawa Hospital"},{"author_name":"Anne Couture","author_inst":"Hopital Maisonneuve-Rosemont"},{"author_name":"Aubert Roy","author_inst":"McGill University Faculty of Medicine"},{"author_name":"Richard Liu","author_inst":"Jewish General Hospital"},{"author_name":"Yousif Al-ali","author_inst":"Hopital Maisonneuve-Rosemont"},{"author_name":"Yasser Foufa","author_inst":"Montreal Heart Institute"},{"author_name":"Nuha Hejji","author_inst":"University of Ottawa"},{"author_name":"Sukainah AlSulaiman","author_inst":"The Ottawa Hospital, Ottawa"},{"author_name":"Zeinab Shirazi","author_inst":"zshir069@uottawa.ca"},{"author_name":"Eugene Leung","author_inst":"The Ottawa Hospital"},{"author_name":"Ran Klein","author_inst":"The Ottawa Hospital"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Enabled Detection of Vascular Perfusion Defects on Ventilation\/Perfusion (V\/Q) Scintigraphy for Pulmonary Embolism","rel_doi":"10.64898\/2026.06.25.26356599","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356599","rel_abs":"Accurate interpretation of planar ventilation-perfusion (V\/Q) scintigraphy, used for diagnosing pulmonary embolism (PE) based on PIOPED\/EANM guidelines, requires objective assessment of mismatched V\/Q defects. Manual delineation of V\/Q defects is time-consuming, subject to interobserver variability, and rarely performed in practice, limiting standardized reporting and quantification of disease burden. To address these challenges, we evaluated four modern AI models for automated segmentation of vascular perfusion defects in planar V\/Q scans and compared their performance to human annotators. We retrospectively identified 2,118 patients who underwent planar V\/Q scans at The Ottawa Hospital (June 2019-February 2023). Six standard projections (ANT, POST, LAO, RAO, LPO, RPO) were included. Four 2D neural networks (U-Net, nnU-Net, Swin UNETR, and a Bottleneck Transformer U-Net [BTU-Net]) were trained on 1,313 patients (7,878 projections) and validated on 329 (1,974 projections) using physician-annotated defects. A hold-out test set of 46 high probability patients was used to evaluate segmentation quality, and defect detection accuracy using free-response receiver operating characteristic (FROC) analysis, where BTU-Net was the only model performing on par with human readers, showing robust sensitivity across the entire range of segmentation probabilities. At 1.5 false positives per projection rate (FPPR), BTU-Net outperformed other models with a sensitivity of 0.529 {+\/-} 0.026, On a separate hold-out set of low likelihood of disease patients (n=430), the lowest FPPR was 0.08 {+\/-} 0.01 for BTU-Net (P<0.0001). BTU-Net enables rapid, consistent, and accurate interpretation of planar V\/Q scans. Such tools may enhance diagnostic efficiency, standardize reporting, and support non-expert readers in evaluating PE.","rel_num_authors":16,"rel_authors":[{"author_name":"Amir Jabbarpour","author_inst":"Caleton University"},{"author_name":"Eric Moulton","author_inst":"Jubilant DraxImage"},{"author_name":"Sanaz Kaviani","author_inst":"The Ottawa Hospital"},{"author_name":"Wanzhen Zeng","author_inst":"The Ottawa Hospital"},{"author_name":"Siraj Ghassel","author_inst":"University of Ottawa"},{"author_name":"Ramin Akbarian","author_inst":"The Ottawa Hospital"},{"author_name":"Anne Couture","author_inst":"Hopital Maisonneuve-Rosemont"},{"author_name":"Aubert Roy","author_inst":"McGill University Faculty of Medicine"},{"author_name":"Richard Liu","author_inst":"Jewish General Hospital"},{"author_name":"Yousif Al-ali","author_inst":"Hopital Maisonneuve-Rosemont"},{"author_name":"Yasser Foufa","author_inst":"Montreal Heart Institute"},{"author_name":"Nuha Hejji","author_inst":"University of Ottawa"},{"author_name":"Sukainah AlSulaiman","author_inst":"The Ottawa Hospital, Ottawa"},{"author_name":"Zeinab Shirazi","author_inst":"zshir069@uottawa.ca"},{"author_name":"Eugene Leung","author_inst":"The Ottawa Hospital"},{"author_name":"Ran Klein","author_inst":"The Ottawa Hospital"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Retina-derived Quantitative Biomarkers of Brain Health","rel_doi":"10.64898\/2026.07.05.26357344","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357344","rel_abs":"Accurate and scalable assessment of quantitative neuroimaging biomarkers, such as white matter hyperintensities (WMH) and hippocampal (HIP) volumes, is essential for understanding and monitoring brain health, preventing neurological diseases and improving healthspan. However, population-level evaluation of these neuroimaging biomarkers relies on inaccessible, costly and time-consuming magnetic resonance imaging (MRI). Here we propose RetiBrain, a cross-modal deep learning framework that predicts these neuroimaging biomarkers from retinal color fundus photography (CFP) images. By distilling latent structural representations from MRI-based models into a CFP-based model, RetiBrain establishes biologically grounded eye-to-brain mapping. In a CFP-MRI paired cohort, RetiBrain accurately estimates six WMH- and HIP-related biomarkers and outperforms the state-of-the-art retinal foundation model RETFound, improving the mean Pearson correlation coefficient by 0.309 (from 0.240 to 0.549) and achieving a coefficient of 0.640 for periventricular WMH prediction. By integrating structural, topological and geometric feature analyses from CFP images, RetiBrain identifies interpretable retinal representations associated with neurodegeneration and cerebrovascular injury, hallmarks of major neurological diseases such as dementia and stroke. In a longitudinal cohort comprising 2,082 participants (4,164 CFP images with up to 15 years of follow-up), RetiBrain-predicted neuroimaging biomarkers robustly estimated neurological disease risk, as illustrated by dementia prediction (AUROC of 0.824, hazard ratio 2.500 per standard deviation increase, 95% CI: 2.201-2.840). RetiBrain provides a robust, scalable, cost-effective and convenient approach for the assessment of neuroimaging biomarkers, and has potential for long-term brain health monitoring in large-scale general population settings.","rel_num_authors":14,"rel_authors":[{"author_name":"Taizhangtian Ma","author_inst":"Department of Automation, Tsinghua University"},{"author_name":"Tao Yan","author_inst":"Department of Automation, Tsinghua University"},{"author_name":"Jing Sun","author_inst":"Department of Radiology, Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Ning Wu","author_inst":"Department of Medical Imaging Technology, School of Medical Technology, Capital Medical University"},{"author_name":"Mingze Xu","author_inst":"Center for MRI Research, Academy for Advanced Interdisciplinary Studies, Peking University"},{"author_name":"Ruiheng Zhang","author_inst":"Beijing Tongren Hospital"},{"author_name":"Na Zeng","author_inst":"Department of Infection Control, Peking University First Hospital"},{"author_name":"Qi Sun","author_inst":"Precision and Intelligence Medical Imaging Lab, Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Ying Hui","author_inst":"Kailuan General Hospital"},{"author_name":"Yuntao Wu","author_inst":"Kailuan General Hospital"},{"author_name":"Zhenchang Wang","author_inst":"Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Tien Yin Wong","author_inst":"Tsinghua University"},{"author_name":"Han Lv","author_inst":"Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China"},{"author_name":"Hui Qiao","author_inst":"Department of Automation, Tsinghua University"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Retina-derived Quantitative Biomarkers of Brain Health","rel_doi":"10.64898\/2026.07.05.26357344","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357344","rel_abs":"Accurate and scalable assessment of quantitative neuroimaging biomarkers, such as white matter hyperintensities (WMH) and hippocampal (HIP) volumes, is essential for understanding and monitoring brain health, preventing neurological diseases and improving healthspan. However, population-level evaluation of these neuroimaging biomarkers relies on inaccessible, costly and time-consuming magnetic resonance imaging (MRI). Here we propose RetiBrain, a cross-modal deep learning framework that predicts these neuroimaging biomarkers from retinal color fundus photography (CFP) images. By distilling latent structural representations from MRI-based models into a CFP-based model, RetiBrain establishes biologically grounded eye-to-brain mapping. In a CFP-MRI paired cohort, RetiBrain accurately estimates six WMH- and HIP-related biomarkers and outperforms the state-of-the-art retinal foundation model RETFound, improving the mean Pearson correlation coefficient by 0.309 (from 0.240 to 0.549) and achieving a coefficient of 0.640 for periventricular WMH prediction. By integrating structural, topological and geometric feature analyses from CFP images, RetiBrain identifies interpretable retinal representations associated with neurodegeneration and cerebrovascular injury, hallmarks of major neurological diseases such as dementia and stroke. In a longitudinal cohort comprising 2,082 participants (4,164 CFP images with up to 15 years of follow-up), RetiBrain-predicted neuroimaging biomarkers robustly estimated neurological disease risk, as illustrated by dementia prediction (AUROC of 0.824, hazard ratio 2.500 per standard deviation increase, 95% CI: 2.201-2.840). RetiBrain provides a robust, scalable, cost-effective and convenient approach for the assessment of neuroimaging biomarkers, and has potential for long-term brain health monitoring in large-scale general population settings.","rel_num_authors":14,"rel_authors":[{"author_name":"Taizhangtian Ma","author_inst":"Department of Automation, Tsinghua University"},{"author_name":"Tao Yan","author_inst":"Department of Automation, Tsinghua University"},{"author_name":"Jing Sun","author_inst":"Department of Radiology, Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Ning Wu","author_inst":"Department of Medical Imaging Technology, School of Medical Technology, Capital Medical University"},{"author_name":"Mingze Xu","author_inst":"Center for MRI Research, Academy for Advanced Interdisciplinary Studies, Peking University"},{"author_name":"Ruiheng Zhang","author_inst":"Beijing Tongren Hospital"},{"author_name":"Na Zeng","author_inst":"Department of Infection Control, Peking University First Hospital"},{"author_name":"Qi Sun","author_inst":"Precision and Intelligence Medical Imaging Lab, Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Ying Hui","author_inst":"Kailuan General Hospital"},{"author_name":"Yuntao Wu","author_inst":"Kailuan General Hospital"},{"author_name":"Zhenchang Wang","author_inst":"Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Tien Yin Wong","author_inst":"Tsinghua University"},{"author_name":"Han Lv","author_inst":"Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China"},{"author_name":"Hui Qiao","author_inst":"Department of Automation, Tsinghua University"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Beyond Bisulfite Sequencing: Resolving 5-hmC with Nanopore Sequencing Unmasks the True-5mC Methylation Entropy Landscape","rel_doi":"10.64898\/2026.07.08.736699","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.736699","rel_abs":"DNA methylation dynamically regulates cellular function and phenotype. At the tissue level, stochastic variation in methylation patterns, measured as methylation entropy, drives plasticity, development, cancer, and aging. Demethylation is facilitated by erasure of 5-methylcytosine (5mC) via the oxidized intermediate 5-hydroxymethylcytosine (5hmC), but bisulfite sequencing cannot distinguish these modifications, classifying both as 5mC. Using nanopore sequencing with direct detection of 5mC and 5hmC, we quantified how this historical conflation affects genome-wide methylation levels and methylation entropy in kidney cancer and the mouse medial prefrontal cortex. Bisulfite-like analysis introduced systematic, tissue-specific shifts in methylation distributions, influencing biological interpretation. However, these effects were modest in the low-5hmC kidney cancer samples, where pathway-level results remained highly concordant. Our findings demonstrate that True-5mC-based methylation entropy redefines the physical mapping of epigenomes, demonstrating that, in some contexts, what was previously interpreted as stochastic maintenance failure is frequently the structured signature of distinct, mechanistically interpretable cytosine biochemistry.","rel_num_authors":12,"rel_authors":[{"author_name":"Uri Bertocchi","author_inst":"Tel Aviv University"},{"author_name":"Eyal Katz","author_inst":"Tel Aviv University"},{"author_name":"Jonathan Jeffet","author_inst":"Tel Aviv University"},{"author_name":"Assaf Grunwald","author_inst":"Tel-Aviv university"},{"author_name":"Neiv Gabay","author_inst":"Tel Aviv University"},{"author_name":"Jasline Deek","author_inst":"Tel Aviv University"},{"author_name":"Sujal Verma","author_inst":"Tel Aviv University"},{"author_name":"Amit Shwartz","author_inst":"The Hebrew University of Jerusalem"},{"author_name":"Gali Umschweif-Nevo","author_inst":"The Hebrew University of Jerusalem"},{"author_name":"Bernard Lerer","author_inst":"The Hebrew University of Jerusalem"},{"author_name":"Yael Roichman","author_inst":"Tel Aviv University"},{"author_name":"Yuval Ebenstein","author_inst":"Tel Aviv University"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Evolutionarily labile pachytene piRNAs target an altered set of mRNAs in male hybrids of house mouse subspecies","rel_doi":"10.64898\/2026.07.08.737336","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737336","rel_abs":"During male meiosis-I of placental mammals, ~30-nucleotide pachytene PIWI-interacting RNAs (piRNAs) are expressed to regulate genes required for sperm function. Pachytene piRNA genes evolve rapidly. Whether rapid evolutionary turnover of pachytene piRNAs is under positive selective pressure remains enigmatic. Here, we investigate the evolutionary rate of pachytene piRNA genes over a short evolutionary timescale using geographically isolated mouse subspecies. We demarcate the genes producing postnatal piRNAs in PWK\/PhJ and CAST\/EiJ. Comparative genomics reveals 16 subspecies-specific pachytene piRNA loci underscoring how labile pachytene piRNA genes are even during short evolutionary timescale. We report a highly abundant CAST\/EiJ-specific pi17-CAST locus defying the notion that young pachytene piRNA genes do not produce abundant piRNAs. In fact, male hybrids from the reciprocal crossing C57BL\/6J and CAST\/EiJ produce pi17-CAST piRNAs almost exclusively from the CAST\/EiJ allele suggesting that species-specific nucleotide variants are sufficient to turn a locus into piRNA source. Intriguingly, hybrid males with reduced fertility features retain distinct piRNA-mRNA pairs compared to parents. Our work reveals that rapidly evolving pachytene piRNAs can gain or lose targets in the hybrid males of closely related mammalian species.","rel_num_authors":7,"rel_authors":[{"author_name":"Martin Saflund","author_inst":"Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University"},{"author_name":"Masomeh Askari","author_inst":"Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University,"},{"author_name":"Atiyeh Eghbali","author_inst":"Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University"},{"author_name":"Mukhtar Mohamed Abdi","author_inst":"Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University"},{"author_name":"John L. Fitzpatrick","author_inst":"Department of Zoology, Stockholm University"},{"author_name":"Tianxiong Yu","author_inst":"Department of Genomics and Computational Biology, University of Massachusetts Medical School"},{"author_name":"Deniz M. Ozata","author_inst":"Stockholm University"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Evolutionarily labile pachytene piRNAs target an altered set of mRNAs in male hybrids of house mouse subspecies","rel_doi":"10.64898\/2026.07.08.737336","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737336","rel_abs":"During male meiosis-I of placental mammals, ~30-nucleotide pachytene PIWI-interacting RNAs (piRNAs) are expressed to regulate genes required for sperm function. Pachytene piRNA genes evolve rapidly. Whether rapid evolutionary turnover of pachytene piRNAs is under positive selective pressure remains enigmatic. Here, we investigate the evolutionary rate of pachytene piRNA genes over a short evolutionary timescale using geographically isolated mouse subspecies. We demarcate the genes producing postnatal piRNAs in PWK\/PhJ and CAST\/EiJ. Comparative genomics reveals 16 subspecies-specific pachytene piRNA loci underscoring how labile pachytene piRNA genes are even during short evolutionary timescale. We report a highly abundant CAST\/EiJ-specific pi17-CAST locus defying the notion that young pachytene piRNA genes do not produce abundant piRNAs. In fact, male hybrids from the reciprocal crossing C57BL\/6J and CAST\/EiJ produce pi17-CAST piRNAs almost exclusively from the CAST\/EiJ allele suggesting that species-specific nucleotide variants are sufficient to turn a locus into piRNA source. Intriguingly, hybrid males with reduced fertility features retain distinct piRNA-mRNA pairs compared to parents. Our work reveals that rapidly evolving pachytene piRNAs can gain or lose targets in the hybrid males of closely related mammalian species.","rel_num_authors":7,"rel_authors":[{"author_name":"Martin Saflund","author_inst":"Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University"},{"author_name":"Masomeh Askari","author_inst":"Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University,"},{"author_name":"Atiyeh Eghbali","author_inst":"Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University"},{"author_name":"Mukhtar Mohamed Abdi","author_inst":"Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University"},{"author_name":"John L. Fitzpatrick","author_inst":"Department of Zoology, Stockholm University"},{"author_name":"Tianxiong Yu","author_inst":"Department of Genomics and Computational Biology, University of Massachusetts Medical School"},{"author_name":"Deniz M. Ozata","author_inst":"Stockholm University"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Fibulin-2 transduces a matrix-to-metabolism signal in kidney fibrosis","rel_doi":"10.64898\/2026.06.19.733428","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.19.733428","rel_abs":"Fibrotic extracellular matrix (ECM) is not merely a structural scaffold but an instructive signaling interface that shapes epithelial cell state. However, the molecular cues by which matrix remodeling controls tubular metabolism during kidney fibrosis remain poorly defined. Here, we identify Fibulin-2 (FBLN2) as a fibroblast-derived matrix cue that transduces fibrotic ECM remodeling into tubular mitochondrial metabolic reprogramming. Using fibroblast-selective deletion of Smoothened (Smo) across distinct fibroblast subpopulations, we found that loss of fibroblast Smo preserved kidney function and attenuated fibrosis in mouse models of chronic kidney injury. Multi-omics profiling revealed coordinated remodeling of the fibrotic matrisome, highlighted by suppression of FBLN2, an ECM glycoprotein genetically linked to kidney function in humans. Mechanistically, FBLN2 engaged EGFR in tubular epithelial cells and activated EGFR-AKT signaling in a non-canonical ligand-like manner. This signaling axis suppressed acetyl-CoA acetyltransferase 1 (ACAT1), a mitochondrial regulator of fatty acid oxidation and amino acid metabolism. Disruption of fibroblast Smo-FBLN2 signaling restored ACAT1-dependent oxidative metabolism and reduced tubular fibrotic activation. Spatial lipidomics revealed compartment-specific lipid remodeling associated with altered mitochondrial fatty acid metabolism, including acylcarnitine and phospholipid changes linked to reduced fibrotic injury. Together, these findings define a Fibulin-2-EGFR-ACAT1 matrix-to-metabolism signaling axis that couples fibrotic ECM remodeling to tubular mitochondrial metabolism during kidney fibrosis.","rel_num_authors":18,"rel_authors":[{"author_name":"Yuan Gui","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Yuanyuan Wang","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Wenxue Li","author_inst":"Yale University"},{"author_name":"Jia-Jun Liu","author_inst":"University of Pittsburgh"},{"author_name":"Chen Dai","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Samantha Mallari","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Kelly Zheng","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Cameron Jones","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Henry Wells Shaffer","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Liora Yueran Dorsett","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Tessora Chang","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Benjamin Malowitz","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Yanbao Yu","author_inst":"University of Delaware"},{"author_name":"Wei Chen","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Silvia Liu","author_inst":"University of Pittsburgh"},{"author_name":"Hongbo Liu","author_inst":"University of Rochester"},{"author_name":"Yansheng Liu","author_inst":"Yale Cancer Biology Institute, Yale University School of Medicine"},{"author_name":"Dong Zhou","author_inst":"University of Connecticut School of Medicine"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Fibulin-2 transduces a matrix-to-metabolism signal in kidney fibrosis","rel_doi":"10.64898\/2026.06.19.733428","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.19.733428","rel_abs":"Fibrotic extracellular matrix (ECM) is not merely a structural scaffold but an instructive signaling interface that shapes epithelial cell state. However, the molecular cues by which matrix remodeling controls tubular metabolism during kidney fibrosis remain poorly defined. Here, we identify Fibulin-2 (FBLN2) as a fibroblast-derived matrix cue that transduces fibrotic ECM remodeling into tubular mitochondrial metabolic reprogramming. Using fibroblast-selective deletion of Smoothened (Smo) across distinct fibroblast subpopulations, we found that loss of fibroblast Smo preserved kidney function and attenuated fibrosis in mouse models of chronic kidney injury. Multi-omics profiling revealed coordinated remodeling of the fibrotic matrisome, highlighted by suppression of FBLN2, an ECM glycoprotein genetically linked to kidney function in humans. Mechanistically, FBLN2 engaged EGFR in tubular epithelial cells and activated EGFR-AKT signaling in a non-canonical ligand-like manner. This signaling axis suppressed acetyl-CoA acetyltransferase 1 (ACAT1), a mitochondrial regulator of fatty acid oxidation and amino acid metabolism. Disruption of fibroblast Smo-FBLN2 signaling restored ACAT1-dependent oxidative metabolism and reduced tubular fibrotic activation. Spatial lipidomics revealed compartment-specific lipid remodeling associated with altered mitochondrial fatty acid metabolism, including acylcarnitine and phospholipid changes linked to reduced fibrotic injury. Together, these findings define a Fibulin-2-EGFR-ACAT1 matrix-to-metabolism signaling axis that couples fibrotic ECM remodeling to tubular mitochondrial metabolism during kidney fibrosis.","rel_num_authors":18,"rel_authors":[{"author_name":"Yuan Gui","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Yuanyuan Wang","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Wenxue Li","author_inst":"Yale University"},{"author_name":"Jia-Jun Liu","author_inst":"University of Pittsburgh"},{"author_name":"Chen Dai","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Samantha Mallari","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Kelly Zheng","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Cameron Jones","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Henry Wells Shaffer","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Liora Yueran Dorsett","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Tessora Chang","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Benjamin Malowitz","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Yanbao Yu","author_inst":"University of Delaware"},{"author_name":"Wei Chen","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Silvia Liu","author_inst":"University of Pittsburgh"},{"author_name":"Hongbo Liu","author_inst":"University of Rochester"},{"author_name":"Yansheng Liu","author_inst":"Yale Cancer Biology Institute, Yale University School of Medicine"},{"author_name":"Dong Zhou","author_inst":"University of Connecticut School of Medicine"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Fibulin-2 transduces a matrix-to-metabolism signal in kidney fibrosis","rel_doi":"10.64898\/2026.06.19.733428","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.19.733428","rel_abs":"Fibrotic extracellular matrix (ECM) is not merely a structural scaffold but an instructive signaling interface that shapes epithelial cell state. However, the molecular cues by which matrix remodeling controls tubular metabolism during kidney fibrosis remain poorly defined. Here, we identify Fibulin-2 (FBLN2) as a fibroblast-derived matrix cue that transduces fibrotic ECM remodeling into tubular mitochondrial metabolic reprogramming. Using fibroblast-selective deletion of Smoothened (Smo) across distinct fibroblast subpopulations, we found that loss of fibroblast Smo preserved kidney function and attenuated fibrosis in mouse models of chronic kidney injury. Multi-omics profiling revealed coordinated remodeling of the fibrotic matrisome, highlighted by suppression of FBLN2, an ECM glycoprotein genetically linked to kidney function in humans. Mechanistically, FBLN2 engaged EGFR in tubular epithelial cells and activated EGFR-AKT signaling in a non-canonical ligand-like manner. This signaling axis suppressed acetyl-CoA acetyltransferase 1 (ACAT1), a mitochondrial regulator of fatty acid oxidation and amino acid metabolism. Disruption of fibroblast Smo-FBLN2 signaling restored ACAT1-dependent oxidative metabolism and reduced tubular fibrotic activation. Spatial lipidomics revealed compartment-specific lipid remodeling associated with altered mitochondrial fatty acid metabolism, including acylcarnitine and phospholipid changes linked to reduced fibrotic injury. Together, these findings define a Fibulin-2-EGFR-ACAT1 matrix-to-metabolism signaling axis that couples fibrotic ECM remodeling to tubular mitochondrial metabolism during kidney fibrosis.","rel_num_authors":18,"rel_authors":[{"author_name":"Yuan Gui","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Yuanyuan Wang","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Wenxue Li","author_inst":"Yale University"},{"author_name":"Jia-Jun Liu","author_inst":"University of Pittsburgh"},{"author_name":"Chen Dai","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Samantha Mallari","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Kelly Zheng","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Cameron Jones","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Henry Wells Shaffer","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Liora Yueran Dorsett","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Tessora Chang","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Benjamin Malowitz","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Yanbao Yu","author_inst":"University of Delaware"},{"author_name":"Wei Chen","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Silvia Liu","author_inst":"University of Pittsburgh"},{"author_name":"Hongbo Liu","author_inst":"University of Rochester"},{"author_name":"Yansheng Liu","author_inst":"Yale Cancer Biology Institute, Yale University School of Medicine"},{"author_name":"Dong Zhou","author_inst":"University of Connecticut School of Medicine"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"A frameshift mutation drives divergent biosynthesis of metallophores in Methylobacterium extorquens","rel_doi":"10.64898\/2026.07.08.737268","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737268","rel_abs":"Iron is widely considered the first metallocofactor, evolving as iron-sulfur clusters in early life. While iron-chelating siderophores have been widely characterized across microbial life, the lanthanide-chelating metallophore, methylolanthanin, has only recently been described in Methylobacterium extorquens AM1. Methylolanthanin shares structural similarities to the siderophore rhodopetrobactin but contains 4-hydroxybenzoate chelating moieties in place of canonical 3,4-dihydroxybenzoates. Here we compare Methylobacterium extorquens AM1, which produces methylolanthanin, and the closely related Methylobacterium extorquens PA1, which produces rhodopetrobactin. We present a pathway for the biosynthesis of both metallophores and describe the unusual synthesis of the 4-HB moieties of methylolanthanin from tyrosine. We uncover a frameshift mutation in the predicted 3-dehydroshikimate dehydratase, mllF, that prevents production of rhodopetrobactin in AM1 through truncation of the catalytically essential N-terminus. We find that deletion of the uncharacterized gene mllG reveals a cryptic branch of the pathway, leading to production of both methylolanthanin and rhodopetrobactin. Finally, we discover that rhodopetrobactin production in this mutant is enabled through the activity of a 3-dehydroshikimate dehydratase in a separate biosynthetic gene cluster. These insights highlight an evolutionary mechanism for metallophore diversification through pseudogenization and regulation of distinct biosynthetic gene clusters with shared aromatic intermediates.","rel_num_authors":8,"rel_authors":[{"author_name":"Alexa M Zytnick","author_inst":"UC Berkeley"},{"author_name":"Marquis T Yazzie","author_inst":"University of Denver"},{"author_name":"Tashi C.E. Liebergesell","author_inst":"University of Utah"},{"author_name":"Elan H Tran","author_inst":"University of California Berkeley"},{"author_name":"Zachary L Reitz","author_inst":"University of California Santa Barbara"},{"author_name":"Aaron W Puri","author_inst":"University of Utah"},{"author_name":"Allegra T Aron","author_inst":"University of Denver"},{"author_name":"Norma Cecilia Martinez-Gomez","author_inst":"University of California Berkeley"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Female-specific m6A remodeling in the liver correlates with post-transcriptional metabolic adaptation to high fat diet","rel_doi":"10.64898\/2026.06.19.733425","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.19.733425","rel_abs":"Sex differences strongly influence susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD), yet the regulatory mechanisms underlying these differences remain incompletely understood. To examine sex-specific hepatic adaptation to a high-fat (HF) diet mouse model of MASLD, we integrated proteomics, transcriptomics, and Oxford Nanopore direct RNA sequencing for transcriptome-wide m6A profiling in male and female mouse livers. Female mice were relatively protected from HF diet-induced hepatic steatosis and exhibited distinct proteome remodeling enriched for peroxisomal pathways. In contrast, transcriptomic responses in females were dominated by inflammatory signatures and did not recapitulate the metabolic adaptations observed at the protein level, revealing extensive RNA-protein discordance and post-transcriptional remodeling. Integrated RNA-protein analyses identified female-specific amplification of peroxisomal proteins despite modest transcript-level changes. HF diet also induced sex-specific remodeling of m6A RNA methylation and altered regulation of the m6A methylation system. Notably, reduced 3' UTR m6A methylation of peroxisomal transcripts inversely correlated with increased protein abundance relative to RNA expression in female mice. Together, these findings implicate m6A-associated post-transcriptional regulation in sex-specific hepatic adaptation to HF diet exposure and the basis for discordance between many of the mRNAs and proteins in the liver.","rel_num_authors":12,"rel_authors":[{"author_name":"Sofia V. Krylova","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Maxwell Horton","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Giorgia Bucciarelli","author_inst":"University of Trento"},{"author_name":"Li Liu","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jacob Berrigan","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Ronald Cutler","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Kartik Chandran","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Nathaniel W. Snyder","author_inst":"Temple University"},{"author_name":"Toma Tebaldi","author_inst":"University of Trento; Yale University School of Medicine"},{"author_name":"Simone Sidoli","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"author_name":"Kamini Singh","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jeffrey E. Pessin","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Female-specific m6A remodeling in the liver correlates with post-transcriptional metabolic adaptation to high fat diet","rel_doi":"10.64898\/2026.06.19.733425","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.19.733425","rel_abs":"Sex differences strongly influence susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD), yet the regulatory mechanisms underlying these differences remain incompletely understood. To examine sex-specific hepatic adaptation to a high-fat (HF) diet mouse model of MASLD, we integrated proteomics, transcriptomics, and Oxford Nanopore direct RNA sequencing for transcriptome-wide m6A profiling in male and female mouse livers. Female mice were relatively protected from HF diet-induced hepatic steatosis and exhibited distinct proteome remodeling enriched for peroxisomal pathways. In contrast, transcriptomic responses in females were dominated by inflammatory signatures and did not recapitulate the metabolic adaptations observed at the protein level, revealing extensive RNA-protein discordance and post-transcriptional remodeling. Integrated RNA-protein analyses identified female-specific amplification of peroxisomal proteins despite modest transcript-level changes. HF diet also induced sex-specific remodeling of m6A RNA methylation and altered regulation of the m6A methylation system. Notably, reduced 3' UTR m6A methylation of peroxisomal transcripts inversely correlated with increased protein abundance relative to RNA expression in female mice. Together, these findings implicate m6A-associated post-transcriptional regulation in sex-specific hepatic adaptation to HF diet exposure and the basis for discordance between many of the mRNAs and proteins in the liver.","rel_num_authors":12,"rel_authors":[{"author_name":"Sofia V. Krylova","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Maxwell Horton","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Giorgia Bucciarelli","author_inst":"University of Trento"},{"author_name":"Li Liu","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jacob Berrigan","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Ronald Cutler","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Kartik Chandran","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Nathaniel W. Snyder","author_inst":"Temple University"},{"author_name":"Toma Tebaldi","author_inst":"University of Trento; Yale University School of Medicine"},{"author_name":"Simone Sidoli","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"author_name":"Kamini Singh","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jeffrey E. Pessin","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Characterizing dynamic tissue architectures by identifying cell-type-specific spatiotemporal gene programs with stGP","rel_doi":"10.64898\/2026.07.03.736035","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736035","rel_abs":"Cellular gene programs unfold over biological time within spatially organized tissues. The same cell type can activate distinct programs in different spatial domains or multicellular niches. Spatiotemporal transcriptomics enables in situ measurement of these processes; however, the interplay between temporal progression and spatial organization complicates the identification of whether a gene program is influenced by temporal changes, spatial structure, or both. To overcome this challenge, we present spatiotemporal Gene Programs (stGP), a statistical framework for identifying interpretable cell-type-specific gene programs across multi-sample spatiotemporal transcriptomic studies. stGP preserves the molecular identity of each program through shared gene loadings, and decomposes individual cell activity into a temporal component that captures gene program responses over biological time, and a spatial component that characterizes variations within tissue sections. We quantify their relative contributions by estimating their variance components. Through comprehensive simulations and analyses of three spatiotemporal transcriptomic datasets across different tissues and technologies, stGP uncovers spatiotemporal gene programs that distinguish preserved tissue architecture from dynamic remodeling. Our framework delineates age-associated cellular responses and uncovers localized program deployment within anatomical regions, aging hotspots, and multicellular niches. Our results establish stGP as an effective and robust framework for dissecting dynamic tissue architecture, providing insights into how cell-type-specific gene programs are coordinated across time and spatial microenvironments.","rel_num_authors":5,"rel_authors":[{"author_name":"Baichen Yu","author_inst":"Hong Kong University of Science and Technology"},{"author_name":"Ziyue Tan","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Xiaomeng Wan","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Hansheng Wang","author_inst":"Peking University"},{"author_name":"Can Yang","author_inst":"HKUST"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Stromal Prostaglandin is a Dominant Spatial Regulator of Cell-fate Plasticity in Colorectal Cancer","rel_doi":"10.64898\/2026.06.14.732116","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732116","rel_abs":"Colorectal cancer (CRC) tumours with high stromal content have a worse outcome, but the mechanisms governing this are unclear. Using high-throughput single-cell perturbation analysis of CRC patient-derived organoids (PDOs) and cancer-associated fibroblasts (CAFs) we find that epithelial cells with high stromal-communication potential are marked by the transcriptional co-repressor DACH1. To define the causal regulators of stromal-epithelial signalling, we developed a novel CRISPR screening platform to perturb the CAF secretome and measure epithelial stem cell responses at single-cell resolution. Intercellular CRISPR screening and full factorial ligand analysis revealed that stromal Prostaglandin E2 (PGE2) is a dominant regulator of CRC cell-fate plasticity. Stromal PGE2 converts DACH1+ epithelia from a chemosensitive proliferative colonic stem cell (proCSC) fate into a chemorefractory and prometastatic revival colonic stem cell (revCSC) fate. PGE2-driven epithelial transdetermination is rapid and reversible, providing an acute mechanism for stromal-driven plasticity in CRC tumours. Genetic and pharmacological inhibition of stromal COX2 inhibits epithelial plasticity, trapping CRC epithelia in an anti-metastatic and chemosensitive proCSC fate. PTGS2+ CAFs support a spatially resolved revCSC to proCSC plasticity gradient in human CRC tumours marked by increasing DACH1 expression. These results reveal that stromal prostaglandin is a dominant spatial regulator of poor-prognosis cell-fates and may explain the benefit of anti-COX therapies in both preventing and treating CRC.","rel_num_authors":18,"rel_authors":[{"author_name":"Corinne Molyneux","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK"},{"author_name":"Rhianna O'Sullivan","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK"},{"author_name":"Eoghan J. Mulholland-Illingworth","author_inst":"Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK"},{"author_name":"Joshua W. Moore","author_inst":"Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Woodstock Road, Oxford, OX2 6GG, UK"},{"author_name":"Nick Li","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK"},{"author_name":"Petra Vlckova","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK"},{"author_name":"Raheleh Amirkhah","author_inst":"Johnston Cancer Research Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, UK"},{"author_name":"Aurelie Dobric","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK"},{"author_name":"Shauna Crampsie","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK"},{"author_name":"Alistair Wilkinson","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK; Department of Comput"},{"author_name":"Jack Langley","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK"},{"author_name":"Marta Labarquilla Alonso","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK"},{"author_name":"Ashley Campbell","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK"},{"author_name":"Jeroen Claus","author_inst":"Phospho Biomedical Animation, Hoofdkantoor 2G5, Van Nelleweg 1, 3044 BC, Rotterdam, NL"},{"author_name":"Smita Krishnaswamy","author_inst":"Department of Computer Science, Yale University, New Haven, CT, USA"},{"author_name":"Philip D. Dunne","author_inst":"Johnston Cancer Research Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, UK"},{"author_name":"Simon Leedham","author_inst":"Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK"},{"author_name":"Christopher J. Tape","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK; Cancer Research UK S"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Sensory neurons encode long-term inflammatory memory that promotes gastric regeneration and tumorigenesis","rel_doi":"10.64898\/2026.06.15.732199","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732199","rel_abs":"Inflammatory memory has emerged as a fundamental principle by which prior injury shapes future tissue responses, yet whether sensory neurons participate in long-term tissue memory remains unknown. Here, we show that vagal sensory neurons acquire a durable, experience-dependent state following gastric injury or Helicobacter pylori infection, leading to enhanced regeneration, metaplasia, and tumor progression upon re-injury. This neuronal program is stable, functionally transferable, and sufficient to drive epithelial responses in vivo. Mechanistically, injury-activated ILC2s establish sensory neuronal memory through IL-13-dependent epigenetic remodeling, inducing SMYD4-mediated H3K4 trimethylation and promoting CGRP-dependent activation of gastric epithelial cells. Together, our findings support a model in which tissue memory is not restricted to epithelial or immune compartments but emerges through coordinated long-term adaptations across multiple cellular systems. Within this framework, sensory neurons provide a persistent substrate for recall responses, linking prior inflammatory experience to sustained epithelial plasticity and cancer susceptibility.\n\nHIGHLIGHTSO_LISensory neurons function as a durable compartment of tissue memory.\nC_LIO_LICGRP-RAMP1 signaling couples neuronal memory to gastric stem cells.\nC_LIO_LIILC2-derived IL-13 establishes sensory neuronal memory programs.\nC_LIO_LISMYD4-mediated H3K4me3 stabilizes long-term neuronal memory.\nC_LIO_LINeuronal memory promotes gastric regeneration and tumor susceptibility.\nC_LI","rel_num_authors":17,"rel_authors":[{"author_name":"Yi Zeng","author_inst":"Columbia University Medical Center"},{"author_name":"Puran Zhang","author_inst":"Columbia University Medical Center"},{"author_name":"Feijing Wu","author_inst":"Columbia University Medical Center"},{"author_name":"Ruhong Tu","author_inst":"Columbia University Medical Center"},{"author_name":"Xiaofei Zhi","author_inst":"Columbia University Medical Center"},{"author_name":"Hiroki Kobayashi","author_inst":"Columbia University Medical Center"},{"author_name":"Jin Qian","author_inst":"Columbia University Medical Center"},{"author_name":"Yosuke Ochiai","author_inst":"Columbia University Medical Center"},{"author_name":"Biyun Zheng","author_inst":"Columbia University Medical Center"},{"author_name":"Hualong Zheng","author_inst":"Columbia University Medical Center"},{"author_name":"Shuang Li","author_inst":"Columbia University Medical Center"},{"author_name":"Juli Lin","author_inst":"Columbia University Medical Center"},{"author_name":"Masahiro Hata","author_inst":"Columbia University Medical Center"},{"author_name":"Quin T. Waterbury","author_inst":"Columbia University Medical Center"},{"author_name":"Junya Arai","author_inst":"Columbia University Medical Center"},{"author_name":"Leah B. Zamechek","author_inst":"Columbia University Medical Center"},{"author_name":"Timothy Cragin Wang","author_inst":"Columbia University Medical Center"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Integrin-engaged Cellular Patches Mechanically Impose a Mitochondrial Respiratory Bottleneck to Suppress Cancer Cell Motility","rel_doi":"10.64898\/2026.07.03.736349","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736349","rel_abs":"The nanoscale organization of cell-adhesive ligands is increasingly recognized as a determinant of cell behavior, yet whether it directly regulates cellular metabolism remains unclear. Here we show that supramolecular clustering of integrin-binding ligands regulates mitochondrial respiratory capacity through integrin-mediated mechanotransduction. Supramolecular ligand clustering induces integrin redistribution and cytoskeletal remodeling, leading to mitochondrial reorganization and a selective constraint on oxidative phosphorylation. This respiratory limitation functionally constrains tumor cell migration and invasion and cannot be overcome by restoring cytoskeletal contractility, whereas replenishing mitochondrial metabolic substrates effectively rescues motility. In a HeLa xenograft model, the integrin-binding supramolecular system suppresses tumor growth and reduces extracellular matrix deposition. These findings identify mitochondrial respiratory capacity as a critical downstream effector of integrin mechanosignaling and establish extracellular ligand organization as a previously unrecognized driver of mechanically encoded metabolic regulation.","rel_num_authors":9,"rel_authors":[{"author_name":"Qizheng Zhang","author_inst":"City University of Hong Kong"},{"author_name":"Sona Rani Roy","author_inst":"The University of Tokyo"},{"author_name":"Tianrui Zhao","author_inst":"Sun Yat-sen University"},{"author_name":"Wenjing Hou","author_inst":"South China University of Technology"},{"author_name":"Chenjie Xu","author_inst":"City University of Hong Kong"},{"author_name":"Jiancan Yu","author_inst":"Sun Yat-sen University"},{"author_name":"Kai Wu","author_inst":"South China University of Technology"},{"author_name":"Xunwu Hu","author_inst":"Dongguan Institute of Materials Science and Technology, Chinese Academy of Sciences"},{"author_name":"Ye Zhang","author_inst":"Dongguan Institute of Materials Science and Technology, Chinese Academy of Sciences"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Navigating the pangenome coordinate system with Shredtools","rel_doi":"10.64898\/2026.07.03.736354","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736354","rel_abs":"Existing notions of pangenome coordinates rely on hard-to-compute multiple sequence alignments. On the other hand, pangenome-wide exact unique matches (multi-MUMs) can be computed efficiently, and represent conserved stretches of columns in the underlying MSA. We introduce Shredtools, which uses multi-MUMs as pangenome waypoints and allows for sophisticated queries in pangenome coordinates. Its primary query is extract, which takes an interval of one sequence and extracts the smallest window containing it that is syntenic pangenome-wide. Shredtools' extract query can extract a gene region from 476 human genomes in half a second. Other queries help to refine these results, by finding local exact matches to improve the density of multi-MUM coverage (\"enhance\") and by selectively discarding sequences to improve the precision of the syntenic region (\"zoom\"). The Shredtools web interface (available at https:\/\/vikshiv.github.io\/shredtools) allows for client-side handling of extract queries with index queries handled via simple and fast HTTP Range requests, simplifying usage and enabling pangenome-scale discoveries.","rel_num_authors":2,"rel_authors":[{"author_name":"Vikram S Shivakumar","author_inst":"Johns Hopkins University"},{"author_name":"Ben Langmead","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Pitx2 modulates Fgf10 dosage to initiate asymmetric lung morphogenesis","rel_doi":"10.64898\/2026.06.16.732783","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732783","rel_abs":"Most of the visceral organs are anatomically asymmetric across the left-right axis. These asymmetries can be traced to a well-studied molecular cascade leading to left-sided gene expression, including Pitx2, in the mesoderm. Yet how these early differences in gene expression are converted into differential shaping of organs at later stages remains incompletely understood, and for many organs, such as the lung, the question has not even been explored. Meanwhile, the signaling pathways responsible for the morphogenesis of the lung have been intensively studied, but no insight has been reported regarding whether they should differ on the left and right sides. Here we identify Fgf10 as a Pitx2-sensitive signal in the mesenchyme of the developing mouse lung. Fgf10 expression increases as Pitx2 decreases, making the right lung, which lacks Pitx2 expression, grow faster than the left during the budding stage. Modulating Fgf10 dosage in the left mesenchyme is sufficient to alter lung budding asymmetry. At the cellular level, the faster growth of the right lung is established by increased levels of epithelial proliferation, without significant differences in directional migration into the mesenchyme. Conditional genetics further show that Pitx2 acts during the budding stage to establish later branching asymmetry. Thus, Pitx2 converts left-right mesenchymal identity into organ asymmetry by quantitatively tuning Fgf10-dependent epithelial growth during early organogenesis.","rel_num_authors":4,"rel_authors":[{"author_name":"Rui Yan","author_inst":"Harvard Medical School"},{"author_name":"Jared Helms","author_inst":"University of California, San Diego"},{"author_name":"Pulin Li","author_inst":"Whitehead Institute for Biomedical Research \/ MIT"},{"author_name":"Clifford J. Tabin","author_inst":"Harvard Medical School"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"A molecular integrator of sleep duration and interruption","rel_doi":"10.64898\/2026.07.03.736427","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736427","rel_abs":"Sleep is regulated across multiple timescales. Transitions between sleep and wake happen within seconds; individual sleep bouts last minutes to hours; and homeostatic sleep need has classically been tracked across multiple bouts. Rapid sleep-to-wake transitions are driven by identified neurons, circuits, and neuromodulators, while slow wave activity correlates with sleep need across hours. However, no signal has been shown to encode sleep history within individual sleep bouts, the timescale at which the brain must continuously monitor how much sleep has occurred and how likely waking is at any given moment. Biochemical signals downstream of sleep\/wake-associated neuromodulators display slower dynamics than the neuromodulators themselves, making them candidate encoders of within-bout sleep history. Here, by measuring protein kinase A substrate phosphorylation (PKA-SP) in real time in freely behaving mice, we show that membrane PKA-SP decreases exponentially within each sleep bout with consistent kinetics across bouts, integrates sleep duration and sleep interruption, and continuously forecasts moment-to-moment waking probability. Following sleep deprivation, PKA-SP reaches lower levels at the end of sleep bouts, correlating with increased sleep need dissipation. These findings identify a molecular signal encoding within-bout sleep history, revealing how biochemical dynamics bridge fast arousal circuits and the slow timescale of classical sleep homeostasis.","rel_num_authors":9,"rel_authors":[{"author_name":"Elizabeth I. Tilden","author_inst":"Washington University in St. Louis"},{"author_name":"Antonio J. Fontenele","author_inst":"University of Arkansas"},{"author_name":"Kane M. Goggans","author_inst":"Washington University in St. Louis"},{"author_name":"Sophie Ma","author_inst":"Washington University in St. Louis"},{"author_name":"Drake Gorecki","author_inst":"Washington University in St. Louis"},{"author_name":"Zachary D. Berriman-Rozen","author_inst":"Washington University in St. Louis"},{"author_name":"Anna Oldenborg","author_inst":"Washington University in St. Louis"},{"author_name":"Woodrow L. Shew","author_inst":"University of Arkansas"},{"author_name":"Yao Chen","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"A general thermodynamic approach for model reduction of enzyme cycles and electrogenic transporters","rel_doi":"10.64898\/2026.06.16.732208","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732208","rel_abs":"Mathematical models of enzyme cycles form the basis of quantifying key features of metabolism and membrane transport. These models are often integrated into more comprehensive models such as whole-cell models to understand emergent behaviours between interacting components. However, it is currently computationally infeasible to simulate the full dynamical behaviour of every enzyme at a network scale. Model reduction is frequently used to improve computational efficiency, but in general, these approaches do not preserve physical and thermodynamic consistency.\n\nHere, we outline a general method for simplifying enzyme kinetics models while retaining mass, charge and energy balance. We base our approach on the bond graph, which is a general methodology for modelling biological systems from fundamental physical laws. This approach ensures that key physical constraints are enforced in every model, regardless of their complexity. Our thermodynamic model reduction framework is readily extended to electrogenic transporters through the coupling of chemical and electrical processes. Through the application of our approach to both hypothetical enzyme cycles and real data from the Na+\/K+ ATPase, we show that it can rapidly screen for plausible network structures in circumstances where enzyme catalytic mechanisms may not be fully characterised, facilitating biological discovery and drug development.","rel_num_authors":4,"rel_authors":[{"author_name":"Michael Pan","author_inst":"University of New South Wales"},{"author_name":"Peter J. Gawthrop","author_inst":"University of Melbourne"},{"author_name":"Joseph Cursons","author_inst":"Audax Biosciences"},{"author_name":"Edmund J. Crampin","author_inst":"University of Melbourne"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"An in vitro regeneration system with efficient rooting in sweet orange (Citrus sinensis) supports recovery of transgenic plants","rel_doi":"10.64898\/2026.06.16.732047","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732047","rel_abs":"In vitro regeneration of Citrus plants is a widely used method, however, induction of adventitious roots from regenerated shoots remains a major bottleneck, limiting the recovery of healthy plants for commercial production and genomic research for crop improvement. We established an in vitro regeneration system producing profuse, healthy roots for sweet orange (Citrus sinensis cv. Benyenda) by optimising combinations and concentrations of auxins. Prior to optimising the rooting media (RTMs), we obtained a shoot regeneration rate of 90.6% from sweet orange epicotyl explants using a cytokinin, 6-benzylaminopurine (BAP). Across twelve auxin-supplemented RTMs containing different concentrations of indole-3-butyric acid (IBA) and\/or 1-naphthaleneacetic acid (NAA), rooting percentages ranged from 8 - 87.5%. The combination of IBA 1.0 mg L-1 and NAA 0.1 mg L-1 promoted the best overall performance, 75 {+\/-} 7.2% rooting percentage with healthy, callus-free roots ([&ge;]5 cm in length), whereas other RTMs with other auxin combinations induced callus and limited root elongation. The best-performing SRM and RTM were subsequently used for selection and recovery of transgenic sweet orange lines carrying an empty CRISPR\/Cas9 construct, resulting in an 4.8% transformation efficiency. Both transgenic and non-transgenic rooted plantlets were successfully acclimatised under glasshouse conditions with a survival rate of 90%. This enhanced regeneration system overcomes rooting bottleneck and improves plant survival,enabling faster recovery of transgenic citrus lines within four months. It supports accelerated development for commercial applications and advances in citrus genetic improvement.","rel_num_authors":4,"rel_authors":[{"author_name":"Juel Datta","author_inst":"School of Biology and Environmental Science, Queensland University of Technology (QUT), 2 George St, Brisbane, Queensland 4000, Australia"},{"author_name":"Sudipta Das Bhowmik","author_inst":"School of Biology and Environmental Science, Queensland University of Technology (QUT), 2 George St, Brisbane, Queensland 4000, Australia"},{"author_name":"Brett Williams","author_inst":"School of Biology and Environmental Science, Queensland University of Technology (QUT), 2 George St, Brisbane, Queensland 4000, Australia"},{"author_name":"Stephanie C Kerr","author_inst":"School of Biology and Environmental Science, Queensland University of Technology (QUT), 2 George St, Brisbane, Queensland 4000, Australia"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Graph-based modeling of multiparametric MRI deciphers molecular states of high-grade glioma invasion with prognostic implications","rel_doi":"10.64898\/2026.06.18.733053","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733053","rel_abs":"AbstractThe infiltrative, non-enhancing margin of IDH wildtype high grade glioma (IDHwt HGG) harbors distinct molecular programs that drive invasion and therapeutic resistance, yet remains largely unevaluable by conventional tissue sampling approaches and by conventional imaging. Here we show that this invasive architecture is encoded within multiparametric MRI (mpMRI) feature relationships and can be decoded using a graph-based framework trained on multiregional image-localized biopsies. Across 134 spatially matched biopsy-imaging pairs from 35 patients with primary IDHwt HGG (29 glioblastomas (GBM) and 6 non-glioblastoma HGGs), unsupervised graph community detection identifies two imaging-defined clusters that localize to invasive tumor regions without molecular supervision. Transcriptomic profiling associates these clusters with neuronal (NEU) and glycolytic-plurimetabolic (GPM) molecular programs.\n\nBuilding on this framework, a graph convolutional network (GCN) accurately predicts NEU and GPM transcriptional states in independent training and validation cohorts and significantly outperforms conventional convolutional neural networks. Applied to whole-tumor mpMRI volumes, the trained GCN generates spatially resolved probability maps that quantify the distribution and relative burden of NEU and GPM programs across both MRI contrast-enhancing and non-enhancing invasive regions. These imaging-derived molecular maps stratify patients by overall survival. Increased GPM burden is associated with poorer survival, consistent with the aggressive behavior associated with mesenchymal-like transcriptional programs in IDHwt HGG. In contrast, increased NEU burden is associated with improved survival, identifying a previously unrecognized imaging-derived prognostic biomarker that was not detected by biopsy-based molecular classification alone. Together, these findings establish a graph-based imaging framework for spatially resolved molecular classification of invasive IDHwt HGG and demonstrate that whole-tumor molecular state architecture carries prognostic information beyond conventional tissue sampling.","rel_num_authors":24,"rel_authors":[{"author_name":"Matthew Flick","author_inst":"Mayo Clinic"},{"author_name":"Matthew Kenaston","author_inst":"Mayo Clinic"},{"author_name":"Srijon Sarkar","author_inst":"Emory University"},{"author_name":"Gabe Lafond","author_inst":"Mayo Clinic"},{"author_name":"Ian Hart","author_inst":"Mayo Clinic"},{"author_name":"Gina Mazza","author_inst":"Mayo Clinic"},{"author_name":"Justin Cramer","author_inst":"Mayo Clinic"},{"author_name":"Bernard R Bendok","author_inst":"Mayo Clinic"},{"author_name":"Chandan Krishna","author_inst":"Mayo Clinic"},{"author_name":"Richard Zimmerman","author_inst":"Mayo Clinic"},{"author_name":"Jonathon Parker","author_inst":"Mayo Clinic"},{"author_name":"Jing Li","author_inst":"Georgia Institute of Technology"},{"author_name":"Kliment Donev","author_inst":"Mayo Clinic"},{"author_name":"Krishna Bhat","author_inst":"Mayo Clinic"},{"author_name":"Leslie Baxter","author_inst":"Mayo Clinic"},{"author_name":"Yuxiang Zhou","author_inst":"Mayo Clinic"},{"author_name":"Chad C Quarles","author_inst":"Texas MD Anderson"},{"author_name":"David Craig","author_inst":"City of Hope"},{"author_name":"Antonio Iavarone","author_inst":"Sylvester Comprehensive Cancer Center, Miller School of Medicine"},{"author_name":"Shannon Fortin Ensign","author_inst":"Mayo Clinic"},{"author_name":"Michele W Ceccarelli","author_inst":"University of Miami"},{"author_name":"Kasthuri Kannan","author_inst":"United States Army War College"},{"author_name":"Nhan Tran","author_inst":"Translational Genomics Research Institute"},{"author_name":"Leland Hu","author_inst":"Mayo Clinic"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Pan-Cancer Driver Mutation Signatures Define a Molecular Taxonomy of Tumors","rel_doi":"10.64898\/2026.06.17.732825","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732825","rel_abs":"Cancers with similar histology often exhibit divergent clinical behavior, reflecting molecular heterogeneity not captured by current classification systems. Although driver mutations are central to tumorigenesis, their broader systems-level consequences have not been systematically leveraged. We integrated genomic and transcriptomic data across cancers to define driver mutation signatures (DMS), coordinated transcriptional programs associated with cancer driver mutations. From 121 candidate drivers, we derived 90 robust signatures and quantified their activity in individual tumors using mutation signature scores (MSS). DMS analysis revealed a hierarchical organization of tumors into molecular subgroups that transcended tissue boundaries while preserving driver-associated features. Continuous MSS profiles further defined high-resolution molecular fingerprints for individual tumors. DMS provides a quantitative framework for tumor classification and patient stratification and links driver-associated programs to potential therapeutic vulnerabilities. Together, these findings establish a pan-cancer molecular taxonomy that bridges genotype and phenotype and may inform precision oncology.","rel_num_authors":4,"rel_authors":[{"author_name":"Xiaoyun Huang","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Bowang Chen","author_inst":"Intelliphecy"},{"author_name":"Xiaoqing Huang","author_inst":"Intelliphecy"},{"author_name":"Martin Wong","author_inst":"The Chinese University of Hong Kong"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Rapid coordination of followership and leadership roles in homing pigeons navigating with unfamiliar partners","rel_doi":"10.64898\/2026.07.06.736763","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736763","rel_abs":"Collective movement requires coordination between individuals, yet how this emerges during early interactions remains poorly understood. We investigated how partner familiarity influences coordination, leader-follower dynamics, and learning in homing pigeon pairs navigating from novel sites. Birds were released repeatedly with either familiar or unfamiliar partners, followed by solo releases to assess learning. By quantifying bidirectional information flow, we found familiarity influenced information-transfer dynamics during the first release: familiar pairs exhibited more asymmetric information transfer, likely reflecting established leader-follower relationships, whereas unfamiliar pairs showed more symmetric exchange. These differences disappeared after one release. Conversely, familiarity had little effect on cohesion or navigational performance. There was some evidence for an influence on learning: birds from familiar pairings had higher homing efficiency on a subsequent solo release. Finally, across partnerships, followership was more predictable than leadership with respect to individual identity and flight speed, indicating stable variation in individuals' tendency to follow rather than lead. This suggests that a shift in emphasis from leadership to followership might enhance our understanding of collective decision-making dynamics. Our results demonstrate how flight partners rapidly coordinate, producing limited downstream effects on navigation and learning, with implications for many animals that travel in fission-fusion transitory collectives.","rel_num_authors":9,"rel_authors":[{"author_name":"Joe Morford","author_inst":"Department of Brain and Cognitive Sciences, University of Rochester, Rochester, New York, USA"},{"author_name":"Patrick J Lewin","author_inst":"Department of Biology, Oxford University, Oxford, UK"},{"author_name":"Lucy Larkman","author_inst":"Department of Biology, Oxford University, Oxford, UK"},{"author_name":"Gayatri Kumar","author_inst":"Department of Biology, Oxford University, Oxford, UK"},{"author_name":"Joy W Kinuthia","author_inst":"Department of Biology, Oxford University, Oxford, UK"},{"author_name":"Takao Sasaki","author_inst":"Department of Brain and Cognitive Sciences, University of Rochester, Rochester, New York, USA"},{"author_name":"Richard P Mann","author_inst":"Department of Statistics, School of Mathematics, University of Leeds, Leeds, UK"},{"author_name":"Christopher Krupenye","author_inst":"Department of Psychological & Brain Sciences, Johns Hopkins University, Baltimore, Maryland, USA"},{"author_name":"Dora Biro","author_inst":"Department of Brain and Cognitive Sciences, University of Rochester, Rochester, New York, USA"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Conserved and specialized features of thalamocortical wiring revealed by single-cell projection mapping in mouse and marmoset","rel_doi":"10.64898\/2026.07.07.736957","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.07.736957","rel_abs":"Across mammals, brain regions can duplicate, expand, and diversify, requiring long-range connectivity to accommodate species-specific specializations while preserving globally ordered wiring. This challenge is especially pronounced in primate thalamocortical circuits, where select cortical fields and their thalamic partners have expanded disproportionately. Although gene expression in the thalamus follows broad and conserved gradients, how thalamocortical projections are organized at single-neuron resolution, and how this organization is reshaped by expansion, remain unknown. Here, we investigate thalamocortical projection organization by in situ sequencing and BARseq projection mapping in marmosets and mice. We profiled the gene expression of 1.5 million marmoset neurons and jointly measured gene expression and cortical projections in 708 marmoset and 1,518 mouse neurons that spanned multiple thalamic nuclei. In both species, projections of individual neurons targeted diverse areas that together spanned a large fraction of the cortex. Comparing projections at the single-neuron level and local neighborhood level revealed that marmoset thalamocortical projections were more spatially segregated, producing a point-to-point architecture. Strikingly, this local specialization coexisted with a conserved gradient that predominated over discrete anatomical borders: In the higher-order sensory thalamus of both species, gene expression and projections varied continuously across nucleus borders, and borders had only a small effect on projections. Furthermore, in both marmoset and mouse, gene expression gradients were associated with the anteroposterior locations of cortical targets. These results reconcile discrete nucleus and gradient-based models of thalamic organization and suggest that primate circuit specialization is superimposed on a conserved molecular-projection gradient.","rel_num_authors":16,"rel_authors":[{"author_name":"Angela Y Fan","author_inst":"National Institute of Mental Health"},{"author_name":"Jack T Scott","author_inst":"National Institute of Mental Health"},{"author_name":"Noah M Kuehn","author_inst":"National Institute of Mental Health"},{"author_name":"Maryam Majeed","author_inst":"Allen Institute"},{"author_name":"Sabrina Y Cheng","author_inst":"Allen Institute"},{"author_name":"Huihui Qi","author_inst":"Johns Hopkins University"},{"author_name":"Mathew T Summers","author_inst":"Allen Institute"},{"author_name":"John Hover","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Tye Johnson","author_inst":"Allen Institute"},{"author_name":"Ben Ouellette","author_inst":"Allen Institute"},{"author_name":"Alana A Oyama","author_inst":"Allen Institute"},{"author_name":"Diana Ravens","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Huiqing Zhan","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Justus M Kebschull","author_inst":"Johns Hopkins University"},{"author_name":"James A Bourne","author_inst":"National Institute of Mental Health"},{"author_name":"Xiaoyin Chen","author_inst":"Allen Institute"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Conserved and specialized features of thalamocortical wiring revealed by single-cell projection mapping in mouse and marmoset","rel_doi":"10.64898\/2026.07.07.736957","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.07.736957","rel_abs":"Across mammals, brain regions can duplicate, expand, and diversify, requiring long-range connectivity to accommodate species-specific specializations while preserving globally ordered wiring. This challenge is especially pronounced in primate thalamocortical circuits, where select cortical fields and their thalamic partners have expanded disproportionately. Although gene expression in the thalamus follows broad and conserved gradients, how thalamocortical projections are organized at single-neuron resolution, and how this organization is reshaped by expansion, remain unknown. Here, we investigate thalamocortical projection organization by in situ sequencing and BARseq projection mapping in marmosets and mice. We profiled the gene expression of 1.5 million marmoset neurons and jointly measured gene expression and cortical projections in 708 marmoset and 1,518 mouse neurons that spanned multiple thalamic nuclei. In both species, projections of individual neurons targeted diverse areas that together spanned a large fraction of the cortex. Comparing projections at the single-neuron level and local neighborhood level revealed that marmoset thalamocortical projections were more spatially segregated, producing a point-to-point architecture. Strikingly, this local specialization coexisted with a conserved gradient that predominated over discrete anatomical borders: In the higher-order sensory thalamus of both species, gene expression and projections varied continuously across nucleus borders, and borders had only a small effect on projections. Furthermore, in both marmoset and mouse, gene expression gradients were associated with the anteroposterior locations of cortical targets. These results reconcile discrete nucleus and gradient-based models of thalamic organization and suggest that primate circuit specialization is superimposed on a conserved molecular-projection gradient.","rel_num_authors":16,"rel_authors":[{"author_name":"Angela Y Fan","author_inst":"National Institute of Mental Health"},{"author_name":"Jack T Scott","author_inst":"National Institute of Mental Health"},{"author_name":"Noah M Kuehn","author_inst":"National Institute of Mental Health"},{"author_name":"Maryam Majeed","author_inst":"Allen Institute"},{"author_name":"Sabrina Y Cheng","author_inst":"Allen Institute"},{"author_name":"Huihui Qi","author_inst":"Johns Hopkins University"},{"author_name":"Mathew T Summers","author_inst":"Allen Institute"},{"author_name":"John Hover","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Tye Johnson","author_inst":"Allen Institute"},{"author_name":"Ben Ouellette","author_inst":"Allen Institute"},{"author_name":"Alana A Oyama","author_inst":"Allen Institute"},{"author_name":"Diana Ravens","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Huiqing Zhan","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Justus M Kebschull","author_inst":"Johns Hopkins University"},{"author_name":"James A Bourne","author_inst":"National Institute of Mental Health"},{"author_name":"Xiaoyin Chen","author_inst":"Allen Institute"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Odors Smell Like Their Components: A Linear Framework for Predicting Olfactory Mixture Perception","rel_doi":"10.64898\/2026.07.03.736426","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736426","rel_abs":"Most smells, whether in food, perfume, or the environment, are complex mixtures of many odor molecules. A principled framework for modeling natural mixtures has been considered intractable because mixtures are widely assumed to generate nonlinear perceptual interactions that mirror nonlinear responses at the receptor and neural levels. We quantified perceptual interactions across 432 mixtures composed of 144 component odorants using a trained human panel, and nearly all mixtures were explained by a linear average of their component quality profiles. Within this linear modeling framework, averaging component profiles predicted mixture perception significantly better than the previous state-of-the-art and approached the ceiling set by measurement noise. Even mixtures previously reported to exhibit emergence were equally well predicted. These results suggest that the main challenge in modeling odor perception is characterizing individual components, rather than exhaustively mapping odor-odor interactions. Just as additive color mixing enabled colorimetry, linear mixing in olfaction opens the door to quantitative odorimetry, allowing mixtures to be predicted, reconstructed, and optimized computationally.","rel_num_authors":7,"rel_authors":[{"author_name":"Robert Pellegrino","author_inst":"Texas A and M University"},{"author_name":"Emily J Mayhew","author_inst":"Michigan State University"},{"author_name":"Jennifer Margolis","author_inst":"Monell Chemical Senses Center"},{"author_name":"Matthew Andres","author_inst":"Monell Chemical Senses Center"},{"author_name":"Alexander B Wiltschko","author_inst":"Osmo Labs, PBC"},{"author_name":"Richard C Gerkin","author_inst":"Osmo Labs, PBC"},{"author_name":"Joel Drewery Mainland","author_inst":"Monell Chemical Senses Center"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Epigenetic priming with valeric acid unlocks multi-stress resistance in plants by targeted histone deacetylase inhibition","rel_doi":"10.64898\/2026.06.17.732912","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732912","rel_abs":"Progressive climate change is driving increasingly devastating crop losses through droughts, heatwaves and other adverse weather. Combined with shrinking arable land and spreading plant diseases, this makes it crucial to enable crops to grow efficiently in unfavorable, dynamic environments. Because stressors demand prompt, highly coordinated responses, plant stress adaptations rely heavily on epigenetic regulation. Histone deacetylases (HDAs), particularly class I, were recently shown to repress these responses. As constitutive defense is energetically costly, tools enabling temporal modulation of such mechanisms are highly sought after in crop biotechnology. This study evaluated whether valeric acid (VA), a five-carbon carboxylic acid, can inhibit HDA and activate plant defense responses.\n\nHere we show that VA is a potent HDA inhibitor that confers resistance to multiple abiotic and biotic stresses in Arabidopsis, and further validate the abiotic component in maize and tomato. Despite its simple chemical structure, structural and transcriptomic evidence shows that VA acts by selectively inhibiting two major stress-repressing deacetylases, HDA19 and HDA6. By targeting these epigenetic switches, VA activates natural defense and acclimation responses. Time-course transcriptomic analyses further revealed that priming with VA induces transcriptional memory, which, together with VA-induced metabolic rewiring, enables rapid and efficient responses to future stressors. Most importantly, despite activating energetically demanding defenses, VA promotes vegetative growth and increases yield under normal conditions, thereby breaking the growth-defense trade-off.\n\nThese findings establish VA as the first epigenetic biostimulant of its kind, capable of improving plant performance under both abiotic and biotic stress while simultaneously increasing crop yield. As the epigenetic mechanisms underlying its action are evolutionarily conserved, VA priming emerges as a promising universal strategy to mitigate the climate-driven global crisis of crop losses.","rel_num_authors":11,"rel_authors":[{"author_name":"Olaf Geyderowicz","author_inst":"University of Warsaw"},{"author_name":"Marta Gapinska","author_inst":"University of Warsaw"},{"author_name":"Helena Kossowska","author_inst":"University of Warsaw"},{"author_name":"Radoslaw Mazur","author_inst":"University of Warsaw"},{"author_name":"Patrycja Zembek","author_inst":"Institute of Biochemistry and Biophysics, Polish Academy of Sciences"},{"author_name":"Roksana Iwanicka-Nowicka","author_inst":"Institute of Biochemistry and Biophysics, Polish Academy of Sciences"},{"author_name":"Magdalena Krzymowska","author_inst":"Institute of Biochemistry and Biophysics, Polish Academy of Sciences"},{"author_name":"Jaroslaw Poznanski","author_inst":"Institute of Biochemistry and Biophysics, Polish Academy of Sciences"},{"author_name":"Keqiang Wu","author_inst":"National Taiwan University"},{"author_name":"Lucja Kowalewska","author_inst":"University of Warsaw"},{"author_name":"Marta Koblowska","author_inst":"University of Warsaw"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Molecular determinants of Hrp1-RNA recognition underlying yeast RNA Polymerase II transcription attenuation","rel_doi":"10.64898\/2026.06.16.732720","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732720","rel_abs":"Premature termination of transcription (PTT), also known as attenuation, is a conserved gene regulatory mechanism that operates across all domains of life and in viruses. Attenuation enables rapid cellular responses to environmental and metabolic changes and fine-tunes expression of biosynthetic genes. In Saccharomyces cerevisiae, attenuation of RNA Polymerase II (Pol II) transcription was first linked to the Nrd1-Nab3-Sen1 (NNS) termination pathway for non-coding RNAs, and the mRNA 3-end processing factor Hrp1 has been implicated more recently. Substitutions in Hrp1 RNA Recognition Motifs (RRMs) cause attenuator readthrough and reduce RNA-binding affinity in vitro, but direct evidence for Hrp1 functioning at attenuators in vivo remains limited. Here, we characterized 5-end RNA terminator elements from several genes, including RAD3, SNG1, MNR2, and CPR8. Readthrough mutations clustered in AU-rich regions resembling polyadenylation site (pA) efficiency elements, consistent with Hrp1 binding targets. Amino acid substitutions of Hrp1 RRM residue F162 revealed a general requirement for aromaticity in RNA recognition that varied to some degree by gene context. To test Hrp1-RNA interactions independent of other yeast factors, we adapted a bacterial 3-hybrid (B3H) assay. Hrp1 interacted with RNA derived from the GAL7 3-end pA site and 5-end terminator regions of RAD3, MNR2, and CPR8. Mutations in AU-rich RNA regions that disrupted Pol II attenuation in yeast generally impaired B3H interactions. However, some Hrp1 mutants (M191T, I270T, D271G, M275V, T280I) retained binding to CPR8 terminator RNA, suggesting their defects require additional yeast components. These results demonstrate that Hrp1 is sufficient to bind multiple UA-rich attenuator RNAs in vivo, expanding Hrp1 function to include early transcription events.","rel_num_authors":10,"rel_authors":[{"author_name":"Jason N. Kuehner","author_inst":"Emmanuel College"},{"author_name":"Catalina Lujan-Rodriguez","author_inst":"Emmanuel College"},{"author_name":"Max A. Popoloski","author_inst":"Emmanuel College"},{"author_name":"Lane E. Couturier","author_inst":"Emmanuel College"},{"author_name":"Jessica J. Richa","author_inst":"Massachusetts General Hospital"},{"author_name":"Justin M. Talluto","author_inst":"Tufts University School of Medicine"},{"author_name":"Madison E. Lapine","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Mackenzie Roche","author_inst":"Alabama College of Osteopathic Medicine"},{"author_name":"Sidney J. Edouard","author_inst":"Boston University"},{"author_name":"Vincent Pavan","author_inst":"University of California San Diego"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"A variant rRNA serves as a translational repressor in Plasmodium falciparum","rel_doi":"10.64898\/2026.06.17.732804","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732804","rel_abs":"Ribosome composition can vary through differences in associated proteins, post-transcriptional and post-translational modifications. Such heterogeneity enables ribosomes to respond to environmental1 or pathological2,3 conditions, and modulate localized translation4. A long-standing observation has also been the differential expression of variant ribosomal RNA (rRNA) alleles across developmental5-7 or cellular states8-14. Yet how exchanging the catalytic ribosome core could regulate translational outcomes remains unknown. Here, we report the functional characterization of a genomically-encoded, divergent rRNA that serves as a dominant-negative repressor of translation during host-to-vector transmission in the human malaria parasite. This allele only encodes for large subunit rRNAs, lacks ITS2 splicing, yet retains conserved rRNA modification and folding patterns alongside vast expansion segments. The resulting large subunit engages mRNA at translation start sites but appears to elongate inefficiently, likely due to divergences in the peptidyl transferase center obstructing the exit tunnel. Through its precisely timed transcription immediately after transmission, this rRNA represses mRNAs that were highly translated in the human, facilitating the transition of the translational program for mosquito-stage development. Our data identify a repressive ribosome population whose antagonistic function is encoded by an independently evolved, variant rRNA allele, defining the conceptual foundation for an additional layer of inherent translational regulation.","rel_num_authors":12,"rel_authors":[{"author_name":"Tiziano Vignolini","author_inst":"Institut Pasteur"},{"author_name":"Olivia Carril","author_inst":"Institut Pasteur"},{"author_name":"Victor Tobiasson","author_inst":"University of Glasgow"},{"author_name":"Joe Georgeson","author_inst":"Weizmann Institute of Science"},{"author_name":"Justine Couble","author_inst":"Universite de Montpellier"},{"author_name":"Gregory Dore","author_inst":"Institut Pasteur"},{"author_name":"Donna Matzov","author_inst":"Weizmann Institute of Science"},{"author_name":"Sebastian Hutchinson","author_inst":"Quantum-Si"},{"author_name":"Jessica Michelle Bryant","author_inst":"Institut Pasteur"},{"author_name":"Moran Shalev-Benami","author_inst":"Weizmann Institute of Science"},{"author_name":"Schraga Schwartz","author_inst":"Weizmann Institute of Science"},{"author_name":"Sebastian Baumgarten","author_inst":"Institut Pasteur"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Decoupling Choice from Motor Response Reduces Choice-History Effects","rel_doi":"10.64898\/2026.07.02.736214","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736214","rel_abs":"Perception and action form a loop as an organism interacts with its environment. Here, we probe the interdependence between the two in the context of choice-history effects, the tendency of past choices and their outcomes to bias current choices. We investigated if the modulation by previous choices depended on the coupling between perceptual choices and the motor responses reporting these choices. We analyzed data from non-human primates (Macaca mulatta; three females and five males) performing two different perceptual decision-making tasks. Each task had a coupled variant with a fixed mapping between perceptual choices and motor plans used to report the choice, and an uncoupled variant, in which this mapping varied randomly across trials. We found that, in both tasks, the animals in the coupled variant had larger choice-history effects compared to the animals in the uncoupled variant. Decoupling choices from motor responses was further associated with an inability by the animals to learn experimentally induced stimulus sequence regularities. Together, these findings identify choice-response coupling as a factor shaping animals ability to use recent history to guide behavior and highlight the tight link between cognitive and motor processes.","rel_num_authors":5,"rel_authors":[{"author_name":"Sriram Thothathri","author_inst":"Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health, Bethesda, USA"},{"author_name":"Bharath Chandra Talluri","author_inst":"Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health, Bethesda, USA"},{"author_name":"S Shushruth","author_inst":"Center for Neural Basis of Cognition, Department of Neuroscience, University of Pittsburgh, Pittsburgh, USA"},{"author_name":"Michael N Shadlen","author_inst":"Department of Neuroscience, Columbia University, New York, USA"},{"author_name":"Hendrikje Nienborg","author_inst":"Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health, Bethesda, USA"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Model-optimized stimulus distortions for adaptive estimation of individual sensory representations","rel_doi":"10.64898\/2026.07.02.736141","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736141","rel_abs":"Representations of the same physical stimulus vary between individuals. Characterizing individual differences has practical implications, but is challenging because these representations are not directly observable. Given a model of how representations vary within a population, we propose a Bayesian adaptive procedure for estimating an individual observer's representation from a series of targeted perceptual discrimination judgments. A key component of our approach is using Fisher information to identify stimulus distortions that efficiently differentiate observers in the population. As a proof of concept, we focus on individual differences in color perception and simulate observers with cone fundamentals drawn from an individual colorimetric observer model. We demonstrate that our approach can recover key aspects of a sampled observer's cone fundamentals using simulated three-alternative forced-choice oddity judgments with approximately 500 trials, corresponding to an experimental duration of approximately one hour. Our Bayesian adaptive framework provides a promising and generalizable approach to efficiently link behavioral measurements to individual differences in sensory representations.","rel_num_authors":5,"rel_authors":[{"author_name":"Josue Casco-Rodriguez","author_inst":"Rice University"},{"author_name":"Fangfang Hong","author_inst":"University of Pennslyvania"},{"author_name":"David H. Brainard","author_inst":"University of Pennsylvania"},{"author_name":"Jenelle Feather","author_inst":"Carnegie Mellon University"},{"author_name":"David Lipshutz","author_inst":"Baylor College of Medicine"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"The role of electrostatic interactions in the phase separation of HP1\u03b1 and its protein binding partners","rel_doi":"10.64898\/2026.07.06.736852","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736852","rel_abs":"Heterochromatin protein 1 (HP1 is an intrinsic component of heterochromatin domains where it is involved in a diverse set of functions including heterochromatin spreading and organization, chromatin compaction and transcriptional silencing. It has been suggested that HP1 functions through a phase separation mechanism, a process that has been observed in vitro in the presence of N-terminal phosphorylation, nucleic acids and nucleosome arrays. HP1 can also interact with numerous binding partners that contain a specific motif called an HP1 access code (HAC). HACs recognize and bind to an interface formed by the chromoshadow (CSD) domains in the HP1 homodimer, the functional form of the protein. It has been shown that some HP1 binding partners can enhance its phase separation ability while others disrupt the process. Here, we focus on the interactions between HP1 and three binding partners, namely the p150 subunit of the chromatin assembly factor 1 (CAF-1), the N-terminal domain of the lamin B receptor (LBR), and the mitotic protein Shugoshin 1 (Sgo1). Using phase separation assays, we show that CAF-1 prevents HP1 phase separation while LBR and Sgo1 enhance it. Binding assays, mutational studies, NMR spectroscopy and computational analysis allow us to dissect the contributions of the HAC motifs, the charge patterns of the binding partner sequences and the role of N-terminal phosphorylation on HP1 in condensate formation. Our results demonstrate that each binding partner uniquely balances these contributions to modulate the properties of HP1, while electrostatic interactions dominate the regulation of phosphorylated HP1. These results suggest that HP1 binding partners play an important role in the modulation of its properties and the regulation of its functions in distinct biological contexts.","rel_num_authors":7,"rel_authors":[{"author_name":"Cheenou Her","author_inst":"University of California, San Diego"},{"author_name":"Rushabh Bhakta","author_inst":"University of California, San Diego"},{"author_name":"Tonkhla Dankul","author_inst":"University of California, San Diego"},{"author_name":"Tien M Phan","author_inst":"Texas A&M University"},{"author_name":"Lannah S Abasi","author_inst":"University of California, San Diego"},{"author_name":"Jeetain Mittal","author_inst":"Texas A&M University"},{"author_name":"Galia T Debelouchina","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"FEATMAP: Targeted Correction of Acquisition Signatures Harmonizes Medical Foundation Model Embeddings and Enables Robust Task Generalization","rel_doi":"10.64898\/2026.07.02.736184","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736184","rel_abs":"Medical foundation models compress biomedical data into embeddings that support diverse downstream clinical tasks. However, successful model deployment is hampered by performance degradation on external data. It is recognized that embeddings capture acquisition signatures, such as hardware and technical differences, in addition to biology. Effective harmonization must remove the acquisition signature while preserving biological signals, a trade-off that current methods fail to balance adequately. Input-level normalization fails to eliminate acquisition signatures from embeddings, whereas embedding-level methods adjust features in an untargeted manner. We present FEATMAP, a harmonization approach that models acquisition signatures as geometric distortions between manifolds of similarly arranged embeddings. Using paired data that isolate the effect of acquisition signatures, FEATMAP fits a single global affine transformation per foundation model to correct acquisition signatures directly in the embedding space. This targeted, reusable correction aims to preserve biological and demographic variation while harmonizing across acquisition signatures. Across scanner and foundation-model harmonization in digital pathology and field-strength harmonization in brain MRI, FEATMAP improves cross-condition embedding similarity, reduces performance gaps without retraining, and suggests potential for the alignment of disparate embedding spaces.","rel_num_authors":17,"rel_authors":[{"author_name":"Leonhard Donle","author_inst":"University of Chicago"},{"author_name":"Michael Phillips","author_inst":"The University of Chicago"},{"author_name":"Farieda Gaber","author_inst":"Max Delbrueck Center for Molecular Medicine"},{"author_name":"Siddhi Ramesh","author_inst":"The University of Chicago"},{"author_name":"Matteo Sacco","author_inst":"The University of Chicago"},{"author_name":"Sampsa Hautaniemi","author_inst":"University of Helsinki"},{"author_name":"Anni Virtanen","author_inst":"University of Helsinki"},{"author_name":"Keno Bressem","author_inst":"Technical University of Munich"},{"author_name":"Lisa Adams","author_inst":"Technical University of Munich"},{"author_name":"Kelsey Goon","author_inst":"The University of Chicago"},{"author_name":"Elena Nevins","author_inst":"The University of Chicago"},{"author_name":"Ryan A. Robinett","author_inst":"The University of Chicago"},{"author_name":"Sara Kochanny","author_inst":"The University of Chicago"},{"author_name":"Sasha Hassan","author_inst":"The University of Chicago"},{"author_name":"James Dolezal","author_inst":"Geisinger Cancer Institute"},{"author_name":"Alexander T. Pearson","author_inst":"The University of Chicago"},{"author_name":"Ernst Lengyel","author_inst":"The University of Chicago"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"The SEA-AD DREAM Challenge: Community benchmarking human and AI agent solutions for Alzheimer's disease neuropathology prediction from single-nucleus transcriptomics","rel_doi":"10.64898\/2026.07.02.736180","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736180","rel_abs":"Single-nucleus transcriptomic atlases offer an unprecedented opportunity to connect cellular molecular states with Alzheimer's disease (AD) neuropathology, but whether these profiles encode reproducible, predictive information about pathological burden remains unclear. We present the SEA-AD DREAM Challenge, an open, international, model-to-data competition built on the Seattle Alzheimer's Disease Brain Cell Atlas to predict Alzheimer's disease neuropathological severity from single-nucleus RNA-sequencing data. Participants developed containerized models to predict categorical neuropathological staging, including overall Alzheimer's disease neuropathologic change, Braak stage, Thal phase, and CERAD score, as well as quantitative amyloid-{beta} and phospho-tau burden measured by 6E10 and AT8 immunohistochemistry. Across 17 eligible teams from 15 countries, the crowdsourcing framework enabled systematic comparison of diverse computational approaches and surfaced a broad landscape of modeling strategies and candidate predictive features. Top-performing methods achieved near-perfect prediction of categorical staging, with the best submission reaching a quadratic weighted kappa of 1.0 for the Overall AD Neuropathological Change score (ADNC), and competitive prediction of quantitative pathological burden in held-out data, with a best concordance correlation coefficient of 0.48. Post hoc perturbation analyses revealed that top categorical-stage predictions relied heavily on donor-level metadata-driven signals rather than transcriptomic features, whereas quantitative pathology prediction was more robust and supported by transcriptomic and cell-type-associated features with potential biological relevance to AD progression. The challenge also introduced the first AI Agent Track in a DREAM Challenge, providing an early benchmark for autonomous and human-guided agentic model development in single-cell neuroscience. This work demonstrates that single-nucleus transcriptomes encode substantial information about Alzheimer's disease pathology, establishes a reproducible benchmark for molecular neuropathology prediction, and highlights critical principles for designing privacy-preserving, leakage-aware community challenges using deeply phenotyped human brain data.","rel_num_authors":27,"rel_authors":[{"author_name":"Hsin-Yu Lai","author_inst":"Allen Institute"},{"author_name":"Nikolaos Kalavros","author_inst":"Department of Pathology, NYU Grossman School of Medicine"},{"author_name":"Verena Chung","author_inst":"Sage Bionetworks"},{"author_name":"Eitan S Kaplan","author_inst":"Allen Institute"},{"author_name":"Dimitris Anastassiou","author_inst":"Department of Electrical Engineering, Columbia University"},{"author_name":"Lingyi Cai","author_inst":"Department of Electrical Engineering, Columbia University"},{"author_name":"Erica Chen","author_inst":"Computational Medicine Center, Thomas Jefferson University,"},{"author_name":"Ignacio Garach Velez","author_inst":"Department of Computer Engineering, Automation and Robotics (ICAR), University of Granada"},{"author_name":"Gamze Gursoy","author_inst":"Department of Biomedical Informatics and New York Genome Center, Columbia University"},{"author_name":"Luis Javier Herrera","author_inst":"Department of Computer Engineering, Automation and Robotics (ICAR), University of Granada"},{"author_name":"Xiaoting Li","author_inst":"Department of Biomedical Informatics and New York Genome Center, Columbia University"},{"author_name":"Eric Londin","author_inst":"Computational Medicine Center, Thomas Jefferson University"},{"author_name":"Phillipe Loher","author_inst":"Computational Medicine Center, Thomas Jefferson University"},{"author_name":"Iliza Nazeraj","author_inst":"Computational Medicine Center, Thomas Jefferson University"},{"author_name":"Francisco Ortuno","author_inst":"Department of Computer Engineering, Automation and Robotics (ICAR), University of Granada"},{"author_name":"Tai-Hsien Ou Yang","author_inst":"Department of Electrical Engineering, Columbia University"},{"author_name":"Isidore Rigoutsos","author_inst":"Computational Medicine Center, Thomas Jefferson University"},{"author_name":"Ignacio Rojas","author_inst":"Department of Computer Engineering, Automation and Robotics (ICAR), University of Granada"},{"author_name":"Gaia Andreoletti","author_inst":"Sage Bionetworks"},{"author_name":"Luca Foschini","author_inst":"Sage Bionetworks"},{"author_name":"Laura Heath","author_inst":"Sage Bionetworks"},{"author_name":"Tomiko Oskotsky","author_inst":"Bakar Computational Health Sciences Institute, University of California San Francisco"},{"author_name":"Marina Sirota","author_inst":"Bakar Computational Health Sciences Institute, University of California San Francisco"},{"author_name":"Gustavo Stolovitzky","author_inst":"Department of Pathology, NYU Grossman School of Medicine"},{"author_name":"Kyle Javier Travaglini","author_inst":"Allen Institute"},{"author_name":"James Zou","author_inst":"Department of Pathology, NYU Grossman School of Medicine"},{"author_name":"Mariano I Gabitto","author_inst":"Allen Institute"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"The SEA-AD DREAM Challenge: Community benchmarking human and AI agent solutions for Alzheimer's disease neuropathology prediction from single-nucleus transcriptomics","rel_doi":"10.64898\/2026.07.02.736180","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736180","rel_abs":"Single-nucleus transcriptomic atlases offer an unprecedented opportunity to connect cellular molecular states with Alzheimer's disease (AD) neuropathology, but whether these profiles encode reproducible, predictive information about pathological burden remains unclear. We present the SEA-AD DREAM Challenge, an open, international, model-to-data competition built on the Seattle Alzheimer's Disease Brain Cell Atlas to predict Alzheimer's disease neuropathological severity from single-nucleus RNA-sequencing data. Participants developed containerized models to predict categorical neuropathological staging, including overall Alzheimer's disease neuropathologic change, Braak stage, Thal phase, and CERAD score, as well as quantitative amyloid-{beta} and phospho-tau burden measured by 6E10 and AT8 immunohistochemistry. Across 17 eligible teams from 15 countries, the crowdsourcing framework enabled systematic comparison of diverse computational approaches and surfaced a broad landscape of modeling strategies and candidate predictive features. Top-performing methods achieved near-perfect prediction of categorical staging, with the best submission reaching a quadratic weighted kappa of 1.0 for the Overall AD Neuropathological Change score (ADNC), and competitive prediction of quantitative pathological burden in held-out data, with a best concordance correlation coefficient of 0.48. Post hoc perturbation analyses revealed that top categorical-stage predictions relied heavily on donor-level metadata-driven signals rather than transcriptomic features, whereas quantitative pathology prediction was more robust and supported by transcriptomic and cell-type-associated features with potential biological relevance to AD progression. The challenge also introduced the first AI Agent Track in a DREAM Challenge, providing an early benchmark for autonomous and human-guided agentic model development in single-cell neuroscience. This work demonstrates that single-nucleus transcriptomes encode substantial information about Alzheimer's disease pathology, establishes a reproducible benchmark for molecular neuropathology prediction, and highlights critical principles for designing privacy-preserving, leakage-aware community challenges using deeply phenotyped human brain data.","rel_num_authors":27,"rel_authors":[{"author_name":"Hsin-Yu Lai","author_inst":"Allen Institute"},{"author_name":"Nikolaos Kalavros","author_inst":"Department of Pathology, NYU Grossman School of Medicine"},{"author_name":"Verena Chung","author_inst":"Sage Bionetworks"},{"author_name":"Eitan S Kaplan","author_inst":"Allen Institute"},{"author_name":"Dimitris Anastassiou","author_inst":"Department of Electrical Engineering, Columbia University"},{"author_name":"Lingyi Cai","author_inst":"Department of Electrical Engineering, Columbia University"},{"author_name":"Erica Chen","author_inst":"Computational Medicine Center, Thomas Jefferson University,"},{"author_name":"Ignacio Garach Velez","author_inst":"Department of Computer Engineering, Automation and Robotics (ICAR), University of Granada"},{"author_name":"Gamze Gursoy","author_inst":"Department of Biomedical Informatics and New York Genome Center, Columbia University"},{"author_name":"Luis Javier Herrera","author_inst":"Department of Computer Engineering, Automation and Robotics (ICAR), University of Granada"},{"author_name":"Xiaoting Li","author_inst":"Department of Biomedical Informatics and New York Genome Center, Columbia University"},{"author_name":"Eric Londin","author_inst":"Computational Medicine Center, Thomas Jefferson University"},{"author_name":"Phillipe Loher","author_inst":"Computational Medicine Center, Thomas Jefferson University"},{"author_name":"Iliza Nazeraj","author_inst":"Computational Medicine Center, Thomas Jefferson University"},{"author_name":"Francisco Ortuno","author_inst":"Department of Computer Engineering, Automation and Robotics (ICAR), University of Granada"},{"author_name":"Tai-Hsien Ou Yang","author_inst":"Department of Electrical Engineering, Columbia University"},{"author_name":"Isidore Rigoutsos","author_inst":"Computational Medicine Center, Thomas Jefferson University"},{"author_name":"Ignacio Rojas","author_inst":"Department of Computer Engineering, Automation and Robotics (ICAR), University of Granada"},{"author_name":"Gaia Andreoletti","author_inst":"Sage Bionetworks"},{"author_name":"Luca Foschini","author_inst":"Sage Bionetworks"},{"author_name":"Laura Heath","author_inst":"Sage Bionetworks"},{"author_name":"Tomiko Oskotsky","author_inst":"Bakar Computational Health Sciences Institute, University of California San Francisco"},{"author_name":"Marina Sirota","author_inst":"Bakar Computational Health Sciences Institute, University of California San Francisco"},{"author_name":"Gustavo Stolovitzky","author_inst":"Department of Pathology, NYU Grossman School of Medicine"},{"author_name":"Kyle Javier Travaglini","author_inst":"Allen Institute"},{"author_name":"James Zou","author_inst":"Department of Pathology, NYU Grossman School of Medicine"},{"author_name":"Mariano I Gabitto","author_inst":"Allen Institute"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Aging restricts colorectal tumor growth by epigenetically silencing developmental gene programs","rel_doi":"10.64898\/2026.06.12.731922","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731922","rel_abs":"The incidence of early-onset colorectal cancer (CRC) has risen sharply in recent decades1, yet the biological basis underlying the distinct behavior of tumors arising in young versus aged tissues remains poorly understood. Here we show that aging reprograms the epigenetic landscape of the colon, restricting colon tumor growth through stable silencing of developmental and fetal gene programs. We find that colon tumors arising in aged mice are intrinsically less proliferative than those arising in young animals. Multi-omic profiling of normal colon and colon tumors reveals that aging drives DNA hypermethylation, loss of Polycomb-associated chromatin states, and reduced chromatin accessibility at a defined set of developmental genes that are bivalent (marked by both H3K27me3 and H3K4 methylation), transcriptionally active in colon tumors from young animals and repressed in both tumors and normal tissue from old animals. Among the genes most strongly repressed in old animals is Tacstd2 (Trop2), a regulator of fetal intestinal programs and epithelial stemness. Pharmacologic inhibition of DNA methylation reactivates the aging-silenced gene network in organoids from old animals, whereas genetic disruption of Tacstd2 suppresses growth and developmental transcriptional programs in young tumor organoids. TACSTD2, fetal gene signatures, and the aging-associated bivalent gene program are likewise repressed in late-onset vs. early-onset human colorectal cancers. Collectively, these findings identify age-associated epigenetic silencing of developmental gene programs as a causal mechanism that constrains colorectal tumor growth and provide a mechanistic framework for understanding the distinct biology of early-onset colorectal cancer.","rel_num_authors":16,"rel_authors":[{"author_name":"Yang Liu","author_inst":"NIEHS"},{"author_name":"Venkataramana Thiriveedi","author_inst":"Duke"},{"author_name":"Saratchandra Singh Khumukcham","author_inst":"Duke"},{"author_name":"Babak Mirminachi","author_inst":"Duke"},{"author_name":"Reuben R. Cano","author_inst":"Duke"},{"author_name":"Oladimeji Aladelokun","author_inst":"Yale"},{"author_name":"Sahil Choudhri","author_inst":"Duke"},{"author_name":"Vyom Patel","author_inst":"Duke"},{"author_name":"Shahyan R. Khan","author_inst":"Vanderbilt"},{"author_name":"Shabna Mottemal","author_inst":"Vanderbilt"},{"author_name":"Nicholas O. Markham","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sajid A. Khan","author_inst":"Yale"},{"author_name":"Caroline Johnson","author_inst":"Yale School of Public Health"},{"author_name":"Sara A. Grimm","author_inst":"NIEHS"},{"author_name":"Jatin Roper","author_inst":"Duke University"},{"author_name":"Paul Wade","author_inst":"NIH"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Aging restricts colorectal tumor growth by epigenetically silencing developmental gene programs","rel_doi":"10.64898\/2026.06.12.731922","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731922","rel_abs":"The incidence of early-onset colorectal cancer (CRC) has risen sharply in recent decades1, yet the biological basis underlying the distinct behavior of tumors arising in young versus aged tissues remains poorly understood. Here we show that aging reprograms the epigenetic landscape of the colon, restricting colon tumor growth through stable silencing of developmental and fetal gene programs. We find that colon tumors arising in aged mice are intrinsically less proliferative than those arising in young animals. Multi-omic profiling of normal colon and colon tumors reveals that aging drives DNA hypermethylation, loss of Polycomb-associated chromatin states, and reduced chromatin accessibility at a defined set of developmental genes that are bivalent (marked by both H3K27me3 and H3K4 methylation), transcriptionally active in colon tumors from young animals and repressed in both tumors and normal tissue from old animals. Among the genes most strongly repressed in old animals is Tacstd2 (Trop2), a regulator of fetal intestinal programs and epithelial stemness. Pharmacologic inhibition of DNA methylation reactivates the aging-silenced gene network in organoids from old animals, whereas genetic disruption of Tacstd2 suppresses growth and developmental transcriptional programs in young tumor organoids. TACSTD2, fetal gene signatures, and the aging-associated bivalent gene program are likewise repressed in late-onset vs. early-onset human colorectal cancers. Collectively, these findings identify age-associated epigenetic silencing of developmental gene programs as a causal mechanism that constrains colorectal tumor growth and provide a mechanistic framework for understanding the distinct biology of early-onset colorectal cancer.","rel_num_authors":16,"rel_authors":[{"author_name":"Yang Liu","author_inst":"NIEHS"},{"author_name":"Venkataramana Thiriveedi","author_inst":"Duke"},{"author_name":"Saratchandra Singh Khumukcham","author_inst":"Duke"},{"author_name":"Babak Mirminachi","author_inst":"Duke"},{"author_name":"Reuben R. Cano","author_inst":"Duke"},{"author_name":"Oladimeji Aladelokun","author_inst":"Yale"},{"author_name":"Sahil Choudhri","author_inst":"Duke"},{"author_name":"Vyom Patel","author_inst":"Duke"},{"author_name":"Shahyan R. Khan","author_inst":"Vanderbilt"},{"author_name":"Shabna Mottemal","author_inst":"Vanderbilt"},{"author_name":"Nicholas O. Markham","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sajid A. Khan","author_inst":"Yale"},{"author_name":"Caroline Johnson","author_inst":"Yale School of Public Health"},{"author_name":"Sara A. Grimm","author_inst":"NIEHS"},{"author_name":"Jatin Roper","author_inst":"Duke University"},{"author_name":"Paul Wade","author_inst":"NIH"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Interpretable and scalable spatial gene set activity analysis with GESSO uncovers functional tissue architecture","rel_doi":"10.64898\/2026.07.02.736099","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736099","rel_abs":"Recent advances in spatially resolved transcriptomics (SRT) enabled measurement of sets of pathway genes activity within tissues. However, existing gene set activity scoring methods overlook spatial dependencies among tissue locations, restricting their ability to capture region-specific pathway activities associated with disease pathology or cellular communication. Moreover, these methods lack significance-level inference for activity scores, provide limited interpretability of gene-level contribution to a pathway, and scale poorly to advanced large-size SRT datasets. To address these limitations, we present GESSO (Gene sEt activity Score analysis with Spatial lOcation), a spatially informed gene set scoring method adaptable to diverse SRT platforms. GESSO models gene set activity levels through a graph-regularized matrix decomposition algorithm, jointly inferring spatially coherent gene set activity scores (GASs) and interpretable metagene weights that capture gene-level contributions. It further implements a permutation-based local significance test and a stratified low-resolution approximation that scales to high-resolution SRT datasets such as Visium HD, Stereo-seq, and Xenium Prime. Across 13 datasets from five SRT platforms, GESSO outperformed all existing methods in accuracy, calibration, interpretability, and scalability. Applications revealed novel biological programs, including spatially confined EMT activation within tumor-stroma interfaces, developmental signaling gradients across embryonic tissues, and coordinated B-cell, T-cell, and signaling pathways within germinal centers of human lymph node tissue, revealing the spatial organization of immune function at subregional resolution.","rel_num_authors":3,"rel_authors":[{"author_name":"Andrew J Yang","author_inst":"The Warren Alpert Medical School of Brown University"},{"author_name":"Chichun Tan","author_inst":"Brown University"},{"author_name":"Ying Ma","author_inst":"Brown University"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"NinjaSeq: programmable restriction enzyme-based sequencing library preparation with random access for DNA data storage","rel_doi":"10.64898\/2026.06.11.730843","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.730843","rel_abs":"DNA data storage allows sequences to be defined without biological constraints, yet readout workflows still depend on generic end-repair\/dA-tailing chemistry. We developed NinjaSeq, a type IIS restriction endonuclease library-preparation strategy that incorporates recognition sites into primer flanks, enabling digestion to generate adapter-compatible overhangs and eliminating the need for conventional end preparation. By combining this chemistry with constrained coding that excludes internal recognition motifs, NinjaSeq produced sequencing quality and decoding performance consistent with standard protocols while reducing reagent burden and simplifying processing, including compatibility with one-pot restriction-ligation. The same sequence-directed design also enables physical random access during library preparation: targeting file-specific flanking sites enriched a desired file from a mixed pool by about sixteen-fold in a proof-of-concept experiment. These results position NinjaSeq as a practical ONT readout approach for DNA data storage.\n\nHIGHLIGHTSO_LINinjaSeq replaces end-repair\/dA-tailing with REases for nanopore sequencing\nC_LIO_LIConstrained encoding excludes recognition motifs to protect payloads from cleavage\nC_LIO_LINinjaSeq achieves decoding accuracy comparable to standard library preparation\nC_LIO_LIDesigning file-specific RRS enables random access during library preparation\nC_LI","rel_num_authors":12,"rel_authors":[{"author_name":"Ignas Galminas","author_inst":"Genomika"},{"author_name":"Omer Sabary","author_inst":"Technion - Israel Institute of Technology"},{"author_name":"Hadas Abraham","author_inst":"Technion - Israel Institute of Technology"},{"author_name":"Kornelija Kaminskaite","author_inst":"Genomika"},{"author_name":"Tomer Cohen","author_inst":"Technion - Israel Institute of Technology"},{"author_name":"Vakare Gruodyte","author_inst":"Genomika"},{"author_name":"Gediminas Alzbutas","author_inst":"Genomika"},{"author_name":"Zohar Yakhini","author_inst":"Reichman University"},{"author_name":"Ruta Palepsiene","author_inst":"Genomika"},{"author_name":"Lukas Zemaitis","author_inst":"Genomika"},{"author_name":"Eitan Yaakobi","author_inst":"Technion - Israel Institute of Technology"},{"author_name":"Simonas Juzenas","author_inst":"Vilnius University"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Contrasting defensive strategies underlie differential susceptibility of corals to crown-of-thorns sea star (CoTS; Acanthaster cf. solaris) predation","rel_doi":"10.64898\/2026.07.08.737165","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737165","rel_abs":"Crown-of-thorns sea star (CoTS), Acanthaster cf. solaris, outbreaks are a major cause of hard coral cover decline across the west Pacific, threatening coral reefs. Coral taxa vary in susceptibility to CoTS predation from preferred (Acropora spp.) to non-preferred (Porites spp.), yet the mechanisms underlying these differences are poorly understood. We investigated coral defenses during an ongoing CoTS outbreak in Mo'orea, French Polynesia by examining gene expression (including putative toxin genes) in healthy and actively predated colonies of a preferred (Acropora hyacinthus) and a non-preferred (Porites sp.) coral prey species. During predation, A. hyacinthus exhibited molecular signatures of cellular stress responses involving oxidative stress signalling, inflammation, and tissue proteolysis. In contrast, Porites sp. showed enrichment of genes involved in mitochondrial metabolic adjustment and aerobic metabolism, suggesting metabolic compensation to maintain cellular function. Furthermore, A. hyacinthus demonstrated a reactive defense behaviour by differentially expressing toxins (e.g., kunitz-type neurotoxins) while Porites sp. employed constitutive expression of all putative toxins regardless of active predation, suggesting a proactive defense strategy. Together, these findings suggest that preferred and non-preferred coral prey exhibit fundamentally different molecular and defensive strategies during CoTS predation, shedding light on the evolutionary arms race between corals and their predators.","rel_num_authors":7,"rel_authors":[{"author_name":"Lucy Mae Gorman","author_inst":"Marine Biological Association"},{"author_name":"Stella Louise Caon","author_inst":"PSL Universite Paris: EPHE-UPVD-CNRS, UAR 3278 CRIOBE, BP 1013, 98729 Papetoai, Mo'orea, French Polynesia"},{"author_name":"Ariana Snow Huffmyer","author_inst":"School of Aquatic and Fisheries Sciences, University of Washington, Seattle, WA 98195"},{"author_name":"Maria Byrne","author_inst":"Marine Invertebrate Futures Group. School of Life and Environmental Sciences, Marine Science Institute, The University of Sydney, New South Wales, Australia"},{"author_name":"Sebastien Dutertre","author_inst":"IBMM, Universite de Montpellier CNRS, ENSCM, 34095 Montpellier, France"},{"author_name":"Hollie M Putnam","author_inst":"University of Rhode Island"},{"author_name":"Suzanne C. Mills","author_inst":"Institut Universitaire de France"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"ROOTQUANT: AUTOMATED ROOT TRAIT QUANTIFICATION FROMMINIRHIZOTRON IMAGES USING DEEP LEARNING","rel_doi":"10.64898\/2026.07.07.737053","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.07.737053","rel_abs":"Quantifying root traits such as root length (RL) and root surface area (RSA) from minirhizotron imagery is a valuable approach for overcoming the phenotyping bottleneck that limits understanding and improvement of crop productivity, resource use efficiency and resilience in field experiments. However, current approaches remain labor-intensive, and deep learning (DL) methods suffer from limited generalization ability. We present RootQuant, an end-to-end DL model that simultaneously predicts RL and RSA directly from minirhizotron images using only whole-image trait values as supervision, thereby eliminating the need for pixel-level annotations. The models generalization ability was evaluated across species and fine-tuning configurations. The practical applicability of the model was further assessed under field conditions by converting image-derived RL estimates into volumetric root length density (vRLD). Using 118,191 maize and soybean images collected between 2009 and 2020, RootQuant trained on both species achieved an R2 of 0.90 and an RMSE of 2.9 mm for RL, and an R2 of 0.88 and an RMSE of 4.2 mm2 for RSA. The same mixed-species model generalized strongly across species, yielding an 8% relative improvement in R2 and a 30% lower RMSE on maize compared with the same architecture trained on a single species and applied zero-shot. Image-derived RL predictions converted to vRLD showed the expected depth-dependent decline in vRLD, as was also found by coincident destructive quantification of roots washed out of soil cores. By providing a generalist backbone model trained on a large dataset from two major crop species, RootQuant enables high-throughput simultaneous estimation of two relevant root traits directly from raw imagery without task-specific fine-tuning, thereby accelerating in situ root system analysis and phenotyping applications.","rel_num_authors":11,"rel_authors":[{"author_name":"Kinjalk Parth","author_inst":"University of Illinois at Urbana Champaign"},{"author_name":"Sebastian Varela","author_inst":"University of Illinois"},{"author_name":"Zhiru Liu","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"K. Michael Martini Jr.","author_inst":"Emory"},{"author_name":"Ashish Rajurkar","author_inst":"Salk Institute"},{"author_name":"Dylan Allan","author_inst":"University of Illinois at Urbana-Champaign"},{"author_name":"Scott McCoy","author_inst":"University of Illinois at Urbana Champaign"},{"author_name":"Jeremy Ruhter","author_inst":"University of Illinois at Urbana Champaign"},{"author_name":"Samuel Walker","author_inst":"University of Illinois at Urbana-Champaign"},{"author_name":"Nigel Goldenfeld","author_inst":"University of California San Diego"},{"author_name":"Andrew Leakey","author_inst":"University of Illinois at Urbana-Champaign"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Medin-Induced Pro-inflammatory and Prothrombotic Activation of Coronary Artery Endothelial Cells: A Potential Novel Mediator Linking Aging and Atherosclerosis","rel_doi":"10.64898\/2026.07.02.736227","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736227","rel_abs":"Background: Age is the most important risk factor for coronary artery disease (CAD) independent of traditional risk factors. Aging induces classic pro-inflammatory and prothrombotic vascular phenotypic changes whose molecular mediators remain poorly understood. Medin is a common cleavage product protein that accumulates in vasculature with aging and shown to cause endothelial dysfunction. Its role in CAD is unknown. The study aimed to evaluate the effects of medin on human coronary artery endothelial cell (HCAEC) pro-inflammatory and prothrombotic activation and establish the relationship between medin and coronary atherosclerosis in human decedents. Methods: HCAECs were exposed to physiologic dose of medin (5 M) for 20 hours and ribonucleic acid sequencing (RNAseq) with signaling pathway analyses and reverse transcription polymerase chain reaction of select pro-inflammatory and prothrombotic genes performed. Corresponding protein expression was measured by Western blot or enzyme linked immunosorbent assay in HCAECs exposed to medin (5 M) without or with nuclear factor-{kappa}B (NF{kappa}B) inhibitor RO106-9920 (10 M). Coronary arteries from 40 deceased individuals underwent immunohistochemistry and medin and plaque burden were quantified and their relationship evaluated. Results: RNAseq showed predominant pro-inflammatory gene expression changes induced by medin. HCAECs treated with medin showed increased phosphorylated NF{kappa}B, elevated protein expression of interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and plasminogen activator inhibitor (PAI)-1 and reduced protein expression of thrombomodulin; these changes were reversed by RO106-9920 co-treatment. In human tissues, coronary artery medin strongly correlated with plaque burden (R=0.76, p<0.0001) and coronary macrophage content (R=0.72, p<0.0001). Coronary arteries from decedents with myocardial infarction had higher medin than those without (5.53{+\/-}2.67% versus 0.02{+\/-}0.02%, p=0.0005). Conclusions: Medin induced NF{kappa}B-mediated endothelial cell pro-inflammatory and prothrombotic activation and was strongly associated with coronary plaque burden and inflammation. Medin is a novel candidate mediator linking aging and coronary atherosclerosis.","rel_num_authors":11,"rel_authors":[{"author_name":"Kaleb T Morrow","author_inst":"Phoenix Veterans Affairs Health Care System"},{"author_name":"Nina Karamanova","author_inst":"Phoenix Veterans Affairs Health Care System"},{"author_name":"Randy Woltjer","author_inst":"OHSU"},{"author_name":"Victoria Krajbich","author_inst":"Oregon Health & Science University"},{"author_name":"Jingmin Shu","author_inst":"Phoenix VA Health Care System Library"},{"author_name":"Ming Li","author_inst":"Phoenix Veterans Affairs Health Care System"},{"author_name":"Chengyun Tang","author_inst":"Oregon Health & Science University"},{"author_name":"Alana Maerivoet","author_inst":"University of Liverpool"},{"author_name":"Jillian Madine","author_inst":"University of Liverpool"},{"author_name":"Yabing Chen","author_inst":"Oregon Health & Science University"},{"author_name":"Raymond Q Migrino","author_inst":"Phoenix VA Health Care System"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Behavioral and Functional Profiling of Acomys cahirinus Fibroblasts Reveals Enhanced Matrix Remodeling Capacity","rel_doi":"10.64898\/2026.07.07.737114","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.07.737114","rel_abs":"The African spiny mouse (Acomys cahirinus) exhibits a unique capacity among mammals for scarless tissue regeneration, making it a compelling model for investigating the cellular mechanisms underlying regenerative healing. To determine how cellular heterogeneity and specific phenotypes influence fibroblast behavior, we established an immortalized Acomys fibroblast line along with a CRISPR\/Cas9-mediated Col3A1 knockout variant and a DNA damage-induced senescent population. Compared with Mus musculus, NIH 3T3 fibroblasts, Acomys cells displayed distinct morphology, similar migration speeds, reduced directional persistence, and greater biophysical heterogeneity. While previous studies have linked regenerative wound healing to the elevated expression of collagen type III (Col3A1), CRISPR-mediated knockout of Col3A1 in Acomys fibroblasts yielded comparable biophysical profiles to wild-type cells in 2D culture. To examine additional contributors to the enhanced wound-like matrix environment, we established a senescence model in which Acomys fibroblasts exhibited elevated resistance to DNA-damaging agents, complete loss of proliferation, and altered single-cell morphology. In 3D collagen gel contraction assays, Col3A1 knockout attenuated matrix remodeling capacity, whereas the introduction of a small fraction of senescent cells enhanced gel contraction and remodeling dynamics, suggesting that senescent fibroblasts can modulate collective matrix behaviors. Together, these findings demonstrate that both Col3A1 expression and senescence-associated cell states contribute to fibroblast-driven matrix remodeling, highlighting Acomys fibroblasts as a valuable model for investigating how cellular heterogeneity and senescence-associated cell phenotypes could influence regenerative wound healing.","rel_num_authors":7,"rel_authors":[{"author_name":"Nicolas Macaluso","author_inst":"Johns Hopkins University"},{"author_name":"Meera Bhat","author_inst":"Johns Hopkins University"},{"author_name":"Angela Lu","author_inst":"Johns Hopkins University"},{"author_name":"Yuanhui Chen","author_inst":"Johns Hopkins University"},{"author_name":"Long Nguyen","author_inst":"Princeton University"},{"author_name":"Piyush K. Jain","author_inst":"University of Florida"},{"author_name":"Jude Marvin Phillip","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Cold Shock Domain Protein LIN-66 cooperates with microRNA-pathway buffering to safeguard developmental timing","rel_doi":"10.64898\/2026.07.07.737059","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.07.737059","rel_abs":"Robust execution of developmental cell fates requires precise spatiotemporal control of the fate-defining regulators. In Caenorhabditis elegans, temporal patterning of larval hypodermal fates is governed by the heterochronic gene regulatory network, in which microRNAs act as major post-transcriptional regulators by silencing temporal transcripts through 3'UTR-dependent repression. Here, we investigate lin-66, which encodes a nematode-specific cold shock domain protein previously implicated in heterochronic regulation and reported to associate with the miRISC effector protein AIN-1. Using targeted domain mutations and genetic analysis, we show that LIN-66 activity in the hypodermal cell-fate patterning requires its cold shock domain. Loss of lin-66 causes persistent expression of LIN-14 and LIN-28, two early temporal regulators in the hypodermal seam cells that are canonical microRNA targets. Analysis indicates that lin-66 function in seam-cell fate patterning does not depend on the native 3'UTR sequences of lin-14 or lin-28, distinguishing its activity from canonical microRNA repression.. Consistent However, consistent with the a broad functional overlap between LIN-66 function and microRNA-mediated regulation, hypodermal lin-66 loss-of-function phenotypes are strongly enhanced by mutations in alg-1 and ain-1\/2, which encode components of the microRNA-induced silencing complex. Moreover, loss of lin-66 enhances phenotypes in mutants sensitized for microRNA activity outside the hypodermis. Together, these findings identify LIN-66 as a cold shock domain-dependent post-transcriptional regulator that safeguards developmental timing by limiting persistence of early fate regulators through mechanisms that intersect with, but are partly separable from, canonical 3'UTR-mediated microRNA repression.","rel_num_authors":2,"rel_authors":[{"author_name":"Reyyan Bulut","author_inst":"UMass Chan Medical School"},{"author_name":"Victor Ambros","author_inst":"University of Massachusetts Chan Medical School"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Perspectives in conducting task-based research in pediatric surgical epilepsy patients","rel_doi":"10.64898\/2026.07.02.734030","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.734030","rel_abs":"Objective: Pediatric epilepsy patients undergoing stereo-electroencephalography (sEEG) for ictal onset evaluation provide a rare window to study the developing brain. While methodological frameworks for task-based sEEG research are well-established in adults, pediatric-specific guidance remains underdeveloped. Furthermore, many pediatric epilepsy patients have comorbidities that might typically exclude them from participating in research. We examine factors that influence research participation and discuss considerations for conducting sEEG research in children. Methods: Here, we present a retrospective analysis of task-based research participation patterns from an NIH-funded study of speech and language representations (1R01DC018579) in 66 patients (ages 4-24) undergoing sEEG monitoring at Texas Children's Hospital to determine whether specific comorbidities influenced research participation. Results: Eighty-nine percent (n=66) of patients approached for consent agreed to participate in the study. Despite high rates of comorbidities including neurocognitive disorder (66.67%), language delay (31.75%), global developmental delay (23.81%), mood disorders (33.33%), ADHD (46.03%), autism spectrum disorder (14.29%) or other cognitive\/intellectual disabilities (36.51%), all participants engaged in at least one task. While the majority of these diagnoses did not appear to influence subject participation, global developmental delay was associated with a significant reduction in time spent on active tasks. Discussion: Despite high prevalence of neuropsychological comorbidities among participants, our evidence suggests that these participants contribute meaningfully to studies investigating important developmental questions. We suggest strategies for tailoring task-based research to accommodate the unique needs of individuals in this population. Such practices are important for ensuring that research studies reflect the true diversity of the population.","rel_num_authors":9,"rel_authors":[{"author_name":"Jacob P Leisawitz","author_inst":"Baylor College of Medicine"},{"author_name":"Sandra F Georges","author_inst":"Baylor College of Medicine"},{"author_name":"Alyssa M Field","author_inst":"The University of Texas at Austin"},{"author_name":"Saman Asghar","author_inst":"Baylor College of Medicine"},{"author_name":"Gabrielle Foox","author_inst":"Baylor College of Medicine"},{"author_name":"Andrew J Watrous","author_inst":"Baylor College of Medicine"},{"author_name":"Howard L Weiner","author_inst":"Baylor College of Medicine"},{"author_name":"Anne E Anderson","author_inst":"Baylor College of Medicine"},{"author_name":"Liberty S Hamilton","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Beyond infinite sites: Generalized ABBA-BABA statistic for deeper phylogenies","rel_doi":"10.64898\/2026.07.06.736715","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736715","rel_abs":"The Patterson's D statistic detects gene flow from ABBA-BABA site patterns, but its biallelic site patterns fail under deeper divergences where multiple hits cause false positives. We propose two extensions, D+ and D*. Both incorporate multiallelic site patterns to reduce saturation bias under JC and F84 model. Simulations show that D+ and D* both remain correctly null under all conditions and detect gene flow effectively, with distinct advantages: D+ guarantees non-negativity of the denominator, while D* provides greater robustness when mutation rates vary across genomic regions. The source code and binary files are publicly available at https:\/\/github.com\/chaoszhang\/ASTER.","rel_num_authors":2,"rel_authors":[{"author_name":"Chao Zhang","author_inst":"Peking University"},{"author_name":"Rasmus Nielsen","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Beyond infinite sites: Generalized ABBA-BABA statistic for deeper phylogenies","rel_doi":"10.64898\/2026.07.06.736715","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736715","rel_abs":"The Patterson's D statistic detects gene flow from ABBA-BABA site patterns, but its biallelic site patterns fail under deeper divergences where multiple hits cause false positives. We propose two extensions, D+ and D*. Both incorporate multiallelic site patterns to reduce saturation bias under JC and F84 model. Simulations show that D+ and D* both remain correctly null under all conditions and detect gene flow effectively, with distinct advantages: D+ guarantees non-negativity of the denominator, while D* provides greater robustness when mutation rates vary across genomic regions. The source code and binary files are publicly available at https:\/\/github.com\/chaoszhang\/ASTER.","rel_num_authors":2,"rel_authors":[{"author_name":"Chao Zhang","author_inst":"Peking University"},{"author_name":"Rasmus Nielsen","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"EpiBinder: a multimodal framework for cell-type-specific prediction and interpretation of transcription factor binding","rel_doi":"10.64898\/2026.07.06.736502","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736502","rel_abs":"Transcription factor (TF) occupancy in vivo depends not only on the underlying DNA sequence but also on the local epigenetic environment, which varies across cell types and strongly influences whether sequence-encoded binding potential becomes functional. Here we present EpiBinder, a multimodal deep-learning framework for cell-type-specific prediction of TF binding that jointly models DNA sequence with base-resolution epigenetic information, including cytosine methylation from whole-genome bisulfite sequencing and chromatin accessibility from DNase I hypersensitivity data. Across multiple human cell lines, EpiBinder consistently outperforms strong sequence-only baselines, improving TF-binding prediction by up to 10% in area under the precision-recall curve. Beyond predictive performance, EpiBinder provides base-level attribution maps that enable systematic interrogation of regulatory context, including candidate methylation-sensitive loci, contextual motif dependencies, and putative TF-TF interactions. These results position EpiBinder as a practical framework for modeling and exploring the local regulatory grammar underlying cell-type-specific TF occupancy.","rel_num_authors":8,"rel_authors":[{"author_name":"Ruben Solozabal","author_inst":"Mohamed bin Zayed University of Artificial Intelligence"},{"author_name":"Albert Baichorov","author_inst":"Mohamed bin Zayed University of Artificial Intelligence"},{"author_name":"Irina Miodownik","author_inst":"Weizmann Institute of Science"},{"author_name":"Tamir Avioz","author_inst":"Weizmann Institute of Science"},{"author_name":"Le Song","author_inst":"Mohamed bin Zayed University of Artificial Intelligence"},{"author_name":"Marcos Matabuena","author_inst":"Mohamed bin Zayed University of Artificial Intelligence"},{"author_name":"Martin Takac","author_inst":"Mohamed bin Zayed University of Artificial Intelligence"},{"author_name":"Ariel Afek","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Mechanoresponsive modulation of nuclear pore complex structure and function by O-GlcNAc","rel_doi":"10.64898\/2026.07.07.737034","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.07.737034","rel_abs":"Nuclear pore complexes (NPCs) control molecular exchange across the nuclear envelope, but how they tailor their selective permeability to meet the needs of specific cell types and\/or environments remains poorly understood. We demonstrate that the strength of the NPC diffusion barrier differs across cell types, is particularly stringent in cultured neurons, and correlates with the O-linked N-acetylglucosamine (GlcNAc) modification of nucleoporins. Using conditional tools that specifically control nucleoporin GlcNAcylation, we show that GlcNAc modulates NPC permeability. Interestingly, nucleoporin GlcNAcylation is mechanosensitive, increasing in cells plated on stiff substrates, a condition where nuclear pores dilate. Indeed, we demonstrate that increasing or decreasing GlcNAcylation dilates and constricts NPCs, respectively. Further, O-linked N-acetylglucosamine transferase is recruited to modify NPCs upon their acute constriction during osmotic shock. Thus, cells employ GlcNAc to modulate steady-state NPC permeability in response to mechanical inputs and to counteract critical changes to their osmotic environment.","rel_num_authors":5,"rel_authors":[{"author_name":"Sunandini Chandra","author_inst":"Yale School of Medicine"},{"author_name":"Kimberly J Morgan","author_inst":"Yale School of Medicine"},{"author_name":"William L Chadwick","author_inst":"Yale School of Medicine"},{"author_name":"Megan C King","author_inst":"Yale School of Medicine"},{"author_name":"C. Patrick Lusk","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Serotonin reuptake inhibition rapidly enhances affect-reward coupling and improves mood over time","rel_doi":"10.64898\/2026.07.03.736315","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736315","rel_abs":"Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed antidepressants, yet the mechanisms linking their rapid neurobiological effects to more gradual improvements in mood remain unclear. Computational accounts in which mood reflects the integration of reward outcome and reward prediction errors (RPEs) offer a compelling framework for examining SSRI effects, but reliance on laboratory tasks poses a major translational gap, both in timescale and ecological validity. We address this gap by examining the impact of SSRIs on affect-reward dynamics over a clinically relevant timescale using real-world rewards. Across 11 days, 66 healthy participants (n=37 receiving the SSRI citalopram) completed repeated ecological momentary assessments (EMA) of mood and goal-directed activities (up to 8 per day, totaling 3,542 surveys). By probing anticipated reward (pre-activity) and consummatory reward (post-activity), we derived real-world RPEs to test whether SSRIs amplify RPE impacts on momentary mood. Mixed-effects modelling showed that citalopram rapidly amplified the impact of reward outcome and RPEs on momentary mood, and predicted later increases in positive mood. Citalopram also selectively attenuated the impact of negative mood on expectations for future reward. These findings suggest that SSRIs modulate the bidirectional coupling between mood and reward processes in daily life, consistent with a positive feedback loop that could underpin the gradual mood improvement observed for antidepressant treatment. More broadly, our results highlight the utility of EMA as a highly sensitive real-world assay of early pharmacological effects on mood-reward dynamics.","rel_num_authors":5,"rel_authors":[{"author_name":"Regan Mills","author_inst":"University College London"},{"author_name":"Anais Durand","author_inst":"University College London"},{"author_name":"Meggy Croal","author_inst":"University College London"},{"author_name":"Robb B. Rutledge","author_inst":"Yale University"},{"author_name":"Liam Mason","author_inst":"University College London"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Environmentally relevant depleted uranium exposure damages mitochondria, decreases cytosolic reductive capacity, and increases global DNA damage accumulation through a ROS-independent mechanism involving slingshot protein phosphatase 1b enrichment.","rel_doi":"10.64898\/2026.07.02.736169","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736169","rel_abs":"Depleted uranium (DU) is an environmental contaminant with a 30 g\/L (ppb; parts per billion) EPA maximum contaminant level (MCL) for drinking water. The mining of uranium and use of DU in modern weapons underly human exposure that disproportionally impacts military and tribal communities in the United States. Uranium's radiotoxic characteristics are understood, but its chemical hazards much less so. In zebrafish (Danio rerio) and human cell cultures we test the hypothesis that exposure to DU negatively impacts cellular function and development through disruption of mitochondrial metabolism. Using a novel shrapnel model with TEM\/SEM+EDS, we showed uranium microparticles caused proximity-dependent mitochondrial disruption. In waterborne exposure paradigms, larval movement was reduced and hatching delayed as a result of reduced movement and not enzyme deficiencies in response to 18 ppb DU, below the MCL. Increased DNA damage accumulation was detected in exposed larva and cells. DNA-damage quantitative PCR of DU-exposed larvae showed increased damage in the ahr1 locus (nuclear gene) and decreased mitochondrial DNA (mtDNA) copy number, but mtDNA damage levels varied across experiments. Mitochondrial function was assessed using a resazurin-based assay in the presence and absence of antioxidants and showed diminished cytoplasmic reductive capacity. DU exposure alone did not enrich antioxidant gene expression, contrasting with arsenic exposure, a known ROS-inducer and Nrf2-activator. Sulforaphane (SFN), a potent Nrf2-activator, did not blunt the effects of DU exposure, despite activation of antioxidant response element (ARE) genes (gstp and gss), but did blunt the effects of arsenic exposure. The most enriched transcript in DU-exposed larvae coded for slingshot protein phosphatase (ssh), further exploration revealed ssh1b as the zebrafish-specific ortholog activated in response to DU, and inhibition using an identified SSH1 inhibitor, Sennoside A, partially rescued the metabolic and hatching defects observed. Our data points to a cytotoxic mechanism in which DU disrupts mitochondrial function through ssh1b enrichment that impairs normal mitophagy, leading to decreased cellular reductive potential independent of either ROS production or ARE-activation. Our results suggest that health impacts from DU exposure may be directly linked to impaired mitochondrial functions.","rel_num_authors":12,"rel_authors":[{"author_name":"Phillip H Kalaniopio","author_inst":"Northern Arizona University"},{"author_name":"Luke B Gibbons","author_inst":"Northern Arizona University"},{"author_name":"Ronald S Allen Jr.","author_inst":"Northern Arizona University"},{"author_name":"Saoirse M Matthews","author_inst":"Northern Arizona University"},{"author_name":"Oscar R Lujan","author_inst":"Northern Arizona University"},{"author_name":"Elyes Gaaloul","author_inst":"Northern Arizona University"},{"author_name":"Justin Wilbanks","author_inst":"Northern Arizona University"},{"author_name":"Cailyn M Allen","author_inst":"Northern Arizona University"},{"author_name":"Connor A Chassman","author_inst":"Northern Arizona University"},{"author_name":"Tinna Traustadottir","author_inst":"Northern Arizona University"},{"author_name":"Catherine R Propper","author_inst":"Northern Arizona University"},{"author_name":"Matthew C Salanga","author_inst":"Northern Arizona University"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Azacitidine Response in Myelodysplastic Syndromes is Marked by NK-like CD8 T-Cell Expansion and CXCL12+ Reticular Cell Remodeling","rel_doi":"10.64898\/2026.07.07.736922","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.07.736922","rel_abs":"Myelodysplastic syndromes (MDS) are driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs), leading to clonal expansion and ineffective hematopoiesis. Hypomethylating agents (HMAs; azacitidine or decitabine) are the standard of care for higher-risk MDS. However, their effects on the bone marrow (BM) microenvironment, and the extent to which these changes correlate with clinical response, remain poorly understood. We performed longitudinal analyses of BM aspirates, trephine biopsies, and peripheral blood samples from MDS patients treated with azacitidine in a clinical trial (NCT03493646), integrating CyTOF, 5' single-cell RNA and TCR sequencing, plasma proteomics, and multiplex immunofluorescence microscopy to characterize changes associated with azacitidine response. Clinical responders showed expansion of GzmBCD56CD8 T cells together with increased type I and type II interferon signaling within the T-cell compartment. Responders also exhibited marked alterations in circulating platelet- and myeloid-derived factors with the potential to remodel the BM niche. Spatial analyses revealed expansion of neighborhoods enriched for CXCL12-abundant reticular cells and CD8 T cells in responders, whereas HSPC-enriched neighborhoods were largely unchanged. In contrast, several HSPC-enriched neighborhoods expanded in non-responders. These microenvironmental changes were accompanied by evidence of enhanced myelopoiesis in clinical responders. Our findings support a model in which azacitidine response extends beyond direct effects on malignant hematopoietic cells to involve coordinated remodeling of the BM microenvironment which may be reinforced by platelet- and myeloid-derived signals that establish a feed-forward circuit promoting productive hematopoiesis.","rel_num_authors":24,"rel_authors":[{"author_name":"Henry R. Hampton","author_inst":"School of Biomedical Sciences, University of New South Wales, Sydney, Australia."},{"author_name":"Anne Pan","author_inst":"School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China."},{"author_name":"Michael Carnell","author_inst":"Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, Australia"},{"author_name":"Bofei Wang","author_inst":"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States."},{"author_name":"Diana Shinko","author_inst":"Sydney Cytometry, The University of Sydney, Sydney, Australia."},{"author_name":"Maria Kasherman","author_inst":"Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, Australia."},{"author_name":"Iveta Slapetova","author_inst":"Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, Australia."},{"author_name":"Swapna Joshi","author_inst":"School of Biomedical Sciences, University of New South Wales, Sydney, Australia."},{"author_name":"Mary N.T. Nguyen","author_inst":"School of Biomedical Sciences, University of New South Wales, Sydney, Australia."},{"author_name":"Feng Yan","author_inst":"School of Biomedical Sciences, University of New South Wales, Sydney, Australia."},{"author_name":"Sarah Davidson","author_inst":"ANU Clinical Hub for Interventional Research (CHOIR), John Curtin School of Medical Research, Canberra, Australia."},{"author_name":"Nick F.Y. Choi","author_inst":"School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China."},{"author_name":"Jason W.H. Wong","author_inst":"School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China."},{"author_name":"Nicodemus Tedla","author_inst":"School of Biomedical Sciences, University of New South Wales, Sydney, Australia."},{"author_name":"Devendra K. Hiwase","author_inst":"Department of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia."},{"author_name":"Magnus Tobiasson","author_inst":"Department of Hematology, Karolinska University Hospital."},{"author_name":"Mark N. Polizzotto","author_inst":"ANU Clinical Hub for Interventional Research (CHOIR), John Curtin School of Medical Research, Canberra, Australia."},{"author_name":"Helen M McGuire","author_inst":"School of Medical Sciences, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, Australia."},{"author_name":"Hussein A Abbas","author_inst":"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States."},{"author_name":"Asif Javed","author_inst":"School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China."},{"author_name":"Jake Olivier","author_inst":"School of Mathematics and Statistics, University of New South Wales, Sydney, Australia."},{"author_name":"Julie A.I. Thoms","author_inst":"School of Biomedical Sciences, University of New South Wales, Sydney, Australia."},{"author_name":"Christopher J. Jolly","author_inst":"School of Biomedical Sciences, University of New South Wales, Sydney, Australia."},{"author_name":"John E. Pimanda","author_inst":"School of Biomedical Sciences, University of New South Wales, Sydney, Australia."}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Fine-Tuned Large Language Models for Detecting Social Isolation from Unstructured Clinical Notes","rel_doi":"10.64898\/2026.07.05.26357334","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357334","rel_abs":"Objectives: This study aimed to leverage FLAN-T5-Large, BERT, RoBERTa, and Gemma-2-2B, with fine-tuning, to identify instances of social isolation and social support within unstructured clinical notes. Materials and Methods: Annotated clinical note spans containing social context cues were used to fine-tune each model. Performance was evaluated using Accuracy, Precision, Recall, and Macro-F1 score. A structured prompt was used to instruct the model to perform classification task and mitigate overgeneralization. Performance comparisons across the models assessed sensitivity, robustness, and false positive reduction. Results: FLAN-T5-Large achieved highest performance, with Macro-F1 of 0.92{+\/-}0.04, demonstrating balanced results across classes: social isolation (F1 = 0.91{+\/-}0.03), no social isolation (F1 = 0.94{+\/-}0.05), and social support (F1 = 0.90{+\/-}0.04). Gemma-2-2B produced comparable results, with Macro-F1 score of 0.89{+\/-}0.10. BERT and RoBERTa achieved lower Macro-F1 scores of 0.77{+\/-}0.17 and 0.80{+\/-}0.21 respectively, with variability across categories. Discussion: A major contribution of this work is precise identification of multiple concepts related to social connectedness. By integrating annotated examples of both true and false positives, including negations and contextually ambiguous terms, the model better distinguished relevant social context cues from noise. Training on both social isolation and support provided a dual framework for comparative analyses and patient stratification. Conclusion: Transformer-based NLP models, particularly FLAN-T5-Large, demonstrated potential for identifying social isolation and social support in clinical text. These findings support the use of generative AI techniques to enhance detection of social isolation from EHRs, advancing context-aware healthcare analytics.","rel_num_authors":7,"rel_authors":[{"author_name":"Lokesh K Chinthala","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Cindy Lemon","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Arash Shaban-Nejad","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Gregory Farage","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Robert L Davis","author_inst":"The University of Tennessee Health Science Center"},{"author_name":"Hua Xu","author_inst":"Yale University"},{"author_name":"Charisse Madlock-Brown","author_inst":"University of Iowa"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Fine-Tuned Large Language Models for Detecting Social Isolation from Unstructured Clinical Notes","rel_doi":"10.64898\/2026.07.05.26357334","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357334","rel_abs":"Objectives: This study aimed to leverage FLAN-T5-Large, BERT, RoBERTa, and Gemma-2-2B, with fine-tuning, to identify instances of social isolation and social support within unstructured clinical notes. Materials and Methods: Annotated clinical note spans containing social context cues were used to fine-tune each model. Performance was evaluated using Accuracy, Precision, Recall, and Macro-F1 score. A structured prompt was used to instruct the model to perform classification task and mitigate overgeneralization. Performance comparisons across the models assessed sensitivity, robustness, and false positive reduction. Results: FLAN-T5-Large achieved highest performance, with Macro-F1 of 0.92{+\/-}0.04, demonstrating balanced results across classes: social isolation (F1 = 0.91{+\/-}0.03), no social isolation (F1 = 0.94{+\/-}0.05), and social support (F1 = 0.90{+\/-}0.04). Gemma-2-2B produced comparable results, with Macro-F1 score of 0.89{+\/-}0.10. BERT and RoBERTa achieved lower Macro-F1 scores of 0.77{+\/-}0.17 and 0.80{+\/-}0.21 respectively, with variability across categories. Discussion: A major contribution of this work is precise identification of multiple concepts related to social connectedness. By integrating annotated examples of both true and false positives, including negations and contextually ambiguous terms, the model better distinguished relevant social context cues from noise. Training on both social isolation and support provided a dual framework for comparative analyses and patient stratification. Conclusion: Transformer-based NLP models, particularly FLAN-T5-Large, demonstrated potential for identifying social isolation and social support in clinical text. These findings support the use of generative AI techniques to enhance detection of social isolation from EHRs, advancing context-aware healthcare analytics.","rel_num_authors":7,"rel_authors":[{"author_name":"Lokesh K Chinthala","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Cindy Lemon","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Arash Shaban-Nejad","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Gregory Farage","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Robert L Davis","author_inst":"The University of Tennessee Health Science Center"},{"author_name":"Hua Xu","author_inst":"Yale University"},{"author_name":"Charisse Madlock-Brown","author_inst":"University of Iowa"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"In-clinic validation of a smartphone-based finger tapping test for use in neurodegenerative and neurological populations.","rel_doi":"10.64898\/2026.06.25.26356467","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356467","rel_abs":"Background: Motor disturbances are common in neurologic and neurodegenerative syndromes. A standard motor speed and dexterity measure is the finger tapping test (FTT). The FTT has traditionally been administered in clinic using a mechanical FTT, limiting accessibility and early motor change quantification. This study assessed the validity of a smartphone app-based FTT, which may expand access and enable more frequent testing. Methods: The cohort was diagnostically diverse, including participants with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome, primary progressive aphasia, multiple sclerosis, and clinically unimpaired controls. Participants completed a 20-second ALLFTD Mobile App (mApp)-FTT with each hand. Tapping speed metrics were extracted. Participants completed the gold-standard mechanical FTT, a neurologist-administered finger tapping exam, the PSP Rating Scale (PSPRS) and the Unified Parkinson`s Disease Rating Scale (UPDRS). Correlations assessed mApp-FTT and mechanical FTT relationships; regressions evaluated associations with neurologist-rated finger tapping impairment, PSPRS and UPDRS, adjusting for age and sex. Results: The mApp-FTT showed moderate-to-strong correlations with the mechanical FTT (dominant: r=0.63, p<0.001; non-dominant: r=0.55, p<0.001). Taps per second were associated with PSPRS motor severity (dominant hand: std. {beta}=-0.59, 95% CI [-0.91, -0.27], p<0.001) and the UPDRS (dominant hand: std. {beta}=-0.41, 95% CI [-0.82, 0.00], p=0.049). Flight time was modestly associated with neurologist-rated finger tapping impairment (dominant hand: std. {beta}=0.15, 95% CI [0.00, 0.29], p=0.044). Conclusion: These findings support mApp-FTT validity as a measure of motor function across neurodegenerative conditions. Validation in longitudinal and unsupervised remote settings is warranted to understand scalability and evaluate change over time.","rel_num_authors":24,"rel_authors":[{"author_name":"Morgan O'Connor","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA"},{"author_name":"Mark Sanderson-Cimino","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Zi Li","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA"},{"author_name":"Sreya Dhanam","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Anjali Sadarangani","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Joshua Downer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Ray Fregly","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Jack Taylor","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Amy B. Wise","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Kaitlin B. Casaletto","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Leah K. Forsberg","author_inst":"Department of Neurology, Mayo Clinic, Rochester, MN, USA"},{"author_name":"Maria Luisa Gorno-Tempini","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Hilary W. Heuer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Joel H. Kramer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"John Kornak","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA"},{"author_name":"Bruce L Miller","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Emily W Paolillo","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Riley Bove","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Gil Rabinovici","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"William W. Seeley","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Brad F. Boeve","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Howie J. Rosen","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Adam L. Boxer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Adam M. Staffaroni","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Association Between Area Deprivation and Dental Provider Density in California: A Cross-Sectional Ecological Study","rel_doi":"10.64898\/2026.07.04.26357261","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357261","rel_abs":"Abstract Background Neighborhood socioeconomic disadvantage may contribute to inequities in access to dental care by influencing the geographic distribution of providers. The Area Deprivation Index (ADI) is a validated measure of neighborhood deprivation, but its association with dental workforce availability has not been examined statewide in California. This study evaluated the relationship between neighborhood deprivation and dental provider density across California ZIP Code Tabulation Areas (ZCTAs). Methods We conducted a cross-sectional ecological study of California ZCTAs using publicly available data from the National Plan and Provider Enumeration System (April 2026), the Neighborhood Atlas 2023 ADI, and 2024 U.S. Census population estimates. Active dental providers were linked to ZCTAs and provider density was calculated per 10,000 residents. ADI was aggregated to the ZCTA level using the median ADI national percentile. Negative binomial regression was used to assess the association between ADI and dental provider density, with population included as an offset. Secondary analyses examined California-specific ADI quartiles, dental deserts, and specialist versus general dentist availability. Results The final analytic sample included 1,426 California ZCTAs representing 39,016,384 residents and 37,945 active dental providers. Greater neighborhood deprivation was significantly associated with lower dental provider density. Each one-percentile increase in ADI corresponded to a 1.8% reduction in provider density (incidence rate ratio [RR] 0.9823, 95% confidence interval [CI] 0.9799-0.9847; p < 0.001). Compared with the least deprived quartile, the most deprived quartile had 61% fewer dental providers (RR 0.39, 95% CI 0.34-0.45; p < 0.001). Overall, 15.9% of ZCTAs contained no active dental providers, increasing from 6.8% in the least deprived quartile to 31.1% in the most deprived quartile. Specialist availability demonstrated an even steeper deprivation gradient, with specialist density declining by 86% between the least and most deprived quartiles.","rel_num_authors":2,"rel_authors":[{"author_name":"Anna-Lena Asiedu","author_inst":"University of California San Francisco, School of Dentistry"},{"author_name":"Collins Gaba","author_inst":"Boston University School of Social Work"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Prevalence of cancer in patients with cardiovascular diseases and risk factors: a systematic review and meta-analysis","rel_doi":"10.64898\/2026.07.04.26357301","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357301","rel_abs":"Background No systematic review has been conducted to pool the existing evidence and quantify cancer prevalence rates in cardiovascular diseases (CVDs). We aimed to estimate pooled cancer prevalence in coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), hypertension, type 2 diabetes mellitus (DM), stroke, peripheral arterial disease (PAD), and valvular heart diseases (VHD). Methods PubMed, Web of Science, and Scopus were searched from 2010 to July 2024. The outcomes were proportions of patients with active, any, previous, blood, solid, and metastatic cancer. The prevalence rates were estimated via one-step generalized linear mixed models. Results Totally, we retrieved 676 studies with enrollment of roughly 180 million participants. The analysis for active cancer included 59 studies with a population of 4,759,695 patients. The pooled prevalence of active cancer was 4.22% (95% confidence interval (CI) 2.18-5.32), 4.43% (95% CI 2.78-6.38), 4.60% (95% CI 1.72-8.13), 4.61% (95% CI, 2.83-6.97), 4.90% (95% CI 3.84-6.37), and 5.55% (95% CI 3.97-7.01) in patients with type 2 DM, chronic HF, any stroke, CAD, VHD, and AF. For any cancer, prevalence rates ranged from 14.10% (95% CI 12.20-15.99) in AF to 7.04% (95% CI 6.05-8.03) in CAD. Conclusion Pooled prevalence rates demonstrate a measurable burden of cancer among patients with a wide range of CVDs, highlighting the need for multidisciplinary management in this population.","rel_num_authors":15,"rel_authors":[{"author_name":"Akhmetzhan Galimzhanov","author_inst":"Astana Medical University"},{"author_name":"Elif Beytekin","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Leh Chuan Lim","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Abdul Basit Ali Zai","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Gemina Doolub","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Mustafa Aljarshawi","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Balamrit Singh Sokhal","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Andrija Matetic","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Rodrigo Bagur","author_inst":"Department of Cardiology, London Health Sciences Centre Western University London Ontario Canada"},{"author_name":"Louise Sun","author_inst":"Division of Cardiothoracic Anesthesiology, Stanford University School of Medicine, Stanford, California, USA"},{"author_name":"Cheng Han Ng","author_inst":"Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore"},{"author_name":"Miguel Nobre Menezes","author_inst":"Structural and Coronary Heart Disease Unit, Cardio-Oncology Unit CHULN Hospital de Santa Maria, Cardiovascular Center of the University of Lisbon, 1649-028 Lisb"},{"author_name":"Sarah Zaman","author_inst":"Westmead Applied Research Centre, University of Sydney, Sydney, Australia."},{"author_name":"Bonnie Ky","author_inst":"Thalheimer Center for Cardio-Oncology, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"},{"author_name":"Mamas Mamas","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Recalibrating Mendelian randomization under winner's curse, sample structure and polygenicity","rel_doi":"10.64898\/2026.06.25.26356593","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356593","rel_abs":"Recently, Hu et al. (2024) conducted a benchmarking study showing that most existing Mendelian randomization (MR) methods exhibit substantial bias and inflated type-I error rates in real data. They attributed these failures to two largely neglected sources of bias: winners curse and polygenicity-induced bias. Although a few methods have been developed to address one or both of these issues, existing approaches either do not fully account for both biases or are restricted to the univariable setting. In this paper, we propose a multivariable Rao-Blackwellization that corrects winners curse while accounting for polygenicity and sample structure in a unified framework. Unlike univariable Rao-Blackwellization, where instrument selection yields a truncated normal statistic amenable to a Mills-ratio correction, multivariable Rao-Blackwellization conditions on a noncentral{chi} 2 statistic, for which no analogous correction is available. We derive closed-form conditional moments under this instrument selection model and use them to construct bias-corrected summary statistics that can be integrated into a wide range of existing MR methods. Simulations and real data analyses show that, when combined with methods such as MR-cML and MR-BEE, the proposed correction substantially improves type-I error control and yields more robust inference.","rel_num_authors":4,"rel_authors":[{"author_name":"Yihe Yang","author_inst":"Case Western Reserve University"},{"author_name":"Zhaotong Lin","author_inst":"Florida State University"},{"author_name":"Haoran Xue","author_inst":"City University of Hong Kong"},{"author_name":"Xiaofeng Zhu","author_inst":"Case Western Reserve university"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Recalibrating Mendelian randomization under winner's curse, sample structure and polygenicity","rel_doi":"10.64898\/2026.06.25.26356593","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356593","rel_abs":"Recently, Hu et al. (2024) conducted a benchmarking study showing that most existing Mendelian randomization (MR) methods exhibit substantial bias and inflated type-I error rates in real data. They attributed these failures to two largely neglected sources of bias: winners curse and polygenicity-induced bias. Although a few methods have been developed to address one or both of these issues, existing approaches either do not fully account for both biases or are restricted to the univariable setting. In this paper, we propose a multivariable Rao-Blackwellization that corrects winners curse while accounting for polygenicity and sample structure in a unified framework. Unlike univariable Rao-Blackwellization, where instrument selection yields a truncated normal statistic amenable to a Mills-ratio correction, multivariable Rao-Blackwellization conditions on a noncentral{chi} 2 statistic, for which no analogous correction is available. We derive closed-form conditional moments under this instrument selection model and use them to construct bias-corrected summary statistics that can be integrated into a wide range of existing MR methods. Simulations and real data analyses show that, when combined with methods such as MR-cML and MR-BEE, the proposed correction substantially improves type-I error control and yields more robust inference.","rel_num_authors":4,"rel_authors":[{"author_name":"Yihe Yang","author_inst":"Case Western Reserve University"},{"author_name":"Zhaotong Lin","author_inst":"Florida State University"},{"author_name":"Haoran Xue","author_inst":"City University of Hong Kong"},{"author_name":"Xiaofeng Zhu","author_inst":"Case Western Reserve university"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Sickle Cell Disease Demographics and Clinical Epidemiology in Gambian Urban and Rural Cohorts Retrospective Analysis","rel_doi":"10.64898\/2026.07.03.26357219","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357219","rel_abs":"Globally, approximately 75% of sickle cell disease (SCD) cases occur in sub-Saharan Africa, yet empirical data on its natural history, clinical burden, and modifiers remain scarce in the region. This retrospective study describes the demographic characteristics, complications, and routine care and examines how non-genetic factors and blood markers relate to disease severity. We analysed 8402 medical records from 840 SCD patients with confirmed HbSS genotype registered in MRCG Keneba and Fajara clinics (NKeneba=148; NFajara=692). A generalised linear model was employed to estimate the association of non-genetic correlates, blood biomarkers, and routine care medications with disease severity. Here, we showed 67% of patients in the Keneba cohort and 92% of those in the Fajara cohort had no documented SCD-related chronic complication. Despite no documented evidence of hydroxyurea use, rates of SCD crises (Keneba=0.57, Fajara=0.63) and infections (Keneba=0.53, Fajara=0.35), expressed per patient-year, were low in both cohorts, with 99% of patients experiencing less than or equal to 3 SCD crises per patient-year. Age at diagnosis, gender and seasonality were not significantly associated with SCD crises or other clinical outcomes\/events rates. Each additional folic acid prescription was associated with higher haemoglobin(g\/dL) (total folic acid prescriptions: Beta-Fajara=1.31, P=0.005; Beta-Keneba=1.20, P<0.001). Penicillin prophylaxis was associated with a reduced rate of infection (total Pen V prescriptions: IRR-Fajara=0.85, P=0.002; IRR-Keneba=0.93, P=0.002) and SCD crises (IRR-Fajara=0.67, P=0.001; IRR-Keneba=0.87, P=0.001). This study found low acute event rates and chronic complications prevalence in the absence of hydroxyurea use. No significant associations were observed between non-genetic correlates and clinical events, but the study highlighted the need for continued folic acid supplementation and penicillin prophylaxis due to their observed beneficial effects.","rel_num_authors":11,"rel_authors":[{"author_name":"Mustapha Dibbasey","author_inst":"Medical Research Council, the Gambia at London School of Hygiene and Tropical Medicine"},{"author_name":"Kevin Esoh","author_inst":"McKusick-Nathans Institute, and Department of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA"},{"author_name":"Bubacarr Susso","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Karen Forrest","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Bakary Sonko","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Lamin Makalo","author_inst":"Department of Paediatrics, Edward Francis Small Teaching Hospital, Banjul, The Gambia"},{"author_name":"Eniyou Oriero","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Ndong Ignatius Cheng","author_inst":"Department of Epidemiology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana"},{"author_name":"Lucas Amenga-Etego","author_inst":"West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, LG 54, Accra, Ghana"},{"author_name":"Carla Cerami","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Alfred Amambua-Ngwa","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Association of anti-Ro-52 positivity with cardiovascular outcomes in patients with anti-synthetase syndrome","rel_doi":"10.64898\/2026.07.04.26357290","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357290","rel_abs":"Background: Anti-synthetase syndrome (ASyS) is a subgroup of idiopathic inflammatory myopathies that is increasingly recognized as a distinct entity with features of myositis, interstitial lung disease, inflammatory arthritis, and Raynaud phenomenon. Co-reactivity with anti-Ro-52, an antibody directed against the Ro-52 E3 ubiquitin ligase, has been shown to be associated with progressive interstitial lung disease within this patient population. However, less is known regarding the association of anti-Ro-52 positivity with cardiovascular outcomes. Methods: A sub-cohort of patients with anti-synthetase antibodies at a large single institution center was retrospectively analyzed to define presence of anti-Ro-52 positivity (defined as anti-Ro-52 titer greater than or equal to 11 utilizing the line immunoblot platform, Euroline Autoimmune Inflammatory Myopathies, EuroImmun Diagnostics, Lubeck, Germany). Patients who did not meet 2017 ACR\/EULAR classification criteria for idiopathic inflammatory myopathies were excluded from the final analysis. Cardiovascular outcomes ascertained via retrospective chart review included atrial fibrillation, left bundle branch block, right bundle branch block, pulmonary hypertension (confirmed via right heart catheterization), heart failure with reduced ejection fraction (HFrEF, defined as ejection fraction less than or equal to 40 percent), acute coronary syndrome (based on clinical diagnosis and angiography if available), and myocarditis (based on clinician diagnosis and either cardiac MRI or troponin elevation). When a pre-specified cardiac outcome was identified, the date of onset was recorded. Differences in proportions were analyzed via Chi-squared and Fishers exact tests, and time-to-event analyses were performed via Cox Proportional Hazards Models, incorporating a false discovery rate correction for multiple outcomes. All analyses were performed using SAS v9.4. Results: 88 patients were included in the final analysis, of whom 69 (78.4 percent) were categorized as anti-Ro-52 positive. Patients with anti-Ro-52 positivity had a higher maximum recorded serum creatine kinase (median 1297 vs 395 units per liter, p = 0.042). No significant associations between anti-Ro-52 positivity and the pre-defined cardiovascular outcomes were found over median follow up time of 12.5 years. Conclusions: In a large, single-center cohort of patients with ASyS, anti-Ro-52 positivity was not associated with an increased burden of negative cardiovascular outcomes, including the onset of pulmonary hypertension. Future studies may seek to further elucidate the mechanisms underlying the pleiotropic effects of anti-Ro-52 antibodies on the cardiopulmonary system.","rel_num_authors":7,"rel_authors":[{"author_name":"Archit V. Potharazu","author_inst":"Johns Hopkins Medicine"},{"author_name":"Jae-Hoon Chung","author_inst":"Johns Hopkins Medicine"},{"author_name":"Lisa Yanek","author_inst":"Johns Hopkins Medicine"},{"author_name":"Will Kelly","author_inst":"Johns Hopkins Medicine"},{"author_name":"Nisha Gilotra","author_inst":"Johns Hopkins Medicine"},{"author_name":"Luigi Adamo","author_inst":"Johns Hopkins Medicine"},{"author_name":"Julie Paik","author_inst":"Johns Hopkins Medicine"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Neonatal Hypothermia at and after Admission: Burden and Associations with Outside Air Temperature and Neonatal Ward Temperature in Four Sub Saharan African Countries Implementing with the NEST360 Alliance","rel_doi":"10.64898\/2026.07.04.26357151","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357151","rel_abs":"Background: Annually, 2.3 million newborns die, largely from preventable causes. Neonatal hypothermia is an important contributor to morbidity and mortality, particularly in low-resource settings. This study quantified the burden of hypothermia at and after admission in four NEST360-supported countries and examined associations between outside air temperature, ward temperature, and neonatal hypothermia. Methods: We conducted a retrospective analysis of newborn admissions (January 2021 to June 2025) across 66 neonatal units in Kenya, Malawi, Nigeria, and Tanzania. Hypothermia was defined using WHO thresholds (mild: 36.0-36.4{degrees}C, moderate: 32.0-35.9{degrees}C, severe: <32.0{degrees}C). Newborn admission and lowest after admission body temperatures were extracted from routine clinical records. Ward temperatures were captured using the Hadli Monitoring System, and environmental temperatures were obtained from Open-Meteo. Multivariate ordinal logistic regression assessed associations between air temperature, ward temperature, and hypothermia at admission and during admission. Results: Among 418,458 newborn admissions with recorded admission temperatures, 47.3% (n=220,684) were hypothermic at admission (country range: 22.8%-61.9%), while 63.5% (n=48,746) experienced hypothermia during hospital stay (country range: 18.5%-74.4%), based on 76,855 admissions (July 2024-June 2025) with temperature data. Based on admission and subsequent temperature, 28.5% had no documented hypothermia, 8.6% improved to non-hypothermic status, 29.4% developed hypothermia after admission, and 33.5% experienced hypothermia at admission and during hospital stay. Across 59 neonatal units, minimum ward temperatures >26{degrees}C were maintained on 92.6% of 365 days. At admission, ward temperatures of 30-33{degrees}C were associated with 9% lower odds of a lower thermal category versus 26-28{degrees}C (p<0.01). After admission, ward temperatures of 28-30{degrees}C reduced odds by 18% (p<0.05). Warmer outside temperatures (>24{degrees}C day, >21{degrees}C night) were protective, corresponding to 19% and 68% lower odds of a lower thermal category after admission, respectively, compared with 19-24{degrees}C and 15-21{degrees}C reference groups. Newborns had 3.6-fold higher odds of hypothermia at night than during the day. Each 1{degrees}C increase in post-admission temperature reduced odds of death by 6%. Conclusion: Neonatal hypothermia remains highly prevalent despite most units maintaining ward temperatures above WHO minimum standards (26{degrees}C). Strengthening all components of the warm chain, particularly at night and during colder seasons, is essential to reduce hypothermia and improve survival.","rel_num_authors":23,"rel_authors":[{"author_name":"Melissa Mar","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Christine A Bohne","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"John Wainaina","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Mariam Thabit Johari","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"George Okello","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Edith Gicheha","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Catherine Paul","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Rebecca Richards-Kortum","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Maria Oden","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Joy E Lawn","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"Lucas Malla","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"Kristina Shemwell","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"William M Macharia","author_inst":"Department of Paediatrics, Aga Khan University, Nairobi, Kenya"},{"author_name":"Hannah Mwaniki","author_inst":"Department of Paediatrics, Aga Khan University, Nairobi, Kenya"},{"author_name":"Nahya Salim Masoud","author_inst":"Department of Paediatrics and Child Health, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania"},{"author_name":"Samuel K Ngwala","author_inst":"School of Global and Public Health, Kamuzu University of Health Sciences, Blantyre, Malawi"},{"author_name":"Msandeni Chiume","author_inst":"Ministry of Health, Malawi - Reproductive Health Department"},{"author_name":"Veronica Chinyere Ezeaka","author_inst":"Department of Paediatrics, College of Medicine, University of Lagos, Lagos, Nigeria"},{"author_name":"Elizabeth M Molyneux","author_inst":"Department of Paediatrics, Kamuzu University of Health Sciences, Blantyre, Malawi"},{"author_name":"Natasha R Rhoda","author_inst":"Children's Institute, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa"},{"author_name":"Vincent Otieno Ochieng","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Opeyemi Odedere","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Lisa R Hirschhorn","author_inst":"Northwestern University Feinberg School of Medicine, Illinois, USA"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Organised cancer screening among women who receive medically assisted reproduction treatments","rel_doi":"10.64898\/2026.07.05.26357336","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357336","rel_abs":"There are no published data on cancer screening by women using medically assisted reproduction (MAR). Such data would aid interpretation of the cancer incidence and risk profiles for this group. Using linked population-based Australian health registries and administrative datasets, we compared organised publicly funded cervical and breast screening episodes for women who received one of three types of MAR and matched women who did not between 1991 and 2016. We modelled the proportion of women screened in the three years before and after first MAR treatment, adjusting for age, remoteness, parity, socio-economic disadvantage, cancer history, and uptake of the other screening program. After adjustment, a greater proportion of women who received MAR than women who did not had cervical screening before MAR (77.3%-84.1% vs 57.5%-62.0%, depending on treatment) and after MAR (77.0%-78.5% vs 68.1%-68.3%). Contrastingly, breast screening estimates were 7.6%-9.6% vs 9.3%-10.5% before MAR and 11.0%-15.0% vs 12.8%-14.9% after MAR.","rel_num_authors":12,"rel_authors":[{"author_name":"Adrian Raymond Walker","author_inst":"UNSW Sydney"},{"author_name":"Signe Odahl","author_inst":"Norwegian University of Science and Technology"},{"author_name":"Christos Venetis","author_inst":"Aristotle University of Thessaloniki"},{"author_name":"Louisa Jorm","author_inst":"UNSW Sydney"},{"author_name":"Neville F Hacker","author_inst":"UNSW Sydney"},{"author_name":"Michael Chapman","author_inst":"UNSW Sydney"},{"author_name":"Antoinette C Anazodo","author_inst":"UNSW Sydney"},{"author_name":"Robert J Norman","author_inst":"Adelaide University"},{"author_name":"Catharyn Stern","author_inst":"University of Melbourne"},{"author_name":"Ursula M Sansom-Daly","author_inst":"UNSW Sydney"},{"author_name":"Georgina Mary Chambers","author_inst":"UNSW Sydney"},{"author_name":"Claire Melissa Vajdic","author_inst":"UNSW Sydney"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Bench-stepping training improves stair-walking dynamics in older women: evidence from an exploratory nonlinear kinematic analysis","rel_doi":"10.64898\/2026.07.02.26357116","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357116","rel_abs":"Introduction: Stair walking challenges balance and coordination in older people. Bench-stepping training improves stair climbing speed in healthy older women. This study assessed whether bench-stepping also improves dynamic balance and movement complexity during stair walking. Methods: Stair walking data were obtained from a previous study involving 45 healthy older women (69y+\/-4) that assessed the effects of a 12-week bench-stepping intervention with non-training controls. Centre-of-mass acceleration was measured during stair ascent and descent. Linear dynamics included time, acceleration magnitude, and harmonic ratios (HR; indicating symmetry). Movement complexity was quantified using nonlinear dynamics including sample entropy (SE), recurrence quantification analysis (RQA), and fractal dimension (FD). Results: For stair ascent, increased speed (p =0.018, R2partial =0.093,) was accompanied by proportional increases in acceleration magnitudes (p=<0.039, R2partial =0.078-0.101). SE decreased more in the intervention group (p=<0.012, R2partial =0.049-0.101), indicating more predictable dynamics. In contrast, for stair descent, no changes in speed or acceleration magnitudes were observed. However, SE (p =0.001, R2partial =0.082) and maximum RQA line length (p= 0.008, R2partial =0.057) of vertical acceleration increased significantly compared to controls, indicating lower predictability and more persistent recurring patterns. No significant changes were found for other outcomes. Exploratory factor analysis revealed distinct differences in motor behaviour between stair ascent and descent. Conclusion: Bench-stepping training induced measurable changes in stair walking dynamics. Specifically, sample entropy shows potential as a sensitive marker of altered motor complexity, particularly of vertical accelerations. Interestingly, the direction of changes in unpredictability differed between stair ascent and descent, suggesting different underlying control strategies.","rel_num_authors":8,"rel_authors":[{"author_name":"Remco Johan Baggen","author_inst":"Vrije Universiteit Amsterdam\/Neuroscience Research Australia"},{"author_name":"Kimberley Stefanie van Schooten","author_inst":"Neuroscience Research Australia\/University of New South Wales"},{"author_name":"Evelien Van Roie","author_inst":"Hasselt University"},{"author_name":"Sabine Marie Verschueren","author_inst":"KU Leuven"},{"author_name":"Christophe Delecluse","author_inst":"KU Leuven"},{"author_name":"Kim Delbaere","author_inst":"University of New South Wales\/NeuRA"},{"author_name":"Stephen R Lord","author_inst":"Neuroscience Research Australia"},{"author_name":"Jaap H. van Dieen","author_inst":"VU Amsterdam: Vrije Universiteit Amsterdam"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Validation of aEEG-CSA Neonatal Seizure Detection Algorithm on Hypothermia Treated Infants with HIE","rel_doi":"10.64898\/2026.07.02.26356964","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26356964","rel_abs":"ObjectiveTo validate a neonatal seizure detection algorithm that is based on extracted clinical features of the aEEG and CSA on a cohort of cooled neonatal patients with hypoxic ischemic encephalopathy.\n\nMethodsA seizure detection algorithm was designed using aEEG margin features, CSA features, trained on a public dataset of 79 neonatal EEGs with three supervised machine learning classifiers. It was subsequently tested on an inhouse cohort of 23 neonates with asphyxia whose EEGs were collected during cooling therapy.\n\nResultsThe trained Random Forest, Support Vector Machines and Artificial Neural Network classifiers had an AUC of 0.76, 0.77, and 0.77 and an average accuracy of 0.85, 0.86, and 0.85 respectively. Finally, the average AUC across the 10 seizure patients included was 0.85.\n\nConclusionA neonatal seizure detection algorithm that uses a combination of aEEG and CSA clinical features can capture seizures in HIE patients. Performance across seizure patients is not correlated with seizure duration.","rel_num_authors":5,"rel_authors":[{"author_name":"Sylvia Edoigiawerie","author_inst":"Cook County Hospital"},{"author_name":"Julia Henry","author_inst":"AdventHealth for Children"},{"author_name":"Brett Beaulieu-Jones","author_inst":"University of Chicago"},{"author_name":"Henry David","author_inst":"University of Chicago"},{"author_name":"Naoum Issa","author_inst":"University of Chicago"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"GLP Medications and Severe Post-COVID-19 Outcomes Among Individuals with Type 2 Diabetes Mellitus","rel_doi":"10.64898\/2026.07.03.26357246","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357246","rel_abs":"BackgroundGlucagon-like peptide-1 receptor agonist-based therapies (GLP) have recently emerged as promising treatments across a wide range of health conditions. These medications may have protective effects against severe long-term consequences of COVID-19 by promoting weight loss, exerting antihyperglycemic and anti-inflammatory effects, and providing cardiovascular and endothelial protection.\n\nMethodsWe evaluated electronic health record data from a retrospective cohort of individuals in the National Clinical Cohort Collaborative. We included individuals with type 2 diabetes mellitus and comorbid COVID-19 who were prescribed either GLP (treatment) or a sodium-glucose co-transporter 2 inhibitor (SGLT2i) and subsequently developed acute COVID-19 between October 1, 2021, and April 1, 2023. We compared the 12-month cumulative incidence of mortality and Long COVID (Long COVID diagnosis and probable Long COVID via computational phenotype) between groups. We applied targeted maximum likelihood estimation to compare outcome risks by exposure status, controlling for covariates of interest.\n\nResultsWe analyzed data from 14,215 individuals with COVID-19 and comorbid type 2 diabetes (mean age, 60 years; mean BMI, 37). Compared to SGLT2i, a prescription for GLP medication was associated with a lower risk of mortality (adjusted risk ratio [aRR] 0.71; 95% CI 0.53, 0.95), but not Long COVID diagnosis (aRR 1.01; 95% CI 0.80, 1.27) or probable Long COVID (aRR 0.94; 95% CI 0.88, 1.01).\n\nConclusionsWe found that among individuals with type 2 diabetes and comorbid COVID-19, a prescription for GLP vs. SGLT2i medications was associated with a lower risk of mortality, but not Long COVID.","rel_num_authors":14,"rel_authors":[{"author_name":"Zachary Butzin-Dozier","author_inst":"Stanford University, Stanford, CA USA"},{"author_name":"Lin-Chiun Wang","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Yunwen Ji","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Manav Kumar","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"A. Jerrod Anzalone","author_inst":"University of Nebraska Medical Center, Omaha, NE, USA"},{"author_name":"Eric Hurwitz","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Rena C. Patel","author_inst":"University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Ariana Budhihartanto","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"John B. Buse","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Steven Johnson","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Jane Reusch","author_inst":"University of Colorado, Anschutz, Aurora, CO, USA"},{"author_name":"Carolyn Bramante","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Rachel Wong","author_inst":"Renaissance School of Medicine, Stony Brook University, New York, NY, USA"},{"author_name":"- on behalf of the National Clinical Cohort Collaborative","author_inst":"-"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Cardiovascular events in individuals with small\/medium LDL particle discordance","rel_doi":"10.64898\/2026.06.25.26356542","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356542","rel_abs":"AimsDespite similar LDL-C levels, size and composition of LDL particles (LDL-P) varies widely. Among the metabolically perturbed, or those with altered function of lipid regulatory proteins, LDL-C levels mask elevated atherogenic small-medium LDL-P (S\/M LDL-P). We assessed the contribution of such discordance in S\/M LDL-P on major adverse cardiovascular event risk (MACE).\n\nMethods and resultsUK Biobank participants with Nightingale NMR metabolomics (487,521 participants), were classified as high or low cardiometabolic burden. S\/M LDL-P discordance was defined as the difference between LDL-C predicted S\/M LDL-P and observed S\/M LDL-P. Genetic variants encoding cholesterol ester transfer protein (CETP), which regulates cholesterol-triglyceride exchange and the production of small LDL particles, were identified via whole genome sequencing. Adjusted Cox proportional hazard regression was used to estimate MACE associations. S\/M LDL-P discordance showed an LDL-C and Apo-B independent association with MACE (47,935 cases), which differed by cardiometabolic burden group: hazard ratio (HR) per standard deviation 1.09 (95%CI 1.05; 1.13) and HR 1.24 (95%CI 1.21; 1.27) for low\/high burden, respectively. Loss of function (LoF) CETP variants were strongly associated with lower levels of both S\/M LDL-P and S\/M LDL-P discordance. For example, the S\/M LDL-P discordance effect of CETP LoF carriership for low\/high metabolic burden, respectively, was -4.62 nmol\/L (95%CI -8.40; -0.83) compared to -11.10 nmol\/L (95%CI -15.57; -6.63).\n\nConclusionS\/M LDL-P discordance (overabundance) is strongly associated with MACE risk, especially in people with high cardiometabolic burden. S\/M LDL-P discordance is modified by CETP genetic variation, suggesting a role for CETP-mediated lipid remodelling beyond LDL-C changes.\n\nTranslational perspectiveConventional lipid parameters such as LDL-C and apolipoprotein B may underestimate the atherogenic burden conferred by an overabundance of small and medium LDL particles, particularly in patients with diabetes, obesity, or established atherosclerotic disease. We introduce a novel measure of small\/medium LDL particle (S\/M LDL-P) discordance, quantifying the excess of S\/M LDL-P beyond what is predicted by LDL-C alone. S\/M LDL-P discordance is independently associated with time to incident MACE, especially in people with increased cardiometabolic burden. Genetic loss of function in cholesteryl ester transfer protein (CETP), which regulates cholesterol-triglyceride exchange and the production of small LDL particles, reduced S\/M LDL-P discordance, in particular among those with metabolically perturbed states where discordance was otherwise high. Taken together, these findings provide support for the potential role of CETP inhibition, as a therapeutic strategy that may lower cardiovascular risk in part through reduction of S\/M LDL-P discordance. This hypothesis is currently being evaluated with obicetrapib in the PREVAIL trial.","rel_num_authors":10,"rel_authors":[{"author_name":"Amand Floriaan Schmidt","author_inst":"University College London"},{"author_name":"Nikita Hukerikar","author_inst":"University College London"},{"author_name":"Sam Quill","author_inst":"University College London"},{"author_name":"Marion van Vugt","author_inst":"Amsterdam University Medical Centers"},{"author_name":"Mathijs de Kleer","author_inst":"NewAmsterdam Pharma B.V."},{"author_name":"Marc Ditmarsch","author_inst":"NewAmsterdam Pharma B.V."},{"author_name":"Michael Szarek","author_inst":"University of Colorado School of Medicine"},{"author_name":"John J. Kastelein","author_inst":"NewAmsterdam Pharma B.V."},{"author_name":"Kausik K. Ray","author_inst":"Imperial College London"},{"author_name":"Michael H. Davidson","author_inst":"University of Chicago"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Association of Neutrophil-to-Lymphocyte Ratio and Systemic Immune-Inflammation Index With Mortality in Patients With Pericarditis: A Retrospective Dual-Cohort Study Using Two Independent Databases","rel_doi":"10.64898\/2026.06.25.26356550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356550","rel_abs":"BackgroundRisk stratification in pericarditis relies mainly on clinical presentation, suspected etiology, imaging findings, and conventional inflammatory biomarkers. Whether complete blood count-derived inflammatory indices are associated with mortality in pericarditis and reproducible across independent real-world datasets remains unclear.\n\nMethodsWe conducted a retrospective dual-cohort study of hospitalized adults with pericarditis using a Hong Kong cohort from the Clinical Data Analysis and Reporting System (CDARS) as the primary analysis cohort and the Medical Information Mart for Intensive Care IV (MIMIC-IV) cohort as an independent reproducibility cohort. Baseline neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) were analyzed as continuous variables and cohort-specific tertiles. The primary outcome was long-term all-cause mortality in the Hong Kong cohort. Secondary and reproducibility outcomes included 90-day mortality in the Hong Kong cohort and 30-day, 90-day, and observable follow-up mortality in MIMIC-IV. Cox models were adjusted for age, sex, renal disease, diabetes mellitus, hypertension, ischemic heart disease, and malignancy.\n\nResultsAmong 504 patients in the Hong Kong cohort and 464 patients in MIMIC-IV, all-cause mortality occurred in 241 and 113 patients during cohort-specific follow-up, respectively. In the Hong Kong cohort, higher NLR was associated with long-term all-cause mortality after full adjustment. Compared with NLR tertile 1, the adjusted hazard ratio was 1.60 for tertile 3. Higher SII was also associated with long-term mortality, with an adjusted hazard ratio of 1.55 for tertile 3 versus tertile 1. NLR and SII showed directionally consistent associations with 90-day mortality in the Hong Kong cohort and with 30-day, 90-day, and observable follow-up mortality in MIMIC-IV. Sensitivity analyses yielded broadly consistent findings.\n\nConclusionsIn two independent real-world cohorts of hospitalized patients with pericarditis, higher baseline NLR and SII were associated with increased all-cause mortality, with NLR showing the more consistent prognostic signal. These complete blood count-derived indices may provide simple adjunctive information for mortality risk stratification, although prospective validation is needed before incorporation into formal management algorithms.","rel_num_authors":5,"rel_authors":[{"author_name":"Lingyu Mi","author_inst":"Chinese Academy of Medical Sciences & Peking Union Medical College"},{"author_name":"Ishan Lakhani","author_inst":"Chinese University of Hong Kong"},{"author_name":"Wing Tak Wong","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Gary Tse","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Fang Fang","author_inst":"Chinese Academy of Medical Sciences & Peking Union Medical College"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Diagnostic accuracy and acceptability of self- and health worker-collected tongue swabs for Mycobacterium tuberculosis complex detection in adults in South Africa","rel_doi":"10.64898\/2026.07.04.26357275","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357275","rel_abs":"Tongue swabs (TSs) are a non-invasive specimen type for the detection of Mycobacterium tuberculosis complex (MTBC) and can expand access to testing for individuals unable to produce sputum. This study evaluated the diagnostic performance and user acceptability of self-collected and health worker (HW)-collected tongue swabs using the Xpert MTB\/RIF Ultra (Ultra) assay and assessed participant perspectives on self-collection.\n\nIn this prospective, cross-sectional study, symptomatic and asymptomatic adults under investigation for TB were enrolled from a high HIV prevalence setting. Each participant provided both a self-collected and a HW-collected TS, which were tested using Ultra. Ultra TS results were compared to liquid culture as the reference standard and sputum Ultra as a comparator. Participant perspectives on self-collection were captured via questionnaires.\n\nSensitivity on Ultra for both self- and HW-collected TSs was 68% (95% CI:51.9-81.9), compared to liquid culture. This sensitivity was significantly higher than that of sputum smear microscopy (46%, 95% CI: 30.7-62.6; McNemars p = 0.003). Tongue swab sensitivity was lower than sputum Ultra (80.5%; p<0.001) and decreased with low bacillary loads. Importantly, TSs enabled MTBC detection in six participants unable to produce sputum. Most participants (>90%) found self-collection instructions easy to follow, reporting high confidence and comfort, and trust in results from self-collected TSs.\n\nThis study demonstrates that self-collected TSs perform comparably to those collected by health workers for TB detection using Ultra and are both feasible and acceptable in a high TB\/HIV burden setting. To maximize impact, clear training instructions and robust linkage to care remain critical priorities.\n\nImportanceThis study supports the use of tongue swabs (TSs) as a non-invasive alternative for tuberculosis diagnosis, particularly for individuals unable to produce sputum. When tested on the Xpert MTB\/RIF Ultra assay, self-collected TSs performed comparably to health worker-collected swabs, yielding a 68% sensitivity (95% CI: 51.9-81.9) relative to liquid culture. This sensitivity was significantly higher than that of sputum smear microscopy (46%, 95% CI: 30.7-62.6; McNemars p = 0.003). Importantly, TSs successfully detected Mycobacterium tuberculosis complex in six patients who could not provide sputum, underscoring their clinical utility in expanding diagnostic access. Furthermore, high user acceptability (>90%) confirms that self-collection is both feasible and trusted by patients in high TB\/HIV burden settings. To maximize real-world impact, implementing clear training instructions and establishing robust linkage to care, especially following negative results, remain critical programmatic priorities.","rel_num_authors":10,"rel_authors":[{"author_name":"Anura David","author_inst":"University of the Witwatersrand Faculty of Health Sciences"},{"author_name":"Yeonsoo Baik","author_inst":"Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"},{"author_name":"Lesley Scott","author_inst":"University of the Witwatersrand Johannesburg Faculty of Health Sciences"},{"author_name":"Griffiths Kubeka","author_inst":"The Aurum Institute for Health Research, Parktown, Johannesburg, South Africa"},{"author_name":"Adelaide Benoit","author_inst":"Johns Hopkins University School of Public Health, Maryland, USA"},{"author_name":"Lyndel Singh","author_inst":"Wits Diagnostics Innovation Hub, Wits Health Consortium (PTY) Ltd, Johannesburg, South Africa"},{"author_name":"Pedro da Silva","author_inst":"National Priority Programmes, National Health Laboratory Services, Johannesburg, South Africa"},{"author_name":"Wendy Stevens","author_inst":"Wits Diagnostics Innovation Hub, Health Sciences Research Office, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg"},{"author_name":"Gregory P Bisson","author_inst":"Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"},{"author_name":"Salome Charalambous","author_inst":"The Aurum Institute"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"NEXIM: A Nash Equilibrium-Based Framework for Stable Explainable AI in Medical Applications","rel_doi":"10.64898\/2026.06.25.26356568","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356568","rel_abs":"Reliable explanations are important for trustworthy medical applications of artificial intelligence (AI), but attribution-based explanations can vary across model randomization and small analytic changes. We present NEXIM (Nash Equilibrium-based Explainability and Interpretability Model), implemented here as an accuracy-constrained, equilibrium-inspired model-selection framework that jointly evaluates held-out prediction error, explanation stability, and cross-model connectivity. The implementation evaluated ten GradientBoosting Regressor models per prediction horizon, differing only by random seed (0-9), using a fixed 75\/25 patient split. Kernel SHAP attribution vectors were compared using Spearman rank correlation, and graph connectivity summarized whether each model belonged to a dense explanation-similarity region. Candidate models within 0.02 Montreal Cognitive Assessment points of the best root mean squared error (RMSE) were ranked using a multiplicative Explanation Equilibrium Score. In longitudinal Parkinsons Progression Markers Initiative data, NEXIM selected the RMSE-optimal model at the one- and three-year horizons. At the two-year horizon, it selected Model 4 rather than the RMSE-only Model 8, increasing scaled stability from 0.8757 to 0.8847 and normalized graph connectivity from 0.889 to 1.000 while increasing RMSE by only 0.0014. The two models retained the same top-20 feature set but differed modestly in feature order, illustrating that NEXIM primarily acted as a reproducibility screen rather than identifying clinically contradictory explanations. Stability and consensus are treated as reproducibility criteria, not evidence of causal faithfulness, clinical usefulness, or improved patient outcomes. NEXIM may therefore serve as a governance checkpoint for model refresh and documentation, but external validation, stronger model-family baselines, and prospective clinical evaluation remain necessary.","rel_num_authors":4,"rel_authors":[{"author_name":"Dipak P Upadhyaya","author_inst":"Case Western Reserve University"},{"author_name":"Satya S Sahoo","author_inst":"Case Western Reserve University"},{"author_name":"Katrina Prantzalos","author_inst":"Case Western Reserve University"},{"author_name":"Pedram Golnari","author_inst":"Case Western Reserve University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Tacrolimus variability and creatinine predict readmission after liver transplantation","rel_doi":"10.64898\/2026.07.02.26357106","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357106","rel_abs":"Unplanned readmissions after liver transplantation occur in over 30% of recipients, yet no validated prediction models exist, and prior observational studies suffer from immortal time bias. The optimal readmission window for outcome prediction and the feasibility of early risk stratification remain undefined. This study is a retrospective analysis of 922 adult liver transplant recipients (August 2018-August 2025) at a single center. Time-varying Cox regression evaluated 14-, 30-, and 90-day readmission windows as predictors of 1-year mortality, correcting for immortal time bias. Gradient-boosted machine learning models leveraging 528,400 laboratory measurements (28 analytes) predicted 90-day readmission using either complete hospitalization data or data restricted to postoperative day 7. Feature importance was quantified by gain, and clinical utility was assessed through risk stratification. Among 902 hospital survivors, 342 (37.9%) experienced an unplanned readmission within 90 days of initial discharge. Only the 90-day readmission window predicted 1-year mortality in time-varying analysis (HR 1.73, 95% CI 1.17-2.57, p=0.006). The model for readmission using complete data achieved AUC 0.614 (95% CI 0.576-0.652); the postoperative day 7 restricted model achieved AUC 0.615 (95% CI 0.577-0.652), with no meaningful performance difference. The tacrolimus coefficient of variation x peak creatinine interaction was the dominant predictor in both the complete model (17.3% importance, rank 1) and the day 7 restricted model (20.4% importance, rank 2). This interaction stratified patients into high-risk (tacrolimus CV >0.3 and creatinine >2.0 mg\/dL; 49.8% readmission) versus low-risk (24.8% readmission) groups (risk ratio 2.01, p<0.001). These results identify a modifiable biological determinant of readmission and establish a framework for targeted interventions to reduce unplanned readmission and improve post-transplant outcomes.","rel_num_authors":1,"rel_authors":[{"author_name":"Kevin  Marc Korenblat","author_inst":"Washington University School of Medicine in Saint Louis: Washington University in St Louis School of Medicine"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Expanding the Pediatric Heart Donor Pool: National Outcomes of Donation After Circulatory Death Versus Donation After Brain Death Heart Transplantation","rel_doi":"10.64898\/2026.07.03.26357254","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357254","rel_abs":"BackgroundDonation after circulatory death (DCD) is an increasingly accepted strategy to expand the adult heart donor pool, but its use in children remains limited and incompletely characterized. We compared national characteristics and post-transplant outcomes of pediatric DCD versus donation after brain death (DBD) heart transplantation.\n\nMethodsWe performed a retrospective cohort study of the Organ Procurement and Transplantation Network (OPTN) registry, including patients younger than 18 years who underwent primary isolated heart transplantation between January 1993 and March 2025. Recipients were stratified by donor type (DCD vs DBD). Continuous variables were compared with the Mann-Whitney U test and categorical variables with the {chi}2 or Fisher exact test. Survival was estimated by the Kaplan-Meier method and compared using the log-rank test and Cox proportional hazards regression.\n\nResultsOf 10,671 pediatric heart transplant recipients, 33 (approximately 0.3%) received DCD allografts. The first DCD transplant was recorded in 2004, with a marked increase in 2023-2024. Compared with DBD recipients, DCD recipients were more frequently infants (<1 year, 51.5% vs 28.4%) and more often had congenital heart disease (69.7% vs 47.6%; P=0.033); DCD donors were younger (median 0 vs 6 years; P=0.038) and more frequently died of anoxia (72.7% vs 37.0%; P<0.001). Donor and recipient left ventricular mass were lower in the DCD group (P<0.05), but predicted left ventricular mass matching was similar. DCD recipients had longer hospital stays (median 31.5 vs 19 days; P=0.023); rates of treated rejection, dialysis, stroke, and pacemaker implantation were comparable. Early survival did not differ (30-day, 90-day, and 1-year), and Kaplan-Meier survival through 5 years was not significantly different (hazard ratio 1.17; 95% CI 0.49-2.81; log-rank P=0.73). More than 90% of DCD transplants were performed in four UNOS regions (11, 4, 5, and 8).\n\nConclusionsIn this national analysis, pediatric DCD heart transplantation was uncommon but expanding rapidly, concentrated in a few regions, and used preferentially in infants and children with congenital heart disease. Early post-transplant outcomes were not significantly different from DBD, supporting cautious expansion of DCD as a means of enlarging the pediatric donor pool. The small number of DCD recipients and limited follow-up warrant confirmation in larger, longer-term studies.","rel_num_authors":9,"rel_authors":[{"author_name":"Bilal Khan Mohammed","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Rohit Ganduboina","author_inst":"NRI Institute of Medical Sciences"},{"author_name":"Omar Abdel Kerim","author_inst":"University of Miami Miller School of Medicine, Miami"},{"author_name":"Gayatri Muley","author_inst":"Grant Medical College and Sir J.J. Group of Hospitals"},{"author_name":"Palak Dutta","author_inst":"University of Illinois College of Medicine"},{"author_name":"Nitya Krishna Arumugam","author_inst":"Kasturba Medical College, Manipal"},{"author_name":"John Karamichalis","author_inst":", Columbia University Irving Medical Center"},{"author_name":"Yahiya Pasha Quadri Syed","author_inst":"UW Health Swedish American Hospital"},{"author_name":"Sandeep Sainathan","author_inst":"University of Miami Miller School of Medicine"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Saliva cell-free mitochondrial DNA (cf-mtDNA) response during physical and cognitive stress","rel_doi":"10.64898\/2026.07.02.26356953","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26356953","rel_abs":"Emerging evidence suggests that saliva cell-free mitochondrial DNA (cf-mtDNA) increases in response to psychosocial and physical stress. Here, we quantified saliva cf-mtDNA changes in response to acute physical and cognitive stressors as well as identifying potential predictors of these responses, while also exploring the potential modulatory effects of transcranial infrared laser stimulation (TILS). In a crossover design, a total of 47 participants (53% female, ages 18-30) underwent up to three experimental sessions, including an exercise stress task and two cognitive stress tasks. Repeated saliva samples were collected for cf-mtDNA and cell-free nuclear DNA (cf-nDNA) quantification, alongside continuous measurement of heart rate, oxygen consumption, and blood pressure. Our results show that average cf-mtDNA levels increased by 90% after baseline during exercise experiments, and in cognitive stress experiments peaked 160% above average baseline levels during the stress task. Inter-individual differences in response trajectories were associated with differences in factors such as fitness, sleep quality, and stress perception. Notably, participants with higher cf-mtDNA elevations during the exercise experiment reported fewer recent stressful incidents, drank alcohol less frequently, had higher maximum VO2 during exercise, and had lower BMI. More dynamic responses to cognitive stress were observed in participants with poorer sleep quality and greater blood pressure reactivity. These findings provide a foundation for larger studies by highlighting the dynamic behavior of saliva cf-mtDNA following physical and cognitive stressors, and by suggesting potential drivers of individual differences in saliva cf-mtDNA stress reactivity.","rel_num_authors":7,"rel_authors":[{"author_name":"Caroline Trumpff","author_inst":"Columbia University"},{"author_name":"David Shire","author_inst":"Columbia University"},{"author_name":"Tian Wang","author_inst":"Columbia University"},{"author_name":"Shuang Wang","author_inst":"Columbia University"},{"author_name":"Temmie Yu","author_inst":"Columbia University"},{"author_name":"Martin Picard","author_inst":"Columbia University"},{"author_name":"Annie T. Ginty","author_inst":"Baylor University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Maternal Extracellular Vesicles During Pregnancy and Autism Risk in Children","rel_doi":"10.64898\/2026.06.25.26355526","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26355526","rel_abs":"BackgroundDifferences in extracellular vesicles (EVs), bioactive nanoparticles involved in intercellular signaling, have been reported in those with autism. However, little is known about the association between maternal EVs during pregnancy and the likelihood of autism in offspring. This study evaluated the association of the concentration and cargo material of EVs in prenatal maternal plasma with childhood autism likelihood.\n\nMethodsParticipants in the Nulliparous Pregnancy Outcomes Study provided maternal plasma at 15-23 weeks gestational age. EVs were isolated by ultracentrifugation, and concentration, mean size, CD63 levels, and RNA cargo were assessed by nanoparticle tracking analysis, ELISA, and small RNA sequencing. At 4.5-6 years of age, parents completed the Social Communication Questionnaire. Thirty-one children at high-risk for autism were matched to 31 low-risk children on sex, age, and gestational age. Differential RNA transcript analysis and over representation analysis were performed.\n\nResultsThere were no group differences in CD63 levels, mean particle size, or EV concentration (p>0.1). Nominal bin-level differences were observed at 280-290 nm and 430-440 nm before multiple-comparison correction. One hundred forty-five RNAs, including protein-coding RNAs, piRNAs, lncRNAs, miRNAs, snoRNAs, snRNAs, and tRNAs, were differentially contained, most of them downregulated in those at high risk of autism. These RNAs mapped to pathways involved in immune\/inflammatory signaling, intracellular trafficking, protein turnover, and neurodevelopment. Six of the 62 (9.7%) differentially contained protein-coding RNAs overlapped with genes in the SFARI Gene database.\n\nLimitationsLarge studies involving individuals diagnosed with autism are needed to evaluate the role of prenatal EVs in the pathogenesis of the condition. Additionally, prenatal sampling of EVs across multiple timepoints and subsequent deconvolution to determine the source of the EVs will strengthen interpretability and veracity of our findings.\n\nConclusionsThese findings provide preliminary evidence that maternal prenatal EV RNA cargo is associated with childhood autism likelihood.","rel_num_authors":13,"rel_authors":[{"author_name":"Delia McGowan","author_inst":"Barnard College, Columbia University, New York, NY, United States"},{"author_name":"Serena Nencini","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"William Yakah","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Claire-Marie Vacher","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Helene Lacaille","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"David M Haas","author_inst":"Department of Obstetrics and Gynecology, School of Medicine, Indiana University, Indianapolis, IN, United States"},{"author_name":"William A Grobman","author_inst":"Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH, United States"},{"author_name":"Robert M Silver","author_inst":"Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, United States"},{"author_name":"Uma M Reddy","author_inst":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States"},{"author_name":"Ronald J Wapner","author_inst":"Department of Obstetrics and Gynecology, Columbia University Irving Medical Center New York, NY, United States"},{"author_name":"William P Fifer","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States; Department of Psychiatry, Columbia University Irving Medical C"},{"author_name":"Anna A Penn","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Morgan R Firestein","author_inst":"Department of Pediatrics, Child Health Institute of New Jersey, Brain Health Institute, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United St"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Maternal Extracellular Vesicles During Pregnancy and Autism Risk in Children","rel_doi":"10.64898\/2026.06.25.26355526","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26355526","rel_abs":"BackgroundDifferences in extracellular vesicles (EVs), bioactive nanoparticles involved in intercellular signaling, have been reported in those with autism. However, little is known about the association between maternal EVs during pregnancy and the likelihood of autism in offspring. This study evaluated the association of the concentration and cargo material of EVs in prenatal maternal plasma with childhood autism likelihood.\n\nMethodsParticipants in the Nulliparous Pregnancy Outcomes Study provided maternal plasma at 15-23 weeks gestational age. EVs were isolated by ultracentrifugation, and concentration, mean size, CD63 levels, and RNA cargo were assessed by nanoparticle tracking analysis, ELISA, and small RNA sequencing. At 4.5-6 years of age, parents completed the Social Communication Questionnaire. Thirty-one children at high-risk for autism were matched to 31 low-risk children on sex, age, and gestational age. Differential RNA transcript analysis and over representation analysis were performed.\n\nResultsThere were no group differences in CD63 levels, mean particle size, or EV concentration (p>0.1). Nominal bin-level differences were observed at 280-290 nm and 430-440 nm before multiple-comparison correction. One hundred forty-five RNAs, including protein-coding RNAs, piRNAs, lncRNAs, miRNAs, snoRNAs, snRNAs, and tRNAs, were differentially contained, most of them downregulated in those at high risk of autism. These RNAs mapped to pathways involved in immune\/inflammatory signaling, intracellular trafficking, protein turnover, and neurodevelopment. Six of the 62 (9.7%) differentially contained protein-coding RNAs overlapped with genes in the SFARI Gene database.\n\nLimitationsLarge studies involving individuals diagnosed with autism are needed to evaluate the role of prenatal EVs in the pathogenesis of the condition. Additionally, prenatal sampling of EVs across multiple timepoints and subsequent deconvolution to determine the source of the EVs will strengthen interpretability and veracity of our findings.\n\nConclusionsThese findings provide preliminary evidence that maternal prenatal EV RNA cargo is associated with childhood autism likelihood.","rel_num_authors":13,"rel_authors":[{"author_name":"Delia McGowan","author_inst":"Barnard College, Columbia University, New York, NY, United States"},{"author_name":"Serena Nencini","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"William Yakah","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Claire-Marie Vacher","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Helene Lacaille","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"David M Haas","author_inst":"Department of Obstetrics and Gynecology, School of Medicine, Indiana University, Indianapolis, IN, United States"},{"author_name":"William A Grobman","author_inst":"Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH, United States"},{"author_name":"Robert M Silver","author_inst":"Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, United States"},{"author_name":"Uma M Reddy","author_inst":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States"},{"author_name":"Ronald J Wapner","author_inst":"Department of Obstetrics and Gynecology, Columbia University Irving Medical Center New York, NY, United States"},{"author_name":"William P Fifer","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States; Department of Psychiatry, Columbia University Irving Medical C"},{"author_name":"Anna A Penn","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Morgan R Firestein","author_inst":"Department of Pediatrics, Child Health Institute of New Jersey, Brain Health Institute, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United St"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Comparative efficacy and acceptability of cognitive-behavioural therapy for insomnia and its abbreviated versions: a systematic review and network meta-analysis","rel_doi":"10.64898\/2026.07.04.26357278","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357278","rel_abs":"ObjectiveTo assess the comparative efficacy and acceptability of cognitive behavioural therapy for insomnia (CBT-I), its abbreviated versions and control conditions.\n\nDesignSystematic review and network meta-analysis.\n\nMethodsScreening, data extraction, coding, and risk of bias assessment were performed independently and in duplicate. Frequentist, random-effects network meta-analyses estimated odds ratios (ORs) or mean differences with 95% confidence intervals (CIs). The primary outcome was insomnia remission post-treatment. Secondary outcomes included dropout and subjective sleep continuity measures. Quality of the evidence for each arm was graded using the confidence in network meta-analysis (CINeMA).\n\nData sourcesWe searched MEDLINE, Embase, PsycINFO and Cochrane CENTRAL from inception to December 15, 2025, with a medical information specialist.\n\nEligibility criteria for selecting studiesRandomized -controlled trials (RCTs) comparing CBT-I and its abbreviated versions with each other or with control conditions, in adults with insomnia, with or without comorbidities. To reduce clinical heterogeneity related to treatment intensity and adherence, we restricted inclusion to in-person delivery.\n\nResultsWe identified 11,379 records and included 77 RCTs (5,731 participants; mean age 52.2 years; 3,473 female). CBT-I (number of arms k = 53; number of participants n = 2,002), sleep restriction and stimulus control therapy (SRT&SCT; k = 16; n = 549), sleep restriction therapy (SRT; k = 5; n = 196) and stimulus control therapy (SCT; k = 7; n = 144) were associated with higher remission than sleep hygiene, relaxation therapy and other control conditions. These interventions were also effective in improving subjective sleep continuity measures. Cognitive therapy for insomnia (CT-I) was more beneficial than relaxation therapy. Dropout did not differ meaningfully between interventions and controls. Confidence in evidence was moderate for CBT-I, low for SRT&SCT and SRT, very low for SCT. Given the weighted mean proportion of insomnia remission among sleep hygiene arms of 20%, CBT-I probably leads to a remission rate of 41% (95% CI, 34%; 48%), SRT&SCT may lead to a remission rate of 40% (30%; 52%), SCT 43% (25%; 63%), and SRT 41% (26%; 57%).\n\nConclusionsCBT-I doubles the absolute insomnia remission compared with sleep hygiene, and its abbreviated behavioural therapies, namely, SRT&SCT, SCT and SRT may offer similar benefits with lower resource requirements, but evidence is less certain. CT-I needs further investigations. Relaxation therapy was inferior to these therapies. Implementation decisions should consider resource requirements and evidence certainty.\n\nWhat is already known on this topic- Insomnia is prevalent and disabling, and cognitive behavioural therapy for insomnia (CBT-I) is recommended as the first-line treatment.\n\n- CBT-I and its abbreviated versions are recommended in guidelines, but their comparative efficacy and acceptability remain uncertain.\n\nWhat this study adds- CBT-I and its core behavioural components (sleep restriction and stimulus control) probably achieve similar remission rates, offering scalable options where full CBT-I is not available.\n\n- Relaxation therapy was inferior to cognitive behavioural therapy for insomnia, its abbreviated, behavioural interventions, and cognitive therapy for insomnia.\n\n- Dissemination and implementation attempts should balance the confidence in the evidence and simplicity of abbreviated versions.","rel_num_authors":21,"rel_authors":[{"author_name":"Masatsugu Sakata","author_inst":"Department of Neurodevelopmental Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan"},{"author_name":"Shino Kikuchi","author_inst":"Center for Psycho-Oncology and Palliative Care, Core Laboratory, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan"},{"author_name":"Masami Ito","author_inst":"Department of Health Promotion and Behavioral Sciences, Kyoto University Graduate School of Medicine\/School of Public Health, Kyoto, Japan"},{"author_name":"Rie Toyomoto","author_inst":"Department of Health Promotion and Behavioral Sciences, Kyoto University Graduate School of Medicine\/School of Public Health, Kyoto, Japan"},{"author_name":"Hikari N Takashina","author_inst":"Awarefy Mental Research Institute, Awarefy Inc., Japan"},{"author_name":"Shintaro Hara","author_inst":"Graduate School of Education, Joetsu University of Education, Joetsu, Japan"},{"author_name":"Ryuichiro Yamamoto","author_inst":"Department of Psychology and Humanities, Edogawa University, Nagareyama, Japan"},{"author_name":"Shun Nakajima","author_inst":"International Institute for Integrative Sleep Medicine (WPI-IIIS), Tsukuba Institute for Advanced Research (TIAR), University of Tsukuba, Ibaraki, Japan"},{"author_name":"Hiroku Noma","author_inst":"International Institute for Integrative Sleep Medicine (WPI-IIIS), Tsukuba Institute for Advanced Research (TIAR), University of Tsukuba, Ibaraki, Japan"},{"author_name":"Kota Imai","author_inst":"Department of Neuropsychiatry, University of Tokyo, Tokyo, Japan"},{"author_name":"Shunici Sato","author_inst":"Department of Neuropsychiatry, University of Tokyo, Tokyo, Japan"},{"author_name":"Daiki Nagaoka","author_inst":"Department of Neuropsychiatry, University of Tokyo, Tokyo, Japan"},{"author_name":"Yusuke Takahashi","author_inst":"Department of Neuropsychiatry, University of Tokyo, Tokyo, Japan"},{"author_name":"Keita Kawai","author_inst":"Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany."},{"author_name":"Seina Shinno","author_inst":"Department of Medical Education,Graduate School of Medicine, University of Toyama Toyama, Japan"},{"author_name":"Azusa Ishii","author_inst":"International Institute for Integrative Sleep Medicine (WPI-IIIS), Tsukuba Institute for Advanced Research (TIAR), University of Tsukuba, Ibaraki, Japan"},{"author_name":"Michael Perlis","author_inst":"University of Pennsylvania, PA, US"},{"author_name":"Cagdas Turkmen","author_inst":"Department for Research and Development, St. Olavs Hospital PH, Trondheim, Norway"},{"author_name":"Elisabeth Hertenstein","author_inst":"Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland"},{"author_name":"Annemieke van Straten","author_inst":"Department of Clinical, Neuro and Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands"},{"author_name":"Yuki Furukawa","author_inst":"Department of Neuropsychiatry, University of Tokyo, Tokyo, Japan"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Post-vaccination expansion of extrafollicular Th10 and regulatory Tfr cells distinguishes strong from weak influenza vaccine responses in older adults","rel_doi":"10.64898\/2026.07.02.26357118","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357118","rel_abs":"Despite the superior efficacy of high-dose influenza vaccines, over one-third of older adults fail to respond. Yet, the mechanisms underlying this impaired vaccine responsiveness remain poorly understood. Here, we performed longitudinal profiling of older adults (n=60) receiving high-dose influenza vaccination to identify immune programs associated with vaccine responsiveness. Strong responders exhibited a primed baseline immune state characterized by elevated plasma cytokines and chemokines, followed by enhanced IFN-{gamma} responses and coordinated transcriptional and epigenetic activation of cDC2 cells at day 1. By day 7, CD4 T-cell trajectories diverged: strong responders preferentially expanded influenza-specific activated cTfh1 (CXCR5+ CXCR3+ ICOS+ CD38+) and influenza-specific Th10 (CXCR5- CXCR3+ PD1+ IL10) cells, whereas weak responders expanded regulatory cTfr (CXCR5 FOXP3) cells. Th10 expansion correlated with plasmablast and antibody responses and was independently validated in a larger influenza vaccination cohort, including younger adults. Functionally, Th10 cells promoted memory B-cell differentiation into plasmablasts and production of influenza-specific IgGs. TCR analyses revealed minimal clonal overlap between Th10 and cTfh1 cells. Together, these findings identify divergent helper and regulatory CD4 T cell programs associated with vaccine responsiveness and establish Th10 cells as a previously unrecognized component of vaccine-induced humoral immunity.","rel_num_authors":19,"rel_authors":[{"author_name":"Avinash S Mahajan","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Sathyabaarathi Ravichandran","author_inst":"The Jackson laboratory for Genomic Medicine"},{"author_name":"Radu Marches","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Yilmaz Yucehan Yazici","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Sean Nelson","author_inst":"Gale and Ira Drukier Institute for Childrens Health and Department of Pediatrics, Weill Cornell Medicine"},{"author_name":"Teresa Aydillo Gomez","author_inst":"Icahn School of Medicine of Mount Sinai Hospital"},{"author_name":"Kshitija Kshitija","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Amaya Rojo Fernandez","author_inst":"Icahn School of Medicine at Mount Sinai Hospital"},{"author_name":"Djamel Nehar-Belaid","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Lisa Kenyon Pesce","author_inst":"UCONN Center on Aging"},{"author_name":"Daniel Klimes","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Haebeen Jung","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Peter T Sage","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Virginia Pascual","author_inst":"Gale and Ira Drukier Institute for Childrens Health and Department of Pediatrics, Weill Cornell Medicine"},{"author_name":"Patrick Wilson","author_inst":"Weill Cornell Medicine"},{"author_name":"Adolfo Garcia Sastre","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jacques Banchereau","author_inst":"Immunoledge LLC"},{"author_name":"George A Kuchel","author_inst":"UCONN Center on Aging"},{"author_name":"Duygu Ucar","author_inst":"The Jackson Laboratory for Genomic Medicine"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Feature Selection with Quantum Annealing for Biomedical Machine Learning Applications","rel_doi":"10.64898\/2026.07.02.26357174","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357174","rel_abs":"Feature selection is a commonly used method in biomedical artificial intelligence and machine learning to identify a subset of high-quality variables that can be used to train downstream predictive models. It has been suggested that quantum feature selection (QFS), which takes advantage of the properties of quantum computers, may better identify variables that are correlated with the outcome while simultaneously reducing redundancy between selected variables. However, there are a limited number of studies evaluating their performance, particularly in real-world data sets. Here, we assess the performance of two QFS methods compared to random forest (RF) feature selection based on feature stability and the performance of a downstream classification algorithm when used to predict urinary tract infections in the emergency department from 211 original features extracted from the electronic health record. We found that a quantum binary quadratic model (BQM) and constrained quadratic model (CQM) had similar performance to RF feature selection (median F1 score of 0.60, 0.61, and 0.61 respectively) when 10 features were selected for an XGBoost classification model. The BQM and RF also had similar feature stability (0.91 and 0.94, respectively) while the CQM had lower stability (0.72). These findings show that QFS can be used with large, clinical data sets to identify features with high stability and predictive performance. As the capacity and quality of quantum computers continue to increase, these methods may offer additional benefits to classical feature selection methods.","rel_num_authors":8,"rel_authors":[{"author_name":"Sarah N. Dudgeon","author_inst":"Yale University"},{"author_name":"Seung Joo Lee","author_inst":"Yale University"},{"author_name":"Thomas JS Durant","author_inst":"Yale University"},{"author_name":"Brent Nelson","author_inst":"Newport Healthcare"},{"author_name":"H. Patrick Young","author_inst":"Yale University"},{"author_name":"Lucila Ohno-Machado","author_inst":"Yale University"},{"author_name":"R. Andrew Taylor","author_inst":"Yale University"},{"author_name":"Wade L. Schulz","author_inst":"Yale University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Cross-Domain Knowledge Transfer from Expert-Annotated Gated CT via Synthetic Ungated CT Improves Coronary Artery Calcium Scoring on CT Attenuation Correction Scans","rel_doi":"10.64898\/2026.07.02.26356002","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26356002","rel_abs":"BackgroundCoronary artery calcium (CAC) is an established measure of coronary atherosclerosis from computed tomography (CT). While deep learning (DL) can quantify CAC from non-dedicated CT, the accuracy is limited by image quality.\n\nPurposeWe derived and validated a novel method for DL CAC segmentation on ultra-low dose CT attenuation correction (CTAC) scans that is trained with synthetic low-dose, ungated images.\n\nMaterials and MethodsModels were trained using one center and externally tested in two other centers. Synthetic, ungated CT scans were generated so that expert segmentations from dedicated CAC scans could be used as ground truth for perfectly registered synthetic images through knowledge adaptation (KAD-CAC). We evaluated agreement between CAC scoring methods vs expert readers on a per-patient and per-vessel basis, as well as associations with the primary outcome of death or myocardial infarction (MI).\n\nResultsThe DL models were externally tested on 5969 patients with a median age of 64 (IQR 56 - 73), of whom 50.2% were male. The KAD-CAC model had higher Cohens kappa K (0.86, 95% CI 0.85 - 0.87) compared to previous convolutional LSTM model (K 0.78, 95% CI 0.76 - 0.80, p<0.01), or models trained with only gated images (K 0.81, 95% CI 0.80 - 0.82, p<0.01). Net reclassification improvement for CAC stratified risk of death or MI, was greatest for the KAD-CAC model over baseline including age, sex, hypertension, diabetes, dyslipidemia, family history, smoking, stress total perfusion deficit, and left ventricular ejection fraction.\n\nConclusionWe use paired synthetic ungated scans to transfer expert gated CAC annotations into the ungated domain, resulting in substantially better vessel-level CAC scoring and improved risk stratification.\n\nSummary StatementBy transferring information from expert-annotated gated CT to synthetic ungated CT, a knowledge-adapted deep learning model substantially improved coronary artery calcium assessment on low-dose attenuation correction CT.\n\nKey ResultsIn external testing using 5969 patients from two sites, the proposed model had improved agreement with expert segmentation and provided the greatest net reclassification improvement for CAC stratified risk of death or MI over baseline including age, sex, hypertension, diabetes, dyslipidemia, family history, smoking, stress total perfusion deficit, and Left Ventricular Ejection Fraction.","rel_num_authors":16,"rel_authors":[{"author_name":"Aakash Shanbhag","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Robert JH Miller","author_inst":"University of Calgary"},{"author_name":"Aditya Killekar","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Anna M Marcinkiewicz","author_inst":"National Medical Institute of the Ministry of the Interior and Administration"},{"author_name":"Jianhang Zhou","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Mark Lemley","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Assiata Kamagate","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Serge D Van Kriekinge","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Paul B. Kavanagh","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Attila Feher","author_inst":"Yale University School of Medicine"},{"author_name":"Edward J Miller","author_inst":"Yale University School of Medicine"},{"author_name":"Joanna X Liang","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Daniel S Berman","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Damini Dey","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Richard M Leahy","author_inst":"University of Southern California"},{"author_name":"Piotr Slomka","author_inst":"Cedars-Sinai Medical Center"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Brain Ageing in Social Anxiety Disorder: An ENIGMA-Anxiety Mega-Analysis Across 26 International Cohorts","rel_doi":"10.64898\/2026.07.02.26357108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357108","rel_abs":"Social anxiety disorder (SAD) is among the most prevalent anxiety disorders, and it has been associated with signs of advanced biological ageing. Despite this, brain age research on anxiety disorders remains limited. This mega-analysis investigated brain ageing in adults with SAD within the ENIGMA-Anxiety Working Group. Structural MRI scans from 576 participants with SAD and 1 355 non-affected healthy controls (HCs) across 26 international samples were included. Brain age was estimated from 77 cortical and subcortical regions using a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as the difference between brain age and chronological age. Group and subgroup differences (comorbidity, medication) were assessed using linear mixed-effect models. In the full sample, there was no group difference in brain-PAD ({beta}diagnosis (SE)=0.70 (0.37) years, p=0.061). In a subgroup of participants with SAD with comorbid anxiety disorders (n=184 SAD, n=1 355 HCs), a brain-PAD of +2.39 (0.93) years (Cohens d=0.23, pFDR=0.003) was observed. This brain-PAD became smaller after exclusion of participants with comorbid agoraphobia and specific phobia, suggesting that these disorders may partly drive the advanced brain-PAD. In conclusion, this ENIGMA-Anxiety mega-analysis did not find evidence of advanced brain ageing in the full sample of adult participants with SAD relative to HCs. However, a sub-analysis suggested that SAD with co-occurring phobic disorders, or the phobic disorders themselves, are associated with neurostructural patterns typical of older brains. Future research could utilise transdiagnostic samples with information on age of onset and disorder duration to further clarify this relation.","rel_num_authors":97,"rel_authors":[{"author_name":"Kimberly V Blake","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Jonathan C Ipser","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Alyssa R Amod","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Tobias Kaufmann","author_inst":"Department of Psychiatry and Psychotherapy, University of T\u00fcbingen, T\u00fcbingen, Germany"},{"author_name":"Yair Bar-Haim","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Jochen Bauer","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ali Bayram","author_inst":"Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Neuroscience, Turkey"},{"author_name":"Katja Beesdo-Baum","author_inst":"Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, TUD - Dresden University of Technology, Germany"},{"author_name":"Laura Blanco-Hinojo","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Tiana Borgers","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Robin B\u00fclow","author_inst":"Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Marta Cano","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Narcis Cardoner","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Christopher R.K Ching","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Soo-Hee Choi","author_inst":"Department of Psychiatry, Seoul National University College of Medicine and Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea"},{"author_name":"Udo Dannlowski","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christopher G Davey","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexander G. G Doruyter","author_inst":"Division of Nuclear Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Kira Flinkenfl\u00fcgel","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Gregory A Fonzo","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA"},{"author_name":"Tomas Furmark","author_inst":"Department of Psychology, Uppsala University, Uppsala, Sweden"},{"author_name":"Dominik Grotegerd","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Hans J Grabe","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Tim Hahn","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ben J Harrison","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexandre Heeren","author_inst":"Psychological Science Research Institute, Universit\u00e9 Catholique de Louvain, Louvain-la-Neuve, Belgium"},{"author_name":"Kevin Hilbert","author_inst":"Department of Psychology, HMU Health and Medical University Erfurt, Germany"},{"author_name":"Yoshiyuki Hirano","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Joy Hirsch","author_inst":"Departments of Psychiatry, Comparative Medicine, & Neuroscience, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"David Hofmann","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Yuko Isobe","author_inst":"Department of Cognitive Behavioral Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan"},{"author_name":"Neda Jahanshad","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Hamidreza Jamalabadi","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Alec J Jamieson","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Andreas Jansen","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Jaehyun Edmund Kim","author_inst":"Seoul National University, Seoul, Republic of Korea"},{"author_name":"Tilo Kircher","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Hitomi Kitagawa","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Anna Luisa Klahn","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Saskia B. J Koch","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Axel Krug","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Harald Kugel","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Dasom Lee","author_inst":"Department of Psychiatry, Seoul National University Hospital, Seoul, Republic of Korea"},{"author_name":"Elisabeth J Leehr","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christine Lochner","author_inst":"SAMRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Ulrike Lueken","author_inst":"Department of Psychology, Humboldt-Universit\u00e4t zu Berlin, German Center for Mental Health (DZPG), partner site Berlin-Potsdam, Germany"},{"author_name":"Amirhossein Manzouri","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Kristoffer N. T M\u00e5nsson","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Koji Matsumoto","author_inst":"Department of Radiology, Chiba University Hospital, Chiba, Japan"},{"author_name":"Susanne Meinert","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Alicia Menze","author_inst":"Medical Faculty M\u00fcnster, University Hospital M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Markus Muehlhan","author_inst":"Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Benson Mwangi","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Igor Nenadi\u0107","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Ziphozihle Ntwatwa","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Hyuntaek Oh","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Spiro P Pantazatos","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Martin P Paulus","author_inst":"Laureate Institute for Brain Research, Tulsa, OK, USA"},{"author_name":"Jutta Peterburs","author_inst":"Institute of Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Jesus Pujol","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Karin Roelofs","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Ramiro Salas","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Franklin R Schneier","author_inst":"New York State Psychiatric Institute, New York, NY, USA"},{"author_name":"Elisabeth Schrammen","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Eiji Shimizu","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Lisa Sindermann","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Theresa M Slump","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Jair C Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Benjamin Straube","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Thomas Straube","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Murray B Stein","author_inst":"Department of Psychiatry & School of Public Health, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Ardesheer Talati","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Florian Thomas-Odenthal","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Sophia I Thomopoulos","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Ra\u015fit T\u00fckel","author_inst":"Istanbul University, Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey"},{"author_name":"Anna Tyborowska","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Marie-Jos\u00e9 Van Tol","author_inst":"Center for Clinical Neuroscience and Cognition, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands"},{"author_name":"Dick J Veltman","author_inst":"Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands"},{"author_name":"Roman A. Vogler","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Inge Volman","author_inst":"National Education Lab for AI, Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Henry V\u00f6lzke","author_inst":"Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"P. Michiel Westenberg","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Katharina Wittfeld","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Mon-Ju Wu","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Noga Yair","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Tokiko Yoshida","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Chen Zhang","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Xi Zhu","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Giovana B Zunta-Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Peter Zwanzger","author_inst":"Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Germany"},{"author_name":"Daniel S Pine","author_inst":"National Institute of Mental Health, Emotion and Development Branch, USA"},{"author_name":"Moji Aghajani","author_inst":"Institute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden University, Leiden, the Netherlands"},{"author_name":"Paul M Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Nic J.A. van der Wee","author_inst":"Leiden Institute for Brain and Cognition, Leiden, the Netherlands"},{"author_name":"Dan J Stein","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Janna Marie Bas-Hoogendam","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Nynke A Groenewold","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Brain Ageing in Social Anxiety Disorder: An ENIGMA-Anxiety Mega-Analysis Across 26 International Cohorts","rel_doi":"10.64898\/2026.07.02.26357108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357108","rel_abs":"Social anxiety disorder (SAD) is among the most prevalent anxiety disorders, and it has been associated with signs of advanced biological ageing. Despite this, brain age research on anxiety disorders remains limited. This mega-analysis investigated brain ageing in adults with SAD within the ENIGMA-Anxiety Working Group. Structural MRI scans from 576 participants with SAD and 1 355 non-affected healthy controls (HCs) across 26 international samples were included. Brain age was estimated from 77 cortical and subcortical regions using a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as the difference between brain age and chronological age. Group and subgroup differences (comorbidity, medication) were assessed using linear mixed-effect models. In the full sample, there was no group difference in brain-PAD ({beta}diagnosis (SE)=0.70 (0.37) years, p=0.061). In a subgroup of participants with SAD with comorbid anxiety disorders (n=184 SAD, n=1 355 HCs), a brain-PAD of +2.39 (0.93) years (Cohens d=0.23, pFDR=0.003) was observed. This brain-PAD became smaller after exclusion of participants with comorbid agoraphobia and specific phobia, suggesting that these disorders may partly drive the advanced brain-PAD. In conclusion, this ENIGMA-Anxiety mega-analysis did not find evidence of advanced brain ageing in the full sample of adult participants with SAD relative to HCs. However, a sub-analysis suggested that SAD with co-occurring phobic disorders, or the phobic disorders themselves, are associated with neurostructural patterns typical of older brains. Future research could utilise transdiagnostic samples with information on age of onset and disorder duration to further clarify this relation.","rel_num_authors":97,"rel_authors":[{"author_name":"Kimberly V Blake","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Jonathan C Ipser","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Alyssa R Amod","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Tobias Kaufmann","author_inst":"Department of Psychiatry and Psychotherapy, University of T\u00fcbingen, T\u00fcbingen, Germany"},{"author_name":"Yair Bar-Haim","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Jochen Bauer","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ali Bayram","author_inst":"Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Neuroscience, Turkey"},{"author_name":"Katja Beesdo-Baum","author_inst":"Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, TUD - Dresden University of Technology, Germany"},{"author_name":"Laura Blanco-Hinojo","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Tiana Borgers","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Robin B\u00fclow","author_inst":"Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Marta Cano","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Narcis Cardoner","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Christopher R.K Ching","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Soo-Hee Choi","author_inst":"Department of Psychiatry, Seoul National University College of Medicine and Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea"},{"author_name":"Udo Dannlowski","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christopher G Davey","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexander G. G Doruyter","author_inst":"Division of Nuclear Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Kira Flinkenfl\u00fcgel","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Gregory A Fonzo","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA"},{"author_name":"Tomas Furmark","author_inst":"Department of Psychology, Uppsala University, Uppsala, Sweden"},{"author_name":"Dominik Grotegerd","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Hans J Grabe","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Tim Hahn","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ben J Harrison","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexandre Heeren","author_inst":"Psychological Science Research Institute, Universit\u00e9 Catholique de Louvain, Louvain-la-Neuve, Belgium"},{"author_name":"Kevin Hilbert","author_inst":"Department of Psychology, HMU Health and Medical University Erfurt, Germany"},{"author_name":"Yoshiyuki Hirano","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Joy Hirsch","author_inst":"Departments of Psychiatry, Comparative Medicine, & Neuroscience, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"David Hofmann","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Yuko Isobe","author_inst":"Department of Cognitive Behavioral Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan"},{"author_name":"Neda Jahanshad","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Hamidreza Jamalabadi","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Alec J Jamieson","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Andreas Jansen","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Jaehyun Edmund Kim","author_inst":"Seoul National University, Seoul, Republic of Korea"},{"author_name":"Tilo Kircher","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Hitomi Kitagawa","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Anna Luisa Klahn","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Saskia B. J Koch","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Axel Krug","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Harald Kugel","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Dasom Lee","author_inst":"Department of Psychiatry, Seoul National University Hospital, Seoul, Republic of Korea"},{"author_name":"Elisabeth J Leehr","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christine Lochner","author_inst":"SAMRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Ulrike Lueken","author_inst":"Department of Psychology, Humboldt-Universit\u00e4t zu Berlin, German Center for Mental Health (DZPG), partner site Berlin-Potsdam, Germany"},{"author_name":"Amirhossein Manzouri","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Kristoffer N. T M\u00e5nsson","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Koji Matsumoto","author_inst":"Department of Radiology, Chiba University Hospital, Chiba, Japan"},{"author_name":"Susanne Meinert","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Alicia Menze","author_inst":"Medical Faculty M\u00fcnster, University Hospital M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Markus Muehlhan","author_inst":"Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Benson Mwangi","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Igor Nenadi\u0107","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Ziphozihle Ntwatwa","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Hyuntaek Oh","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Spiro P Pantazatos","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Martin P Paulus","author_inst":"Laureate Institute for Brain Research, Tulsa, OK, USA"},{"author_name":"Jutta Peterburs","author_inst":"Institute of Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Jesus Pujol","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Karin Roelofs","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Ramiro Salas","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Franklin R Schneier","author_inst":"New York State Psychiatric Institute, New York, NY, USA"},{"author_name":"Elisabeth Schrammen","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Eiji Shimizu","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Lisa Sindermann","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Theresa M Slump","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Jair C Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Benjamin Straube","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Thomas Straube","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Murray B Stein","author_inst":"Department of Psychiatry & School of Public Health, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Ardesheer Talati","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Florian Thomas-Odenthal","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Sophia I Thomopoulos","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Ra\u015fit T\u00fckel","author_inst":"Istanbul University, Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey"},{"author_name":"Anna Tyborowska","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Marie-Jos\u00e9 Van Tol","author_inst":"Center for Clinical Neuroscience and Cognition, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands"},{"author_name":"Dick J Veltman","author_inst":"Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands"},{"author_name":"Roman A. Vogler","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Inge Volman","author_inst":"National Education Lab for AI, Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Henry V\u00f6lzke","author_inst":"Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"P. Michiel Westenberg","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Katharina Wittfeld","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Mon-Ju Wu","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Noga Yair","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Tokiko Yoshida","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Chen Zhang","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Xi Zhu","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Giovana B Zunta-Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Peter Zwanzger","author_inst":"Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Germany"},{"author_name":"Daniel S Pine","author_inst":"National Institute of Mental Health, Emotion and Development Branch, USA"},{"author_name":"Moji Aghajani","author_inst":"Institute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden University, Leiden, the Netherlands"},{"author_name":"Paul M Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Nic J.A. van der Wee","author_inst":"Leiden Institute for Brain and Cognition, Leiden, the Netherlands"},{"author_name":"Dan J Stein","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Janna Marie Bas-Hoogendam","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Nynke A Groenewold","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Brain Ageing in Social Anxiety Disorder: An ENIGMA-Anxiety Mega-Analysis Across 26 International Cohorts","rel_doi":"10.64898\/2026.07.02.26357108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357108","rel_abs":"Social anxiety disorder (SAD) is among the most prevalent anxiety disorders, and it has been associated with signs of advanced biological ageing. Despite this, brain age research on anxiety disorders remains limited. This mega-analysis investigated brain ageing in adults with SAD within the ENIGMA-Anxiety Working Group. Structural MRI scans from 576 participants with SAD and 1 355 non-affected healthy controls (HCs) across 26 international samples were included. Brain age was estimated from 77 cortical and subcortical regions using a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as the difference between brain age and chronological age. Group and subgroup differences (comorbidity, medication) were assessed using linear mixed-effect models. In the full sample, there was no group difference in brain-PAD ({beta}diagnosis (SE)=0.70 (0.37) years, p=0.061). In a subgroup of participants with SAD with comorbid anxiety disorders (n=184 SAD, n=1 355 HCs), a brain-PAD of +2.39 (0.93) years (Cohens d=0.23, pFDR=0.003) was observed. This brain-PAD became smaller after exclusion of participants with comorbid agoraphobia and specific phobia, suggesting that these disorders may partly drive the advanced brain-PAD. In conclusion, this ENIGMA-Anxiety mega-analysis did not find evidence of advanced brain ageing in the full sample of adult participants with SAD relative to HCs. However, a sub-analysis suggested that SAD with co-occurring phobic disorders, or the phobic disorders themselves, are associated with neurostructural patterns typical of older brains. Future research could utilise transdiagnostic samples with information on age of onset and disorder duration to further clarify this relation.","rel_num_authors":97,"rel_authors":[{"author_name":"Kimberly V Blake","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Jonathan C Ipser","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Alyssa R Amod","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Tobias Kaufmann","author_inst":"Department of Psychiatry and Psychotherapy, University of T\u00fcbingen, T\u00fcbingen, Germany"},{"author_name":"Yair Bar-Haim","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Jochen Bauer","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ali Bayram","author_inst":"Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Neuroscience, Turkey"},{"author_name":"Katja Beesdo-Baum","author_inst":"Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, TUD - Dresden University of Technology, Germany"},{"author_name":"Laura Blanco-Hinojo","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Tiana Borgers","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Robin B\u00fclow","author_inst":"Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Marta Cano","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Narcis Cardoner","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Christopher R.K Ching","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Soo-Hee Choi","author_inst":"Department of Psychiatry, Seoul National University College of Medicine and Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea"},{"author_name":"Udo Dannlowski","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christopher G Davey","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexander G. G Doruyter","author_inst":"Division of Nuclear Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Kira Flinkenfl\u00fcgel","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Gregory A Fonzo","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA"},{"author_name":"Tomas Furmark","author_inst":"Department of Psychology, Uppsala University, Uppsala, Sweden"},{"author_name":"Dominik Grotegerd","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Hans J Grabe","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Tim Hahn","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ben J Harrison","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexandre Heeren","author_inst":"Psychological Science Research Institute, Universit\u00e9 Catholique de Louvain, Louvain-la-Neuve, Belgium"},{"author_name":"Kevin Hilbert","author_inst":"Department of Psychology, HMU Health and Medical University Erfurt, Germany"},{"author_name":"Yoshiyuki Hirano","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Joy Hirsch","author_inst":"Departments of Psychiatry, Comparative Medicine, & Neuroscience, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"David Hofmann","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Yuko Isobe","author_inst":"Department of Cognitive Behavioral Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan"},{"author_name":"Neda Jahanshad","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Hamidreza Jamalabadi","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Alec J Jamieson","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Andreas Jansen","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Jaehyun Edmund Kim","author_inst":"Seoul National University, Seoul, Republic of Korea"},{"author_name":"Tilo Kircher","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Hitomi Kitagawa","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Anna Luisa Klahn","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Saskia B. J Koch","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Axel Krug","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Harald Kugel","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Dasom Lee","author_inst":"Department of Psychiatry, Seoul National University Hospital, Seoul, Republic of Korea"},{"author_name":"Elisabeth J Leehr","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christine Lochner","author_inst":"SAMRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Ulrike Lueken","author_inst":"Department of Psychology, Humboldt-Universit\u00e4t zu Berlin, German Center for Mental Health (DZPG), partner site Berlin-Potsdam, Germany"},{"author_name":"Amirhossein Manzouri","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Kristoffer N. T M\u00e5nsson","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Koji Matsumoto","author_inst":"Department of Radiology, Chiba University Hospital, Chiba, Japan"},{"author_name":"Susanne Meinert","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Alicia Menze","author_inst":"Medical Faculty M\u00fcnster, University Hospital M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Markus Muehlhan","author_inst":"Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Benson Mwangi","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Igor Nenadi\u0107","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Ziphozihle Ntwatwa","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Hyuntaek Oh","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Spiro P Pantazatos","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Martin P Paulus","author_inst":"Laureate Institute for Brain Research, Tulsa, OK, USA"},{"author_name":"Jutta Peterburs","author_inst":"Institute of Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Jesus Pujol","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Karin Roelofs","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Ramiro Salas","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Franklin R Schneier","author_inst":"New York State Psychiatric Institute, New York, NY, USA"},{"author_name":"Elisabeth Schrammen","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Eiji Shimizu","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Lisa Sindermann","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Theresa M Slump","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Jair C Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Benjamin Straube","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Thomas Straube","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Murray B Stein","author_inst":"Department of Psychiatry & School of Public Health, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Ardesheer Talati","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Florian Thomas-Odenthal","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Sophia I Thomopoulos","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Ra\u015fit T\u00fckel","author_inst":"Istanbul University, Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey"},{"author_name":"Anna Tyborowska","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Marie-Jos\u00e9 Van Tol","author_inst":"Center for Clinical Neuroscience and Cognition, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands"},{"author_name":"Dick J Veltman","author_inst":"Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands"},{"author_name":"Roman A. Vogler","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Inge Volman","author_inst":"National Education Lab for AI, Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Henry V\u00f6lzke","author_inst":"Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"P. Michiel Westenberg","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Katharina Wittfeld","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Mon-Ju Wu","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Noga Yair","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Tokiko Yoshida","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Chen Zhang","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Xi Zhu","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Giovana B Zunta-Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Peter Zwanzger","author_inst":"Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Germany"},{"author_name":"Daniel S Pine","author_inst":"National Institute of Mental Health, Emotion and Development Branch, USA"},{"author_name":"Moji Aghajani","author_inst":"Institute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden University, Leiden, the Netherlands"},{"author_name":"Paul M Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Nic J.A. van der Wee","author_inst":"Leiden Institute for Brain and Cognition, Leiden, the Netherlands"},{"author_name":"Dan J Stein","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Janna Marie Bas-Hoogendam","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Nynke A Groenewold","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Brain Ageing in Social Anxiety Disorder: An ENIGMA-Anxiety Mega-Analysis Across 26 International Cohorts","rel_doi":"10.64898\/2026.07.02.26357108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357108","rel_abs":"Social anxiety disorder (SAD) is among the most prevalent anxiety disorders, and it has been associated with signs of advanced biological ageing. Despite this, brain age research on anxiety disorders remains limited. This mega-analysis investigated brain ageing in adults with SAD within the ENIGMA-Anxiety Working Group. Structural MRI scans from 576 participants with SAD and 1 355 non-affected healthy controls (HCs) across 26 international samples were included. Brain age was estimated from 77 cortical and subcortical regions using a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as the difference between brain age and chronological age. Group and subgroup differences (comorbidity, medication) were assessed using linear mixed-effect models. In the full sample, there was no group difference in brain-PAD ({beta}diagnosis (SE)=0.70 (0.37) years, p=0.061). In a subgroup of participants with SAD with comorbid anxiety disorders (n=184 SAD, n=1 355 HCs), a brain-PAD of +2.39 (0.93) years (Cohens d=0.23, pFDR=0.003) was observed. This brain-PAD became smaller after exclusion of participants with comorbid agoraphobia and specific phobia, suggesting that these disorders may partly drive the advanced brain-PAD. In conclusion, this ENIGMA-Anxiety mega-analysis did not find evidence of advanced brain ageing in the full sample of adult participants with SAD relative to HCs. However, a sub-analysis suggested that SAD with co-occurring phobic disorders, or the phobic disorders themselves, are associated with neurostructural patterns typical of older brains. Future research could utilise transdiagnostic samples with information on age of onset and disorder duration to further clarify this relation.","rel_num_authors":97,"rel_authors":[{"author_name":"Kimberly V Blake","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Jonathan C Ipser","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Alyssa R Amod","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Tobias Kaufmann","author_inst":"Department of Psychiatry and Psychotherapy, University of T\u00fcbingen, T\u00fcbingen, Germany"},{"author_name":"Yair Bar-Haim","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Jochen Bauer","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ali Bayram","author_inst":"Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Neuroscience, Turkey"},{"author_name":"Katja Beesdo-Baum","author_inst":"Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, TUD - Dresden University of Technology, Germany"},{"author_name":"Laura Blanco-Hinojo","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Tiana Borgers","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Robin B\u00fclow","author_inst":"Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Marta Cano","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Narcis Cardoner","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Christopher R.K Ching","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Soo-Hee Choi","author_inst":"Department of Psychiatry, Seoul National University College of Medicine and Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea"},{"author_name":"Udo Dannlowski","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christopher G Davey","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexander G. G Doruyter","author_inst":"Division of Nuclear Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Kira Flinkenfl\u00fcgel","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Gregory A Fonzo","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA"},{"author_name":"Tomas Furmark","author_inst":"Department of Psychology, Uppsala University, Uppsala, Sweden"},{"author_name":"Dominik Grotegerd","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Hans J Grabe","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Tim Hahn","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ben J Harrison","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexandre Heeren","author_inst":"Psychological Science Research Institute, Universit\u00e9 Catholique de Louvain, Louvain-la-Neuve, Belgium"},{"author_name":"Kevin Hilbert","author_inst":"Department of Psychology, HMU Health and Medical University Erfurt, Germany"},{"author_name":"Yoshiyuki Hirano","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Joy Hirsch","author_inst":"Departments of Psychiatry, Comparative Medicine, & Neuroscience, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"David Hofmann","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Yuko Isobe","author_inst":"Department of Cognitive Behavioral Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan"},{"author_name":"Neda Jahanshad","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Hamidreza Jamalabadi","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Alec J Jamieson","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Andreas Jansen","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Jaehyun Edmund Kim","author_inst":"Seoul National University, Seoul, Republic of Korea"},{"author_name":"Tilo Kircher","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Hitomi Kitagawa","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Anna Luisa Klahn","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Saskia B. J Koch","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Axel Krug","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Harald Kugel","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Dasom Lee","author_inst":"Department of Psychiatry, Seoul National University Hospital, Seoul, Republic of Korea"},{"author_name":"Elisabeth J Leehr","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christine Lochner","author_inst":"SAMRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Ulrike Lueken","author_inst":"Department of Psychology, Humboldt-Universit\u00e4t zu Berlin, German Center for Mental Health (DZPG), partner site Berlin-Potsdam, Germany"},{"author_name":"Amirhossein Manzouri","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Kristoffer N. T M\u00e5nsson","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Koji Matsumoto","author_inst":"Department of Radiology, Chiba University Hospital, Chiba, Japan"},{"author_name":"Susanne Meinert","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Alicia Menze","author_inst":"Medical Faculty M\u00fcnster, University Hospital M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Markus Muehlhan","author_inst":"Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Benson Mwangi","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Igor Nenadi\u0107","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Ziphozihle Ntwatwa","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Hyuntaek Oh","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Spiro P Pantazatos","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Martin P Paulus","author_inst":"Laureate Institute for Brain Research, Tulsa, OK, USA"},{"author_name":"Jutta Peterburs","author_inst":"Institute of Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Jesus Pujol","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Karin Roelofs","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Ramiro Salas","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Franklin R Schneier","author_inst":"New York State Psychiatric Institute, New York, NY, USA"},{"author_name":"Elisabeth Schrammen","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Eiji Shimizu","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Lisa Sindermann","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Theresa M Slump","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Jair C Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Benjamin Straube","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Thomas Straube","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Murray B Stein","author_inst":"Department of Psychiatry & School of Public Health, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Ardesheer Talati","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Florian Thomas-Odenthal","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Sophia I Thomopoulos","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Ra\u015fit T\u00fckel","author_inst":"Istanbul University, Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey"},{"author_name":"Anna Tyborowska","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Marie-Jos\u00e9 Van Tol","author_inst":"Center for Clinical Neuroscience and Cognition, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands"},{"author_name":"Dick J Veltman","author_inst":"Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands"},{"author_name":"Roman A. Vogler","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Inge Volman","author_inst":"National Education Lab for AI, Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Henry V\u00f6lzke","author_inst":"Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"P. Michiel Westenberg","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Katharina Wittfeld","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Mon-Ju Wu","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Noga Yair","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Tokiko Yoshida","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Chen Zhang","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Xi Zhu","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Giovana B Zunta-Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Peter Zwanzger","author_inst":"Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Germany"},{"author_name":"Daniel S Pine","author_inst":"National Institute of Mental Health, Emotion and Development Branch, USA"},{"author_name":"Moji Aghajani","author_inst":"Institute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden University, Leiden, the Netherlands"},{"author_name":"Paul M Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Nic J.A. van der Wee","author_inst":"Leiden Institute for Brain and Cognition, Leiden, the Netherlands"},{"author_name":"Dan J Stein","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Janna Marie Bas-Hoogendam","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Nynke A Groenewold","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"its2s: a Python package for two-stage interrupted time series analysis using machine learning","rel_doi":"10.64898\/2026.07.02.26357175","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357175","rel_abs":"1When randomized controlled trials are infeasible, researchers may leverage natural experiments for causal inference. Interrupted time-series (ITS) designs compare observed post-event trends to counterfactual predictions from pre-event data. Two-stage ITS designs use flexible models to generate optimized counterfactual predictions in the first stage, then estimate intervention effects by comparing observed to predicted outcomes in the second stage. Fitting high-dimensional versions of these models is challenging, requiring systematic infrastructure to ensure rigor and reproducibility. In response, we developed its2s, an open-source Python package implementing the two-stage ITS design with machine learning. its2s allows users to specify an intervention date and training\/testing periods, select among built-in model architectures (e.g., Prophet-XGBoost, NeuralProphet), and generate confidence intervals via moving block bootstrap, preserving temporal autocorrelation in residuals. its2s layers defaults, configuration files, and runtime overrides to support workflows ranging from rapid default implementations to highly tailored analyses. We validated its2s using two case studies: a simulation with a 12% policy effect, recovering the true effect as 11.77%, and an analysis of the 2021 Pacific Northwest heat dome, finding 53% excess injury mortality over the following three weeks. its2s provides a flexible, reproducible framework for ITS-based quasi-experimental research, lowering barriers to rigorous machine learning-based counterfactual modeling.","rel_num_authors":7,"rel_authors":[{"author_name":"Lauren Wilner","author_inst":"University of Washington"},{"author_name":"Joan A Casey","author_inst":"University of Washington"},{"author_name":"Stephen J Mooney","author_inst":"University of Washington"},{"author_name":"Vivian Do","author_inst":"Scripps Institution of Oceanography, University of California San Diego"},{"author_name":"Yiqun Ma","author_inst":"Scripps Institution of Oceanography, University of California San Diego"},{"author_name":"Tarik Benmarhnia","author_inst":"Scripps Institution of Oceanography, University of California San Diego"},{"author_name":"Arnab K Dey","author_inst":"Scripps Institution of Oceanography, University of California San Diego"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Association between glycated hemoglobin A1c and automated abdominal aortic calcification: the UK Biobank Imaging Study","rel_doi":"10.64898\/2026.07.02.26357193","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357193","rel_abs":"BackgroundPoor glycemic control is associated with cardiovascular disease (CVD) risk. However, it is unknown whether glycemic control is related to abdominal aortic calcification (AAC), a marker of subclinical CVD. We investigated the association between glycated hemoglobin (HbA1c) and moderate-to-high automated AAC among middle-aged to older adults from the general population.\n\nMethodsWe included UK Biobank Imaging Study participants free of atherosclerotic CVD at baseline. HbA1c was measured at baseline (2006-2010) and categorized as normoglycemia (<39.0 mmol\/mol), prediabetes (39.0-47.9 mmol\/mol), undiagnosed diabetes (HbA1c [&ge;]48 mmol\/mol) and diagnosed diabetes. Machine learning derived AAC24 (ML-AAC24) scores were estimated using a validated automated algorithm applied to dual-energy X-ray absorptiometry lateral spine images (2014-2022). The associations of HbA1c with Moderate-to-high ML-AAC24 (defined as a score [&ge;]2) were assessed using logistic regression adjusting for cardiovascular risk factors.\n\nResultsOf the included 48,912 participants (mean {+\/-} SD age 55 {+\/-} 7.6 years, 52% women), 9.7% had prediabetes (HbA1c 39.0-47.9 mmol\/mol [5.7-6.4%]), 0.4% had undiagnosed diabetes and 2.7% diagnosed diabetes. Each 1-SD increase in log-transformed HbA1c was associated with higher odds of moderate-to-high ML-AAC24 (adjusted odds ratio [aOR] 1.12, 95%CI: 1.09-1.16). Amongst individuals with normal HbA1c this association was consistent but somewhat weaker for each 1-SD increase in log-transformed HbA1c (aOR 1.07, 95%CI 1.03-1.10). Compared to participants with normal HbA1c, those with prediabetes (aOR 1.19, 95%CI: 1.08-1.30) or diagnosed diabetes (1.64, 95%CI: 1.39-1.94) had higher odds of moderate-to-high ML-AAC24. These associations were consistent in stratified analyses by sex, age groups, body mass index, smoking status and total cholesterol\n\nConclusionsLinear associations between HbA1c levels and ML-AAC24 were observed in UK adults, even in those with normal HbA1c level. These findings indicate that AAC may develop early in the dysglycemic continuum, supporting earlier cardiometabolic risk assessment even amongst people with \"normal\" levels.","rel_num_authors":14,"rel_authors":[{"author_name":"Haftom Niguse Abraha","author_inst":"Edith Cowan University School of Medical and Health Sciences"},{"author_name":"Abadi Kahsu Gebre","author_inst":"Edith Cowan University School of Medical and Health Sciences"},{"author_name":"Cassandra Smith","author_inst":"Edith Cowan University School of Medical and Health Sciences"},{"author_name":"Lakshini Y. Herat","author_inst":"The University of Western Australia"},{"author_name":"James Webster","author_inst":"University of Oxford"},{"author_name":"Afsah Saleem","author_inst":"Edith Cowan University"},{"author_name":"Zulqarnain Gilani","author_inst":"Edith Cowan University"},{"author_name":"Christian M. Girgis","author_inst":"The University of Sydney"},{"author_name":"Nicklas H. Rasmussen","author_inst":"Aalborg Universitetshospital"},{"author_name":"William D. Leslie","author_inst":"University of Manitoba"},{"author_name":"John T. Schousboe","author_inst":"HealthPartners Institute"},{"author_name":"Nicholas C Harvey","author_inst":"MRC lifecourse Epidemiology unit"},{"author_name":"Marc Sim","author_inst":"Edith Cowan University"},{"author_name":"Joshua Richard Lewis","author_inst":"Edith Cowan University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Efficacy and safety of triple versus dual combinations of antihypertensive drugs: A systematic review and meta-analysis of double-blind randomized clinical trials","rel_doi":"10.64898\/2026.07.03.26356990","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26356990","rel_abs":"We evaluated the blood pressure (BP)-lowering efficacy and safety of triple vs dual therapy of antihypertensive drug (AHTD) combinations, among adults with hypertension. Seventeen randomized, double-blind trials (41 comparisons and 13,461 participants) comparing triple versus dual therapy for [&ge;]3 weeks identified by multiple literature databases searches including PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) until October 2024 were included in the meta-analysis.\n\nTriple therapy achieved a greater reduction in systolic BP (SBP) compared with dual therapy (26.9 vs. 21.7 mmHg, mean difference 5.4 mmHg [95% CI, 4.7-6.2]). Among patients receiving dual therapy at submaximal and maximal doses, the addition of a third drug further reduced SBP by 7.5 and 3.6 mmHg, respectively. BP control was significantly better with triple therapy (60% vs. 47%, RR=1.34 [1.27-1.41]). Withdrawal due to adverse events was slightly higher in the triple therapy group (4% vs. 3%, RR=1.5 [1.2-1.8]). Triple AHTD therapy provides superior BP reduction and is well-tolerated compared to dual therapy.","rel_num_authors":6,"rel_authors":[{"author_name":"Rupasvi Dhurjati","author_inst":"The George Institute for Global Health"},{"author_name":"Rashmi Pant","author_inst":"The George Institute for Global Health"},{"author_name":"Gautam Satheesh","author_inst":"University of Sydney"},{"author_name":"Anshika Mittal","author_inst":"The George Institute for Global Health"},{"author_name":"Anthony Rodgers","author_inst":"School of Population Health, UNSW Sydney, Sydney, NSW, Australia"},{"author_name":"Abdul Salam","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India; The George Institute for Global Health, University of New South Wales, Sydney, New South Wa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Efficacy and safety of triple versus dual combinations of antihypertensive drugs: A systematic review and meta-analysis of double-blind randomized clinical trials","rel_doi":"10.64898\/2026.07.03.26356990","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26356990","rel_abs":"We evaluated the blood pressure (BP)-lowering efficacy and safety of triple vs dual therapy of antihypertensive drug (AHTD) combinations, among adults with hypertension. Seventeen randomized, double-blind trials (41 comparisons and 13,461 participants) comparing triple versus dual therapy for [&ge;]3 weeks identified by multiple literature databases searches including PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) until October 2024 were included in the meta-analysis.\n\nTriple therapy achieved a greater reduction in systolic BP (SBP) compared with dual therapy (26.9 vs. 21.7 mmHg, mean difference 5.4 mmHg [95% CI, 4.7-6.2]). Among patients receiving dual therapy at submaximal and maximal doses, the addition of a third drug further reduced SBP by 7.5 and 3.6 mmHg, respectively. BP control was significantly better with triple therapy (60% vs. 47%, RR=1.34 [1.27-1.41]). Withdrawal due to adverse events was slightly higher in the triple therapy group (4% vs. 3%, RR=1.5 [1.2-1.8]). Triple AHTD therapy provides superior BP reduction and is well-tolerated compared to dual therapy.","rel_num_authors":6,"rel_authors":[{"author_name":"Rupasvi Dhurjati","author_inst":"The George Institute for Global Health"},{"author_name":"Rashmi Pant","author_inst":"The George Institute for Global Health"},{"author_name":"Gautam Satheesh","author_inst":"University of Sydney"},{"author_name":"Anshika Mittal","author_inst":"The George Institute for Global Health"},{"author_name":"Anthony Rodgers","author_inst":"School of Population Health, UNSW Sydney, Sydney, NSW, Australia"},{"author_name":"Abdul Salam","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India; The George Institute for Global Health, University of New South Wales, Sydney, New South Wa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Comparing cutaneous NO-dependent vasodilation between young males and females","rel_doi":"10.64898\/2026.07.02.26357121","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357121","rel_abs":"BackgroundDespite the common use of local heating and intradermal microdialysis perfusion of acetylcholine (ACh) to probe cutaneous endothelium and nitric oxide (NO)-dependent dilation, sex differences in microvascular responsiveness to these stimuli in healthy young adults remain incompletely understood.\n\nMethodsCutaneous vasodilation was assessed in response to local heating to 39{degrees}C and 42{degrees}C and graded perfusion of ACh (10-10 to 10-1 mol\/L) alone or concurrently with 15 mM NG-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor) using laser-Doppler flowmetry coupled with intradermal microdialysis in 80 young adults (40 females).\n\nResultsLocal heating to 42{degrees}C elicited greater endothelium- and NO-dependent dilation than heating to 39{degrees}C in both groups (p<0.001), but no sex differences were observed at either temperature (p=0.65). ACh-induced endothelium-dependent dilation also was not different between sexes (p=0.08), but the NO-dependent component was greater in females than in males (p=0.01). In young females, menstrual cycle day (range: day 2-33) was not associated with endothelium- or NO-dependent dilation in response to any stimulus (all p[&ge;]0.19), regardless of hormonal contraceptive use.\n\nConclusionsTaken together, these findings suggest that sex differences in microvascular NO bioavailability in healthy young adults depend on the stimulus used to elicit cutaneous vasodilation and, in females, microvascular endothelium- and NO-dependent dilation are not meaningfully influenced by menstrual cycle phase.","rel_num_authors":5,"rel_authors":[{"author_name":"Madison G Evering","author_inst":"University of Delaware"},{"author_name":"Kelsey S. Schwartz","author_inst":"The University of Iowa"},{"author_name":"Claire E. Goebel","author_inst":"The University of Iowa"},{"author_name":"Anna E. Stanhewicz","author_inst":"The University of Iowa"},{"author_name":"Jody L. Greaney","author_inst":"University of Delaware"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Microvascular responses to common endothelial stimuli are not related in humans","rel_doi":"10.64898\/2026.07.02.26357129","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357129","rel_abs":"BackgroundCutaneous microvascular responses to local heating and acetylcholine perfusion are widely used to assess nitric oxide (NO)-mediated endothelium-dependent dilation in human health and disease. Despite the increasingly common usage of these approaches, no studies have directly compared responses to these stimuli within individuals. Therefore, we assessed endothelium- and NO-dependent dilation in 80 young adults (40 males\/40 females; 22{+\/-}3 years) to determine the extent to which microvascular responses to these endothelium-dependent stimuli are comparable within an individual.\n\nMethodsWe examined cutaneous vascular conductance responses to (1) standardized local heating protocols to 39{degrees}C and 42{degrees}C, and (2) graded infusions of acetylcholine (10-10-10-1 M) alone or with 15 mM NG-nitro-l-arginine methyl ester (L-NAME; NO synthase inhibitor). Endothelium- and NO-dependent dilation were calculated and expressed in multiple ways based on commonly published analyses to allow for a thorough comparison within and between each stimulus.\n\nResultsLocal heating-induced endothelium- and NO-dependent dilation were lower at 39{degrees}C compared with 42{degrees}C (P<0.001). The magnitude of local heating-induced endothelium-dependent dilation was significantly related to the NO-dependent contribution of that response at 39{degrees}C (R2= 0.79) and 42{degrees}C (R2= 0.56). Local heating-induced NO-dependent dilation at 39{degrees}C was not related to that at 42{degrees}C (P>0.05). Acetylcholine-induced endothelium- and NO-dependent dilation were not related to local heating-induced responses (all P>0.05).\n\nConclusionsThese data demonstrate that while local heating and acetylcholine perfusion produce robust endothelium- and NO-dependent cutaneous vasodilation, these responses are not comparable within an individual.\n\nClinical Trial RegistrationURL: https:\/\/www.clinicaltrials.gov\/ Unique identifier: NCT06499844\n\nNovelty and RelevanceO_ST_ABSWhat Is New?C_ST_ABSO_LILocal thermal heating and acetylcholine perfusion each produce robust endothelium- and nitric oxide-dependent cutaneous vasodilation. However, these responses are not directly comparable within an individual.\nC_LI\n\nWhat Is Relevant?O_LIChanges in microvascular function precede and predict adverse changes in conduit vessels and are reversible before the onset of overt vascular disease and target organ damage.\nC_LI\n\nClinical\/Pathophysiological Implications?O_LIThese approaches are widely used by investigators to interrogate mechanisms of microvascular function and dysfunction in humans. Selection of the appropriate approach should be based on the specific research question and pathophysiological mechanism under investigation.\nC_LI","rel_num_authors":5,"rel_authors":[{"author_name":"Kelsey S. Schwartz","author_inst":"The University of Iowa"},{"author_name":"Madison G Evering","author_inst":"University of Delaware"},{"author_name":"Claire E. Goebel","author_inst":"The University of Iowa"},{"author_name":"Jody L. Greaney","author_inst":"University of Delaware"},{"author_name":"Anna E. Stanhewicz","author_inst":"The University of Iowa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Anti-HBsAg antibody mAb19-LS enhances antiviral immunity in humans with chronic hepatitis B","rel_doi":"10.64898\/2026.07.03.26357226","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357226","rel_abs":"Chronic infection with hepatitis B virus (HBV) is characterized by persistent expression of hepatitis B surface antigen (HBsAg), which is associated with profound immune tolerance. Although nucleos(t)ide analogue therapy effectively suppresses viral replication, it neither eliminates HBV nor reverses virus-specific immune dysfunction. Here, we report the results of two parallel first-in-human, dose-escalation studies evaluating a single infusion of mAb19-LS, a long-acting IgG1 monoclonal antibody targeting HBsAg, in individuals with chronic HBV infection receiving nucleos(t)ide analogue therapy. mAb19-LS was generally safe and well tolerated and induced a mean 11-fold increase in antigen clearance. The magnitude and duration of HBsAg suppression were dependent on both baseline antigen levels and mAb19-LS dose, with suppression maintained for more than 36 weeks in individuals receiving the highest dose. Reduction of circulating HBsAg was associated with uptake of HBsAg-IgG immune complexes by monocytes and dendritic cells and inflammatory reprogramming of these antigen-presenting cells. Notably, proliferation of both CD4+ and CD8+ T cells, as well as interferon-{gamma} and TNF- production in response to HBV antigens, were significantly increased 24 weeks after infusion. Together, these findings demonstrate that mAb19-LS is generally safe and effectively accelerates HBsAg clearance while activating antigen presenting cells and enhancing antiviral T cell responses.","rel_num_authors":41,"rel_authors":[{"author_name":"Zijun Wang","author_inst":"The Rockefeller University"},{"author_name":"Mary Tenuta","author_inst":"The Rockefeller University"},{"author_name":"Han Ngoc Le","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Siri Nana Halling Scensgaard","author_inst":"Aarhus University Hospital"},{"author_name":"Gabriela S Silva Santos","author_inst":"The Rockefeller University"},{"author_name":"Daniel B Reeves","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Gaelle Breton","author_inst":"The Rockefeller University"},{"author_name":"Vanessa Igbokwe","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Andre Moraes Nicola","author_inst":"The Rockefeller University"},{"author_name":"Katrina Millard","author_inst":"The Rockefeller University"},{"author_name":"Sidsel Dahl Winther Andersen","author_inst":"Aarhus University Hospital"},{"author_name":"Henriette Graversen","author_inst":"Aarhus University Hospital"},{"author_name":"Caroline Zollner","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Martin Kluge","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Rachel Scheck","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Nina Weis","author_inst":"Copenhagen University Hospital - Amager and Hvidovre"},{"author_name":"Isik Johansen","author_inst":"Odense University Hospital"},{"author_name":"Deanna Dong","author_inst":"The Rockefeller University"},{"author_name":"Brianna Hernandez","author_inst":"The Rockefeller University"},{"author_name":"Irina Shimeliovich","author_inst":"The Rockefeller University"},{"author_name":"Juan Dizon","author_inst":"The Rockefeller University"},{"author_name":"Valeska Viera","author_inst":"The Rockefeller University"},{"author_name":"Frank Fabris","author_inst":"The Rockefeller University"},{"author_name":"Magdalena Schwarzmuller","author_inst":"Aarhus University Hospital"},{"author_name":"Pinkus Tober-Lau","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"David Hillus","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Munevver Demir","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Anna Gazumyan","author_inst":"The Rockefeller University"},{"author_name":"Frank Tacke","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Leif Erik Sander","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Florian Kurth","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Thomas Rasmussen","author_inst":"Aarhus University Hospital"},{"author_name":"Hector Ye","author_inst":"Medical Procare PLC"},{"author_name":"Calvin Pan","author_inst":"New York University Langone Health"},{"author_name":"Ira Jacobson","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Qiao Wang","author_inst":"The Rockefeller University"},{"author_name":"Jesper Damsgaard Gunst","author_inst":"Aarhus University Hospital"},{"author_name":"Christian Gaebler","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Ole S Sogaard","author_inst":"Aarhus University Hospital"},{"author_name":"Marina Caskey","author_inst":"The Rockefeller University"},{"author_name":"Michel Nussenzweig","author_inst":"The Rockefeller University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Anti-HBsAg antibody mAb19-LS enhances antiviral immunity in humans with chronic hepatitis B","rel_doi":"10.64898\/2026.07.03.26357226","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357226","rel_abs":"Chronic infection with hepatitis B virus (HBV) is characterized by persistent expression of hepatitis B surface antigen (HBsAg), which is associated with profound immune tolerance. Although nucleos(t)ide analogue therapy effectively suppresses viral replication, it neither eliminates HBV nor reverses virus-specific immune dysfunction. Here, we report the results of two parallel first-in-human, dose-escalation studies evaluating a single infusion of mAb19-LS, a long-acting IgG1 monoclonal antibody targeting HBsAg, in individuals with chronic HBV infection receiving nucleos(t)ide analogue therapy. mAb19-LS was generally safe and well tolerated and induced a mean 11-fold increase in antigen clearance. The magnitude and duration of HBsAg suppression were dependent on both baseline antigen levels and mAb19-LS dose, with suppression maintained for more than 36 weeks in individuals receiving the highest dose. Reduction of circulating HBsAg was associated with uptake of HBsAg-IgG immune complexes by monocytes and dendritic cells and inflammatory reprogramming of these antigen-presenting cells. Notably, proliferation of both CD4+ and CD8+ T cells, as well as interferon-{gamma} and TNF- production in response to HBV antigens, were significantly increased 24 weeks after infusion. Together, these findings demonstrate that mAb19-LS is generally safe and effectively accelerates HBsAg clearance while activating antigen presenting cells and enhancing antiviral T cell responses.","rel_num_authors":41,"rel_authors":[{"author_name":"Zijun Wang","author_inst":"The Rockefeller University"},{"author_name":"Mary Tenuta","author_inst":"The Rockefeller University"},{"author_name":"Han Ngoc Le","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Siri Nana Halling Scensgaard","author_inst":"Aarhus University Hospital"},{"author_name":"Gabriela S Silva Santos","author_inst":"The Rockefeller University"},{"author_name":"Daniel B Reeves","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Gaelle Breton","author_inst":"The Rockefeller University"},{"author_name":"Vanessa Igbokwe","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Andre Moraes Nicola","author_inst":"The Rockefeller University"},{"author_name":"Katrina Millard","author_inst":"The Rockefeller University"},{"author_name":"Sidsel Dahl Winther Andersen","author_inst":"Aarhus University Hospital"},{"author_name":"Henriette Graversen","author_inst":"Aarhus University Hospital"},{"author_name":"Caroline Zollner","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Martin Kluge","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Rachel Scheck","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Nina Weis","author_inst":"Copenhagen University Hospital - Amager and Hvidovre"},{"author_name":"Isik Johansen","author_inst":"Odense University Hospital"},{"author_name":"Deanna Dong","author_inst":"The Rockefeller University"},{"author_name":"Brianna Hernandez","author_inst":"The Rockefeller University"},{"author_name":"Irina Shimeliovich","author_inst":"The Rockefeller University"},{"author_name":"Juan Dizon","author_inst":"The Rockefeller University"},{"author_name":"Valeska Viera","author_inst":"The Rockefeller University"},{"author_name":"Frank Fabris","author_inst":"The Rockefeller University"},{"author_name":"Magdalena Schwarzmuller","author_inst":"Aarhus University Hospital"},{"author_name":"Pinkus Tober-Lau","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"David Hillus","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Munevver Demir","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Anna Gazumyan","author_inst":"The Rockefeller University"},{"author_name":"Frank Tacke","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Leif Erik Sander","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Florian Kurth","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Thomas Rasmussen","author_inst":"Aarhus University Hospital"},{"author_name":"Hector Ye","author_inst":"Medical Procare PLC"},{"author_name":"Calvin Pan","author_inst":"New York University Langone Health"},{"author_name":"Ira Jacobson","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Qiao Wang","author_inst":"The Rockefeller University"},{"author_name":"Jesper Damsgaard Gunst","author_inst":"Aarhus University Hospital"},{"author_name":"Christian Gaebler","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Ole S Sogaard","author_inst":"Aarhus University Hospital"},{"author_name":"Marina Caskey","author_inst":"The Rockefeller University"},{"author_name":"Michel Nussenzweig","author_inst":"The Rockefeller University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Clinical Impact, Diagnostic Performance, and Prognostic Implications of Plasma Metagenomic Next-Generation Sequencing in Solid Organ Transplant Recipients","rel_doi":"10.64898\/2026.07.02.26357172","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357172","rel_abs":"IntroductionPlasma metagenomic next-generation sequencing (mNGS) may detect pathogens in solid organ transplant (SOT) recipients, but optimal patient selection and result interpretation remain uncertain.\n\nMethodsIn a retrospective cohort study, physicians reviewed SOT recipients with first-instance clinical plasma mNGS testing (Karius, Inc.) and determined microbiological diagnoses, clinical impact of results, diagnostic yield, and clinical outcome. mNGS results were compared to microbiological diagnoses. A HIPAA-compliant large language model (GPT-4) was used to analyze electronic medical record (EMR) data and predict risk of infection with atypical bacteria, invasive fungi, mycobacteria, or parasites (collectively: pre-specified organisms of presumed significance, POPS) and identify patients with positive-impact mNGS testing.\n\nResultsOf 145 SOT recipients, 119 (82.1%) had positive tests, 42 (29.0%) had [&ge;] 1 POPS organism, and 27 (19.1%) had [&ge;] 1 organism causing positive clinical impact. Positive impact was highly correlated with POPS status, with 24 (88.9%) of 27 positive-impact organisms categorized as POPS (P<0.001). GPT-4 scores accurately identified patients with POPS diagnoses (AUC 0.86), and assigned higher scores to patients with positive-impact tests (P=0.001). mNGS testing had highest sensitivity for atypical bacteria (82.4% sensitivity) and lower sensitivity for Aspergillus spp (53.3% sensitivity). Detection of greater numbers of organisms by mNGS was associated with increased mortality (odds ratio 1.32 per organism detected).\n\nDiscussionPlasma mNGS is a valuable clinical tool in SOT recipients. Positive clinical impact is associated with detection of atypical bacteria, fungi, mycobacteria, or parasites. GPT-4 analysis of EMR data identifies patients at risk of infection from these organisms and most likely to benefit from mNGS testing.\n\nSummaryThe optimal use of plasma mNGS in solid organ transplant recipients remains uncertain. We demonstrate that mNGS is most impactful when atypical bacteria, fungi, or parasites are detected, and create an artificial intelligence tool to identify patients with those infections.","rel_num_authors":9,"rel_authors":[{"author_name":"Natasha Spottiswoode","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Pedro S Marra","author_inst":"University of California San Francisco School of Medicine, San Francisco, CA, USA"},{"author_name":"Emily C Lydon","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Victoria T Chu","author_inst":"University of California San Francisco"},{"author_name":"Nathan Radakovich","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Julieta Rodriguez","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Hoang Van Phan","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Charles R Langelier","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Monica Fung","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"}],"rel_date":"2026-07-06","rel_site":"medrxiv"}]}