{"gname":"Columbia University","grp_id":"27","rels":[{"rel_title":"Nocturnal Respiratory Rate and Variability Predict Long-term Mortality in Stable Outpatients with Cardiovascular Disease","rel_doi":"10.64898\/2026.06.12.26355214","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355214","rel_abs":"Background: Respiratory rate (RR) predicts short-term mortality in acute care settings, yet its prognostic significance in clinically stable outpatients remains poorly defined. Objectives: To determine whether the median and variability of nocturnal respiratory rate (NRR) are independently associated with long-term cardiovascular and all-cause mortality in outpatients with cardiovascular disease. Methods: We analyzed overnight chest belt waveforms from elective polysomnography in 5,679 older adults with cardiovascular disease enrolled in the Sleep Heart Health Study (SHHS). NRR was quantified at 30-second resolution, and per-subject median NRR and within-night variability (standard deviation) were derived. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate associations with cardiovascular and all-cause mortality over 3-year and 15-year follow-up periods, adjusting for demographic characteristics, cardiopulmonary comorbidities, and sleep apnea severity. Results: Higher median NRR and greater NRR variability were each associated with increased cardiovascular and all-cause mortality. Combining these metrics identified a high-risk group characterized by elevated median and high variability of NRR, with approximately five-fold higher 3-year all-cause mortality compared with a low-risk group; this association remained significant in Cox models (unadjusted HR: 2.61; 95% CI: 1.65, 4.14; p<0.001; adjusted HR: 2.15; 95% CI: 1.30, 3.55; p=0.003). Conclusions: Both the baseline level and variability of NRR independently predict mortality in clinically stable outpatients with cardiovascular disease. Densely profiled NRR represents a promising, underutilized biomarker for long-term risk stratification.","rel_num_authors":8,"rel_authors":[{"author_name":"Raimon Pedros-Valls","author_inst":"University of California San Diego"},{"author_name":"Keshav S Gupta","author_inst":"University of California San Diego"},{"author_name":"Nicholas Harrington","author_inst":"Nightingale Labs"},{"author_name":"Justin D Yu","author_inst":"University of California San Diego"},{"author_name":"Jeremy Orr","author_inst":"University of California San Diego"},{"author_name":"Robert L Owens","author_inst":"University of California San Diego"},{"author_name":"David Torres Barba","author_inst":"University of California San Diego"},{"author_name":"Kevin R King","author_inst":"University of California San Diego"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"Rationale: Fibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses. Objectives: To identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response. Methods: We performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models. Results: Two molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process. Conclusion: Multi-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"Rationale: Fibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses. Objectives: To identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response. Methods: We performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models. Results: Two molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process. Conclusion: Multi-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"Rationale: Fibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses. Objectives: To identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response. Methods: We performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models. Results: Two molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process. Conclusion: Multi-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"Rationale: Fibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses. Objectives: To identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response. Methods: We performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models. Results: Two molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process. Conclusion: Multi-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Non-invasive intracranial pressure waveform reconstruction with deep learning","rel_doi":"10.64898\/2026.06.07.26354958","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354958","rel_abs":"Purpose: Continuous intracranial pressure (ICP) monitoring requires invasive instrumentation, reaching only a narrow subset of critically ill patients. We tested whether deep learning models trained on routinely acquired extracranial signals can reconstruct continuous ICP waveforms at clinically relevant accuracy in an independent external cohort. Methods: In adults admitted to the ICU at a single quaternary health system, five deep learning architectures were trained on high-frequency arterial blood pressure (ABP), photoplethysmography (PPG), and electrocardiography (ECG) waveforms, using invasive (intraparenchymal) ICP as ground truth. Two fusion strategies (early and late) and three training objectives (waveform-morphology, baseline robust regression, and weighted robust regression) were evaluated. Models were externally validated on the held-out MIMIC-III Waveform Database. Performance was assessed by mean absolute error (MAE) and waveform similarity by Pearson correlation (r). Results: We analyzed data from 158 critically ill adults (~5,322 hours) across two quaternary health systems (Johns Hopkins Hospital, Baltimore; Beth Israel Deaconess Medical Center, Boston). Validation MAE ranged from 4.276 mmHg [95% CI 4.269, 4.283] (gated recurrent, late fusion) to 4.946 mmHg [95% CI 4.938, 4.956] (attention-based, early fusion), with Pearson r ranging from 0.599 [95% CI 0.599, 0.600] to 0.722 [95% CI 0.722, 0.723]. The multiscale encoder-decoder model demonstrated the most favorable MAE-correlation tradeoff. Conclusion: This is the first demonstration that continuous ICP waveform reconstruction from bedside signals generalizes across institutions at clinically relevant accuracy, establishing a foundation for non-invasive ICP monitoring and motivating validation across broader populations and ICP ranges.","rel_num_authors":4,"rel_authors":[{"author_name":"Ansh Goyal","author_inst":"Johns Hopkins University"},{"author_name":"Veet Zaveri","author_inst":"Johns Hopkins University"},{"author_name":"Carl W Harris","author_inst":"Johns Hopkins University"},{"author_name":"Robert David Stevens","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Multi-domain AD risk burden and plasma biomarkers in cognitively unimpaired adults","rel_doi":"10.64898\/2026.06.11.26355499","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355499","rel_abs":"Introduction: Alzheimer's disease (AD) pathology accumulates decades before symptom onset, yet how the cumulative effect of genetic, familial, and modifiable lifestyle risk burden jointly affects plasma biomarker levels and trajectories in cognitively unimpaired older adults remains unknown. Methods: We analyzed data from 261 participants in the PREVENT-AD cohort. A composite risk score integrating APOE e4 status, polygenic score, family history, and modifiable\/lifestyle risk was examined against six plasma biomarkers using linear regression and linear mixed-effects models. Results: APOE e4 was the strongest predictor of plasma biomarker levels. Higher composite risk burden was associated with elevated ptau181, ptau217, ptau217\/Ab42, and GFAP levels, and lower Ab42\/40 levels. A higher risk burden was predictive of accelerated ptau181 accumulation. Discussion: Cumulative AD risk burden is broadly associated with plasma biomarker levels and specifically predicts accelerated ptau181 accumulation in cognitively unimpaired older adults, supporting structured composite risk profiling as a framework for AD risk stratification.","rel_num_authors":5,"rel_authors":[{"author_name":"Michelle Y Li","author_inst":"University of California, San Francisco"},{"author_name":"Paulina Tolosa-Tort","author_inst":"University of California, San Francisco"},{"author_name":"Margo B Heston","author_inst":"University of California, San Francisco"},{"author_name":"Philip Insel","author_inst":"University of California, San Francisco"},{"author_name":"Shea J Andrews","author_inst":"University of California San Francisco"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Fanconi Anemia as a Window into Premalignant Field Cancerization of the Oral Mucosa","rel_doi":"10.64898\/2026.06.13.26354719","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26354719","rel_abs":"Head and neck squamous cell carcinoma (HNSCC) evolves through stepwise clonal expansion within genetically altered mucosa fields, yet actionable biomarkers remain undefined. Leveraging Fanconi anemia (FA), a cancer predisposition syndrome with extreme HNSCC risk due to defective DNA interstrand crosslink repair, we profiled premalignant changes in the oral cavity using noninvasive brush biopsies. Consistent with our prior demonstration of genomic instability in FA-associated SCCs, we detected pathogenic TP53 variants in 26% and copy number alterations in 60.5% in clinically normal-appearing oral mucosa of individuals with FA. These subclinical clonal expansions define candidate biomarkers of early clonal evolution amenable to serial sampling for risk stratification and prevention studies. Since FA-associated SCCs share genomic features with sporadic HNSCC, these findings may extend to the broader population. We also identify somatic reversion of a pathogenic FANCB variant, providing evidence of genomic self-correction and suggesting a potential avenue for gene-based cancer prevention in FA.","rel_num_authors":24,"rel_authors":[{"author_name":"Tamar Berger","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Frank X. Donovan","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Yu-Chien Lin","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Shivatheja Soma","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Francis May","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Kinjal Bhadresha","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Christine Krieg","author_inst":"Fanconi-Anamie Hilfe e.V, Eschau, Germany"},{"author_name":"Neelam Giri","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Lisa J McReynolds","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Armando Filie","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Zohreh Khavandgar","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Denise M Laronde","author_inst":"University of British Columbia, Vancouver, BC, Canada"},{"author_name":"Martial Guillaud","author_inst":"British Columbia Cancer Research Centre, Vancouver, BC, Canada"},{"author_name":"Sharon A Savage","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"David I. Kutler","author_inst":"Weill Cornell Medical College, New York, NY, USA"},{"author_name":"Wayne Crismani","author_inst":"The University of Melbourne, Parkville, Victoria, Australia"},{"author_name":"Eunike Velleuer","author_inst":"University of Dusseldorf, Germany"},{"author_name":"Rachel Uppgaard","author_inst":"University of Minnesota, Minneapolis, USA"},{"author_name":"Ursula L. Harper","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"K. Olivia Alston","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"James W. Thomas","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Arleen D. Auerbach","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Settara C. Chandrasekharappa","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Agata Smogorzewska","author_inst":"The Rockefeller University, New York, NY, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/Objective: Genitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers. Materials\/Methods: A systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study. Results: Consensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis. Conclusions: The consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/Objective: Genitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers. Materials\/Methods: A systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study. Results: Consensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis. Conclusions: The consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/Objective: Genitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers. Materials\/Methods: A systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study. Results: Consensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis. Conclusions: The consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/Objective: Genitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers. Materials\/Methods: A systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study. Results: Consensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis. Conclusions: The consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/Objective: Genitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers. Materials\/Methods: A systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study. Results: Consensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis. Conclusions: The consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Using wastewater surveillance to explore community-level dietary intake in sewered and non-sewered sanitation systems in Malawi, Africa","rel_doi":"10.64898\/2026.06.07.26354900","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354900","rel_abs":"Wastewater can be used to measure biomarkers that reflect population-level dietary intake and diversity; however, how this approach may apply in a low-income country remains a knowledge gap. This study aims to evaluate whether select dietary-related metabolites can be detected in wastewater and environmental surveillance (WES) samples from both sewered and non-sewered sanitation systems in Malawi, Africa. Fourteen WES samples were collected and analyzed from two university campuses in Mzuzu and Thyolo, Malawi. Four targets were analyzed: N-methyl-2-pyridone-5-carboxamide (2PY; a biomarker of vitamin B3), 4-pyridoxic acid (4-PA; a biomarker of vitamin B6), as well as enterodiol and enterolactone (biomarkers of dietary fiber and polyphenol consumption). An 18-question survey, paired spatiotemporally with the WES measurements, assessed self-reported daily dietary intake, food insecurity, and nutrient deficiency symptoms among 500 respondents. Among the 14 WES samples, 2PY, 4-PA, and enterolactone were detected, while enterodiol was not detected above the method limit (<0.3 mg\/kg). Most respondents (79%; 397\/500) reported consuming foods associated with the 2PY biomarker. Many respondents (62%; 311\/500) also reported consuming foods linked to the 4-PA biomarker. Fewer respondents (36%; 181\/500) reported consuming foods associated with enterodiol or enterolactone, such as whole grains (e.g., millet) and other fiber-rich plant foods (e.g., beans, chickpeas, or pigeon peas). This study demonstrates the potential feasibility of monitoring dietary-related metabolites in both sewered and non-sewered sanitation systems in a low-income country to augment community-level nutrition data. 2PY, 4-PA, and enterolactone were detectable in WES samples, supporting the advancement of this emerging field in nutrition and food security research.","rel_num_authors":10,"rel_authors":[{"author_name":"Rochelle H Holm","author_inst":"University of Louisville"},{"author_name":"Petros Chigwechokha","author_inst":"Malawi University of Science and Technology"},{"author_name":"Chisomo Kaponda","author_inst":"Malawi University of Science and Technology"},{"author_name":"Makayla Stephens","author_inst":"University of Louisville"},{"author_name":"Hannah Limbong","author_inst":"University of Louisville"},{"author_name":"Ayse Ercumen","author_inst":"North Carolina State University"},{"author_name":"Joy Hart","author_inst":"University of Louisville"},{"author_name":"Cassandra  L Workman","author_inst":"University of North Carolina at Greensboro"},{"author_name":"Francis  L. de los Reyes","author_inst":"North Carolina State University"},{"author_name":"Brighton  Austin Chunga","author_inst":"Mzuzu University"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Instrumental Activities of Daily Living in Older Adults with Epilepsy: A Cross-Sectional and Longitudinal Multicenter Study","rel_doi":"10.64898\/2026.06.13.26355582","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355582","rel_abs":"Objective: Instrumental activities of daily living (IADLs) represent a critical but understudied measure of day-to-day function in persons with epilepsy(PWE). In the multicenter Brain Aging and Cognition in Epilepsy (BrACE) study of PWE aged greater than or equal to 55 years, we examined the proportion, clinical correlates, epilepsy-related predictors, and longitudinal trajectory of IADL impairment. Methods: IADLs were assessed using the Functional Activities Questionnaire (FAQ; range=0 to 30; higher=more impaired); a FAQ greater than or equal to 2 defines MCI-level impairment, and a FAQ greater than or equal to 5 defines dementia-level functional impairment. Multivariable logistic regression identified predictors of baseline function. Global cognition (Montreal Cognitive Assessment [MoCA]), individual cognitive measures, and quality of life (QOL) were compared between the impaired and unimpaired groups. Linear regression evaluated predictors of longitudinal functional decline. Results: Of 57 participants (mean age=66.6 years; female=52.6%), 38.6% (n=22) had MCI-level functional impairment and 17.5% (n=10) had dementia-level functional impairment. In univariate analyses, worse FAQ scores were associated with lower education, higher area deprivation index, early-onset epilepsy (EOE less than 60 years), antiseizure medication polytherapy, and epilepsy localization. In multivariable analysis, temporal lobe epilepsy (OR=4.46, 95% CI=1.09, 21.83,p=0.047), EOE(OR=7.14, 95% CI=1.16, 59.97, p=0.046), and lower education(OR=0.70,95% CI=0.49, 0.93, p=0.025) remained independently associated with baseline MCI-level functional-impairment. Lower education (OR=0.55,95% CI=0.29, 0.84, p=0.021) was the only factor associated with dementia-level IADL-impairment. IADL-impaired participants demonstrated lower verbal memory scores (adjusted p=0.041) and MoCA scores (adjusted p<0.001), particularly in the visuospatial\/executive function, attention, and memory subscores, and worse QOL (adjusted p=0.041). IADL impairment was greatest in financially-mediated and memory-dependent tasks. Longitudinally, EOE (beta=7.51,95% CI=1.92, 13.10, p=0.017) and older age(beta=0.38,95% CI=0.12-0.65, p=0.012) predicted greater functional decline. Nearly one-third progressed to significantly worse function over a two-year period, with 15.4% progressing from MCI-level to dementia-level impairment and 15.4% from normal function to MCI-level IADL-impairment. Conclusions: Functional impairment affects ~40% of older PWE, with ~1-in-6 experiencing functional impairment comparable to overt dementias. Temporal lobe localization, EOE, lower education, and poorer cognition are important determinants of baseline functional status. EOE and older age predict accelerated functional decline, suggesting that cumulative disease burden and aging-related processes may drive functional deterioration. These findings provide one of the first epilepsy-specific longitudinal characterizations of IADL impairment and support routine functional assessment in PWE.","rel_num_authors":17,"rel_authors":[{"author_name":"Ifrah Zawar","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Anny Reyes","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Kayela Arrotta","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Bruce P. Hermann","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Robyn M. Busch","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Mark Quigg","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Jaideep Kapur","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Aaron F. Struck","author_inst":"Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"},{"author_name":"Vineet Punia","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Alena Stasenko","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"McKenna E. Williams","author_inst":"Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Katherine J. Bangen","author_inst":"Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Irene Wang","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jerry J. Shih","author_inst":"Department of Neurology, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Lisa Ferguson","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jana E. Jones","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Carrie R. McDonald","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA | Department of Psychiatry, University of Californ"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Instrumental Activities of Daily Living in Older Adults with Epilepsy: A Cross-Sectional and Longitudinal Multicenter Study","rel_doi":"10.64898\/2026.06.13.26355582","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355582","rel_abs":"Objective: Instrumental activities of daily living (IADLs) represent a critical but understudied measure of day-to-day function in persons with epilepsy(PWE). In the multicenter Brain Aging and Cognition in Epilepsy (BrACE) study of PWE aged greater than or equal to 55 years, we examined the proportion, clinical correlates, epilepsy-related predictors, and longitudinal trajectory of IADL impairment. Methods: IADLs were assessed using the Functional Activities Questionnaire (FAQ; range=0 to 30; higher=more impaired); a FAQ greater than or equal to 2 defines MCI-level impairment, and a FAQ greater than or equal to 5 defines dementia-level functional impairment. Multivariable logistic regression identified predictors of baseline function. Global cognition (Montreal Cognitive Assessment [MoCA]), individual cognitive measures, and quality of life (QOL) were compared between the impaired and unimpaired groups. Linear regression evaluated predictors of longitudinal functional decline. Results: Of 57 participants (mean age=66.6 years; female=52.6%), 38.6% (n=22) had MCI-level functional impairment and 17.5% (n=10) had dementia-level functional impairment. In univariate analyses, worse FAQ scores were associated with lower education, higher area deprivation index, early-onset epilepsy (EOE less than 60 years), antiseizure medication polytherapy, and epilepsy localization. In multivariable analysis, temporal lobe epilepsy (OR=4.46, 95% CI=1.09, 21.83,p=0.047), EOE(OR=7.14, 95% CI=1.16, 59.97, p=0.046), and lower education(OR=0.70,95% CI=0.49, 0.93, p=0.025) remained independently associated with baseline MCI-level functional-impairment. Lower education (OR=0.55,95% CI=0.29, 0.84, p=0.021) was the only factor associated with dementia-level IADL-impairment. IADL-impaired participants demonstrated lower verbal memory scores (adjusted p=0.041) and MoCA scores (adjusted p<0.001), particularly in the visuospatial\/executive function, attention, and memory subscores, and worse QOL (adjusted p=0.041). IADL impairment was greatest in financially-mediated and memory-dependent tasks. Longitudinally, EOE (beta=7.51,95% CI=1.92, 13.10, p=0.017) and older age(beta=0.38,95% CI=0.12-0.65, p=0.012) predicted greater functional decline. Nearly one-third progressed to significantly worse function over a two-year period, with 15.4% progressing from MCI-level to dementia-level impairment and 15.4% from normal function to MCI-level IADL-impairment. Conclusions: Functional impairment affects ~40% of older PWE, with ~1-in-6 experiencing functional impairment comparable to overt dementias. Temporal lobe localization, EOE, lower education, and poorer cognition are important determinants of baseline functional status. EOE and older age predict accelerated functional decline, suggesting that cumulative disease burden and aging-related processes may drive functional deterioration. These findings provide one of the first epilepsy-specific longitudinal characterizations of IADL impairment and support routine functional assessment in PWE.","rel_num_authors":17,"rel_authors":[{"author_name":"Ifrah Zawar","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Anny Reyes","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Kayela Arrotta","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Bruce P. Hermann","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Robyn M. Busch","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Mark Quigg","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Jaideep Kapur","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Aaron F. Struck","author_inst":"Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"},{"author_name":"Vineet Punia","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Alena Stasenko","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"McKenna E. Williams","author_inst":"Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Katherine J. Bangen","author_inst":"Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Irene Wang","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jerry J. Shih","author_inst":"Department of Neurology, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Lisa Ferguson","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jana E. Jones","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Carrie R. McDonald","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA | Department of Psychiatry, University of Californ"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Pulmonary extracellular vesicles drive alveolar macrophage dysfunction via microRNA transfer in Acute Respiratory Distress Syndrome","rel_doi":"10.64898\/2026.06.13.26355564","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355564","rel_abs":"Background: Alveolar macrophage (AM) dysfunction contributes to Acute Respiratory Distress Syndrome (ARDS) pathogenesis. We investigated the role of extracellular vesicles (EVs) in mediating this dysfunction. Methods: Pulmonary EVs were isolated from broncho-alveolar lavage and non-directed bronchial lavage samples of ventilated sepsis patients with and without ARDS, and post-operative control patients via ultracentrifugation. AMs were isolated from lung tissue resections of lobectomy patients. AMs were treated with pooled EVs for 24 hours prior to functional, metabolic and autophagy profiling. EV cargo was profiled via small RNA transcriptomics and proteomics. Mechanistic role of EV microRNAs was assessed via mimic \/ antagomir transfection. Results: Pulmonary EVs from sepsis patients with ARDS impaired AM efferocytosis, and control EVs had no effect. ARDS EV treatment enhanced AM mitochondrial-linked respiration, but not glycolysis. ARDS EV treatment impaired LC3B-II and LAMP1 expression, indicating dysregulated AM autophagy-lysosomal machinery. Proteomics revealed downregulation of innate immune pathways in ARDS EVs. Transcriptomics revealed enrichment of 24 microRNAs in ARDS EVs; miR-652-3p was the most enriched, validated by RT-qPCR. EV miR-652-3p was associated with 90-day mortality (9.20 vs 0.59 RQ, p=0.0295) and inversely correlated with oxygenation (PaO2\/FiO2). AM transfection with miR-652-3p mimic induced similar dysregulation of function and autophagy as ARDS EVs. Transfection of ARDS EVs with antagomirs to miR-652-3p prior to AM treatment partially rescued efferocytosis and autophagy. Conclusions: Targeting EV miR-652-3p may restore alveolar macrophage function and reduce excessive inflammation, thus offering a novel therapeutic strategy for patients with ARDS.","rel_num_authors":16,"rel_authors":[{"author_name":"Katie L. Spencer","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Charlie Mafham","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Joshua Price","author_inst":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, U"},{"author_name":"Ellen Jenkins","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Celine H. Chen","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Samuel Quarton","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Louise E. Crowley","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Xiaohong Jiang","author_inst":"Department of Geriatric Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China"},{"author_name":"Jose R. Hombrebueno","author_inst":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, U"},{"author_name":"Michael A. Matthay","author_inst":"Cardiovascular Research Institute, Department of Medicine, and Department of Anaesthesia, University of California San Francisco, San Francisco, California, U.S"},{"author_name":"Mark Lindsay","author_inst":"Department of Life Sciences, University of Bath, Bath, UK"},{"author_name":"Babu Naidu","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"David R Thickett","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Dhruv Parekh","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Aaron Scott","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Rahul Y Mahida","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Based Detection of Airway Mucus Plugs on CT and Associations With Clinical Outcomes in COPDGene","rel_doi":"10.64898\/2026.06.10.26355393","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355393","rel_abs":"RATIONALE: Airway mucus plugging is a clinically relevant manifestation of airway pathology in chronic obstructive pulmonary disease (COPD) and is associated with increased mortality even in early disease; however, visual computed tomography (CT) assessment is subjective and labor intensive. OBJECTIVES: To develop an AI-based quantitative CT method for automated detection of airway mucus plugging and evaluate associations with physiologic impairment and clinical outcomes. METHODS: Inspiratory CT scans from 8,971 COPDGene Phase 1 (GOLD 0-4 and PRISm) participants were analyzed. An AI-based framework combining 3D airway segmentation discontinuities and convolutional neural network classification identified mucus plug obstructions, yielding mucus plug burden (total plug count). Associations with outcomes were evaluated using covariate-adjusted models. MEASUREMENTS AND MAIN RESULTS : Higher mucus plug burden was associated with lower post-bronchodilator FEV % predicted ({rho} = -0.41; P < 0.001), greater air trapping (LAA < -856 HU; {rho} = 0.33; P < 0.001), worse health status (SGRQ; {rho} = 0.31; P < 0.001), and shorter 6-minute walk distance ({rho} = -0.26; P < 0.001). Among GOLD 1-4 participants, mucus plug presence was independently associated with increased all-cause mortality (adjusted hazard ratio, 1.28; P < 0.005) and exacerbation frequency (adjusted incidence rate ratio, 1.32; P < 0.005). Plug presence was also associated with increased respiratory mortality across GOLD categories and cardiovascular mortality in GOLD 1-2. CONCLUSIONS: AI-based quantitative CT assessment of airway mucus plugging provides a scalable, reproducible measure associated with physiologic impairment and adverse outcomes in COPD, supporting its role in risk stratification and future therapeutic studies.","rel_num_authors":11,"rel_authors":[{"author_name":"John Oyer","author_inst":"University of Michigan"},{"author_name":"Ali Namvar","author_inst":"University of Michigan"},{"author_name":"Benjamin A Hoff","author_inst":"University of Michigan"},{"author_name":"Christopher Bosma","author_inst":"University of Michigan"},{"author_name":"Wassim L Labaki","author_inst":"University of Michigan"},{"author_name":"Ella A Kazerooni","author_inst":"University of Michigan"},{"author_name":"Fernando J Martinez","author_inst":"University of Massachusetts, Worcester"},{"author_name":"Charles R Hatt","author_inst":"4D Medical Inc."},{"author_name":"Meilan K Han","author_inst":"University of Michigan"},{"author_name":"Craig J Galban","author_inst":"University of Michigan"},{"author_name":"Sundaresh Ram","author_inst":"Emory University & Georgia Institute of Technology"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Based Detection of Airway Mucus Plugs on CT and Associations With Clinical Outcomes in COPDGene","rel_doi":"10.64898\/2026.06.10.26355393","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355393","rel_abs":"RATIONALE: Airway mucus plugging is a clinically relevant manifestation of airway pathology in chronic obstructive pulmonary disease (COPD) and is associated with increased mortality even in early disease; however, visual computed tomography (CT) assessment is subjective and labor intensive. OBJECTIVES: To develop an AI-based quantitative CT method for automated detection of airway mucus plugging and evaluate associations with physiologic impairment and clinical outcomes. METHODS: Inspiratory CT scans from 8,971 COPDGene Phase 1 (GOLD 0-4 and PRISm) participants were analyzed. An AI-based framework combining 3D airway segmentation discontinuities and convolutional neural network classification identified mucus plug obstructions, yielding mucus plug burden (total plug count). Associations with outcomes were evaluated using covariate-adjusted models. MEASUREMENTS AND MAIN RESULTS : Higher mucus plug burden was associated with lower post-bronchodilator FEV % predicted ({rho} = -0.41; P < 0.001), greater air trapping (LAA < -856 HU; {rho} = 0.33; P < 0.001), worse health status (SGRQ; {rho} = 0.31; P < 0.001), and shorter 6-minute walk distance ({rho} = -0.26; P < 0.001). Among GOLD 1-4 participants, mucus plug presence was independently associated with increased all-cause mortality (adjusted hazard ratio, 1.28; P < 0.005) and exacerbation frequency (adjusted incidence rate ratio, 1.32; P < 0.005). Plug presence was also associated with increased respiratory mortality across GOLD categories and cardiovascular mortality in GOLD 1-2. CONCLUSIONS: AI-based quantitative CT assessment of airway mucus plugging provides a scalable, reproducible measure associated with physiologic impairment and adverse outcomes in COPD, supporting its role in risk stratification and future therapeutic studies.","rel_num_authors":11,"rel_authors":[{"author_name":"John Oyer","author_inst":"University of Michigan"},{"author_name":"Ali Namvar","author_inst":"University of Michigan"},{"author_name":"Benjamin A Hoff","author_inst":"University of Michigan"},{"author_name":"Christopher Bosma","author_inst":"University of Michigan"},{"author_name":"Wassim L Labaki","author_inst":"University of Michigan"},{"author_name":"Ella A Kazerooni","author_inst":"University of Michigan"},{"author_name":"Fernando J Martinez","author_inst":"University of Massachusetts, Worcester"},{"author_name":"Charles R Hatt","author_inst":"4D Medical Inc."},{"author_name":"Meilan K Han","author_inst":"University of Michigan"},{"author_name":"Craig J Galban","author_inst":"University of Michigan"},{"author_name":"Sundaresh Ram","author_inst":"Emory University & Georgia Institute of Technology"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Challenges and opportunities of gap score methods for studying psychopathology resilience and vulnerability","rel_doi":"10.64898\/2026.06.13.26355592","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355592","rel_abs":"Background: The widespread prevalence of psychopathology, which affects approximately 50% of the global population, often manifests during adolescence. Understanding why some individuals remain resilient while others experience mental health challenges despite similar environmental risks is essential for developing early interventions. However, past efforts have faced challenges with the retrospective definition of resilience. Here, we aim to address these challenges by quantifying resilience to psychopathology at the individual level. Methods: In the Adolescent Brain and Cognitive Development (ABCD) Study(R) (N = 11,868), we utilized gradient-boosted tree regression to predict 2-year follow-up psychopathology from 208 Social Determinants of Health features. We used the \"gap score\" method--the difference between model-predicted and reported psychopathology--to quantify individual differences in psychopathology resilience and susceptibility, defined as the Resilience-Susceptibility Gap (RS-Gap). We validated the RS-Gap against independent 3-year follow-up clinical and quality-of-life outcomes. Results: Collinearity between gap scores and reported symptoms was high (r=-0.84), requiring further correction. Four bias-correction techniques were implemented and compared. After appropriate bias-correction, greater RS-Gap scores were associated with a higher likelihood of poor academic and social outcomes one year later, suggesting that early adaptation to adversity may carry a latent long-term cost. Conclusions: Dependency between RS-Gap and psychopathology scores is a statistical challenge for gap score resilience methods. Our comparisons demonstrate that correction is mandatory to separate resilience signal from shared variance with psychopathology scores. Findings converged across different bias correction methods, providing a validated framework for using gap scores to identify high-risk developmental trajectories in youth.","rel_num_authors":7,"rel_authors":[{"author_name":"Hailey Modi","author_inst":"Washington University in St. Louis"},{"author_name":"David AA Baranger","author_inst":"Medical College of Wisconsin"},{"author_name":"Jared V Balbona","author_inst":"Virginia Commonwealth University"},{"author_name":"Samuel Naranjo Rinc\u00f3n","author_inst":"Washington University in St. Louis"},{"author_name":"Aaron John Gorelik","author_inst":"Washington University in St. Louis"},{"author_name":"Ryan Bogdan","author_inst":"Washington University in St. Louis"},{"author_name":"Janine D Bijsterbosch","author_inst":"Washington University in St Louis"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Latent tuberculosis infection workflows in four primary healthcare systems in the United States","rel_doi":"10.64898\/2026.06.12.26355200","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355200","rel_abs":"Background: Latent tuberculosis - infection (LTBI) reactivation accounts for most tuberculosis (TB) cases in the United States (U.S.). Expanding primary care LTBI services can improve detection and treatment, but real-world implementation is not well described. Objective: Describe how LTBI screening and treatment workflows are operationalized into practice in diverse U.S. primary care health systems. Design: Descriptive, multi-site study. Setting: Four U.S. primary care health systems participating in the U.S. Centers for Disease Control and Prevention (CDC) Tuberculosis Epidemiologic Studies Consortium III (TBESC-III, 2020-2022). Patients: Patients visiting any study site (N = 3,522,077). Measurements: Electronic medical record (EMR) data on patient demographics, TB test type, and results. Using narrative reporting and study documentation, LTBI care workflows were summarized by site into six domains: patient registration, TB testing evaluation, TB testing, TB disease assessment, LTBI diagnosis, and LTBI treatment. Results: Sites implemented recommended practices for testing and treatment: interferon-gamma release assays were the predominant test, and short-course rifamycin-based regimens were the primary treatment. Follow-up care practices and documentation of treatment outcomes varied. Country of birth was not consistently recorded at all sites, limiting TB screening capability based on nativity. Physician training, EMR decision-support tools, and patient education resources differed in scope and availability. Limitations: Descriptive design using self-reported workflows; may not generalize to all primary care settings or reflect physician-level variations. Conclusion: We provide a descriptive snapshot showing how LTBI care workflows varied in approach and consistency at four primary care systems with integrated LTBI services. These real-world examples may serve as templates for U.S. primary care systems seeking to expand TB testing and treatment. Primary Funding Source: U.S. Centers for Disease Control and Prevention (TBESC-III).","rel_num_authors":10,"rel_authors":[{"author_name":"Julie Espey","author_inst":"Centers for Disease Control and Prevention, Atlanta"},{"author_name":"Julie Venci","author_inst":"Denver Health and Hospital Authority"},{"author_name":"Paul Y Wada","author_inst":"Kaiser Permanente Northern California, Oakland"},{"author_name":"Yoseph Sorri","author_inst":"Public Health-Seattle and King County, Seattle"},{"author_name":"Amy Tang","author_inst":"North East Medical Services, San Francisco"},{"author_name":"Beatrice Francis","author_inst":"Public Health Institute at Denver Health, Denver"},{"author_name":"Jacek Skarbinski","author_inst":"Kaiser Permanente Northern California, Oakland"},{"author_name":"Masahiro Narita","author_inst":"Public Health-Seattle and King County, Seattle"},{"author_name":"Priya B Shete","author_inst":"University of California San Franciso Medical Center Neurosurgery Clinic"},{"author_name":"Winglee Kathryn","author_inst":"Centers for Disease Control and Prevention, Atlanta"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Bidirectional associations between cannabis use, oddball performance, and P3 event-related potential","rel_doi":"10.64898\/2026.06.09.26355188","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355188","rel_abs":"Importance: Cannabis use remains prevalent in youth despite concerns regarding its potential impact on cognitive function. Unraveling whether the association between cannabis use and cognition is partially due to preexisting differences or primarily related to use is vital to understanding underlying mechanisms. Objective: To estimate the longitudinal association between cannabis initiation and cognitive trajectories, indexed by task performance and P3 event-related potential (ERP), and to estimate whether baseline cognition is associated with cannabis initiation. Design: Data were analyzed from the ongoing longitudinal Collaborative Study on the Genetics of Alcoholism (COGA) cohort, which was followed up approximately every 2-5 years from 2004 to 2025. Setting: 6 sites across the United States. Participants: Adolescent and young adult offspring of past COGA participants and control families who reported on their cannabis use and who had Visual Oddball (VOP) performance and P3 ERP data (N=4814; 52.4% female, 68.4% white) were grouped based on the timing of cognitive data collection relative to cannabis initiation into Pre-onset (n=2,449; [&ge;]1 assessment) and Post-onset (n=998; [&ge;]3 assessments) subsamples. Main Outcomes and Measures: VOP measures include performance accuracy (%), reaction times (ms), and P3 amplitude (V) and latency (ms) during target trials. Cannabis measures included lifetime use of cannabis (i.e., ever used) and age at first use. Results: High P3 amplitude, and prolonged P3 latency and reaction time were associated with a reduced hazard of cannabis initiation (All Hazards Ratio, [H.R.s]< 0.91, p's<.008). Following initiation, cannabis use was associated with steeper declines in P3 amplitude (b=-0.29, p=0.02) and stabilized reaction time (b=0.35; p=0.005). Steeper decline in P3 amplitude (i.e., slope) was associated with greater cannabis progression (e.g., Cannabis Use Disorder, Odds Ratio, [O.R.]=2.34, p<.001), whereas steeper decline in reaction time was associated with reduced progression (O.R.=.79, p=.002). Conclusion: Baseline P3 indices and reaction time were associated with cannabis initiation, while cannabis use was associated with subsequent changes in P3 amplitude and reaction time trajectories. These findings indicate that accelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, may further contribute to neurocognitive changes that deepen cannabis involvement.","rel_num_authors":22,"rel_authors":[{"author_name":"Christina Garasky","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Kellyn Spychala","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Fanghong Dong","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Andrey Anokhin","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Ryan Bogdan","author_inst":"Washington University in St. Louis"},{"author_name":"Grace Chan","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Victor Hesselbrock","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Chella Kamarajan","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sivan Kinreich","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sally Kuo","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jodi Kutzner","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Alex P Miller","author_inst":"Indiana University School of Medicine"},{"author_name":"Ashwini Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Gayathri Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Martin Plawecki","author_inst":"Indiana University School of Medicine"},{"author_name":"Jessica Salvatore","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Marc Schuckit","author_inst":"University of California San Diego Medical School"},{"author_name":"Kathleen Bucholz","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Vivia McCutcheon","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Bernice Porjesz","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Jacquelyn Meyers","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Bidirectional associations between cannabis use, oddball performance, and P3 event-related potential","rel_doi":"10.64898\/2026.06.09.26355188","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355188","rel_abs":"Importance: Cannabis use remains prevalent in youth despite concerns regarding its potential impact on cognitive function. Unraveling whether the association between cannabis use and cognition is partially due to preexisting differences or primarily related to use is vital to understanding underlying mechanisms. Objective: To estimate the longitudinal association between cannabis initiation and cognitive trajectories, indexed by task performance and P3 event-related potential (ERP), and to estimate whether baseline cognition is associated with cannabis initiation. Design: Data were analyzed from the ongoing longitudinal Collaborative Study on the Genetics of Alcoholism (COGA) cohort, which was followed up approximately every 2-5 years from 2004 to 2025. Setting: 6 sites across the United States. Participants: Adolescent and young adult offspring of past COGA participants and control families who reported on their cannabis use and who had Visual Oddball (VOP) performance and P3 ERP data (N=4814; 52.4% female, 68.4% white) were grouped based on the timing of cognitive data collection relative to cannabis initiation into Pre-onset (n=2,449; [&ge;]1 assessment) and Post-onset (n=998; [&ge;]3 assessments) subsamples. Main Outcomes and Measures: VOP measures include performance accuracy (%), reaction times (ms), and P3 amplitude (V) and latency (ms) during target trials. Cannabis measures included lifetime use of cannabis (i.e., ever used) and age at first use. Results: High P3 amplitude, and prolonged P3 latency and reaction time were associated with a reduced hazard of cannabis initiation (All Hazards Ratio, [H.R.s]< 0.91, p's<.008). Following initiation, cannabis use was associated with steeper declines in P3 amplitude (b=-0.29, p=0.02) and stabilized reaction time (b=0.35; p=0.005). Steeper decline in P3 amplitude (i.e., slope) was associated with greater cannabis progression (e.g., Cannabis Use Disorder, Odds Ratio, [O.R.]=2.34, p<.001), whereas steeper decline in reaction time was associated with reduced progression (O.R.=.79, p=.002). Conclusion: Baseline P3 indices and reaction time were associated with cannabis initiation, while cannabis use was associated with subsequent changes in P3 amplitude and reaction time trajectories. These findings indicate that accelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, may further contribute to neurocognitive changes that deepen cannabis involvement.","rel_num_authors":22,"rel_authors":[{"author_name":"Christina Garasky","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Kellyn Spychala","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Fanghong Dong","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Andrey Anokhin","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Ryan Bogdan","author_inst":"Washington University in St. Louis"},{"author_name":"Grace Chan","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Victor Hesselbrock","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Chella Kamarajan","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sivan Kinreich","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sally Kuo","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jodi Kutzner","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Alex P Miller","author_inst":"Indiana University School of Medicine"},{"author_name":"Ashwini Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Gayathri Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Martin Plawecki","author_inst":"Indiana University School of Medicine"},{"author_name":"Jessica Salvatore","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Marc Schuckit","author_inst":"University of California San Diego Medical School"},{"author_name":"Kathleen Bucholz","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Vivia McCutcheon","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Bernice Porjesz","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Jacquelyn Meyers","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Bidirectional associations between cannabis use, oddball performance, and P3 event-related potential","rel_doi":"10.64898\/2026.06.09.26355188","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355188","rel_abs":"Importance: Cannabis use remains prevalent in youth despite concerns regarding its potential impact on cognitive function. Unraveling whether the association between cannabis use and cognition is partially due to preexisting differences or primarily related to use is vital to understanding underlying mechanisms. Objective: To estimate the longitudinal association between cannabis initiation and cognitive trajectories, indexed by task performance and P3 event-related potential (ERP), and to estimate whether baseline cognition is associated with cannabis initiation. Design: Data were analyzed from the ongoing longitudinal Collaborative Study on the Genetics of Alcoholism (COGA) cohort, which was followed up approximately every 2-5 years from 2004 to 2025. Setting: 6 sites across the United States. Participants: Adolescent and young adult offspring of past COGA participants and control families who reported on their cannabis use and who had Visual Oddball (VOP) performance and P3 ERP data (N=4814; 52.4% female, 68.4% white) were grouped based on the timing of cognitive data collection relative to cannabis initiation into Pre-onset (n=2,449; [&ge;]1 assessment) and Post-onset (n=998; [&ge;]3 assessments) subsamples. Main Outcomes and Measures: VOP measures include performance accuracy (%), reaction times (ms), and P3 amplitude (V) and latency (ms) during target trials. Cannabis measures included lifetime use of cannabis (i.e., ever used) and age at first use. Results: High P3 amplitude, and prolonged P3 latency and reaction time were associated with a reduced hazard of cannabis initiation (All Hazards Ratio, [H.R.s]< 0.91, p's<.008). Following initiation, cannabis use was associated with steeper declines in P3 amplitude (b=-0.29, p=0.02) and stabilized reaction time (b=0.35; p=0.005). Steeper decline in P3 amplitude (i.e., slope) was associated with greater cannabis progression (e.g., Cannabis Use Disorder, Odds Ratio, [O.R.]=2.34, p<.001), whereas steeper decline in reaction time was associated with reduced progression (O.R.=.79, p=.002). Conclusion: Baseline P3 indices and reaction time were associated with cannabis initiation, while cannabis use was associated with subsequent changes in P3 amplitude and reaction time trajectories. These findings indicate that accelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, may further contribute to neurocognitive changes that deepen cannabis involvement.","rel_num_authors":22,"rel_authors":[{"author_name":"Christina Garasky","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Kellyn Spychala","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Fanghong Dong","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Andrey Anokhin","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Ryan Bogdan","author_inst":"Washington University in St. Louis"},{"author_name":"Grace Chan","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Victor Hesselbrock","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Chella Kamarajan","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sivan Kinreich","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sally Kuo","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jodi Kutzner","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Alex P Miller","author_inst":"Indiana University School of Medicine"},{"author_name":"Ashwini Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Gayathri Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Martin Plawecki","author_inst":"Indiana University School of Medicine"},{"author_name":"Jessica Salvatore","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Marc Schuckit","author_inst":"University of California San Diego Medical School"},{"author_name":"Kathleen Bucholz","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Vivia McCutcheon","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Bernice Porjesz","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Jacquelyn Meyers","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Bidirectional associations between cannabis use, oddball performance, and P3 event-related potential","rel_doi":"10.64898\/2026.06.09.26355188","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355188","rel_abs":"Importance: Cannabis use remains prevalent in youth despite concerns regarding its potential impact on cognitive function. Unraveling whether the association between cannabis use and cognition is partially due to preexisting differences or primarily related to use is vital to understanding underlying mechanisms. Objective: To estimate the longitudinal association between cannabis initiation and cognitive trajectories, indexed by task performance and P3 event-related potential (ERP), and to estimate whether baseline cognition is associated with cannabis initiation. Design: Data were analyzed from the ongoing longitudinal Collaborative Study on the Genetics of Alcoholism (COGA) cohort, which was followed up approximately every 2-5 years from 2004 to 2025. Setting: 6 sites across the United States. Participants: Adolescent and young adult offspring of past COGA participants and control families who reported on their cannabis use and who had Visual Oddball (VOP) performance and P3 ERP data (N=4814; 52.4% female, 68.4% white) were grouped based on the timing of cognitive data collection relative to cannabis initiation into Pre-onset (n=2,449; [&ge;]1 assessment) and Post-onset (n=998; [&ge;]3 assessments) subsamples. Main Outcomes and Measures: VOP measures include performance accuracy (%), reaction times (ms), and P3 amplitude (V) and latency (ms) during target trials. Cannabis measures included lifetime use of cannabis (i.e., ever used) and age at first use. Results: High P3 amplitude, and prolonged P3 latency and reaction time were associated with a reduced hazard of cannabis initiation (All Hazards Ratio, [H.R.s]< 0.91, p's<.008). Following initiation, cannabis use was associated with steeper declines in P3 amplitude (b=-0.29, p=0.02) and stabilized reaction time (b=0.35; p=0.005). Steeper decline in P3 amplitude (i.e., slope) was associated with greater cannabis progression (e.g., Cannabis Use Disorder, Odds Ratio, [O.R.]=2.34, p<.001), whereas steeper decline in reaction time was associated with reduced progression (O.R.=.79, p=.002). Conclusion: Baseline P3 indices and reaction time were associated with cannabis initiation, while cannabis use was associated with subsequent changes in P3 amplitude and reaction time trajectories. These findings indicate that accelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, may further contribute to neurocognitive changes that deepen cannabis involvement.","rel_num_authors":22,"rel_authors":[{"author_name":"Christina Garasky","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Kellyn Spychala","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Fanghong Dong","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Andrey Anokhin","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Ryan Bogdan","author_inst":"Washington University in St. Louis"},{"author_name":"Grace Chan","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Victor Hesselbrock","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Chella Kamarajan","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sivan Kinreich","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Sally Kuo","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jodi Kutzner","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Alex P Miller","author_inst":"Indiana University School of Medicine"},{"author_name":"Ashwini Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Gayathri Pandey","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Martin Plawecki","author_inst":"Indiana University School of Medicine"},{"author_name":"Jessica Salvatore","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Marc Schuckit","author_inst":"University of California San Diego Medical School"},{"author_name":"Kathleen Bucholz","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Vivia McCutcheon","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Bernice Porjesz","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Jacquelyn Meyers","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Prevalence and Clinical Impact of Pathogenic Variants in Cardiomyopathy Genes Among Individuals with Cardiac Conduction Disorders","rel_doi":"10.64898\/2026.06.13.26355581","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355581","rel_abs":"Importance: Cardiac conduction disorders have traditionally been regarded as a secondary manifestation of underlying structural heart diseases. However, isolated conduction disorders may precede the onset of heart failure (HF) suggesting shared mechanisms. Objective: To evaluate the prevalence and clinical significance of pathogenic\/likely pathogenic (P\/LP) rare variants in cardiomyopathy genes among individuals with conduction disorders. Design, Setting, and Participants: Biobank analysis of 192,834 participants with whole genome sequence data from Vanderbilt's BioVU and 353,092 participants from the All of Us Research Program (AoU). Participants with primary conduction disorder (left bundle branch block [LBBB], right bundle branch block [RBBB], high-grade atrioventricular block [AVB]) were identified after excluding secondary causes. Exposures: P\/LP variants in cardiomyopathy genes. Main Outcomes and Measures: Primary outcome was P\/LP carrier status by age and HF status. Secondary outcomes included incident HF and composite ventricular arrhythmias\/sudden cardiac death\/mortality (VA\/SCD\/mortality). Results: Among 16,959 participants with conduction disorders in BioVU and 13,442 in AoU, 432 (2.6%) and 206 (1.5%) were P\/LP carriers, respectively. Conduction disorder was independently associated with carrier status (BioVU p<0.001; AoU p=0.005). Carrier probability varied by age at conduction disorder onset and HF status. Among participants with HF at age 30 years, predicted carrier probability for LBBB was 7.5% in BioVU and 20.2% in AoU; for high-grade AVB, 7.7% and 8.5%, respectively, compared with 3.7% and 2.9% among those with HF without conduction disorder. P\/LP carrier status among participants with conduction disorders was associated with increased risk of incident HF (BioVU p<0.001; AoU p<0.001) and ventricular arrhythmia\/sudden death\/mortality (BioVU p<0.001; AoU p<0.001). Carriers also demonstrated increased susceptibility to conduction disorder following HF diagnosis, including more than two-fold higher risk of third-degree AVB (BioVU aOR 2.48, 95% CI 1.85-3.32; AoU aOR 2.26, 95% CI 1.35-3.80). Conclusions: Adults with primary conduction disorders have an increased prevalence of P\/LP variants in cardiomyopathy genes, which is most pronounced with diagnoses at early ages of adulthood. Furthermore, there is evidence of an interaction between P\/LP carrier status and conduction disorder to increase HF risk and composite cardiovascular outcomes, underscoring the potential role of genetic evaluation in patients with primary conduction disorders to inform long-term outcomes.","rel_num_authors":14,"rel_authors":[{"author_name":"Temidayo A. Abe","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Favour E. Markson","author_inst":"Jefferson Health-Einstein Hospital"},{"author_name":"Quinn S. Wells","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Megan C. Lancaster","author_inst":"The Ohio State University"},{"author_name":"William G. Stevenson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Benjamin M. Shoemaker","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Luke Laws","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Majd A. El-Harasis","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Harikrishna Tandri","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Travis D. Richardson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jay A. Montgomery","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Arvindh N. Kanagasundram","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Dan M. Roden","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Giovanni E. Davogustto","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Quality Improvement Based Implementation and Evaluation of a Decision Aid for Patients with Nephrolithiasis","rel_doi":"10.64898\/2026.06.12.26355535","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355535","rel_abs":"Introduction Patients with nephrolithiasis face challenges in making a high-quality, preference sensitive decision. Our prior work established feasibility and patient acceptance of a software-based decision aid (DA). The objectives for this study were to identify implementation strategies for the DA in routine care and determine whether DA implementation enhances decisional quality for patients. Methods New nephrolithiasis patients were recruited from the institution Medical Center from June 2018 to April 2024 to receive a software-based pre-visit DA that measured care preferences and used decision analysis to rank treatments. The RE-AIM framework and Plan-Do-Study-Act (PDSA) cycles were used to improve implementation outcomes. Patients completed survey instruments evaluating decisional conflict, shared decision-making, care satisfaction, and treatment choice following their provider visit. These metrics were compared in the DA cohort (n=81) to those in a usual care cohort (n=78) with Wilcoxon rank-sum and Chi-square (or Fishers exact) tests. Results Implementation data revealed sustained reach and progressive improvement in fidelity. The DA cohort reported higher decisional quality relative to controls (p=0.003) and reported greater support\/advice to make a choice (p=0.005). The DA cohort more often discussed options with their doctor (87.5% vs 69.2%, p=0.005) and were more likely to be promoters of their provider (p<0.001) and health system (p=0.029). The DA cohort was less likely to have switched their treatment preference post-consultation (32.1% vs 71.8%, p<0.001) suggesting greater consistency in decision-making. Conclusions Software-based DAs in nephrolithiasis can mitigate decisional conflict, improve SDM, and improve patient satisfaction. Further work should explore broader implementation and long-term clinical outcomes.","rel_num_authors":12,"rel_authors":[{"author_name":"Austin Lee","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Saam Kazemi","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Patrick Wilson","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Karan Thaker","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Lorna Kwan","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"John Cabri","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Kevin Li","author_inst":"Department of Urology, UCSF School of Medicine, University of California San Francisco, San Francisco, CA, United States."},{"author_name":"Matthew Dunn","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Alan Yaghoubian","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Fuad Elkhoury","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Kymora Scotland","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."},{"author_name":"Christopher Saigal","author_inst":"Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States."}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"A controlled human infection model for symptomatic pertussis in North America using the pertactin-producing clinical isolate D420","rel_doi":"10.64898\/2026.06.09.26355227","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355227","rel_abs":"Background Despite widespread vaccination, pertussis remains a poorly controlled disease globally and results in substantial annual morbidity and mortality, particularly in young children. Controlled human infection models (CHIMs) using the causative agent Bordetella pertussis are promising systems to enable the study of pertussis disease pathogenesis and immunology and to rapidly assess vaccines and therapeutics. While a pertussis CHIM that produces asymptomatic infection has been established in Europe, the development of a CHIM that leads to symptomatic illness would be advantageous for evaluating vaccine efficacy against both infection and disease. Methods Healthy participants 18-40 years of age were inoculated intranasally with one of eight doses (ranging from 104 to 108 colony forming units (CFU)) of the pertactin-producing B. pertussis isolate D420 at the challenge facility within the Canadian Center for Vaccinology (Nova Scotia, Canada). The study occurred in two stages. In stage one, the B. pertussis dose was escalated in cohort groups of five to six participants until reaching an endpoint where 70-90% of participants exhibited mild (non-severe, Grade 1 or 2) symptomatic infection, defined as the Human Infectious Dose 70-90 (HID70-90). In stage two, additional challenges were conducted for doses below, at, and above the identified HID70-90 to characterize the emerging pertussis model. For all challenge doses, participants were closely monitored during an inpatient stay of up to 24 days and post-discharge for laboratory-confirmed infection, pertussis symptoms, safety, and IgG antibody responses to four B. pertussis antigens including pertussis toxin, filamentous hemagglutinin, fimbriae, and pertactin. All participants received a five-day course of azithromycin, where timing of initiation depended on B. pertussis testing and symptoms. The study was conducted between July 4, 2022 and March 19, 2025. Findings Seventy-five participants were inoculated with one of the eight B. pertussis D420 challenge doses and completed the inpatient stay. From the stage-one dose escalation, we found that 107 CFU of B. pertussis D420 was the lowest dose that achieved the HID70-90, where 9 of 12 participants (75.0%) exhibited mild symptomatic infection. Following stage-two challenges, 16 of 22 total participants at 107 CFU (72.7%) developed mild symptomatic infection, thus verifying the HID70-90. The symptomatic infection rate below the HID70-90 at 5x106 CFU of D420 was 20.0% and above the HID70-90 at 5x107 and 108 CFU were 58.3% and 55.6%, respectively. Symptoms with elevated frequency for symptomatic infection (relative to background symptoms in non-infected) included nasal congestion, runny nose, fatigue, malaise, and cough. At the HID70-90, 50% of symptomatic infections included cough. Serological analyses of the four highest (stage-two) challenge doses (5x106, 107, 5x107, 108 CFU) revealed that antibody titres increased over time post-challenge. Seroconversion for at least one of the four studied antibodies was nearly twice as common for symptomatic (70.0%) than asymptomatic (35.7%) infection and was absent (0%) for non-infected. All infections were cleared following azithromycin treatment (100%) and there were no study-related serious adverse events. Interpretation A safe and reproducible symptomatic pertussis CHIM was achieved, providing a model for research on pertussis disease pathogenesis and immunology and for assessing vaccines and therapeutics. (Clinicaltrials.gov, NCT05136599).","rel_num_authors":20,"rel_authors":[{"author_name":"May S ElSherif","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Kara L Redden","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Joanne M Langley","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Lingyun Ye","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Wade Blanchard","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Bruce Smith","author_inst":"Department of Mathematics and Statistics, Dalhousie University, Halifax, Nova Scotia, Canada"},{"author_name":"Jun Wang","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Bahaa Abu-Raya","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Jillian H Filliter","author_inst":"Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada"},{"author_name":"Kathryn M Edwards","author_inst":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"C Buddy Creech","author_inst":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Shelly McNeil","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Todd F Hatchette","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Jason J LeBlanc","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Susan Hariri","author_inst":"Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"},{"author_name":"Lucia Pawloski","author_inst":"Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"},{"author_name":"Panagiotis Maniatis","author_inst":"Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"},{"author_name":"LeAnne M Fox","author_inst":"Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"},{"author_name":"Carrie A Whittle","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"},{"author_name":"Scott A Halperin","author_inst":"Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Midwifery Practice in Conflict Contexts: Lived Experiences from Somalia and Nigeria","rel_doi":"10.64898\/2026.06.07.26355130","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26355130","rel_abs":"Background: Midwives are a central cadre in the health system, particularly in conflict-affected settings where they are sometimes the primary or even only skilled providers available. Yet, despite their critical role, there is limited qualitative evidence capturing their lived experiences and how these shape workforce entry, retention, and overall well-being. Methods: Drawing on a phenomenological research methodology, this qualitative study was embedded within a larger prospective longitudinal cohort of midwifery students and graduates in Somalia and Nigeria. We conducted focus group discussions with graduate midwives (n=48 in Nigeria; n=63 in Somalia) to explore their experiences transitioning into the workforce and their realities working in health systems impacted by conflict and violent insecurity. Data were analysed using inductive thematic analysis. Results: Five themes emerged from the data: (1) job search and workforce entry, which was described as fraught with challenges and shaped by a set of formal systems in Nigeria but informal networks and structural barriers in Somalia (2) working conditions that were marked by resource scarcity, infrastructural challenges, and heavy and unreasonable workloads, (3) safety, security and coping strategies that differed across the two contexts but reflected persistent exposure to violence and a reliance on ad hoc and personal coping in lieu of systematic protection, (4) community perceptions of midwives, shaped and constrained by social and gender norms and (5) mental health and emotional wellbeing, highlighting stress, burnout and moral injury experienced by this cadre. Conclusion: Our findings highlight the profound challenges faced by midwives working in conflict-affected settings, and they shine a light on the urgent need to support and invest in this critical and predominantly female health workforce.","rel_num_authors":13,"rel_authors":[{"author_name":"Shatha Elnakib","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Emilia Ngozi Iwu","author_inst":"Institute of Human Virology"},{"author_name":"Asia Mohammed","author_inst":"Somali Research & Development Institute"},{"author_name":"Hawa Abdullahi Mohammed","author_inst":"Somali Research & Development Institute"},{"author_name":"Meighan Mary","author_inst":"JHU: Johns Hopkins University"},{"author_name":"Hannah Tappis","author_inst":"Johns Hopkins University"},{"author_name":"Maina Charity","author_inst":"Institute of Human Virology"},{"author_name":"Abimiku Rejoice Helma","author_inst":"Institute of Human Virology"},{"author_name":"Sussan Israel-Isah","author_inst":"Institute of Human Virology"},{"author_name":"Ayodeji Kazeem Olalekan","author_inst":"Institute of Human Virology"},{"author_name":"George Odonye","author_inst":"Institute of Human Virology"},{"author_name":"Maryan Ahmed","author_inst":"Somali Research & Development Institute"},{"author_name":"Salomine Ekambi","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Modelling the public-health impact of indoor air quality interventions on respiratory virus transmission","rel_doi":"10.64898\/2026.06.06.26355067","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26355067","rel_abs":"Respiratory virus transmission occurs in indoor settings where ventilation, occupancy, and dwell time determine exposure levels. Improving indoor air quality (IAQ) therefore could help reduce disease burden associated with respiratory viruses, yet its population-level impact remains poorly quantified. Here, we develop an individual-based transmission modelling framework that links within-location airborne dynamics to individual infection risk and population-level spread, whilst explicitly incorporating heterogeneity in ventilation and baseline indoor air quality across locations. We use this modelling approach to evaluate IAQ-improving interventions (air-quality interventions or AQIs), using hypothetical endemic and pandemic pathogen archetypes with properties similar to SARS-CoV-2 and influenza, and evaluate how effects on key epidemiological metrics (such as annualized incidence and epidemic final size) depend on AQI coverage, efficacy and allocation strategy. At 20% AQI intervention coverage and 80% efficacy, annualized incidence was reduced by approximately 7.2% for an endemic 'SARS-CoV-2-like' respiratory virus, and 17.0% for an endemic 'influenza-like' virus; at 60% coverage (80% efficacy) the reductions were 26.3% and 56.4%, respectively. Targeting AQI installation to the highest-risk locations outperformed random allocation: for SARS-CoV-2-like transmission, 20% coverage at 80% efficacy cut absolute incidence by 10.8% when targeted versus 7.2% when random; for influenza-like transmission, this comparison was 28.9% versus 17.0%. In epidemic scenarios, random installation at 40% coverage and 60% efficacy reduced final size by 23.7% (influenza-like) versus 6.3% (SARS-CoV-2-like). These results support treating clean indoor air as core public-health infrastructure and prioritising risk-based deployment of IAQ-improving interventions to maximise population-level benefit within budgetary and operational constraints.","rel_num_authors":14,"rel_authors":[{"author_name":"Adam Howes","author_inst":"Independent"},{"author_name":"Geetha Jeyapragasan","author_inst":"Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, USA; Computational Precision Health, Uni"},{"author_name":"Richard Williamson","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"David Carel","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"Harrison Koos","author_inst":"Department of Health Policy, Stanford University, Stanford, California, USA"},{"author_name":"Jacob L. Swett","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"James Montavon","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"Vivian Belenky","author_inst":"Center for Radiological Research, Columbia University Irving Medical Center, New York, NY, USA"},{"author_name":"Paul Lietar","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Richard Fitzjohn","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Giovanni Charles","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Serina Chang","author_inst":"Computational Precision Health, University of California, Berkeley and University of California, San Francisco, Berkeley, CA, USA; Electrical Engineering and Co"},{"author_name":"Thomas Brewer","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Charles Whittaker","author_inst":"Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, USA; Computational Precision Health, Uni"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Modelling the public-health impact of indoor air quality interventions on respiratory virus transmission","rel_doi":"10.64898\/2026.06.06.26355067","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26355067","rel_abs":"Respiratory virus transmission occurs in indoor settings where ventilation, occupancy, and dwell time determine exposure levels. Improving indoor air quality (IAQ) therefore could help reduce disease burden associated with respiratory viruses, yet its population-level impact remains poorly quantified. Here, we develop an individual-based transmission modelling framework that links within-location airborne dynamics to individual infection risk and population-level spread, whilst explicitly incorporating heterogeneity in ventilation and baseline indoor air quality across locations. We use this modelling approach to evaluate IAQ-improving interventions (air-quality interventions or AQIs), using hypothetical endemic and pandemic pathogen archetypes with properties similar to SARS-CoV-2 and influenza, and evaluate how effects on key epidemiological metrics (such as annualized incidence and epidemic final size) depend on AQI coverage, efficacy and allocation strategy. At 20% AQI intervention coverage and 80% efficacy, annualized incidence was reduced by approximately 7.2% for an endemic 'SARS-CoV-2-like' respiratory virus, and 17.0% for an endemic 'influenza-like' virus; at 60% coverage (80% efficacy) the reductions were 26.3% and 56.4%, respectively. Targeting AQI installation to the highest-risk locations outperformed random allocation: for SARS-CoV-2-like transmission, 20% coverage at 80% efficacy cut absolute incidence by 10.8% when targeted versus 7.2% when random; for influenza-like transmission, this comparison was 28.9% versus 17.0%. In epidemic scenarios, random installation at 40% coverage and 60% efficacy reduced final size by 23.7% (influenza-like) versus 6.3% (SARS-CoV-2-like). These results support treating clean indoor air as core public-health infrastructure and prioritising risk-based deployment of IAQ-improving interventions to maximise population-level benefit within budgetary and operational constraints.","rel_num_authors":14,"rel_authors":[{"author_name":"Adam Howes","author_inst":"Independent"},{"author_name":"Geetha Jeyapragasan","author_inst":"Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, USA; Computational Precision Health, Uni"},{"author_name":"Richard Williamson","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"David Carel","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"Harrison Koos","author_inst":"Department of Health Policy, Stanford University, Stanford, California, USA"},{"author_name":"Jacob L. Swett","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"James Montavon","author_inst":"Blueprint Biosecurity, Washington, DC, USA"},{"author_name":"Vivian Belenky","author_inst":"Center for Radiological Research, Columbia University Irving Medical Center, New York, NY, USA"},{"author_name":"Paul Lietar","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Richard Fitzjohn","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Giovanni Charles","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Serina Chang","author_inst":"Computational Precision Health, University of California, Berkeley and University of California, San Francisco, Berkeley, CA, USA; Electrical Engineering and Co"},{"author_name":"Thomas Brewer","author_inst":"MRC Centre for Global Infectious Disease Analysis, Imperial College London, UK"},{"author_name":"Charles Whittaker","author_inst":"Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, USA; Computational Precision Health, Uni"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Quantitative insights into the role of phages and plasmids in the persistence of nontuberculous mycobacteria in chloraminated drinking water","rel_doi":"10.64898\/2026.06.11.26355408","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355408","rel_abs":"Nontuberculous mycobacteria (NTM) are opportunistic pathogens that persist in chloraminated drinking water systems, yet the roles of phages and plasmids in their persistence remain largely unexplored. Using genome-resolved and quantitative metagenomics, we characterized NTM, phages, prophages, and plasmids in a chloraminated building plumbing system. Bacterial metagenome-assembled genomes (MAGs) and viral operational taxonomic units (vOTUs) were quantified at mean concentrations of 8.41 * 10^7 and 8.00 * 10^8 copies\/L, respectively, including seven NTM MAGs at a mean total concentration of 4.01 * 10^5 copies\/L. NTM concentrations were highest at the site with the lowest bacterial and viral diversity. Predicted NTM-infecting virus concentrations were inversely related to NTM concentrations across sites, suggesting complex phage-host dynamics that warrant direct experimental investigation. NTM, putative phages, prophages, and plasmids encoded functions related to disinfectant tolerance, stress response, metal resistance, and secretion. These findings identify phage interactions, prophages, and plasmids as overlooked genomic and ecological dimensions of NTM persistence in engineered water systems.","rel_num_authors":10,"rel_authors":[{"author_name":"Soojung Lee","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Kathryn Langenfeld","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Sarah Potgieter","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Sadia Marjia Ferdous","author_inst":"Case Western Reserve University"},{"author_name":"Shruti Vasagiri","author_inst":"Case Western Reserve University"},{"author_name":"G. Eric Bastien","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Melissa Duhaime","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Krista Wigginton","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Lutgarde Raskin","author_inst":"University of Michigan - Ann Arbor"},{"author_name":"Bridget Hegarty","author_inst":"Case Western Reserve University"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Recruitment, Retention Approaches and Community Engagement in the THRIVE pilot Trial: Lessons Learned from a Food is Medicine Trial","rel_doi":"10.64898\/2026.06.12.26355557","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355557","rel_abs":"Background: Recruitment of underrepresented populations, including Black and Hispanic populations, for Food is Medicine (FIM) and cardiovascular trials, may pose significant challenges. Methods: We implemented a multi-component recruitment approach for the THRIVE (AdapTive personalized dietitian coacHing and messaging with pRoduce prescrIptions to improVE healthy dietary behaviors) pilot trial to engage primarily Black and Hispanic adults in a Food is Medicine for hypertension intervention. The recruitment approaches included community engagement at approximately 40 community events (cultural festivals and neighborhood gatherings); partnerships with 8 community and faith-based service hubs and food distribution sites; recruitment through safety net primary care clinics, digital outreach via the study website, and social media campaigns; and direct recruitment at places of worship. We report lessons learned from the community engagement process, recruitment efficiency, representativeness, and retention outcomes. Results: Within 6 months, the enrollment target was exceeded by 40%, with an accrual index of 1.04. Over 1,000 individuals were reached through the direct-to-community engagement process, while faith-based partnerships engaged about 900 adults. There were 2,673 visits to the study webpage, and social media achieved 12,259 impressions with 399 clicks. About 95% of participants resided within 10 miles of the faith-based recruitment sites. Face-to-face engagement at the food distribution sites within faith-based organizations or community service hubs outperformed digital methods. Faith leader endorsements and follow-up in-person meetings (following unsuccessful email outreach) dramatically increased recruitment. Regarding retention, pre-randomization attrition was 6%, and 82% of participants completed the study. Conclusion: Culturally tailored, community-engaged recruitment grounded in faith-based and local community partnerships, was highly effective in engaging Black and Hispanic populations in this FIM cardiovascular trial. This provides a replicable model for implementing equitable and sustainable cardiovascular health interventions.","rel_num_authors":24,"rel_authors":[{"author_name":"Mojisola Olusola-Bello","author_inst":"Johns Hopkins University"},{"author_name":"Elohor Oborevwori","author_inst":"Johns Hopkins University School of Nursing"},{"author_name":"Khadijat Adeleye","author_inst":"University of Massachusetts Amherst - School of Nursing"},{"author_name":"Irma Irma Iribe","author_inst":"Johns Hopkins University"},{"author_name":"Adeline Assani-Uva","author_inst":"Holycross Engineering College"},{"author_name":"D?Janee Kyeremeh","author_inst":"Johns Hopkins University"},{"author_name":"Oluwatosin Tomiwa","author_inst":"Johns Hopkins University"},{"author_name":"Janice Adukwei Dugbartey","author_inst":"Johns Hopkins University"},{"author_name":"Maricielo Saldarriaga Noel","author_inst":"Johns Hopkins University"},{"author_name":"India E. Washington","author_inst":"Johns Hopkins University"},{"author_name":"Samuel Gledhill","author_inst":"Johns Hopkins University"},{"author_name":"Chelsea Akubo","author_inst":"Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Siddharth Dhadi","author_inst":"Johns Hopkins University Zanvyl Krieger School of Arts and Sciences"},{"author_name":"Mary Alawode","author_inst":"Johns Hopkins University Carey Business School"},{"author_name":"Jennifer Freeman","author_inst":"Community FarmShare"},{"author_name":"Kendra Smith","author_inst":"Kingdom Cares,  Kingdom Fellowship AME Church"},{"author_name":"Rose Bernard","author_inst":"Bread of Life Bible Church"},{"author_name":"Marie Antoinette Davis","author_inst":"Harvest Intercontinental Church"},{"author_name":"Channa Wilson","author_inst":"Harvest Intercontinental Church"},{"author_name":"Anna Maria Izquierdo Porerra","author_inst":"Tidal Health"},{"author_name":"Lisa A. Cooper","author_inst":"Johns Hopkins University"},{"author_name":"Cheryl R. Dennison Himmelfarb","author_inst":"Johns Hopkins University"},{"author_name":"Yvonne Commodore-Mensah","author_inst":"Johns Hopkins University School of Nursing"},{"author_name":"Oluwabunmi Ogungbe","author_inst":"John Hopkins School of Nursing"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Reaching out-of-school girls with HPV vaccination: A qualitative evaluation in six low- and middle-income countries using the RE-AIM framework","rel_doi":"10.64898\/2026.06.11.26355432","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355432","rel_abs":"Background  Infection with human papillomavirus (HPV), the primary cause of cervical cancer, disproportionately affects women in low- and middle-income countries (LMICs). While school-based vaccination of adolescent girls against HPV is highly effective, this strategy systematically excludes out-of-school (OOS) girls. Using the RE-AIM framework, we explored strategies to reach OOS girls with HPV vaccination across six African and Asian LMICs.   Methods  We conducted semi-structured key informant interviews with 32 vaccination program stakeholders from Cambodia, Cameroon, Kenya, Malawi, Mozambique, and Uganda between May and September 2024. Interviews explored countries implementation successes, challenges, and strategies to reach OOS girls with HPV vaccination and sustainability considerations. Data were analyzed using a hybrid team-based thematic analysis approach guided by the RE-AIM framework.   Results  Community outreach-based strategies, typically integrated into routine immunization outreach, were identified as the most effective approach to reach OOS girls with HPV vaccination. Targeted strategies, such as locating outreach clinics in community venues frequented by OOS girls (e.g., churches, markets) enhanced implementation. Perceived effectiveness of these strategies varied across participants, and formal assessment of effectiveness was constrained by the absence of disaggregated vaccination coverage data by school enrollment status. Some subpopulations of OOS girls (i.e., girls in nomadic or migrant communities, urban OOS girls) were not readily reached through standard outreach approaches, prompting implementation of adapted and tailored strategies for these subpopulations. Costs associated with conducting outreach in harder-to-reach areas were major barriers to reaching OOS girls, presenting challenges to the sustainability and cost-effectiveness of these approaches. Conclusions  Routine community outreach platforms were widely perceived as most effective for reaching OOS girls. Strengthening disaggregated monitoring systems, adapting outreach for harder-to-reach subpopulations of OOS girls, and financing delivery models for tailored outreach strategies will be critical to improving equitable HPV vaccine coverage among OOS girls.","rel_num_authors":7,"rel_authors":[{"author_name":"Leanne Zhang","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Erica Rosser","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Megan  D Wysong","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Pamela  J Surkan","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Joseph  G Rosen","author_inst":"Brown University School of Public Health"},{"author_name":"Rupali  J Limaye","author_inst":"George Mason University"},{"author_name":"Soim Park","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Reaching out-of-school girls with HPV vaccination: A qualitative evaluation in six low- and middle-income countries using the RE-AIM framework","rel_doi":"10.64898\/2026.06.11.26355432","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355432","rel_abs":"Background  Infection with human papillomavirus (HPV), the primary cause of cervical cancer, disproportionately affects women in low- and middle-income countries (LMICs). While school-based vaccination of adolescent girls against HPV is highly effective, this strategy systematically excludes out-of-school (OOS) girls. Using the RE-AIM framework, we explored strategies to reach OOS girls with HPV vaccination across six African and Asian LMICs.   Methods  We conducted semi-structured key informant interviews with 32 vaccination program stakeholders from Cambodia, Cameroon, Kenya, Malawi, Mozambique, and Uganda between May and September 2024. Interviews explored countries implementation successes, challenges, and strategies to reach OOS girls with HPV vaccination and sustainability considerations. Data were analyzed using a hybrid team-based thematic analysis approach guided by the RE-AIM framework.   Results  Community outreach-based strategies, typically integrated into routine immunization outreach, were identified as the most effective approach to reach OOS girls with HPV vaccination. Targeted strategies, such as locating outreach clinics in community venues frequented by OOS girls (e.g., churches, markets) enhanced implementation. Perceived effectiveness of these strategies varied across participants, and formal assessment of effectiveness was constrained by the absence of disaggregated vaccination coverage data by school enrollment status. Some subpopulations of OOS girls (i.e., girls in nomadic or migrant communities, urban OOS girls) were not readily reached through standard outreach approaches, prompting implementation of adapted and tailored strategies for these subpopulations. Costs associated with conducting outreach in harder-to-reach areas were major barriers to reaching OOS girls, presenting challenges to the sustainability and cost-effectiveness of these approaches. Conclusions  Routine community outreach platforms were widely perceived as most effective for reaching OOS girls. Strengthening disaggregated monitoring systems, adapting outreach for harder-to-reach subpopulations of OOS girls, and financing delivery models for tailored outreach strategies will be critical to improving equitable HPV vaccine coverage among OOS girls.","rel_num_authors":7,"rel_authors":[{"author_name":"Leanne Zhang","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Erica Rosser","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Megan  D Wysong","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Pamela  J Surkan","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Joseph  G Rosen","author_inst":"Brown University School of Public Health"},{"author_name":"Rupali  J Limaye","author_inst":"George Mason University"},{"author_name":"Soim Park","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Association of Genetic Liability to Psychiatric Disorders with Peripheral Metabolic Dysregulation","rel_doi":"10.64898\/2026.06.06.26354927","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26354927","rel_abs":"Importance: Individuals with psychiatric disorders face elevated cardiometabolic risk which is linked to increased mortality. The extent to which this reflects shared pathogenesis or the downstream effects of illness and treatment remains poorly understood. Objective: To characterize the direct pleiotropic effects of psychiatric genetic liability on circulating metabolites and aggregate cardiometabolic risk, independent of psychiatric diagnosis and psychotropic medication use. Design: Cohort study. Setting: Mass General Brigham Biobank (MGBB). Participants: MGBB participants with metabolomic profiling, genomic data, and linked electronic health records. Exposures: Genetic liability to nine psychiatric disorders quantified using polygenic risk scores (PRS): attention deficit\/hyperactivity disorder (ADHD), anorexia nervosa (ANO), anxiety disorder (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), PTSD, schizophrenia (SCZ), and substance use disorder (SUD). Main Outcomes and Measures: 249 circulating metabolites and four metabolomic risk scores (MRS) for type 2 diabetes, myocardial infarction, ischemic stroke, and vascular dementia. PRS-metabolite associations were estimated using nested models adjusting for lifetime psychiatric diagnosis and psychotropic medication use. Results: Across 25,290 participants, we identified 604 significant PRS-metabolite associations (Bonferroni p< 1.36 x 10-4), of which 89% persisted after adjustment for lifetime diagnosis and medication use, suggesting that the direct genetic effects on metabolism are largely independent of illness or treatment. PRS for MDD, PTSD, and ADHD showed the most extensive dysregulation, with a transdiagnostic pattern of elevated lipids and systemic inflammation, specifically triglycerides ({beta} = 0.04 to 0.05, all p< 4.4 x10-13) and glycoprotein acetyls ({beta} = 0.05, all p< 2.2 x10-16). Notably, PRS for SCZ and BD showed minimal metabolite dysregulation despite having the strongest association with their target diagnoses. PRS for MDD, PTSD, ADHD, and SUD were associated with increased MRS across cardiometabolic conditions ({beta} = 0.03 to 0.08, all p< 2.1 x10-4). Sensitivity analyses controlling for BMI or excluding participants without any psychiatric history (N: 21,305 and 11,150, respectively) showed a similar pattern. Conclusions and Relevance: Psychiatric genetic liability is associated with systemic metabolic dysregulation independent of illness onset or treatment, supporting a partially pleiotropic basis for psychiatric-cardiometabolic comorbidity.","rel_num_authors":11,"rel_authors":[{"author_name":"Juan F De la Hoz","author_inst":"Massachusetts General Hospital"},{"author_name":"Younga Heather Lee","author_inst":"Massachusetts General Hospital"},{"author_name":"Justin D Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"William Meyerson","author_inst":"Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA"},{"author_name":"Mihael Cudic","author_inst":"Massachuetts General Hospital"},{"author_name":"Devon Watts","author_inst":"Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA"},{"author_name":"Yen-Chen Anne Feng","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan"},{"author_name":"Yulu Chen","author_inst":"Channing Division of Network Medicine, Brigham and Womens Hospital, Boston, MA"},{"author_name":"Jessica A. Lasky-Su","author_inst":"Brigham and Women's Hospital"},{"author_name":"Tian Ge","author_inst":"Psychiatric and Neurodevelopment Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA"},{"author_name":"Jordan W Smoller","author_inst":"Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"The clinical utility of functional testing in fibroblasts to diagnose primary mitochondrial disease","rel_doi":"10.64898\/2026.06.12.26355546","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355546","rel_abs":"Genome sequencing of the heterogeneous primary mitochondrial disorders (PMD) frequently reveals variants of uncertain significance that require functional tests for diagnosis, and does not identify variants in all patients. We analyzed mitochondrial enzyme assays, blue native polyacrylamide gel electrophoresis (BN-PAGE) with in-gel activity staining, complex I assembly blot, and select protein abundances in fibroblasts of a case series of 204 PMD patients divided into functional classes, in comparison to 51 controls and 53 differential diagnostic conditions. Overall, sensitivity and specificity for respiratory chain enzyme assays were 46% and 93% respectively, for BN-PAGE 40% and 98%, for complex I assembly assay 49% and 99%. The overall sensitivity of all tests was 76%, specificity 93%, with positive predictive value 96% and negative predictive value 67%. Categories with high sensitivity were isolated complex deficiencies, nuclear DNA-encoded mitochondrial protein synthesis defects, co-factor defects, and mitochondrial amino-acyl-tRNA synthetase conditions when aided by protein abundance. Mitochondrial DNA mutations and maintenance disorders showed poor sensitivities. Secondary dysfunctions were rare. A complete battery of functional tests showed strong diagnostic clinical utility in fibroblasts.","rel_num_authors":46,"rel_authors":[{"author_name":"Johan L.K. Van Hove","author_inst":"University of Colorado"},{"author_name":"Marisa W Friederich","author_inst":"University of Colorado"},{"author_name":"Roxanne A Van Hove","author_inst":"University of Colorado"},{"author_name":"Jessica C. Lee","author_inst":"University of Colorado"},{"author_name":"Kaz M Knight","author_inst":"University of Colorado"},{"author_name":"Tonia E Donovan","author_inst":"Children's Hospital Colorado"},{"author_name":"Lori Silveira","author_inst":"University of Colorado"},{"author_name":"Rebecca Ganetzky","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Michio Hirano","author_inst":"Columbia University Medical Center"},{"author_name":"Jose E Abdenur","author_inst":"CHOC Children's Division of Metabolic Disorders"},{"author_name":"Merlin G Butler","author_inst":"University of Kansas"},{"author_name":"David Cassiman","author_inst":"University of Leuven"},{"author_name":"Bruce H Cohen","author_inst":"Akron Children's Hospital"},{"author_name":"Sarah H Elsea","author_inst":"Baylor College of Medicine"},{"author_name":"Gregory M. Enns","author_inst":"Stanford"},{"author_name":"William A Gahl","author_inst":"National Human Genome Research Institute"},{"author_name":"Ralitza Gavrilova","author_inst":"Mayo Clinic"},{"author_name":"Gabriella C Geddes","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma E Glamuzima","author_inst":"Starship Children's Hospital"},{"author_name":"Amy C Goldstein","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Richard H Haas","author_inst":"University of California at San Diego"},{"author_name":"Aneal Khan","author_inst":"MAGIC Clinic"},{"author_name":"Kimberly A Kripps","author_inst":"Oregon Health & Science University"},{"author_name":"Austin Larson","author_inst":"Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA"},{"author_name":"April N Lehman","author_inst":"Nationwide Children's Hospital"},{"author_name":"Uta Lichter-Konecki","author_inst":"University of Pittsburg"},{"author_name":"Johannes A Mayr","author_inst":"Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria"},{"author_name":"Eva Morava","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"James T Peterson","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Jill A Rosenfeld","author_inst":"Baylor College of Medicine"},{"author_name":"Russel P Saneto","author_inst":"Seattle Children's Hospital"},{"author_name":"Fernando Scaglia","author_inst":"Baylor College of Medicine"},{"author_name":"Emily Shelkowitz","author_inst":"University of Washington"},{"author_name":"Mariella T Simon","author_inst":"University of California"},{"author_name":"Jo\u00e9l EG Smet","author_inst":"Ghent University"},{"author_name":"Wendy E Smith","author_inst":"Maine Medical Center"},{"author_name":"Claudia Soler-Alfonso","author_inst":"Baylor College of Medicine"},{"author_name":"Mark A. Tarnopolsky","author_inst":"McMaster University"},{"author_name":"Rudy N.A. Van Coster","author_inst":"Ghent University"},{"author_name":"Arnaud V Vanlander","author_inst":"Ghent University"},{"author_name":"Pieter Vermeersch","author_inst":"University Hospitals Leuven"},{"author_name":"Gerard Vockley","author_inst":"University of Pittsburgh"},{"author_name":"Kristen Wigby","author_inst":"University of California at San Diego"},{"author_name":"Lynne Wolfe","author_inst":"National Institutes of Health"},{"author_name":"Saskia Brigitte Wortmann","author_inst":"Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU)"},{"author_name":"Jennifer H Yang","author_inst":"University of California San Diego"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"The clinical utility of functional testing in fibroblasts to diagnose primary mitochondrial disease","rel_doi":"10.64898\/2026.06.12.26355546","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355546","rel_abs":"Genome sequencing of the heterogeneous primary mitochondrial disorders (PMD) frequently reveals variants of uncertain significance that require functional tests for diagnosis, and does not identify variants in all patients. We analyzed mitochondrial enzyme assays, blue native polyacrylamide gel electrophoresis (BN-PAGE) with in-gel activity staining, complex I assembly blot, and select protein abundances in fibroblasts of a case series of 204 PMD patients divided into functional classes, in comparison to 51 controls and 53 differential diagnostic conditions. Overall, sensitivity and specificity for respiratory chain enzyme assays were 46% and 93% respectively, for BN-PAGE 40% and 98%, for complex I assembly assay 49% and 99%. The overall sensitivity of all tests was 76%, specificity 93%, with positive predictive value 96% and negative predictive value 67%. Categories with high sensitivity were isolated complex deficiencies, nuclear DNA-encoded mitochondrial protein synthesis defects, co-factor defects, and mitochondrial amino-acyl-tRNA synthetase conditions when aided by protein abundance. Mitochondrial DNA mutations and maintenance disorders showed poor sensitivities. Secondary dysfunctions were rare. A complete battery of functional tests showed strong diagnostic clinical utility in fibroblasts.","rel_num_authors":46,"rel_authors":[{"author_name":"Johan L.K. Van Hove","author_inst":"University of Colorado"},{"author_name":"Marisa W Friederich","author_inst":"University of Colorado"},{"author_name":"Roxanne A Van Hove","author_inst":"University of Colorado"},{"author_name":"Jessica C. Lee","author_inst":"University of Colorado"},{"author_name":"Kaz M Knight","author_inst":"University of Colorado"},{"author_name":"Tonia E Donovan","author_inst":"Children's Hospital Colorado"},{"author_name":"Lori Silveira","author_inst":"University of Colorado"},{"author_name":"Rebecca Ganetzky","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Michio Hirano","author_inst":"Columbia University Medical Center"},{"author_name":"Jose E Abdenur","author_inst":"CHOC Children's Division of Metabolic Disorders"},{"author_name":"Merlin G Butler","author_inst":"University of Kansas"},{"author_name":"David Cassiman","author_inst":"University of Leuven"},{"author_name":"Bruce H Cohen","author_inst":"Akron Children's Hospital"},{"author_name":"Sarah H Elsea","author_inst":"Baylor College of Medicine"},{"author_name":"Gregory M. Enns","author_inst":"Stanford"},{"author_name":"William A Gahl","author_inst":"National Human Genome Research Institute"},{"author_name":"Ralitza Gavrilova","author_inst":"Mayo Clinic"},{"author_name":"Gabriella C Geddes","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma E Glamuzima","author_inst":"Starship Children's Hospital"},{"author_name":"Amy C Goldstein","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Richard H Haas","author_inst":"University of California at San Diego"},{"author_name":"Aneal Khan","author_inst":"MAGIC Clinic"},{"author_name":"Kimberly A Kripps","author_inst":"Oregon Health & Science University"},{"author_name":"Austin Larson","author_inst":"Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA"},{"author_name":"April N Lehman","author_inst":"Nationwide Children's Hospital"},{"author_name":"Uta Lichter-Konecki","author_inst":"University of Pittsburg"},{"author_name":"Johannes A Mayr","author_inst":"Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria"},{"author_name":"Eva Morava","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"James T Peterson","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Jill A Rosenfeld","author_inst":"Baylor College of Medicine"},{"author_name":"Russel P Saneto","author_inst":"Seattle Children's Hospital"},{"author_name":"Fernando Scaglia","author_inst":"Baylor College of Medicine"},{"author_name":"Emily Shelkowitz","author_inst":"University of Washington"},{"author_name":"Mariella T Simon","author_inst":"University of California"},{"author_name":"Jo\u00e9l EG Smet","author_inst":"Ghent University"},{"author_name":"Wendy E Smith","author_inst":"Maine Medical Center"},{"author_name":"Claudia Soler-Alfonso","author_inst":"Baylor College of Medicine"},{"author_name":"Mark A. Tarnopolsky","author_inst":"McMaster University"},{"author_name":"Rudy N.A. Van Coster","author_inst":"Ghent University"},{"author_name":"Arnaud V Vanlander","author_inst":"Ghent University"},{"author_name":"Pieter Vermeersch","author_inst":"University Hospitals Leuven"},{"author_name":"Gerard Vockley","author_inst":"University of Pittsburgh"},{"author_name":"Kristen Wigby","author_inst":"University of California at San Diego"},{"author_name":"Lynne Wolfe","author_inst":"National Institutes of Health"},{"author_name":"Saskia Brigitte Wortmann","author_inst":"Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU)"},{"author_name":"Jennifer H Yang","author_inst":"University of California San Diego"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"The clinical utility of functional testing in fibroblasts to diagnose primary mitochondrial disease","rel_doi":"10.64898\/2026.06.12.26355546","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355546","rel_abs":"Genome sequencing of the heterogeneous primary mitochondrial disorders (PMD) frequently reveals variants of uncertain significance that require functional tests for diagnosis, and does not identify variants in all patients. We analyzed mitochondrial enzyme assays, blue native polyacrylamide gel electrophoresis (BN-PAGE) with in-gel activity staining, complex I assembly blot, and select protein abundances in fibroblasts of a case series of 204 PMD patients divided into functional classes, in comparison to 51 controls and 53 differential diagnostic conditions. Overall, sensitivity and specificity for respiratory chain enzyme assays were 46% and 93% respectively, for BN-PAGE 40% and 98%, for complex I assembly assay 49% and 99%. The overall sensitivity of all tests was 76%, specificity 93%, with positive predictive value 96% and negative predictive value 67%. Categories with high sensitivity were isolated complex deficiencies, nuclear DNA-encoded mitochondrial protein synthesis defects, co-factor defects, and mitochondrial amino-acyl-tRNA synthetase conditions when aided by protein abundance. Mitochondrial DNA mutations and maintenance disorders showed poor sensitivities. Secondary dysfunctions were rare. A complete battery of functional tests showed strong diagnostic clinical utility in fibroblasts.","rel_num_authors":46,"rel_authors":[{"author_name":"Johan L.K. Van Hove","author_inst":"University of Colorado"},{"author_name":"Marisa W Friederich","author_inst":"University of Colorado"},{"author_name":"Roxanne A Van Hove","author_inst":"University of Colorado"},{"author_name":"Jessica C. Lee","author_inst":"University of Colorado"},{"author_name":"Kaz M Knight","author_inst":"University of Colorado"},{"author_name":"Tonia E Donovan","author_inst":"Children's Hospital Colorado"},{"author_name":"Lori Silveira","author_inst":"University of Colorado"},{"author_name":"Rebecca Ganetzky","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Michio Hirano","author_inst":"Columbia University Medical Center"},{"author_name":"Jose E Abdenur","author_inst":"CHOC Children's Division of Metabolic Disorders"},{"author_name":"Merlin G Butler","author_inst":"University of Kansas"},{"author_name":"David Cassiman","author_inst":"University of Leuven"},{"author_name":"Bruce H Cohen","author_inst":"Akron Children's Hospital"},{"author_name":"Sarah H Elsea","author_inst":"Baylor College of Medicine"},{"author_name":"Gregory M. Enns","author_inst":"Stanford"},{"author_name":"William A Gahl","author_inst":"National Human Genome Research Institute"},{"author_name":"Ralitza Gavrilova","author_inst":"Mayo Clinic"},{"author_name":"Gabriella C Geddes","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma E Glamuzima","author_inst":"Starship Children's Hospital"},{"author_name":"Amy C Goldstein","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Richard H Haas","author_inst":"University of California at San Diego"},{"author_name":"Aneal Khan","author_inst":"MAGIC Clinic"},{"author_name":"Kimberly A Kripps","author_inst":"Oregon Health & Science University"},{"author_name":"Austin Larson","author_inst":"Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA"},{"author_name":"April N Lehman","author_inst":"Nationwide Children's Hospital"},{"author_name":"Uta Lichter-Konecki","author_inst":"University of Pittsburg"},{"author_name":"Johannes A Mayr","author_inst":"Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria"},{"author_name":"Eva Morava","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"James T Peterson","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Jill A Rosenfeld","author_inst":"Baylor College of Medicine"},{"author_name":"Russel P Saneto","author_inst":"Seattle Children's Hospital"},{"author_name":"Fernando Scaglia","author_inst":"Baylor College of Medicine"},{"author_name":"Emily Shelkowitz","author_inst":"University of Washington"},{"author_name":"Mariella T Simon","author_inst":"University of California"},{"author_name":"Jo\u00e9l EG Smet","author_inst":"Ghent University"},{"author_name":"Wendy E Smith","author_inst":"Maine Medical Center"},{"author_name":"Claudia Soler-Alfonso","author_inst":"Baylor College of Medicine"},{"author_name":"Mark A. Tarnopolsky","author_inst":"McMaster University"},{"author_name":"Rudy N.A. Van Coster","author_inst":"Ghent University"},{"author_name":"Arnaud V Vanlander","author_inst":"Ghent University"},{"author_name":"Pieter Vermeersch","author_inst":"University Hospitals Leuven"},{"author_name":"Gerard Vockley","author_inst":"University of Pittsburgh"},{"author_name":"Kristen Wigby","author_inst":"University of California at San Diego"},{"author_name":"Lynne Wolfe","author_inst":"National Institutes of Health"},{"author_name":"Saskia Brigitte Wortmann","author_inst":"Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU)"},{"author_name":"Jennifer H Yang","author_inst":"University of California San Diego"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"The clinical utility of functional testing in fibroblasts to diagnose primary mitochondrial disease","rel_doi":"10.64898\/2026.06.12.26355546","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355546","rel_abs":"Genome sequencing of the heterogeneous primary mitochondrial disorders (PMD) frequently reveals variants of uncertain significance that require functional tests for diagnosis, and does not identify variants in all patients. We analyzed mitochondrial enzyme assays, blue native polyacrylamide gel electrophoresis (BN-PAGE) with in-gel activity staining, complex I assembly blot, and select protein abundances in fibroblasts of a case series of 204 PMD patients divided into functional classes, in comparison to 51 controls and 53 differential diagnostic conditions. Overall, sensitivity and specificity for respiratory chain enzyme assays were 46% and 93% respectively, for BN-PAGE 40% and 98%, for complex I assembly assay 49% and 99%. The overall sensitivity of all tests was 76%, specificity 93%, with positive predictive value 96% and negative predictive value 67%. Categories with high sensitivity were isolated complex deficiencies, nuclear DNA-encoded mitochondrial protein synthesis defects, co-factor defects, and mitochondrial amino-acyl-tRNA synthetase conditions when aided by protein abundance. Mitochondrial DNA mutations and maintenance disorders showed poor sensitivities. Secondary dysfunctions were rare. A complete battery of functional tests showed strong diagnostic clinical utility in fibroblasts.","rel_num_authors":46,"rel_authors":[{"author_name":"Johan L.K. Van Hove","author_inst":"University of Colorado"},{"author_name":"Marisa W Friederich","author_inst":"University of Colorado"},{"author_name":"Roxanne A Van Hove","author_inst":"University of Colorado"},{"author_name":"Jessica C. Lee","author_inst":"University of Colorado"},{"author_name":"Kaz M Knight","author_inst":"University of Colorado"},{"author_name":"Tonia E Donovan","author_inst":"Children's Hospital Colorado"},{"author_name":"Lori Silveira","author_inst":"University of Colorado"},{"author_name":"Rebecca Ganetzky","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Michio Hirano","author_inst":"Columbia University Medical Center"},{"author_name":"Jose E Abdenur","author_inst":"CHOC Children's Division of Metabolic Disorders"},{"author_name":"Merlin G Butler","author_inst":"University of Kansas"},{"author_name":"David Cassiman","author_inst":"University of Leuven"},{"author_name":"Bruce H Cohen","author_inst":"Akron Children's Hospital"},{"author_name":"Sarah H Elsea","author_inst":"Baylor College of Medicine"},{"author_name":"Gregory M. Enns","author_inst":"Stanford"},{"author_name":"William A Gahl","author_inst":"National Human Genome Research Institute"},{"author_name":"Ralitza Gavrilova","author_inst":"Mayo Clinic"},{"author_name":"Gabriella C Geddes","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma E Glamuzima","author_inst":"Starship Children's Hospital"},{"author_name":"Amy C Goldstein","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Richard H Haas","author_inst":"University of California at San Diego"},{"author_name":"Aneal Khan","author_inst":"MAGIC Clinic"},{"author_name":"Kimberly A Kripps","author_inst":"Oregon Health & Science University"},{"author_name":"Austin Larson","author_inst":"Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA"},{"author_name":"April N Lehman","author_inst":"Nationwide Children's Hospital"},{"author_name":"Uta Lichter-Konecki","author_inst":"University of Pittsburg"},{"author_name":"Johannes A Mayr","author_inst":"Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria"},{"author_name":"Eva Morava","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"James T Peterson","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Jill A Rosenfeld","author_inst":"Baylor College of Medicine"},{"author_name":"Russel P Saneto","author_inst":"Seattle Children's Hospital"},{"author_name":"Fernando Scaglia","author_inst":"Baylor College of Medicine"},{"author_name":"Emily Shelkowitz","author_inst":"University of Washington"},{"author_name":"Mariella T Simon","author_inst":"University of California"},{"author_name":"Jo\u00e9l EG Smet","author_inst":"Ghent University"},{"author_name":"Wendy E Smith","author_inst":"Maine Medical Center"},{"author_name":"Claudia Soler-Alfonso","author_inst":"Baylor College of Medicine"},{"author_name":"Mark A. Tarnopolsky","author_inst":"McMaster University"},{"author_name":"Rudy N.A. Van Coster","author_inst":"Ghent University"},{"author_name":"Arnaud V Vanlander","author_inst":"Ghent University"},{"author_name":"Pieter Vermeersch","author_inst":"University Hospitals Leuven"},{"author_name":"Gerard Vockley","author_inst":"University of Pittsburgh"},{"author_name":"Kristen Wigby","author_inst":"University of California at San Diego"},{"author_name":"Lynne Wolfe","author_inst":"National Institutes of Health"},{"author_name":"Saskia Brigitte Wortmann","author_inst":"Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU)"},{"author_name":"Jennifer H Yang","author_inst":"University of California San Diego"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Biological meaning in protein embedding space is resolution-dependent","rel_doi":"10.64898\/2026.06.12.730559","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.730559","rel_abs":"Protein language model embeddings are increasingly used to organise biological sequences, yet how biological meaning is encoded within embedding neighbourhoods remains poorly understood. Using two independent hierarchical enzyme systems, carbohydrate-active enzymes and peptidases, we investigated how biological interpretation changes across embedding organisations aligned to different levels of biological hierarchy. Different embedding organisations give rise to distinct neighbourhood semantics. When aligned to membership-boundary resolution, embeddings robustly separated artefacts and unrelated proteins from members of the target category. However, embeddings aligned to functional-grouping resolution maintained compositional neighbourhood structure for multi-domain proteins spanning more than one functional or catalytic group. Finally, embeddings aligned to local-family resolution recovered compact family-like neighbourhoods, including families withheld from training, while weakening broader membership-boundary and functional-grouping relationships. Moreover, embeddings optimised toward the same level of biological organisation retain different biological relationships depending on optimisation trajectory employed. Together, our results show that proximity in protein embedding space has no fixed biological interpretation. Instead, biological meaning emerges across embedding resolutions through selective preservation of different forms of biological organisation.","rel_num_authors":5,"rel_authors":[{"author_name":"Licheng Zong","author_inst":"European Bioinformatics Institute; University of Bath; The Chinese University of Hong Kong"},{"author_name":"Jinzheng Ren","author_inst":"European Bioinformatics Institute; University of Bath; Australian National University"},{"author_name":"Yu Li","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Robert D. Finn","author_inst":"European Bioinformatics Institute"},{"author_name":"Jiawei Wang","author_inst":"European Bioinformatics Institute; University of Bath"}],"rel_date":"2026-06-15","rel_site":"biorxiv"},{"rel_title":"Parallel evolution of chimeric genes in microbial evolution experiments","rel_doi":"10.64898\/2026.06.14.732165","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732165","rel_abs":"Recombination can generate new or improved proteins by merging pieces of pre-existing genes into a new whole. Here, when we reanalyzed genomic data from several laboratory evolution experiments with Escherichia coli, evidence for the convergent evolution of chimeric genes became apparent. In these experiments, a pair of paralogous genes were recombined into a single hybrid copy by large genomic deletions. In one case, the excision of a cryptic e14 prophage occurred in 6 out of 8 replicates of a 22-day fluoroquinolone-resistance evolution experiment. These parallel prophage excisions recombined an icd isocitrate dehydrogenase gene with a homologous icdC C-terminal fragment pseudogene. In the other case, convergent 23 kB deletions recombined cpsG paralogs across replicate populations of the Lenski long-term evolution experiment with Escherichia coli (LTEE), generating a chimeric phosphomannomutase. Together, these results indicate that chimeric genes evolve rapidly in bacteria and are more common than previously believed, because they are easily missed by standard genomic analyses. Experiments are needed to determine whether these chimeric proteins are adaptive, are by-products of adaptive genomic deletions, or both.","rel_num_authors":2,"rel_authors":[{"author_name":"Rohan Maddamsetti","author_inst":"Rutgers University"},{"author_name":"Mehmet Orman","author_inst":"University of Wisconsin"}],"rel_date":"2026-06-15","rel_site":"biorxiv"},{"rel_title":"A pleiotropic EPAS1 enhancer mediating Tibetan adaptation to hypoxia is active in adipocytes","rel_doi":"10.64898\/2026.06.11.730447","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.730447","rel_abs":"In response to hypoxic stress at high altitudes, variation at the EPAS1 locus has experienced strong selection in Tibetans. Functional dissection of the selection signals at this locus identified ENH5, an enhancer within the adaptive haplotype that has a blunted response to hypoxic stress in Tibetans. ENH5 was shown to be pleiotropic in several tissues related to hypoxia response, suggesting that a possible mechanism behind the strong selection signatures could be adaptive pleiotropy. Tibetans not only experience hypoxic conditions, but also cold temperatures due to the altitude and climate of the Tibetan Plateau. However, it is unclear whether cold temperatures affect ENH5 activity possibly contributing to the selective pressure at this locus. Here, we further characterized the role of ENH5 in subcutaneous white adipose tissue, an important tissue type that regulates body temperature in response to cold temperatures by releasing stored fat as heat through a process called thermogenesis. In this work, we investigated the role of ENH5 in adipocytes using ENH5 knockout mice (ENH5 KO), which phenocopy the reduced activity of the Tibetan allele. We show that ENH5 KO mice at normoxia and room temperature do not have significant differences in organismal phenotypes related to adiposity and metabolism compared to WT mice on a high fat diet. However, we detected effects of ENH5 conditional on thermogenic stimulation and hypoxia exposure, independently, in adipocytes cultured in vitro. Under either of these conditions, ENH5 KO has stronger differential expression of key genes involved in thermogenesis activity and adipocyte differentiation compared to WT. This differential response to thermogenic stimulation expands on the pleiotropic effects of the Tibetan ENH5 allele(s), in addition to those previously shown in well-established hypoxia-responsive tissues. Our results raise the possibility that pleiotropic effects of ENH5 may implicate unforeseen mechanisms, such as cellular energetics and thermogenesis, possibly contributing to the phenotypic adaptation to high altitude in Tibetans.","rel_num_authors":14,"rel_authors":[{"author_name":"Alexis G Thornburg","author_inst":"University of Chicago"},{"author_name":"Soo-Young Park","author_inst":"University of Chicago"},{"author_name":"Li Zhang","author_inst":"University of Chicago"},{"author_name":"Ivy Aneas","author_inst":"University of Chicago"},{"author_name":"D\u00e9bora R Sobreira","author_inst":"University of California, Los Angeles"},{"author_name":"Isabella M Salamone","author_inst":"University of Chicago"},{"author_name":"Noboru J Sakabe","author_inst":"University of Chicago"},{"author_name":"Kathryn M Farris","author_inst":"University of Chicago"},{"author_name":"Zachary T Weber","author_inst":"University of Chicago"},{"author_name":"Olivia A Gray","author_inst":"University of Chicago"},{"author_name":"Jennifer Yoo","author_inst":"University of Chicago"},{"author_name":"Hae Kyung Im","author_inst":"University of Chicago"},{"author_name":"Anna Di Rienzo","author_inst":"University of Chicago"},{"author_name":"Marcelo A N\u00f3brega","author_inst":"University of Chicago"}],"rel_date":"2026-06-15","rel_site":"biorxiv"},{"rel_title":"RepGene: Toward a Unified Gene Representation Space Robust to Missing Biological Views","rel_doi":"10.64898\/2026.06.11.731512","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731512","rel_abs":"Genes can be described through multiple heterogeneous biological views, including genomic sequence, transcript sequence, protein sequence, textual knowledge, and single-cell expression context, yet existing gene embeddings remain largely modality-specific and difficult to compare or reuse when many views are unavailable. We study a narrower but practically important question: whether pretrained embeddings from these distinct sources can be organized into a shared gene representation interface that remains usable under severe missing-modality conditions. To investigate this question, we introduce RepGene, a lightweight single-branch framework that combines modality adapters, a shared encoder, presence-aware fusion, and self-supervised cross-view objectives to map five biological views into one latent space. Our goal is not to claim a new multimodal learning principle or to establish superiority over all simpler fusion strategies, but to provide an initial technical instantiation for testing whether such a shared interface is feasible in a fixed-feature setting. Under a two-stage protocol in which RepGene is trained self-supervised on frozen upstream embeddings and evaluated by downstream linear probing, we find preliminary evidence that the learned representation is broadly competitive in the full-modality setting and remains informative when only partial modality subsets are observed at inference time. The strongest signal in our study is robustness under missing views: average performance changes are often limited when one modality is removed, and even single-view inference remains non-trivial in the evaluated benchmark regime.These results do not resolve unified biological representation learning, and they should be interpreted in light of incomplete simple-fusion baselines, limited architectural ablation, benchmark dependence, and possible upstream feature exposure. We therefore position RepGene as a feasibility study and a starting point for stronger comparisons, broader benchmarks, and leakage-aware validation.","rel_num_authors":8,"rel_authors":[{"author_name":"Haiyang Hou","author_inst":"School of Artificial Intelligence, University of Chinese Academy of Sciences"},{"author_name":"Tianyi Xia","author_inst":"BGI-Research, Beijing"},{"author_name":"Luni Hu","author_inst":"BGI Research, Beijing"},{"author_name":"Hua Qin","author_inst":"BGI Research, Beijing"},{"author_name":"Yong Zhang","author_inst":"BGI Research, Wuhan"},{"author_name":"Yuxiang Li","author_inst":"BGI Research, Wuhan"},{"author_name":"Shuangsang Fang","author_inst":"BGI Research, Beijing"},{"author_name":"Lei Cao","author_inst":"BGI Research, Beijing"}],"rel_date":"2026-06-15","rel_site":"biorxiv"},{"rel_title":"An ancient receptor family illuminates the evolution of animal sensation","rel_doi":"10.64898\/2026.06.15.732144","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732144","rel_abs":"Animals use nervous systems to sense and respond to their environment. Yet single-celled organisms can also detect cues to execute diverse behaviors, suggesting that core components for animal sensation predate multicellularity and nervous systems. Here, we report that choanoflagellates, the closest living animal relatives, use an ancient sensory receptor family to detect bacterial prey. These receptors are related to transient receptor potential ion channels but are distinguished by WD40 domains, defining TRPW. TRPW1 detects specific bacterial lipids to modulate flagellar beating, providing a mechanism for attraction towards prey. TRPW emerged in early eukaryotes and reveals ancestral architectural and lig-and-binding features that predate animal somatosensory receptors. In multicellular choanoflagellates, TRPW1 elicits collective responses, linking bacterial ecology to the evolution of receptors, sensory orga-nelles, and multicellular life.","rel_num_authors":12,"rel_authors":[{"author_name":"Maxwell C. Coyle","author_inst":"Harvard University"},{"author_name":"John K. Nunnally","author_inst":"Columbia University"},{"author_name":"Yeun-Hyeok Shin","author_inst":"Harvard Medical School"},{"author_name":"Yury A. Trofimov","author_inst":"Research Institute for Systems Biology and Medicine"},{"author_name":"Irina I. Veretenenko","author_inst":"Research Institute for Systems Biology and Medicine"},{"author_name":"Jack Thibodeau","author_inst":"Harvard University"},{"author_name":"Irina A. Talyzina","author_inst":"Columbia University"},{"author_name":"Riya Sivakumar","author_inst":"Harvard University"},{"author_name":"Roman G. Efremov","author_inst":"Research Institute for Systems Biology and Medicine"},{"author_name":"Jon Clardy","author_inst":"Harvard Medical School"},{"author_name":"Alexander I. Sobolevsky","author_inst":"Columbia University"},{"author_name":"Nicholas W. Bellono","author_inst":"Harvard University"}],"rel_date":"2026-06-15","rel_site":"biorxiv"},{"rel_title":"Scout-based Multi-Echo NAvigator (SMENA) for high temporal resolution motion and B0 estimation and correction: applications to multi-echo GRE and EPTI","rel_doi":"10.64898\/2026.06.10.731422","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731422","rel_abs":"Purpose: To develop a data-driven technique, Scout-based Multi-Echo NAvigator (SMENA), for joint estimation of motion and B0 inhomogeneity ({delta}B0) at a temporal resolution of ~200 ms with minimal additional scan time for gradient-echo acquisition. Methods: SMENA consists of two key acquisition components: SMENA-scout and SMENA-nav. SMENA-scout is a rapid 3D 4-mm multi-echo acquisition completed in less than 8 seconds, providing images with matched contrast and phase at multiple echo times. SMENA-nav captures signal variations induced by motion and {delta}B0 during the scan using compact multi-echo navigator trajectories (3.5 ms) embedded within each TR. Motion and {delta}B0 maps were jointly estimated every ~200 ms through a model-based optimization framework relating SMENA-scout to SMENA-nav. The estimation accuracy and correction performance of SMENA were evaluated in simulations and in vivo using multi-echo GRE and GRE-EPTI acquisitions. Multiple prospective motion experiments, including large continuous movement and deep breathing, were investigated. Results: In both simulations and in vivo experiments, accurate motion and {delta}B0 estimation were achieved. Compared with motion-only estimation, joint estimation reduced rotation and translation errors. Joint motion and {delta}B0 correction resulted in substantial improvements in image quality, particularly at longer echo times, producing an NRMSE of 10.4% compared to 31.6% with motion-only correction. High-temporal-resolution tracking of motion and {delta}B0 enabled improved reconstruction quality in scenarios involving continuous motion and deep breathing. Conclusion: SMENA enables high-temporal-resolution joint estimation of motion and {delta}B0 with minimal additional acquisition cost, providing a practical solution for motion- and {delta}B0-robust MRI.","rel_num_authors":9,"rel_authors":[{"author_name":"Nan Wang","author_inst":"Stanford University"},{"author_name":"Yimeng Lin","author_inst":"Department of Radiology, Stanford University, Stanford, CA, United States"},{"author_name":"Yannick Brackenier","author_inst":"King's College London"},{"author_name":"Aizada Nurdinova","author_inst":"Department of Radiology, Stanford University"},{"author_name":"Zihan Zhou","author_inst":"Department of Radiology, Stanford University"},{"author_name":"Daniel Abraham","author_inst":"Department of Electrical Engineering, Stanford University"},{"author_name":"Xiaozhi Cao","author_inst":"Department of Radiology, Stanford University"},{"author_name":"Congyu Liao","author_inst":"Department of Radiology, University of California, San Francisco"},{"author_name":"Kawin Setsompop","author_inst":"Department of Radiology, Stanford University"}],"rel_date":"2026-06-15","rel_site":"biorxiv"},{"rel_title":"SMS: Symmetric Mediation Statistics for Powerful High-Dimensional Mediation Analysis","rel_doi":"10.64898\/2026.06.10.730748","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.730748","rel_abs":"Background: Mediation analysis of high-dimensional features, particularly molecular-level omics features, provides important opportunities to uncover biological mechanisms underlying human health and disease. However, two central statistical challenges remain: testing the composite-null hypothesis and maintaining power when the exposure-mediator and mediator-outcome associations differ substantially in statistical significance. Existing methods typically rely on accurate estimation of the proportions of the three null types or on the maximum of the two association p-values, and may not always control the FDR well and may have limited power under imbalanced significance. Methods: We propose SMS, a new statistical framework based on symmetric mediation statistics. By exploiting symmetry, SMS calibrates the composite null distribution as a whole for FDR control. It also allows flexible combinations of the two association p-values, including the maximum, and then enables construction of an omnibus test. Moreover, it permits direct use of effect-size estimates, bypassing the need to compute p-values. Results: SMS controlled the FDR across a wide range of simulation scenarios while achieving a substantial sensitivity gain, often around 20 percentage points, over existing methods including HDMT, DACT, and DEI-B. Applications to a metabolomics dataset and a DNA methylation dataset further corroborated these findings. Notably, SMS discovered five plausible mediators in the metabolomics dataset that were missed by all existing methods considered.","rel_num_authors":4,"rel_authors":[{"author_name":"Yi Wang","author_inst":"Peking University"},{"author_name":"Shiyu Yan","author_inst":"Peking University"},{"author_name":"Hai-Jun Wang","author_inst":"Peking University"},{"author_name":"Yi-Juan Hu","author_inst":"Peking University"}],"rel_date":"2026-06-15","rel_site":"biorxiv"},{"rel_title":"SMLMFlow: Improving Structural Resolution in Single Molecule Localization Microscopy with Flow Matching","rel_doi":"10.64898\/2026.06.11.731424","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731424","rel_abs":"While Single Molecule Localization Microscopy (SMLM) aims to generate precise coordinates of molecular targets in cells, the resulting point clouds are inherently blurred by additive noise sources across the experimental, imaging, and processing workflow. This blurring often limits SMLM's ability to accurately quantify complex assembled structures required to address biological issues, despite reported localization precision down to a couple of nanometers. Here, we present SMLMFlow, a machine learning framework for improving structural resolution in SMLM datasets that combines a graph neural network and a hierarchical transformer with flow matching. We show that SMLMFlow improves structural resolution and downstream quantification across different structures, including filaments and protein nano-clusters, and generalizes to new unseen photophysics models.","rel_num_authors":7,"rel_authors":[{"author_name":"Sebastian Bauer","author_inst":"Stockholm University, Science of Life Laboratory"},{"author_name":"Luca Panconi","author_inst":"Stockholm University, Science of Life Laboratory"},{"author_name":"Ines Cunha","author_inst":"Stockholm University, Science for Life Laboratory"},{"author_name":"Emma Latron","author_inst":"Stockholm University, Science of Life Laboratory"},{"author_name":"Daniel Sage","author_inst":"EPFL"},{"author_name":"Ruby Peters","author_inst":"The University of Sheffield"},{"author_name":"Juliette Griffie","author_inst":"Stockholm University, Science of Life Laboratory"}],"rel_date":"2026-06-15","rel_site":"biorxiv"},{"rel_title":"Erythrocyte Count and the Human Natural Lifespan Limit: Evidence from the Long Life Family Study","rel_doi":"10.64898\/2026.06.08.730977","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730977","rel_abs":"Erythropoiesis is the most replication-intensive process in the body. Its lifelong replicative demands may erode hematopoietic cells' replicative capacity, leading to a decline in erythrocyte count (EC) in older individuals and limiting their lifespan. We examined the relationship between EC and mortality among 1,620 participants aged [&ge;]70 years in the Long Life Family Study, among whom lower EC further augmented the exponential age-dependent rise in mortality. We identified an EC threshold (ECT) (~3.8x1012\/L) below which mortality was amplified (p=9.3x10-6). As EC declined with age (p=8.2x10-18), it fell below this threshold in many participants, sharply increasing their mortality risk. This mortality-based ECT in older individuals emerged from modeling, independent of the WHO anemia definition based on statistical thresholds (5th centiles) of hemoglobin distribution in populations [&le;] 65 years. Thus, declining EC may be one of the biological factors imposing a natural lifespan limit on many older individuals.","rel_num_authors":16,"rel_authors":[{"author_name":"Konstantin G. Arbeev","author_inst":"Duke University"},{"author_name":"Olivia Bagley","author_inst":"Duke University"},{"author_name":"Joanne M. Murabito","author_inst":"Boston University School of Medicine"},{"author_name":"Harvey J. Cohen","author_inst":"Duke University"},{"author_name":"Brandon L. Pierce","author_inst":"University of Chicago"},{"author_name":"William Evan Johnson","author_inst":"Rutgers University"},{"author_name":"Dan T. A. Eisenberg","author_inst":"University of Washington"},{"author_name":"Milind C. Mahajan","author_inst":"Rutgers University"},{"author_name":"Stacy L. Andersen","author_inst":"Boston University"},{"author_name":"Kaare Christensen","author_inst":"University of Southern Denmark"},{"author_name":"Joseph M. Zmuda","author_inst":"University of Pittsburgh"},{"author_name":"Bharat Thyagarajan","author_inst":"University of Minnesota"},{"author_name":"Sheng Luo","author_inst":"Duke University"},{"author_name":"Anatoliy I. Yashin","author_inst":"Duke University"},{"author_name":"Michael A. Province","author_inst":"Washington University School of Medicine"},{"author_name":"Abraham Aviv","author_inst":"New Jersey Medical School"}],"rel_date":"2026-06-15","rel_site":"biorxiv"},{"rel_title":"Erythrocyte Count and the Human Natural Lifespan Limit: Evidence from the Long Life Family Study","rel_doi":"10.64898\/2026.06.08.730977","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730977","rel_abs":"Erythropoiesis is the most replication-intensive process in the body. Its lifelong replicative demands may erode hematopoietic cells' replicative capacity, leading to a decline in erythrocyte count (EC) in older individuals and limiting their lifespan. We examined the relationship between EC and mortality among 1,620 participants aged [&ge;]70 years in the Long Life Family Study, among whom lower EC further augmented the exponential age-dependent rise in mortality. We identified an EC threshold (ECT) (~3.8x1012\/L) below which mortality was amplified (p=9.3x10-6). As EC declined with age (p=8.2x10-18), it fell below this threshold in many participants, sharply increasing their mortality risk. This mortality-based ECT in older individuals emerged from modeling, independent of the WHO anemia definition based on statistical thresholds (5th centiles) of hemoglobin distribution in populations [&le;] 65 years. Thus, declining EC may be one of the biological factors imposing a natural lifespan limit on many older individuals.","rel_num_authors":16,"rel_authors":[{"author_name":"Konstantin G. Arbeev","author_inst":"Duke University"},{"author_name":"Olivia Bagley","author_inst":"Duke University"},{"author_name":"Joanne M. Murabito","author_inst":"Boston University School of Medicine"},{"author_name":"Harvey J. Cohen","author_inst":"Duke University"},{"author_name":"Brandon L. Pierce","author_inst":"University of Chicago"},{"author_name":"William Evan Johnson","author_inst":"Rutgers University"},{"author_name":"Dan T. A. Eisenberg","author_inst":"University of Washington"},{"author_name":"Milind C. Mahajan","author_inst":"Rutgers University"},{"author_name":"Stacy L. Andersen","author_inst":"Boston University"},{"author_name":"Kaare Christensen","author_inst":"University of Southern Denmark"},{"author_name":"Joseph M. Zmuda","author_inst":"University of Pittsburgh"},{"author_name":"Bharat Thyagarajan","author_inst":"University of Minnesota"},{"author_name":"Sheng Luo","author_inst":"Duke University"},{"author_name":"Anatoliy I. Yashin","author_inst":"Duke University"},{"author_name":"Michael A. Province","author_inst":"Washington University School of Medicine"},{"author_name":"Abraham Aviv","author_inst":"New Jersey Medical School"}],"rel_date":"2026-06-15","rel_site":"biorxiv"},{"rel_title":"Erythrocyte Count and the Human Natural Lifespan Limit: Evidence from the Long Life Family Study","rel_doi":"10.64898\/2026.06.08.730977","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730977","rel_abs":"Erythropoiesis is the most replication-intensive process in the body. Its lifelong replicative demands may erode hematopoietic cells' replicative capacity, leading to a decline in erythrocyte count (EC) in older individuals and limiting their lifespan. We examined the relationship between EC and mortality among 1,620 participants aged [&ge;]70 years in the Long Life Family Study, among whom lower EC further augmented the exponential age-dependent rise in mortality. We identified an EC threshold (ECT) (~3.8x1012\/L) below which mortality was amplified (p=9.3x10-6). As EC declined with age (p=8.2x10-18), it fell below this threshold in many participants, sharply increasing their mortality risk. This mortality-based ECT in older individuals emerged from modeling, independent of the WHO anemia definition based on statistical thresholds (5th centiles) of hemoglobin distribution in populations [&le;] 65 years. Thus, declining EC may be one of the biological factors imposing a natural lifespan limit on many older individuals.","rel_num_authors":16,"rel_authors":[{"author_name":"Konstantin G. Arbeev","author_inst":"Duke University"},{"author_name":"Olivia Bagley","author_inst":"Duke University"},{"author_name":"Joanne M. Murabito","author_inst":"Boston University School of Medicine"},{"author_name":"Harvey J. Cohen","author_inst":"Duke University"},{"author_name":"Brandon L. Pierce","author_inst":"University of Chicago"},{"author_name":"William Evan Johnson","author_inst":"Rutgers University"},{"author_name":"Dan T. A. Eisenberg","author_inst":"University of Washington"},{"author_name":"Milind C. Mahajan","author_inst":"Rutgers University"},{"author_name":"Stacy L. Andersen","author_inst":"Boston University"},{"author_name":"Kaare Christensen","author_inst":"University of Southern Denmark"},{"author_name":"Joseph M. Zmuda","author_inst":"University of Pittsburgh"},{"author_name":"Bharat Thyagarajan","author_inst":"University of Minnesota"},{"author_name":"Sheng Luo","author_inst":"Duke University"},{"author_name":"Anatoliy I. Yashin","author_inst":"Duke University"},{"author_name":"Michael A. Province","author_inst":"Washington University School of Medicine"},{"author_name":"Abraham Aviv","author_inst":"New Jersey Medical School"}],"rel_date":"2026-06-15","rel_site":"biorxiv"},{"rel_title":"Generative design of antigen-specific T-cell receptor sequences with a conditional diffusion model","rel_doi":"10.64898\/2026.06.10.730756","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.730756","rel_abs":"T cell receptor (TCR)-based immunotherapy holds immense potential for treating cancers and infectious diseases, where highly antigen-specific TCR recognition is crucial for adaptive immunity against tumors and pathogens. Engineering or de novo generation of the complementarity-determining region 3 (CDR3) loops of TCRs using artificial intelligence offers a powerful alternative to designing reactive TCRs rather than laborious experimental screening. However, current in silico approaches are constrained by weak conditional guidance, limited flexibility, and a lack of rigorous functional validation. To address these limitations, we introduce TCRDiff, a generative diffusion framework for designing antigen-specific TCRs conditioned on peptide-MHC (pMHC) targets and germline-encoded variable genes. By leveraging pre-trained knowledge from massive T-cell repertoires and TCR-pMHC recognition data, TCRDiff generates CDR3{beta} sequences with state-of-the-art fidelity to native binding TCRs through a denoising diffusion process. Furthermore, incorporating the interface geometry features generated TCR-pMHC complexes with superior structural plausibility. As a proof of concept, we deployed TCRDiff in a systematic pipeline to design candidate TCRs for immunotherapy. In vitro activation assays validated that TCRDiff-generated TCRs specifically recognize the MAGE-A3 epitope with minimized off-target cross-reactivity. Together, TCRDiff establishes a powerful, validated computational paradigm to accelerate the development of TCR-based immunotherapies.","rel_num_authors":9,"rel_authors":[{"author_name":"Yumeng Zhang","author_inst":"Monash University"},{"author_name":"Wenhua Liang","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Shuting Xu","author_inst":"Monash University"},{"author_name":"Matthew Witney","author_inst":"Monash University"},{"author_name":"Jamie Rossjohn","author_inst":"Monash University"},{"author_name":"Xiaodong Su","author_inst":"Peking University"},{"author_name":"Anthony W Purcell","author_inst":"Monash University"},{"author_name":"Feng Wang","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Jiangning Song","author_inst":"Monash University"}],"rel_date":"2026-06-14","rel_site":"biorxiv"},{"rel_title":"Internal decay in living trees: a quantitative tomography framework and its application in a temperate forest","rel_doi":"10.64898\/2026.06.10.730433","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.730433","rel_abs":"Internal decay in living trees is an important component of carbon and nutrient cycling as well as species and structural diversity maintenance in forest ecosystems. We used sonic and electrical resistance tomography to evaluate and compare the prevalence and severity of stem decay in 57 living trees among four common species (Acer rubrum L., Nyssa sylvatica Marsh., Quercus rubra L., and Tsuga canadensis (L.) Carriere)) with overlapping and non-overlapping distributions across wetland and upland habitat types at the Harvard Forest in Petersham, MA, USA. Independent of tree size, site identity best explained variation in the prevalence of decay across trees sampled, whereas species identity best explained the severity of decay. We categorized trees as having no decay, incipient decay, active decay, or cavities based on combined sonic and electrical resistance metrics, the latter generated by a custom image analysis application. About 31% of wetland trees exhibited incipient decay (compared to 11% in the upland), whereas about 32% of upland trees exhibited active decay (compared to 10% in the wetland). Our study highlights a new quantitative framework for decay categorization through normalized principal component analysis (PCA) and decay analysis software that complements dual tomographic methodology for future investigations of ecological drivers of decay presence and susceptibility.","rel_num_authors":9,"rel_authors":[{"author_name":"Grace Thompson","author_inst":"Harvard Forest"},{"author_name":"Maxwell P Lutz","author_inst":"Harvard Forest"},{"author_name":"Taylor K Lucey","author_inst":"University of Massachusetts Amherst"},{"author_name":"Bethany Duncan","author_inst":"Columbia University"},{"author_name":"Masako Yang","author_inst":"Harvard University"},{"author_name":"Sam Jurado","author_inst":"Yale University"},{"author_name":"Jaclyn Hatala Matthes","author_inst":"Harvard Forest"},{"author_name":"Robert E Marra","author_inst":"The Connecticut Agricultural Experiment Station"},{"author_name":"Jonathan Gewirtzman","author_inst":"Yale University"}],"rel_date":"2026-06-14","rel_site":"biorxiv"},{"rel_title":"Internal decay in living trees: a quantitative tomography framework and its application in a temperate forest","rel_doi":"10.64898\/2026.06.10.730433","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.730433","rel_abs":"Internal decay in living trees is an important component of carbon and nutrient cycling as well as species and structural diversity maintenance in forest ecosystems. We used sonic and electrical resistance tomography to evaluate and compare the prevalence and severity of stem decay in 57 living trees among four common species (Acer rubrum L., Nyssa sylvatica Marsh., Quercus rubra L., and Tsuga canadensis (L.) Carriere)) with overlapping and non-overlapping distributions across wetland and upland habitat types at the Harvard Forest in Petersham, MA, USA. Independent of tree size, site identity best explained variation in the prevalence of decay across trees sampled, whereas species identity best explained the severity of decay. We categorized trees as having no decay, incipient decay, active decay, or cavities based on combined sonic and electrical resistance metrics, the latter generated by a custom image analysis application. About 31% of wetland trees exhibited incipient decay (compared to 11% in the upland), whereas about 32% of upland trees exhibited active decay (compared to 10% in the wetland). Our study highlights a new quantitative framework for decay categorization through normalized principal component analysis (PCA) and decay analysis software that complements dual tomographic methodology for future investigations of ecological drivers of decay presence and susceptibility.","rel_num_authors":9,"rel_authors":[{"author_name":"Grace Thompson","author_inst":"Harvard Forest"},{"author_name":"Maxwell P Lutz","author_inst":"Harvard Forest"},{"author_name":"Taylor K Lucey","author_inst":"University of Massachusetts Amherst"},{"author_name":"Bethany Duncan","author_inst":"Columbia University"},{"author_name":"Masako Yang","author_inst":"Harvard University"},{"author_name":"Sam Jurado","author_inst":"Yale University"},{"author_name":"Jaclyn Hatala Matthes","author_inst":"Harvard Forest"},{"author_name":"Robert E Marra","author_inst":"The Connecticut Agricultural Experiment Station"},{"author_name":"Jonathan Gewirtzman","author_inst":"Yale University"}],"rel_date":"2026-06-14","rel_site":"biorxiv"},{"rel_title":"Organelle Capture, Lineage-Specific Genomic Responses, and the Lability of Dioecy in Amaranthus","rel_doi":"10.64898\/2026.06.13.732039","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.13.732039","rel_abs":"The transition from combined to separate sexes in plants drives genomic change, from recombination suppression at sex-determining loci to shifts in selection across autosomes and cytoplasmic genomes. In Amaranthus, a genus that includes ancient grain crops and noxious weeds, separate sexes arose twice through non-homologous sex-determining architectures, with at least one reversion to monoecy, yet plastid and mitochondrial phylogenies group the two dioecious lineages together despite independent origins. The source of this discordance and whether independent origins of dioecy produced parallel or lineage-specific genomic responses remain unknown. We sampled nuclear, plastid, and mitochondrial genomes across 19 species, resolving the backbone phylogeny of the genus and dating the crown to 2--5~Ma. Coalescent simulations rejected incomplete lineage sorting in favor of multiple organelle capture events, implying historical exchange across reproductive barriers separating the two dioecious clades. Nuclear allele sharing was concentrated within each dioecious clade rather than between them, consistent with recombination eroding nuclear donor ancestry while captured cytoplasmic genomes persist. Dioecy was associated with genome-wide shifts in selection intensity, with positive selection concentrated on the stems of each dioecious clade but targeting largely non-overlapping genes and leaving little signature within sex-determining regions. Plastid coding sequences evolved under relaxed purifying selection, and nuclear-encoded plastid-targeted genes were enriched for episodic positive selection, consistent with compensatory cytonuclear evolution. The probable reversion to monoecy in A. pumilus, within a lineage shaped by repeated organelle capture, raises the possibility that hybridization and the lability of separate sexes are connected in this group.","rel_num_authors":3,"rel_authors":[{"author_name":"David Timerman","author_inst":"Columbia University"},{"author_name":"Jason Leung","author_inst":"Columbia University"},{"author_name":"Deren A.R. Eaton","author_inst":"Columbia University"}],"rel_date":"2026-06-14","rel_site":"biorxiv"},{"rel_title":"Robust integration of weakly anchored spatial multi-omics","rel_doi":"10.64898\/2026.06.10.731246","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731246","rel_abs":"Spatial multi-omics holds great promise for dissecting complex biological processes, though inherent technical constraints continue to limit its widespread adoption. Currently, most studies therefore measure distinct omics features on separate tissue sections, necessitating spatial diagonal integration. An emerging practical solution is to leverage hematoxylin and eosin (H&E) images as an integration anchor, given their ubiquity, low cost, and compatibility across tissue preparations. However, this anchor is frequently compromised in real-world settings by variations in H&E staining style, absence of reliable histological landmarks, and mismatches in spatial resolutions across omics modalities. To address this, we introduce SpaWeaver, a computational framework that couples a pathology foundation model with a graph Transformer and a latent feature aligner module, providing a highly robust solution for weakly anchored spatial omics data diagonal integration. Extensive experiments demonstrate that SpaWeaver exhibits superior robustness against isolated or synergistic weak-anchoring factors. The spatial multi-omics profiles generated by SpaWeaver link molecular features originally separated on two sections, unlocking diverse downstream analyses once exclusive to co-assayed spatial multi-omics data, including niche-aware cell-cell communication inference and multi-omics resolved cell state. In this study, it unveils tumor-distance-dependent fibroblast-CD4+ T-cell signaling in human colon adenocarcinoma and identifies a hypoxic glycolytic tumor state with pyknotic nuclei in human ovarian cancer. Overall, our approach bridges readily accessible single-omics measurements across weakly anchored tissue sections, enabling unified spatial multi-omics characterization and system-level tissue analysis.","rel_num_authors":16,"rel_authors":[{"author_name":"Chuyao Wang","author_inst":"Key Laboratory of Symbolic Computation and Knowledge Engineering of the Ministry of Education, College of Computer Science and Technology, Jilin University, Cha"},{"author_name":"Yonghao Liu","author_inst":"Key Laboratory of Symbolic Computation and Knowledge Engineering of the Ministry of Education, College of Computer Science and Technology, Jilin University, Cha"},{"author_name":"Zhikang Wang","author_inst":"Institute of Science and Technology for Brain-Inspired Intelligence, Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudo"},{"author_name":"Pinli Sun","author_inst":"Department of Pathology, the Second Hospital of Jilin University, Jilin University, Changchun, China"},{"author_name":"Zhi Li","author_inst":"National Clinical Research Center for Laboratory Medicine, Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, China"},{"author_name":"Jieming Li","author_inst":"Key Laboratory of Symbolic Computation and Knowledge Engineering of the Ministry of Education, College of Computer Science and Technology, Jilin University, Cha"},{"author_name":"Xueting Wang","author_inst":"Key Laboratory of Symbolic Computation and Knowledge Engineering of the Ministry of Education, College of Computer Science and Technology, Jilin University, Cha"},{"author_name":"Ke Chen","author_inst":"Key Laboratory of Symbolic Computation and Knowledge Engineering of the Ministry of Education, College of Computer Science and Technology, Jilin University, Cha"},{"author_name":"Qi Zou","author_inst":"Institute of Science and Technology for Brain-Inspired Intelligence, Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudo"},{"author_name":"Zhang Daoliang","author_inst":"Institute of Science and Technology for Brain-Inspired Intelligence, Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudo"},{"author_name":"Zheqi Hu","author_inst":"Institute of Science and Technology for Brain-Inspired Intelligence, Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudo"},{"author_name":"Yixuan Du","author_inst":"Institute of Science and Technology for Brain-Inspired Intelligence, Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudo"},{"author_name":"Binzhi Qian","author_inst":"Center for Integrative Spatial-Omics Research, Fudan University, Shanghai, China; Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medi"},{"author_name":"Xiaoyue Feng","author_inst":"Key Laboratory of Symbolic Computation and Knowledge Engineering of the Ministry of Education, College of Computer Science and Technology, Jilin University, Cha"},{"author_name":"Zhiyuan Yuan","author_inst":"Institute of Science and Technology for Brain-Inspired Intelligence, Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudo"},{"author_name":"Renchu Guan","author_inst":"Key Laboratory of Symbolic Computation and Knowledge Engineering of the Ministry of Education, College of Computer Science and Technology, Jilin University, Cha"}],"rel_date":"2026-06-14","rel_site":"biorxiv"},{"rel_title":"Cardiomyocytes Undergo a Mesenchymal-Like Fate Transition in Myocardial Fibrosis","rel_doi":"10.64898\/2026.06.10.731493","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731493","rel_abs":"BACKGROUND Myocardial fibrosis, a pathological hallmark of adverse cardiac remodeling and heart failure, has been conventionally attributed to the activation of resident fibroblasts. Although recent studies suggest contributions from non-fibroblast lineages, direct in vivo genetic evidence that cardiomyocytes can undergo a mesenchymal-like fate transition during myocardial fibrosis remains absent. This study aims to investigate whether such a transition occurs and to elucidate the underlying regulatory mechanisms. METHODS Human myocardial infarction (MI) tissues were analyzed by immunohistochemistry and integrated with public single nucleus RNA sequencing (snRNA seq) data to detect mesenchymal like signatures in cardiomyocytes. Genetic lineage-tracing was performed in MI mice, and in cardiomyocyte-specific Hgs (hepatocyte growth factor-regulated tyrosine kinase substrate) gene knockout mice, to map the fate of cardiomyocyte-derived cells. Mechanistic insights were obtained through proteomic and snRNA-seq analysis of Hgs knockout hearts and validated through gain- and loss-of-function experiments targeting Aldh1a2 (aldehyde dehydrogenase 1 family member A2). RESULTS In human MI samples, a subset of cardiomyocytes showed reduced expression of cardiomyocyte markers concurrent with acquisition of mesenchymal-associated markers. Genetic lineage tracing demonstrated that adult cardiomyocytes can adopt a mesenchymal-like cell fate during post MI remodeling. We identify HGS as a factor constraining this transition. Hgs knockout in adult cardiomyocytes upregulated Aldh1a2, triggered the mesenchymal-like fate transition, and gave rise to cells expressing markers of activated fibroblasts or osteoblasts, accompanied by pronounced myocardial fibrosis and calcification. Forced Aldh1a2 overexpression in cardiomyocytes drove the mesenchymal-like fate transition in vitro and in vivo, whereas Aldh1a2 deletion in cardiomyocytes mitigated MI-induced myocardial fibrosis. CONCLUSIONS This study provides in vivo genetic evidence that adult cardiomyocytes possess the capacity to undergo a mesenchymal-like fate transition under pathological conditions. Our data suggest that HGS and ALDH1A2 serve as regulators of the transition, offering a new basis for understanding cellular and molecular mechanisms of myocardial fibrosis.","rel_num_authors":17,"rel_authors":[{"author_name":"Tianle Wang","author_inst":"Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics"},{"author_name":"Chunyu Zhou","author_inst":"Peking University"},{"author_name":"Mengdi Liu","author_inst":"State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences(Beijing), Beijing Institute of Lifeomic"},{"author_name":"Yujia Xing","author_inst":"State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences(Beijing), Beijing Institute of Lifeomic"},{"author_name":"Chunguang Han","author_inst":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing)"},{"author_name":"Runhan Li","author_inst":"Peking University"},{"author_name":"Yu Huang","author_inst":"State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University"},{"author_name":"Zhenhua Li","author_inst":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing)"},{"author_name":"Yan Teng","author_inst":"Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics"},{"author_name":"Guan Yang","author_inst":"State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics"},{"author_name":"Wenjia Liu","author_inst":"State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics"},{"author_name":"Ping Xu","author_inst":"State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics"},{"author_name":"Shi-Qiang Wang","author_inst":"Peking University"},{"author_name":"Bin Zhou","author_inst":"Chinese Academy of Sciences"},{"author_name":"Jing-Dong Jackie Han","author_inst":"Peking University"},{"author_name":"Jian Wang","author_inst":"State Key Laboratory of Medical Proteomics , National Center for Protein Sciences(Beijing)"},{"author_name":"Xiao Yang","author_inst":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing)"}],"rel_date":"2026-06-14","rel_site":"biorxiv"},{"rel_title":"Lipid Flippase Mediated Membrane Asymmetry Governs Extracellular Vesicles Biogenesis and Host Interactions in Cryptococcus neoformans","rel_doi":"10.64898\/2026.06.12.731820","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731820","rel_abs":"Cryptococcus neoformans is the leading cause of fungal meningitis in immunocompromised patients. Alveolar macrophages are the first line of defense against Cryptococcus infection. Our previous study showed that deletion of Cdc50, the regulatory subunit of P4-ATPase (lipid flippase) complex, results in increased phagocytosis and macrophage killing, and avirulence in animal models. However, how fungal flippase dysfunction modulates Cryptococcus-macrophage interaction remains unknown. Here we identify Cdc50 as a central determinant of membrane lipid homeostasis, extracellular vesicle (EV) biogenesis and macrophage responses in C. neoformans. Our whole cell lipidomic analysis revealed that loss of Cdc50 disrupted membrane lipid homeostasis leading to phospholipid enrichment in cdc50{Delta} mutant, and a reduction in fatty acid production accompanied by pronounced ultrastructural defects in membrane architecture. Loss of Cdc50 also induced a hyper-vesiculating phenotype, with cdc50{Delta}producing significantly more extracellular vesicles (EVs) than wild type H99 cells. Lipidomic profiling of cdc50{Delta} EVs revealed enrichment of phospholipids, including phosphatidylserine (PS), indicating active lipid sorting during vesicle biogenesis. Functional analysis showed that EVs from the wildtype H99 suppress phagocytosis whereas cdc50{Delta} EVs enhance phagocytosis, indicating a differential macrophage priming. Despite increased PS externalization in cdc50{Delta} cells and EVs, macrophage recognition and uptake occur independent of PS-mediated efferocytosis pathways, including PS receptor MertK. Following macrophage uptake, cdc50{Delta} were intrinsically vulnerable to macrophage killing due to rapid phagosome acidification. Together, we demonstrate that Cdc50 dependent lipid homeostasis regulates EV production, lipid composition, membrane architecture and drives the intracellular fate of C. neoformans.","rel_num_authors":7,"rel_authors":[{"author_name":"Siddhi Pawar","author_inst":"Rutgers School Of Graduate Studies"},{"author_name":"Yu Zhnag","author_inst":"Rutgers University School of Graduate Studies"},{"author_name":"Christopher Varsanayi","author_inst":"Rutgers University School of Graduate Studies"},{"author_name":"Varsha Gadiyar","author_inst":"Rutgers University School of Graduate Studies"},{"author_name":"Samantha Avina","author_inst":"Rutgers Biomedical and Health Sciences"},{"author_name":"Raymond Birge","author_inst":"Rutgers School of Biomedical and Health Sciences"},{"author_name":"Chaoyang Xue","author_inst":"Rutgers University School of Graduate Studies"}],"rel_date":"2026-06-13","rel_site":"biorxiv"},{"rel_title":"Sociodemographic and health correlates of reimbursement authorizations for cannabis for medical purposes in Canadian veterans: A cross-sectional study linking the Life After Services Studies 2019 and Health Administrative Databases","rel_doi":"10.64898\/2026.06.10.26355368","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355368","rel_abs":"BackgroundEvidence on factors associated with cannabis for medical purposes (CMP) authorizations among Veterans Affairs Canada (VAC) clients remains limited and inconsistent, particularly concerning mental health and posttraumatic stress disorder (PTSD), a leading indication for use. We investigated demographic, clinical and service characteristics associated with VAC authorizations for CMP reimbursement.\n\nMethodWe linked VAC administrative CMP program data with responses from the 2019 Life After Services Studies cross-sectional survey of Regular Force veterans released between 1998 and 2018. Multivariable logistic regressions examined associations between CMP reimbursement (yes\/no) and demographic, clinical and well-being factors, with analyses stratified by PTSD status.\n\nResultsAmong 1,289 respondents (weighted n=33,131), 18.4% were authorized for CMP reimbursement. Younger age (<40 vs. [&ge;]60 years: OR 4.78, 95% CI: 2.24-10.21), unemployment with inability to work vs. employed (OR 3.10, 95% CI: 1.78-5.40), land service vs. air (OR 2.07, 95% CI: 1.22-3.50), PTSD (OR 2.81, 95% CI: 1.69-4.66), anxiety (OR 2.32, 95% CI: 1.45-3.70), and severe pain vs. no pain (OR 3.61, 95% CI: 1.97-6.60) were independently associated with authorization. Unemployment and severe pain were consistent correlates across PTSD strata. Among those without PTSD, younger age, multiple physical conditions, and frequent mental health visits were significant; among those with PTSD, shorter service, witnessing destruction, and suicidal ideation were additional factors.\n\nConclusionsCMP authorization patterns among Canadian veterans reflect the intersection of mental health, pain, and functional impairment, with variation by PTSD status. These findings underscore the need for longitudinal research on CMP mechanisms, effectiveness and safety.","rel_num_authors":12,"rel_authors":[{"author_name":"Tetyana Kendzerska","author_inst":"University of Ottawa"},{"author_name":"Juli\u00e1n Reyes","author_inst":"Veterans Affairs Canada"},{"author_name":"Noah Poirier","author_inst":"Veterans Affairs Canada"},{"author_name":"Alain Poirier","author_inst":"Veterans Affairs Canada"},{"author_name":"Alex Cull","author_inst":"Veterans Affairs Canada"},{"author_name":"Anthony Murkar","author_inst":"University of Ottawa"},{"author_name":"Mouaz Saymeh","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Stephanie Belanger","author_inst":"College Militaire Royal du Canada: Royal Military College of Canada"},{"author_name":"Monnica Williams","author_inst":"University of Ottawa"},{"author_name":"Jakov Shlik","author_inst":"University of Ottawa Faculty of Graduate and Postdoctoral Studies: University of Ottawa"},{"author_name":"Rakesh Jetly","author_inst":"University of Ottawa"},{"author_name":"Rebecca Robillard","author_inst":"University of Ottawa"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Sociodemographic and health correlates of reimbursement authorizations for cannabis for medical purposes in Canadian veterans: A cross-sectional study linking the Life After Services Studies 2019 and Health Administrative Databases","rel_doi":"10.64898\/2026.06.10.26355368","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355368","rel_abs":"BackgroundEvidence on factors associated with cannabis for medical purposes (CMP) authorizations among Veterans Affairs Canada (VAC) clients remains limited and inconsistent, particularly concerning mental health and posttraumatic stress disorder (PTSD), a leading indication for use. We investigated demographic, clinical and service characteristics associated with VAC authorizations for CMP reimbursement.\n\nMethodWe linked VAC administrative CMP program data with responses from the 2019 Life After Services Studies cross-sectional survey of Regular Force veterans released between 1998 and 2018. Multivariable logistic regressions examined associations between CMP reimbursement (yes\/no) and demographic, clinical and well-being factors, with analyses stratified by PTSD status.\n\nResultsAmong 1,289 respondents (weighted n=33,131), 18.4% were authorized for CMP reimbursement. Younger age (<40 vs. [&ge;]60 years: OR 4.78, 95% CI: 2.24-10.21), unemployment with inability to work vs. employed (OR 3.10, 95% CI: 1.78-5.40), land service vs. air (OR 2.07, 95% CI: 1.22-3.50), PTSD (OR 2.81, 95% CI: 1.69-4.66), anxiety (OR 2.32, 95% CI: 1.45-3.70), and severe pain vs. no pain (OR 3.61, 95% CI: 1.97-6.60) were independently associated with authorization. Unemployment and severe pain were consistent correlates across PTSD strata. Among those without PTSD, younger age, multiple physical conditions, and frequent mental health visits were significant; among those with PTSD, shorter service, witnessing destruction, and suicidal ideation were additional factors.\n\nConclusionsCMP authorization patterns among Canadian veterans reflect the intersection of mental health, pain, and functional impairment, with variation by PTSD status. These findings underscore the need for longitudinal research on CMP mechanisms, effectiveness and safety.","rel_num_authors":12,"rel_authors":[{"author_name":"Tetyana Kendzerska","author_inst":"University of Ottawa"},{"author_name":"Juli\u00e1n Reyes","author_inst":"Veterans Affairs Canada"},{"author_name":"Noah Poirier","author_inst":"Veterans Affairs Canada"},{"author_name":"Alain Poirier","author_inst":"Veterans Affairs Canada"},{"author_name":"Alex Cull","author_inst":"Veterans Affairs Canada"},{"author_name":"Anthony Murkar","author_inst":"University of Ottawa"},{"author_name":"Mouaz Saymeh","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Stephanie Belanger","author_inst":"College Militaire Royal du Canada: Royal Military College of Canada"},{"author_name":"Monnica Williams","author_inst":"University of Ottawa"},{"author_name":"Jakov Shlik","author_inst":"University of Ottawa Faculty of Graduate and Postdoctoral Studies: University of Ottawa"},{"author_name":"Rakesh Jetly","author_inst":"University of Ottawa"},{"author_name":"Rebecca Robillard","author_inst":"University of Ottawa"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Heterogeneity of Treatment Effect of Aspirin and Clinically Significant Bleeding in Older Adults","rel_doi":"10.64898\/2026.06.10.26355385","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355385","rel_abs":"AimThe global population of older adults is growing, and older age is linked to higher bleeding risk. Although guidelines discourage aspirin for primary prevention in healthy older adults due to bleeding harms outweighing benefits, many continue taking it without a clear indication. It remains unclear whether all older adults face uniform aspirin-related bleeding risk or if certain subgroups are more vulnerable.\n\nMethodsWe analyzed data from 19,114 ASPREE trial participants to develop machine learning models using 116 baseline variables. Random forest (RF) and random survival forest (RSF) models predicted 5-year bleeding risk, and participants were stratified into low, intermediate, and high-risk groups based on the 20th and 80th percentiles of predicted risk. We assessed heterogeneity of treatment effect (HTE) by testing treatment-by-risk group interactions on the relative scale using Fine-Gray models, and on the absolute scale using observed 5-year cumulative incidence rates.\n\nResultsOver a median follow-up of 4.7 years, 626 major bleeding events occurred. The RF model had moderate discrimination (AUC = 0.65, 95% CI: 0.63-0.67) and good calibration (Brier = 0.032, 95% CI: 0.029-0.034). Statistically significant HTE was observed on the relative scale, with the greatest relative increase in bleeding risk seen in the low-risk group (subdistribution hazard ratio = 2.26, 95% CI: 1.27-4.01). On the absolute scale, low-risk participants experienced higher bleeding with aspirin (absolute risk difference (ARD) = 1.17%, 95% CI: 0.37-1.95), but heterogeneity in ARDs was not statistically significant (Cochrans Q p > 0.45). Similar findings were observed when using the RSF model.\n\nConclusionParticipants at lowest baseline bleeding risk experienced the greatest relative increase in bleeding risk with aspirin therapy. We found statistically significant heterogeneity in treatment effects on the relative but not absolute scale. These findings support an individualized, risk-based approach to aspirin therapy decision-making in older adults.","rel_num_authors":12,"rel_authors":[{"author_name":"Giorgos Tzimas","author_inst":"DePaul University"},{"author_name":"Roselyne B. Tchoua","author_inst":"DePaul University"},{"author_name":"Joseph C Vanghelof","author_inst":"Rush University"},{"author_name":"Rory C Wolfe","author_inst":"Monash University"},{"author_name":"Geoffrey Cloud","author_inst":"Monash University"},{"author_name":"Suzanne Mahady","author_inst":"Monash University"},{"author_name":"Lianlian Du","author_inst":"Rush University Medical Center"},{"author_name":"Michael E. Ernst","author_inst":"The University of Iowa"},{"author_name":"Erica M Wood","author_inst":"Monash University"},{"author_name":"Daniela S Raicu","author_inst":"DePaul University"},{"author_name":"Shara Ket","author_inst":"Monash University"},{"author_name":"Raj C. Shah","author_inst":"Rush University Medical Center"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Home-based binocular serious games in virtual reality to treat visual acuity and stereovision in residual amblyopia: AMBER study","rel_doi":"10.64898\/2026.06.12.26355255","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355255","rel_abs":"ObjectivesAmblyopia is a pediatric visual disorder traditionally treated by patching the fellow eye, though many patients retain residual amblyopia post-treatment. Increasing evidence suggests that visual plasticity allows treatment beyond the classical therapeutic window. AMBER evaluated the efficacy of binocular serious games in virtual reality (VR) in residual amblyopia.\n\nMethods and AnalysisThe monocentric, prospective, randomized, crossover trial (reported as case series) included 14 anisometropic, strabismic, or mixed residual amblyopia patients (6-35 years; 5 children, 9 adults). Participants underwent two 2-month intervention phases: optical correction (standard care) and standard care plus VR games (2.5 h\/week), each with a 2-month follow-up. Best-corrected visual acuity (BCVA), stereoacuity, and reading speed were assessed (5 timepoints) using the Sloan and Landolt charts, the Titmus, TNO, Lang II, Asteroid, and Mnread tests. Compliance and adverse events (AE) were recorded.\n\nResultsVR training improved BCVA in 10 amblyopic eyes (Landolt and Sloan), with more pronounced effects in anisometropic patients. Six patients showed improved stereoacuity (Titmus; 4x mixed, 1x anisometropic, 1x strabismic amblyopia), persistent only in children (1x strabismic, 1x mixed amblyopia). Four improvements were observed with TNO (1x), Lang II (1x), Asteroid (0x), and MNread (1x). Despite positive trends, when comparing results of individual patients, between both eyes, and with standard treatment, consistency of improvements cannot be conclusively demonstrated. One non-severe AE (dizziness) was reported.\n\nConclusionsFollowing individual cases, VR training improved BCVA and stereoacuity, particularly in children and patients with high compliance. However, considering the cohort as a whole, consistency of effects has to be confirmed in larger groups. Thus, the methodologically sophisticated AMBER study revealed differences in VR treatment efficacy between amblyopia types, children\/adults, endpoints and tests, offering precious data for the design of meaningful future studies. It shows that neurovisual plasticity gauged by VR-games offers safe, engaging treatment options for residual amblyopia.\n\nWhat is already known on this topicO_LIBinocular treatment approaches have shown promise in efficiently treating amblyopia for which the standard treatment, patching, is effective but is limited by factors such as poor compliance and a narrow treatment window.\nC_LI\n\nWhat this study addsO_LIThe study investigated the benefits of binocular serious games in virtual reality for both children and adults with residual amblyopia and compared various tests to assess outcomes. This comprehensive approach allowed for a comparison of treatment efficacy across different age groups and types of amblyopia, as well as an evaluation of the suitability of the various tests for determining treatment outcomes.\nC_LI\n\nHow this study might affect research, practice or policyO_LIThe findings support the hypothesis that binocular training can effectively treat amblyopia demonstrating highest safety and benefits even beyond the classical treatment window, and in residual amblyopia, which could affect clinical practice of ophthalmologists who offer such therapies, at least as a supplement to standard treatment.\nC_LIO_LIAssessment of various tests will help uniformize future studies, thus, increase studies comparability and, finally, allow conclusive analyses and formulation of treatment recommendations.\nC_LI","rel_num_authors":15,"rel_authors":[{"author_name":"Aurelia Aurilia","author_inst":"Department of Ophthalmology, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Nour-Louise Martin","author_inst":"Department of Ophthalmology, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Cristina Simon-Martinez","author_inst":"Institute of Informatics, School of Management, University of Applied Sciences Western Switzerland Valais-Wallis, Sierre, Switzerland"},{"author_name":"Maria-Paraskevi Antoniou","author_inst":"Institute of Informatics, School of Management, University of Applied Sciences Western Switzerland Valais-Wallis, Sierre, Switzerland"},{"author_name":"Walid Bouthour","author_inst":"Department of Ophthalmology, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Daphne Bavelier","author_inst":"Faculty of Psychology and Education Sciences, University of Geneva, Geneva, Switzerland"},{"author_name":"Benjamin T. Backus","author_inst":"Vivid Vision, Inc, 424 Treat Ave., Ste B, San Francisco, CA 94110, USA"},{"author_name":"Brian Dornbos","author_inst":"Vivid Vision, Inc, 424 Treat Ave., Ste B, San Francisco, CA 94110, USA"},{"author_name":"James J. Blaha","author_inst":"Vivid Vision, Inc, 424 Treat Ave., Ste B, San Francisco, CA 94110, USA"},{"author_name":"Martina Kropp","author_inst":"Department of Ophthalmology, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Henning Muller","author_inst":"Institute of Informatics, School of Management, University of Applied Sciences Western Switzerland Valais-Wallis, Sierre, Switzerland"},{"author_name":"Micah M. Murray","author_inst":"Department of Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland"},{"author_name":"Gabriele Thumann","author_inst":"Department of Ophthalmology, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Heimo Steffen","author_inst":"Department of Ophthalmology, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Pawel J. Matusz","author_inst":"Institute of Health Sciences, School of Health Sciences, HES-SO Valais-Wallis, Sion, Switzerland"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Genomic wastewater surveillance of seasonal and zoonotic influenza A viruses in California during the 2024-2025 flu season","rel_doi":"10.64898\/2026.06.10.26355323","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355323","rel_abs":"BackgroundWastewater genomic surveillance provides an opportunity to detect human and animal influenza A virus (IAV). We aimed to implement an IAV genomic surveillance framework agnostic to subtype, which enables recovery of IAV from multiple hosts and estimation of proportions across subtypes.\n\nMethodsWe conducted IAV genomic surveillance in wastewater during the 2024-2025 flu season at multiple sites in California and compared these data with available human clinical IAV sequences and test positivity. We applied a custom whole-genome, multi-host IAV probe enrichment panel and adapted our custom expectation-maximization (EM) algorithm to deconvolute IAV mixtures in wastewater and infer subtype relative abundances. Absolute IAV concentrations were quantified using RT-PCR-based assays. H5N1 wastewater and clinical sequences were further characterized by constructing a whole-genome maximum-likelihood phylogenetic tree. Finally, we performed variant analysis to examine amino acid substitutions detected in wastewater.\n\nFindingsOur IAV probe enrichment method and EM algorithm successfully enriched all eight segments of three circulating IAV subtypes and accurately estimated subclade relative abundances for mixed IAV samples. Seasonal human H1N1pdm09 and H3N2 were detected throughout the study period from both wastewater and clinical sequencing data, with H1N1 subclades 6B.1A.5a.2a.1 and 6B.1A.5a.2a co-circulating, and H3N2 dominated by subclade 3C.2a1b.2a.2a.3a.1. Wastewater surveillance consistently detected H5N1 clade 2.3.4.4b across three monitored wastewater sites, while clinical H5N1 detections, from anywhere in CA, were sporadic and rare. Whole-genome phylogenetic analysis revealed that wastewater H5N1 sequences clustered with reference sequences associated with dairy cow and avian infections, while all human clinical H5N1 sequences clustered exclusively with reference sequences associated with dairy cow infections. Amino acid substitutions were identified across viral segments, and no mutations associated with mammalian adaptation were observed from wastewater samples.\n\nInterpretationWhen IAV concentrations were dominated by seasonal human subtypes rather than H5N1, subtype patterns aligned between wastewater and clinical data. While sequencing IAV in wastewater was unable to distinguish if H5N1 detections were due to human or animal infections, it was able to provide clade-level information about H5N1 found in wastewater that could be useful in the future. Wastewater genomic surveillance can complement clinical surveillance, increasing ability to detect all circulating IAV subtypes and enhancing public health preparedness from a One Health perspective.\n\nFundingUCOP Lab Fees CRT Award (L22CR4507) and NIH R00 Award (4R00GM144747-03)\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSSequencing IAV in wastewater has been shown to detect circulating subtypes from human and animal hosts, with potential to improve public health response, enhance surveillance for novel pandemic threats, and inform vaccine design. However, methodological improvements are needed for this potential to be fully realized. Targeted enrichment methods designed for whole-genome sequencing from wastewater can substantially improve genome coverage and sensitivity for low-abundance IAV. Approaches have included tiled amplicon, universal amplicon, and probe-capture enrichment. Tiled-amplicon methods provide high sensitivity and specificity but are less tolerant to sequence mismatches, and typically restrict primer design to a limited set of segments and a narrow range of subtypes. The universal amplicon approach was designed for clinical sequencing, where intact genomes from single isolates are available, and previous studies showed low recovery when applied to wastewater samples. In contrast, probe-capture enrichment tolerates mismatches and is therefore more resilient to RNA degradation and better suited to capture novel or divergent variants. However, current commercial probe-capture panels are pan-viral, which reduces sensitivity for IAV due to the high number of reads corresponding to other higher-abundance targets. The segmented nature of the IAV genome introduces additional challenges for downstream bioinformatic analysis. Existing deconvolution tools for wastewater sequencing have been developed primarily for SARS-CoV-2 and are not readily applicable to IAV. When applied to IAV, existing tools often demix only one subtype at a time, inferring clade-level relative abundance for that specific subtype. This limitation arises because different IAV subtypes require distinct reference genomes, unlike SARS-CoV-2, where a single reference can support alignment of multiple variants. Given that wastewater samples often contain multiple IAV subtypes simultaneously, it would be more useful to deconvolute clade-level relative abundances for all subtypes in parallel, underscoring the need for a more robust method tailored to the genomic complexity of IAV in wastewater.\n\nAdded value of this studyTo our knowledge, this is the first study to apply an IAV-specific probe-capture enrichment panel to monitor IAV in wastewater, targeting all eight segments of the genome and subtypes across human, avian, dairy cattle, and other mammalian hosts. Unlike studies that prioritize either high coverage of very few subtypes or broad detection with limited genomic resolution, our study achieves a balance between capturing multiple IAV clades and maintaining reasonable coverage across segments. Additionally, we adapted a probabilistic expectation-maximization (EM) model to infer clade-level relative abundances from wastewater sequencing data. Our method includes imputation and retains fine-scale genomic differences, reducing bias when genome coverage is incomplete, which is a common scenario for low-abundance IAV in wastewater. While several bioinformatic tools have been developed to deconvolute SARS-CoV-2 mixtures in wastewater, comparable approaches have not been tailored for IAV, whose segmented genome and extensive subtype diversity pose unique challenges. Our framework fills this gap by enabling robust subclade-resolution surveillance across multiple subtypes and hosts using sequence data from wastewater samples.\n\nImplications of all the available evidenceOur findings demonstrate a framework for wastewater genomic surveillance for tracking human IAV while also detecting animal-associated IAV. From a public health perspective, multi-host wastewater genomic surveillance offers two key benefits. First, it strengthens existing human IAV surveillance, because sequencing of clinical flu samples is limited and may not be representative of circulating subtypes, especially across regions with differing resources. Wastewater surveillance captures a larger and less biased sample population and has the potential to detect and track new subtypes more efficiently than clinical surveillance. Second, the ability to detect animal-associated IAV in wastewater supports pandemic preparedness by enabling monitoring for IAV of zoonotic potential and of genetic markers indicative of potentially increased human adaptation. This is especially beneficial where active surveillance of animal hosts is limited.","rel_num_authors":10,"rel_authors":[{"author_name":"Audrey Li-Wen Wang","author_inst":"University of California, Berkeley"},{"author_name":"Alexandra Lamtyugina","author_inst":"University of Hawaii at Manoa"},{"author_name":"Minxi Jiang","author_inst":"University of California, Berkeley"},{"author_name":"Alexander T. Yu","author_inst":"California Department of Public Health"},{"author_name":"Chunye Lu","author_inst":"California Department of Public Health"},{"author_name":"Debra Wadford","author_inst":"California Department of Public Health"},{"author_name":"Elisabeth Burnor","author_inst":"California Department of Public Health"},{"author_name":"Lenore Pipes","author_inst":"University of Hawaii at Manoa"},{"author_name":"Rose Kantor","author_inst":"Lawrence Livermore National Laboratory"},{"author_name":"Kara L Nelson","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Disentangling Confounders from Pathology in Long-COVID Trajectory Prediction for Women: An Interpretable Large-Language-Model Approach","rel_doi":"10.64898\/2026.06.10.26355420","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355420","rel_abs":"ObjectivePost-acute sequelae of SARS-CoV-2 infection (PASC, \"Long COVID\") disproportionately affects women, in whom hallmark symptoms--insomnia, fatigue, palpitations, cognitive difficulty--overlap with comorbidities and hormonal transitions such as menopause. This diagnostic overlap is a confounding problem: models that forecast future symptom severity risk attributing baseline physiological noise to viral pathology. We ask whether an interpretable, causally disentangled language model can separate true pathological signal from such confounders while remaining competitive with strong predictors of future PASC severity.\n\nMaterials and methodsRetrospective cohort of 1,155 adult women (median age 61) from the NIH RECOVER program, combining static clinical profiles, longitudinal symptom surveys, and four weeks of mean-aggregated consumer-wearable physiology (heart rate, sleep, activity). We render each patient as a natural-language clinical narrative and fine-tune a small open-weight language model (Qwen2.5-0.5B, LoRA) with an attention-based disentanglement layer that gates the latent state into a causal and a confounder component, trained with an environment-mixing InfoNCE objective. We predict the PASC index at 3-, 6-, and 9-month horizons and benchmark against last-value carry-forward, Lasso, Ridge, gradient-boosted trees (XGBoost), a deep MLP, a tabular ResNet, and a self-attention network, over 20 stratified resamples with paired significance tests. We further stratify by trajectory phenotype (Protected \/ Responder \/ Refractory).\n\nResultsLong-COVID severity is strongly autocorrelated, so last-value carry-forward is a hard reference and is the most accurate method on the full cohort (MAE 3.02\/1.99\/1.52 at 3\/6\/9 months). Among learned models the LLM regressor had the lowest MAE at every horizon (e.g. 3.11 vs. XGBoost 3.57 at 3 months; paired p [&le;] 0.01). In the Responder phenotype-- patients whose trajectories actually move--the LLM was the most accurate method overall at 3 and 6 months (MAE 4.72, 4.06), though its advantage over carry-forward was not statistically significant (p = 0.70, 0.29). The disentanglement layer assigned maximal saliency to direct pathology tokens (breathlessness, malaise; 1.00) while suppressing confounders (menopause, diabetes; < 0.27) and linguistic filler (< 0.17).\n\nConclusionFor static, slowly evolving patients a simple carry-forward forecast is hard to beat and should be the reference any PASC model is judged against. The value of a learned, disentangled model is (i) better accuracy where trajectories are dynamic and (ii) an interpretable, \"clinically honest\" attribution that down-weights confounders such as menopause--reducing the risk of misattributing baseline physiology to Long COVID.\n\nAuthor summaryLong COVID is more common and often more severe in women, but many of its symptoms look like other common conditions or like the normal changes of menopause. When a computer model tries to predict how a patients symptoms will evolve, it can be fooled into blaming Long COVID for what is really background physiology. We built a model based on a small language model that reads a written summary of each patient--their history, comorbidities, and a month of wearable-device data--and is explicitly trained to separate \"true disease signal\" from \"background noise.\" We tested it against standard predictors at 3, 6, and 9 months. We report an finding that is easy to overlook: because Long COVID severity changes slowly, simply assuming a patients next score equals their last score is very accurate and hard to beat for stable patients. Our models advantage appears where it matters clinically--patients whose symptoms are actually changing--and, importantly, the model shows which words drove its prediction, correctly emphasizing symptoms like breathlessness while down-weighting confounders like menopause. We argue this interpretability, not a small accuracy gain, is the real contribution.","rel_num_authors":9,"rel_authors":[{"author_name":"Jing Wang","author_inst":"NIH: National Institutes of Health"},{"author_name":"Zorina Galis","author_inst":"National Institute of Health Sciences"},{"author_name":"Tong Zhang","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Yiming Luo","author_inst":"Columbia University"},{"author_name":"Amar Sra","author_inst":"George Washington University Medical Center"},{"author_name":"Xing Niu","author_inst":"Amazon.com Dedc LLC"},{"author_name":"Jie Shen","author_inst":"Stevens Institute of Technology"},{"author_name":"Qiaomin Xie","author_inst":"UW Madison: University of Wisconsin Madison"},{"author_name":"Jeremy  C Weiss","author_inst":"National Institute of Health Sciences"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Genome-wide association and multi-omics functional screens reveal the genetic architecture of foveal development","rel_doi":"10.64898\/2026.06.11.26355452","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355452","rel_abs":"Foveal hypoplasia causes visual impairment across congenital eye disorders, yet the genetic programmes governing foveal development remain poorly characterised and no tractable model exists for foveal disease. In the first genome-wide association study of foveal hypoplasia, we identified 42 sentinel variants mapping to 54 effector genes supported by [&ge;] 2 criteria from a variant-to-gene framework incorporating developmental multi-omics. Disruption of six effector genes using mutant lines and CRISPR knockouts in the zebrafish high acuity zone recapitulates structural, functional, and ultrastructural hallmarks of foveal hypoplasia, establishing the first vertebrate disease model. Integration with human foetal single-cell and spatial transcriptomics reveals two temporal waves of effector gene expression and identifies Muller glia as critical mediators of foveal patterning. Phenome-wide analyses reveal foveal variants are pleiotropic with refractive, lenticular, and metabolic traits, connecting foveal development to anterior segment and systemic disease biology. These findings should inform mechanistic studies of macular disease.","rel_num_authors":44,"rel_authors":[{"author_name":"Callum Hunt","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester,"},{"author_name":"Manjiri Patil","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester"},{"author_name":"Hammad Syed","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Ha-Jun Yoon","author_inst":"Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"author_name":"Tingting Yang","author_inst":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Vanessa Rodwell","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Zhanhan Tu","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Gail DE Maconachie","author_inst":"The School of AHPPNM, Faculty of Health, Division of Ophthalmology and Orthoptics, The University of Sheffield, Sheffield, United Kingdom"},{"author_name":"Kayesha Coley","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Alvin Lirio","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Nick Shrine","author_inst":"University of Leicester"},{"author_name":"Richard Packer","author_inst":"University of Leicester"},{"author_name":"Mahmoud Fassad","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"RIDDHI SHENOY","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Natalie Allcock","author_inst":"Electron Microscopy Facility Core Biotechnology Services, College of Life Sciences, University of Leicester, Leicester, UK."},{"author_name":"Brandon Lim","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Helen J Kuht","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Girish Varma","author_inst":"International Institute of Information Technology Hyderabad, Gachibowli, Telangana, India"},{"author_name":"Irem Karaer","author_inst":"University of Leicester"},{"author_name":"Ranjit Injety","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"William Jakins","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Reenette Savant","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Rishi Sekhri","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Michael Hisaund","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Jinu Han","author_inst":"Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea (the Republic of)"},{"author_name":"Seema Teli","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Jun Wang","author_inst":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Zhen Zuo","author_inst":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Josh Whittingham","author_inst":"Electron Microscopy Facility Core Biotechnology Services, College of Life Sciences, University of Leicester, Leicester, UK."},{"author_name":"Gareth Douglas","author_inst":"School of Engineering, University of Leicester, Leicester, UK"},{"author_name":"Nicolas Sylvius","author_inst":"NUCLEUS Genomics, Core Biotechnology Services, University of Leicester, Leicester, UK"},{"author_name":"Pradeep C Vasudevan","author_inst":"University Hospitals of Leicester NHS Trust, Leicester, UK"},{"author_name":"Ala Moshiri","author_inst":"Department of Ophthalmology & Vision Science, University of California Davis School of Medicine, Sacramento, California, United States"},{"author_name":"Jonathan Zippin","author_inst":"Department of Dermatology, Weill Cornell Medical College of Cornell University, New York, New York, United States"},{"author_name":"Brian  P Brooks","author_inst":"National Institute of Health"},{"author_name":"Lluis Montoliu","author_inst":"Department of Molecular and Cellular Biology, National Centre for Biotechnology (CNB-CSIC), Madrid, Spain"},{"author_name":"Irene Gottlob","author_inst":"Neurology, Cooper University Health Care, Camden, New Jersey, United States"},{"author_name":"Ko-Fan Chen","author_inst":"Division of Genetics and Genome Biology, University of Leicester, Leicester, UK"},{"author_name":"Takeshi Yoshimatsu","author_inst":"Department of Ophthalmology and Visual Sciences, Washington University in St Louis School of Medicine, St. Louis, USA"},{"author_name":"Martin D Tobin","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"William HJ Norton","author_inst":"The University of Leicester, Division of Biosciences Education"},{"author_name":"Rui Chen","author_inst":"Brunson Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology and Visual Sciences, University of California, Irvine"},{"author_name":"Chiara Batini","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Mervyn G Thomas","author_inst":"University of Leicester"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Genome-wide association and multi-omics functional screens reveal the genetic architecture of foveal development","rel_doi":"10.64898\/2026.06.11.26355452","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355452","rel_abs":"Foveal hypoplasia causes visual impairment across congenital eye disorders, yet the genetic programmes governing foveal development remain poorly characterised and no tractable model exists for foveal disease. In the first genome-wide association study of foveal hypoplasia, we identified 42 sentinel variants mapping to 54 effector genes supported by [&ge;] 2 criteria from a variant-to-gene framework incorporating developmental multi-omics. Disruption of six effector genes using mutant lines and CRISPR knockouts in the zebrafish high acuity zone recapitulates structural, functional, and ultrastructural hallmarks of foveal hypoplasia, establishing the first vertebrate disease model. Integration with human foetal single-cell and spatial transcriptomics reveals two temporal waves of effector gene expression and identifies Muller glia as critical mediators of foveal patterning. Phenome-wide analyses reveal foveal variants are pleiotropic with refractive, lenticular, and metabolic traits, connecting foveal development to anterior segment and systemic disease biology. These findings should inform mechanistic studies of macular disease.","rel_num_authors":44,"rel_authors":[{"author_name":"Callum Hunt","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester,"},{"author_name":"Manjiri Patil","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester"},{"author_name":"Hammad Syed","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Ha-Jun Yoon","author_inst":"Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"author_name":"Tingting Yang","author_inst":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Vanessa Rodwell","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Zhanhan Tu","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Gail DE Maconachie","author_inst":"The School of AHPPNM, Faculty of Health, Division of Ophthalmology and Orthoptics, The University of Sheffield, Sheffield, United Kingdom"},{"author_name":"Kayesha Coley","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Alvin Lirio","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Nick Shrine","author_inst":"University of Leicester"},{"author_name":"Richard Packer","author_inst":"University of Leicester"},{"author_name":"Mahmoud Fassad","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"RIDDHI SHENOY","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Natalie Allcock","author_inst":"Electron Microscopy Facility Core Biotechnology Services, College of Life Sciences, University of Leicester, Leicester, UK."},{"author_name":"Brandon Lim","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Helen J Kuht","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Girish Varma","author_inst":"International Institute of Information Technology Hyderabad, Gachibowli, Telangana, India"},{"author_name":"Irem Karaer","author_inst":"University of Leicester"},{"author_name":"Ranjit Injety","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"William Jakins","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Reenette Savant","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Rishi Sekhri","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Michael Hisaund","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Jinu Han","author_inst":"Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea (the Republic of)"},{"author_name":"Seema Teli","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Jun Wang","author_inst":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Zhen Zuo","author_inst":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Josh Whittingham","author_inst":"Electron Microscopy Facility Core Biotechnology Services, College of Life Sciences, University of Leicester, Leicester, UK."},{"author_name":"Gareth Douglas","author_inst":"School of Engineering, University of Leicester, Leicester, UK"},{"author_name":"Nicolas Sylvius","author_inst":"NUCLEUS Genomics, Core Biotechnology Services, University of Leicester, Leicester, UK"},{"author_name":"Pradeep C Vasudevan","author_inst":"University Hospitals of Leicester NHS Trust, Leicester, UK"},{"author_name":"Ala Moshiri","author_inst":"Department of Ophthalmology & Vision Science, University of California Davis School of Medicine, Sacramento, California, United States"},{"author_name":"Jonathan Zippin","author_inst":"Department of Dermatology, Weill Cornell Medical College of Cornell University, New York, New York, United States"},{"author_name":"Brian  P Brooks","author_inst":"National Institute of Health"},{"author_name":"Lluis Montoliu","author_inst":"Department of Molecular and Cellular Biology, National Centre for Biotechnology (CNB-CSIC), Madrid, Spain"},{"author_name":"Irene Gottlob","author_inst":"Neurology, Cooper University Health Care, Camden, New Jersey, United States"},{"author_name":"Ko-Fan Chen","author_inst":"Division of Genetics and Genome Biology, University of Leicester, Leicester, UK"},{"author_name":"Takeshi Yoshimatsu","author_inst":"Department of Ophthalmology and Visual Sciences, Washington University in St Louis School of Medicine, St. Louis, USA"},{"author_name":"Martin D Tobin","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"William HJ Norton","author_inst":"The University of Leicester, Division of Biosciences Education"},{"author_name":"Rui Chen","author_inst":"Brunson Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology and Visual Sciences, University of California, Irvine"},{"author_name":"Chiara Batini","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Mervyn G Thomas","author_inst":"University of Leicester"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Deconvolution-based cell-type specific DNA methylation-wide and transcriptome-wide association studies identify risk CpG sites and genes associated with colorectal cancer risk","rel_doi":"10.64898\/2026.06.11.26355460","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355460","rel_abs":"Bulk tissue-based DNA methylation-wide (MWAS) and transcriptome-wide association studies (TWAS) have identified CpG sites and genes associated with colorectal cancer (CRC) risk, but do not account for cellular heterogeneity. To address this, we developed a deconvolution-informed framework to infer cell-type specific DNA methylation and gene expression profiles from bulk normal colon tissues using reference single-cell epigenomic and transcriptomic datasets. We performed cell-type specific MWAS (ctMWAS) using deconvoluted DNA methylation data from 293 normal colon samples and conducted cell-type specific TWAS (ctTWAS) using deconvoluted gene expression data from 707 normal colon samples. Genetically predicted methylation and expression models were integrated with CRC GWAS summary statistics (78,473 cases and 107,143 controls) to identify risk-associated CpG sites and genes. Through ctMWAS, ctTWAS, and colocalization analyses, we identified 178 high-confidence cell-type-specific CpG sites and 68 genes associated with CRC across 26 previously unreported GWAS loci. Through additional integrative methylation-gene analysis, we prioritized 132 candidate risk genes, the majority of which were supported by multi-omics evidence and stage-specific dysregulation across the adenoma-carcinoma and serrated-carcinoma progression pathways. Pathway enrichment analyses implicated pathways involved in DNA double-strand break repair, TP53 regulation, TGF-{beta} signaling, and innate immune responses. Among prioritized genes, 14 were identified as putative druggable targets linked to 90 FDA-approved or clinical-stage drugs. Experimental validation supports an oncogenic role for SF3A3. These findings demonstrate that deconvolution-informed integrative analyses enable cell-type-resolved identification of epigenetic and transcriptional mechanisms underlying CRC susceptibility and provide insights into disease biology, prevention, and therapeutic target discovery.\n\nSignificanceWe developed a deconvolution-informed, cell-type specific multi-omics framework that identified CRC risk-associated CpG sites and susceptibility genes, revealing cell-type specific regulatory mechanisms, key biological pathways, and druggable targets relevant to CRC prevention, therapeutic development, and drug repurposing. Functional validation further supports SF3A3 as a potential oncogenic driver in colorectal carcinogenesis.","rel_num_authors":18,"rel_authors":[{"author_name":"Qing Li","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Lili Xu","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Jifeng Wang","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Chao Li","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Wanqing Wen","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Xiang Shu","author_inst":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Yaohua Yang","author_inst":"Department of Genome Sciences, UVA Comprehensive Cancer Center, School of Medicine, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Xiao-ou Shu","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Qiuyin Cai","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Jirong Long","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Bhuminder Singh","author_inst":"Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Ken S Lau","author_inst":"Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA."},{"author_name":"Zhijun Yin","author_inst":"Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Graham Casey","author_inst":"Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA."},{"author_name":"Mingyang Song","author_inst":"Departments of Epidemiology and Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA"},{"author_name":"Ulrike Peters","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA."},{"author_name":"Wei Zheng","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Xingyi Guo","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Deconvolution-based cell-type specific DNA methylation-wide and transcriptome-wide association studies identify risk CpG sites and genes associated with colorectal cancer risk","rel_doi":"10.64898\/2026.06.11.26355460","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355460","rel_abs":"Bulk tissue-based DNA methylation-wide (MWAS) and transcriptome-wide association studies (TWAS) have identified CpG sites and genes associated with colorectal cancer (CRC) risk, but do not account for cellular heterogeneity. To address this, we developed a deconvolution-informed framework to infer cell-type specific DNA methylation and gene expression profiles from bulk normal colon tissues using reference single-cell epigenomic and transcriptomic datasets. We performed cell-type specific MWAS (ctMWAS) using deconvoluted DNA methylation data from 293 normal colon samples and conducted cell-type specific TWAS (ctTWAS) using deconvoluted gene expression data from 707 normal colon samples. Genetically predicted methylation and expression models were integrated with CRC GWAS summary statistics (78,473 cases and 107,143 controls) to identify risk-associated CpG sites and genes. Through ctMWAS, ctTWAS, and colocalization analyses, we identified 178 high-confidence cell-type-specific CpG sites and 68 genes associated with CRC across 26 previously unreported GWAS loci. Through additional integrative methylation-gene analysis, we prioritized 132 candidate risk genes, the majority of which were supported by multi-omics evidence and stage-specific dysregulation across the adenoma-carcinoma and serrated-carcinoma progression pathways. Pathway enrichment analyses implicated pathways involved in DNA double-strand break repair, TP53 regulation, TGF-{beta} signaling, and innate immune responses. Among prioritized genes, 14 were identified as putative druggable targets linked to 90 FDA-approved or clinical-stage drugs. Experimental validation supports an oncogenic role for SF3A3. These findings demonstrate that deconvolution-informed integrative analyses enable cell-type-resolved identification of epigenetic and transcriptional mechanisms underlying CRC susceptibility and provide insights into disease biology, prevention, and therapeutic target discovery.\n\nSignificanceWe developed a deconvolution-informed, cell-type specific multi-omics framework that identified CRC risk-associated CpG sites and susceptibility genes, revealing cell-type specific regulatory mechanisms, key biological pathways, and druggable targets relevant to CRC prevention, therapeutic development, and drug repurposing. Functional validation further supports SF3A3 as a potential oncogenic driver in colorectal carcinogenesis.","rel_num_authors":18,"rel_authors":[{"author_name":"Qing Li","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Lili Xu","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Jifeng Wang","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Chao Li","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Wanqing Wen","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Xiang Shu","author_inst":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Yaohua Yang","author_inst":"Department of Genome Sciences, UVA Comprehensive Cancer Center, School of Medicine, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Xiao-ou Shu","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Qiuyin Cai","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Jirong Long","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Bhuminder Singh","author_inst":"Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Ken S Lau","author_inst":"Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA."},{"author_name":"Zhijun Yin","author_inst":"Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Graham Casey","author_inst":"Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA."},{"author_name":"Mingyang Song","author_inst":"Departments of Epidemiology and Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA"},{"author_name":"Ulrike Peters","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA."},{"author_name":"Wei Zheng","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Xingyi Guo","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Molecular and ecological determinants of effective reassortment in orthohantaviruses","rel_doi":"10.64898\/2026.06.10.731004","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731004","rel_abs":"A central unsolved problem in RNA virus evolution is understanding why some viral reassortants establish and persist while others do not. To answer this question, we reconstructed reassortant histories across 553 viral genomes from seven orthohantavirus species between 1983 and 2024 using phylogenetic reconciliation and molecular dating. We found that the frequency of retained reassortants varied among orthohantaviruses. For example, reassortment ranged from absent in Andes virus to frequent in Dobrava-Belgrade, Sin Nombre, Seoul, Puumala, and Tula viruses, showing that effective reassortment is not a genus-wide constant. Our Bayesian hierarchical models identified local host overlap as the strongest ecological factor associated with viral reassortment, while cross-segment linkage and terminal RNA structure serve as a molecular filter. We found that the probability of reassortment establishment is highest when ecological opportunity is paired with molecular permissiveness, with their interaction term inferred as the strongest signal in our establishment models (posterior probability = 0.97). These results suggest that reassortment in orthohantaviruses is a sequentially filtered evolutionary process in which divergent lineages must first meet in a host through ecological overlap, exchange segments that are molecularly compatible, and do so within a lineage background permissive to establishment in the host population.","rel_num_authors":10,"rel_authors":[{"author_name":"Ricardo Rivero","author_inst":"Washington State University"},{"author_name":"David Simons","author_inst":"Pennsylvania State University"},{"author_name":"Lambodhar Damodaran","author_inst":"Emory University"},{"author_name":"Irene Karegi","author_inst":"Washington State University"},{"author_name":"Sarah Gurev","author_inst":"Harvard Medical School"},{"author_name":"Daniel J Becker","author_inst":"University of Oklahoma"},{"author_name":"Dan L Warren","author_inst":"Charles Sturt University"},{"author_name":"Nicola F Mueller","author_inst":"University of California San Francisco"},{"author_name":"David A Rasmussen","author_inst":"North Carolina State University"},{"author_name":"Stephanie N Seifert","author_inst":"Washington State University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Molecular and ecological determinants of effective reassortment in orthohantaviruses","rel_doi":"10.64898\/2026.06.10.731004","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731004","rel_abs":"A central unsolved problem in RNA virus evolution is understanding why some viral reassortants establish and persist while others do not. To answer this question, we reconstructed reassortant histories across 553 viral genomes from seven orthohantavirus species between 1983 and 2024 using phylogenetic reconciliation and molecular dating. We found that the frequency of retained reassortants varied among orthohantaviruses. For example, reassortment ranged from absent in Andes virus to frequent in Dobrava-Belgrade, Sin Nombre, Seoul, Puumala, and Tula viruses, showing that effective reassortment is not a genus-wide constant. Our Bayesian hierarchical models identified local host overlap as the strongest ecological factor associated with viral reassortment, while cross-segment linkage and terminal RNA structure serve as a molecular filter. We found that the probability of reassortment establishment is highest when ecological opportunity is paired with molecular permissiveness, with their interaction term inferred as the strongest signal in our establishment models (posterior probability = 0.97). These results suggest that reassortment in orthohantaviruses is a sequentially filtered evolutionary process in which divergent lineages must first meet in a host through ecological overlap, exchange segments that are molecularly compatible, and do so within a lineage background permissive to establishment in the host population.","rel_num_authors":10,"rel_authors":[{"author_name":"Ricardo Rivero","author_inst":"Washington State University"},{"author_name":"David Simons","author_inst":"Pennsylvania State University"},{"author_name":"Lambodhar Damodaran","author_inst":"Emory University"},{"author_name":"Irene Karegi","author_inst":"Washington State University"},{"author_name":"Sarah Gurev","author_inst":"Harvard Medical School"},{"author_name":"Daniel J Becker","author_inst":"University of Oklahoma"},{"author_name":"Dan L Warren","author_inst":"Charles Sturt University"},{"author_name":"Nicola F Mueller","author_inst":"University of California San Francisco"},{"author_name":"David A Rasmussen","author_inst":"North Carolina State University"},{"author_name":"Stephanie N Seifert","author_inst":"Washington State University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"The missing part of the DMSP cycle in coral holobionts: Endozoicomonas exports acetate derived from DMSP degradation","rel_doi":"10.64898\/2026.06.12.731890","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731890","rel_abs":"Endozoicomonas, a dominant symbiotic bacterium in coral holobionts, is noted for its ability to degrade dimethylsulfoniopropionate (DMSP) so as to generate acetate. While acetate is a well-known short-chain fatty acid in metabolic cross-feeding relationships, it remains unclear whether acetate derived from bacterial DMSP degradation is available to corals and their other symbionts. In this study, we employed Endozoicomonas ruthgatesiae strain 8E (herein referred as 8E) as a model to examine availability of DMSP-derived acetate for other symbionts. Using gas chromatography-mass spectrometry (GC-MS), we observed a significant increase in acetate excretion in 8E upon exposure to DMSP. Stable isotope labeling further confirmed that this elevated acetate efflux originated directly from DMSP, suggesting a complete cycle of DMSP-derived carbon among coral symbionts. Transcriptomic analysis revealed that DMSP exposure upregulated dddD expression and triggered a systemic reconfiguration of metabolism, characterized by down-regulation of the TCA cycle and the Pta-AckA pathway, with carbon flux redirected to the glyoxylate shunt. These findings suggest that upon exposure to DMSP, metabolism of 8E shifts from biomass production to DMSP catabolism, resulting in acetate efflux. Notably, we found that elevated temperature diminishes DMSP cleavage activity of 8E, indicating thermal sensitivity of this bacterial metabolic activity.","rel_num_authors":9,"rel_authors":[{"author_name":"Ying-Chieh Chen","author_inst":"Academia Sinica"},{"author_name":"Jui-Hung Yen","author_inst":"Academia Sinica"},{"author_name":"Ting-Chang Hsu","author_inst":"Academia Sinica"},{"author_name":"Wan-Ting Liao","author_inst":"Academia Sinica"},{"author_name":"Hsin-Feng Chang","author_inst":"Academia Sinica"},{"author_name":"Chih-Ying Lu","author_inst":"Academia Sinica"},{"author_name":"Li-Rong Lin","author_inst":"Academia Sinica"},{"author_name":"Sen-Lin Tang","author_inst":"Academia Sinica"},{"author_name":"Po-Shun Chuang","author_inst":"Biodiversity Research Center Academia Sinica"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Comparative genomics of Dolichospermum circinale strains with differential paralytic shellfish toxin profiles","rel_doi":"10.64898\/2026.06.11.731795","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731795","rel_abs":"The cyanobacterium Dolichospermum circinale is a known producer of the neurotoxin saxitoxin and its analogues, collectively known as the paralytic shellfish toxins (PSTs). PSTs vary in potency, and the reported toxin profiles of D. circinale blooms vary in the quantities of individual PSTs, with the regulation of these profiles being poorly understood. In this study, we present the genomes of four D. circinale strains (ACBU01, ACMB03, ACMB13 and FSS-124) with unique PST profiles and perform genome-wide comparisons and specific analysis of the PST-producing biosynthetic gene cluster (sxt) to understand the variability in PST quotas. A reassessment of the previously published D. circinale AWQC131C genome was also performed to collate genomic variation between all strains. Analysis at the nucleotide and amino acid sequence level revealed that toxic strains maintain high genome-wide similarities, corroborated by the analysis of the pan- and variable genomes of each strain. Specifically, the sxt gene sequences were 99-100% identical across all strains. Novel tailoring (sxtSUL, sxtDIOX) and transport (sxtM4) genes were identified within the sxt cluster that were not reported previously in D. circinale. Taken together, these results indicate that the genetic machinery involved in PST production is conserved in this species, suggesting that the regulation of PST biosynthesis in D. circinale does not occur at the genomic level.","rel_num_authors":5,"rel_authors":[{"author_name":"Joao P.A. Pereyra","author_inst":"University of New South Wales"},{"author_name":"Paul D'Agostino","author_inst":"Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)"},{"author_name":"Verlaine J. Timms","author_inst":"University of Newcastle Australia"},{"author_name":"Torsten Thomas","author_inst":"University of New South Wales"},{"author_name":"Brett A Neilan","author_inst":"University of Newcastle"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Mechanistic simulation identifies predictive dose-dependent biomarkers of propofol anesthesia","rel_doi":"10.64898\/2026.06.10.731411","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731411","rel_abs":"Understanding how receptor-level pharmacological modulation reorganizes large-scale brain circuits remains a central challenge in neuropharmacology. We introduce a multiscale mechanistic model with explicit core-matrix thalamocortical architecture, driven solely by GABA-A modulation without parameter fitting to any anesthesia data, to examine how propofol reorganizes brainwide activity from individual receptors to systems-level circuits. The model exhibits anesthetic effects spanning individual synaptic conductances to widespread changes in spiking, field potentials, and coherence. Without training on any task-specific data, our simulation of sensory processing in a standard auditory oddball paradigm matches independent macaque datasets. The same simulation, unmodified, also reproduces changes to functional connectivity in anesthetized humans, exhibiting selective attenuation of matrix thalamocortical loops relative to core loops. Most importantly, the simulation identified a dose-dependent biomarker of propofol concentration - elevated residual inter-stimulus cortical activity - that was subsequently confirmed in empirical macaque data where it had previously gone unnoticed. This simulation-first discovery, arising from mechanistic circuit dynamics rather than statistical comparison of clinical populations, illustrates a generative framework for translating receptor-level modulation into circuit-scale biomarkers with potential applications across predictive neuropharmacology.","rel_num_authors":10,"rel_authors":[{"author_name":"Anand Pathak","author_inst":"Dartmouth"},{"author_name":"Scott L Brincat","author_inst":"MIT"},{"author_name":"Yihan Xiong","author_inst":"Vanderbilt University"},{"author_name":"Haris Organtzidis","author_inst":"Stony Brook University"},{"author_name":"Mason Protter","author_inst":"Stony Brook University"},{"author_name":"Vincent Du","author_inst":"Stony Brook University"},{"author_name":"Helmut H Strey","author_inst":"Stony Brook University"},{"author_name":"Lilianne Rivka Mujica-Parodi","author_inst":"Stony Brook University"},{"author_name":"Earl K Miller","author_inst":"MIT"},{"author_name":"Richard Granger","author_inst":"Dartmouth"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Scaling Across Environments: Temperature and nutrition independently shape the genetics of size plasticity and morphological scaling","rel_doi":"10.64898\/2026.06.10.731218","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731218","rel_abs":"Across animals, variation in adult body size is accompanied by coordinated variation in the size of individual morphological traits. However, the same morphological trait can scale differently with body size depending on what drives the size variation. In Drosophila melanogaster, for example, wing size scales differently with body size when size varies because of developmental nutrition versus developmental temperature. Whether the genetic basis of size plasticity and scaling is shared across different environmental regulators of size remains unclear, but is central to predicting how selection acts on the developmental mechanisms that regulate trait size, plasticity and morphological scaling. Using ~200 isogenic D. melanogaster lineages, we measured wing and leg size across nutritional and thermal treatments. For each lineage, we estimated nutritional and thermal plasticity for both traits, as well as the wing-leg individual-level scaling relationship, or ILSR, generated by each environmental source of size variation. We found extensive genetic variation in both thermal and nutritional plasticity for wings and legs, and in the slope of the ILSR between them. However, a lineages thermal plasticity was genetically uncorrelated with its nutritional plasticity for either trait, and we detected no genetic correlation between the slopes of thermal and nutritional wing-leg ILSRs. We also found no genetic correlation in the slope of nutritional wing-leg ILSRs across temperatures. Thus, the slope of a lineages nutritional ILSR at 17{degrees}C was not predictive of its slope at 25{degrees}C of 28{degrees}C. Nevertheless, the overall pattern of nutritional ILSRs was conserved across temperatures. These results suggest that the genetic architecture of size plasticity and scaling depends on the environmental source of size variation. Consequently, the evolutionary response of scaling to selection in heterogeneous environments may not be predictable from genetic variation measured in any single environment.","rel_num_authors":5,"rel_authors":[{"author_name":"Shampa M Ghosh","author_inst":"Kalinga Institute of Industrial Technology (KIIT),"},{"author_name":"Isabelle M Vea","author_inst":"University of Illinois Chicago"},{"author_name":"Austin S Wilcox","author_inst":"University of Illinois Chicago"},{"author_name":"W.Anthony Frankino","author_inst":"University of Houston"},{"author_name":"Alexander W Shingleton","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Genetic Modeling of Dyadic Behavioral Traits: Implications for Estimation and Interpretation of Variance Components","rel_doi":"10.64898\/2026.06.10.731434","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731434","rel_abs":"Studying the genomic control of dyadic social interactions is gaining traction in animal genetics. However, genetic modeling of social interactions poses several challenges, one of which is whether social interactions should be treated as dyadic traits or as aggregated traits at the individual level. In this study, we systematically compared two approaches: dyadic models using dyadic traits and marginal models using marginally aggregated traits and we derived the algebraic relationships between their variance components. In the application, we used a published dataset on post-mixing aggression in pigs, including both directed and undirected aggression records collected during the 9-hour period after mixing among 797 finishing pigs in 59 social groups, as an example to show how model choice can affect variance estimation. Results showed that dyadic models can estimate genetic effects and permanent environmental effects by exploiting repeated dyadic interaction records, thereby enabling a more complete understanding of the sources of variation underlying social interactions. In contrast, marginal models can bias the estimation and interpretation of genetic components, as the aggregated genetic variance may be confounded with other variance components due to the aggregation of dyadic traits. Marginal models may also lead to overestimation of social group and residual variance. These results can provide useful guidance for choosing appropriate modeling strategies for social interaction traits.","rel_num_authors":3,"rel_authors":[{"author_name":"Xiaohan Jiang","author_inst":"Iowa State University"},{"author_name":"Janice Siegford","author_inst":"Michigan State University"},{"author_name":"Juan Pedro Steibel","author_inst":"Iowa State University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Genetic Modeling of Dyadic Behavioral Traits: Implications for Estimation and Interpretation of Variance Components","rel_doi":"10.64898\/2026.06.10.731434","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731434","rel_abs":"Studying the genomic control of dyadic social interactions is gaining traction in animal genetics. However, genetic modeling of social interactions poses several challenges, one of which is whether social interactions should be treated as dyadic traits or as aggregated traits at the individual level. In this study, we systematically compared two approaches: dyadic models using dyadic traits and marginal models using marginally aggregated traits and we derived the algebraic relationships between their variance components. In the application, we used a published dataset on post-mixing aggression in pigs, including both directed and undirected aggression records collected during the 9-hour period after mixing among 797 finishing pigs in 59 social groups, as an example to show how model choice can affect variance estimation. Results showed that dyadic models can estimate genetic effects and permanent environmental effects by exploiting repeated dyadic interaction records, thereby enabling a more complete understanding of the sources of variation underlying social interactions. In contrast, marginal models can bias the estimation and interpretation of genetic components, as the aggregated genetic variance may be confounded with other variance components due to the aggregation of dyadic traits. Marginal models may also lead to overestimation of social group and residual variance. These results can provide useful guidance for choosing appropriate modeling strategies for social interaction traits.","rel_num_authors":3,"rel_authors":[{"author_name":"Xiaohan Jiang","author_inst":"Iowa State University"},{"author_name":"Janice Siegford","author_inst":"Michigan State University"},{"author_name":"Juan Pedro Steibel","author_inst":"Iowa State University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Antigen Stimulation Reactivates HIV-1 Proviruses Despite Integration in Repressive Chromatin","rel_doi":"10.64898\/2026.06.11.731680","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731680","rel_abs":"Intact HIV-1 proviruses become progressively enriched in transcriptionally repressive genomic regions during long-term antiretroviral therapy (ART) and in elite controllers, raising questions about their capacity for reactivation in vivo. We used an antigen-restricted quantitative viral outgrowth assay (ag qVOA) to test whether cognate antigen stimulation can reverse latency of proviruses integrated within repressive chromatin. Using cells from two people with HIV (PWH) on ART, one on long-term treatment and one an elite controller, we show that antigen-specific stimulation induces viral outgrowth from intact proviruses integrated into a pericentromeric transition region and a zinc finger gene, respectively. These findings demonstrate that antigen recognition can overcome epigenetic constraints to reactivate proviruses with low inducibility and suggest that proviruses in so-called \"deeper latency\" may contribute to residual viremia and viral rebound following treatment interruption.","rel_num_authors":14,"rel_authors":[{"author_name":"Angelica Camilo-Contreras","author_inst":"Johns Hopkins University"},{"author_name":"Filippo Dragoni","author_inst":"Johns Hopkins University"},{"author_name":"Hao Zhang","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Junlin Zhuo","author_inst":"Johns Hopkins University"},{"author_name":"Daniel F Smith","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Arturo Casadevall","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Jun Lai","author_inst":"Johns Hopkins School of Medicine: The Johns Hopkins University School of Medicine"},{"author_name":"Pablo Tebas","author_inst":"University of Pennsylvania"},{"author_name":"Janet D Siliciano","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Robert F Siliciano","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Stuart Ray","author_inst":"Johns Hopkins University"},{"author_name":"Luis J. Montaner","author_inst":"The Wistar Institute"},{"author_name":"Joel N. Blankson","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Francesco Roberto Simonetti","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Type I interferon primes the alveolar epithelium to receive reparative signals from tissue-resident macrophages","rel_doi":"10.64898\/2026.06.10.731366","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731366","rel_abs":"Lung repair in response to viral infection requires integrated communication between epithelial and immune compartments, yet the impact of antiviral mediators on epithelial regenerative capacity remains poorly defined. Here, we demonstrate that type I interferon (IFN-I) signaling primes the lung for alveolar renewal following viral challenge. IFN-I contributes to the induction of an interferon-stimulated gene (ISG)hi Sca-1Pos population of alveolar type II (ATII) epithelial cells. Sca-1Pos ATIIs exhibit enhanced proliferative capacity and increased organoid-forming efficiency compared with their Sca-1Neg counterparts. Viral challenge concurrently drives phenotypic reprogramming of tissue-resident alveolar macrophages (trAMs). Sca-1Pos ATIIs display heightened responsiveness to oncostatin M (OSM) and, following viral challenge, require trAM-derived OSM for their proliferation. Together, these findings reveal that viral stimuli induce coordinated IFN-I-dependent epithelial and macrophage states that poise the lung for regeneration, positioning IFN-I not only as a central antiviral defense mechanism but as a priming signal that prepares lung tissue for renewal.","rel_num_authors":18,"rel_authors":[{"author_name":"Alan Y Baez Vazquez","author_inst":"Harvard University, Harvard Medical School"},{"author_name":"Daisy A Hoagland","author_inst":"Harvard Medical School"},{"author_name":"Alexander O Mann","author_inst":"Harvard Medical School"},{"author_name":"Yunkang Lin","author_inst":"Harvard Medical School"},{"author_name":"Susanna M Dang","author_inst":"Boston Children's Hospital"},{"author_name":"Max Hauptschein","author_inst":"Harvard Medical School"},{"author_name":"Louison Thorens","author_inst":"Northeastern University"},{"author_name":"Shahinoor Begum","author_inst":"Harvard Medical School"},{"author_name":"Martha A Castro","author_inst":"Harvard Medical School"},{"author_name":"Patricia Rodriguez-Morales","author_inst":"Harvard Medical School"},{"author_name":"Alicia Lai","author_inst":"Harvard Medical School"},{"author_name":"Irving Barrera","author_inst":"Broad Institute"},{"author_name":"Dawei Sun","author_inst":"Broad Institute"},{"author_name":"Andrea Shehaj","author_inst":"Boston Children's Hospital"},{"author_name":"Fei Chen","author_inst":"Broad Institute"},{"author_name":"Christophe Benoist","author_inst":"Harvard Medical School"},{"author_name":"Carla F Kim","author_inst":"Boston Children's Hospital"},{"author_name":"Ruth A Franklin","author_inst":"Harvard University, Harvard Medical School"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Type I interferon primes the alveolar epithelium to receive reparative signals from tissue-resident macrophages","rel_doi":"10.64898\/2026.06.10.731366","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731366","rel_abs":"Lung repair in response to viral infection requires integrated communication between epithelial and immune compartments, yet the impact of antiviral mediators on epithelial regenerative capacity remains poorly defined. Here, we demonstrate that type I interferon (IFN-I) signaling primes the lung for alveolar renewal following viral challenge. IFN-I contributes to the induction of an interferon-stimulated gene (ISG)hi Sca-1Pos population of alveolar type II (ATII) epithelial cells. Sca-1Pos ATIIs exhibit enhanced proliferative capacity and increased organoid-forming efficiency compared with their Sca-1Neg counterparts. Viral challenge concurrently drives phenotypic reprogramming of tissue-resident alveolar macrophages (trAMs). Sca-1Pos ATIIs display heightened responsiveness to oncostatin M (OSM) and, following viral challenge, require trAM-derived OSM for their proliferation. Together, these findings reveal that viral stimuli induce coordinated IFN-I-dependent epithelial and macrophage states that poise the lung for regeneration, positioning IFN-I not only as a central antiviral defense mechanism but as a priming signal that prepares lung tissue for renewal.","rel_num_authors":18,"rel_authors":[{"author_name":"Alan Y Baez Vazquez","author_inst":"Harvard University, Harvard Medical School"},{"author_name":"Daisy A Hoagland","author_inst":"Harvard Medical School"},{"author_name":"Alexander O Mann","author_inst":"Harvard Medical School"},{"author_name":"Yunkang Lin","author_inst":"Harvard Medical School"},{"author_name":"Susanna M Dang","author_inst":"Boston Children's Hospital"},{"author_name":"Max Hauptschein","author_inst":"Harvard Medical School"},{"author_name":"Louison Thorens","author_inst":"Northeastern University"},{"author_name":"Shahinoor Begum","author_inst":"Harvard Medical School"},{"author_name":"Martha A Castro","author_inst":"Harvard Medical School"},{"author_name":"Patricia Rodriguez-Morales","author_inst":"Harvard Medical School"},{"author_name":"Alicia Lai","author_inst":"Harvard Medical School"},{"author_name":"Irving Barrera","author_inst":"Broad Institute"},{"author_name":"Dawei Sun","author_inst":"Broad Institute"},{"author_name":"Andrea Shehaj","author_inst":"Boston Children's Hospital"},{"author_name":"Fei Chen","author_inst":"Broad Institute"},{"author_name":"Christophe Benoist","author_inst":"Harvard Medical School"},{"author_name":"Carla F Kim","author_inst":"Boston Children's Hospital"},{"author_name":"Ruth A Franklin","author_inst":"Harvard University, Harvard Medical School"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Gonadal regulation of sex-specific immunity in tuberculosis: enhanced lymphocyte function in females and dysfunctional myeloid responses in males","rel_doi":"10.64898\/2026.06.11.731661","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731661","rel_abs":"Tuberculosis (TB), the worlds deadliest infection, shows higher prevalence and mortality in males than females (M\/F ratio >1.7). Using Four Core Genotype (FCG) mice to decouple gonadal from chromosomal sex (XX, XY gonadal males and XX, XY gonadal females), we show that gonadal males develop accelerated disease driven by dysfunctional myeloid responses rather than impaired bacterial recognition. Both XX and XY males exhibited increased mortality, higher Mycobacterium tuberculosis (Mtb) burden, and severe lung pathology. Mechanistically, gonadal male susceptibility involved early myeloid priming, excessive neutrophil recruitment, CCR2 monocyte accumulation, and hyperinflammation, with enhanced neutrophil extracellular trap (NET) formation and disorganized granulomas, implicating testes and androgens as key drivers of male susceptibility. While XY gonadal females were less susceptible, XX gonadal females showed the greatest resistance, associated with coordinated T- and B-cell responses and enhanced B-cell follicle formation. Together, these findings identify gonad-driven myeloid dysregulation as a central mechanism underlying male TB susceptibility.","rel_num_authors":13,"rel_authors":[{"author_name":"Manish Gupta","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Nishtha Nayyar","author_inst":"ICAR-NBAIR, Bengaluru, India"},{"author_name":"Jessica Shen","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Shichun Lun","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Sabal Chaulagain","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Nikita Mangla","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Oscar Nino Meza","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Stefanie Krug","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Geetha Srikrishna","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Joseph P. Hoffmann","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Eileen Scully","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Sabra L. Klein","author_inst":"Johns Hopkins Bloomberg School of Public Health; Johns Hopkins University School of Medicine"},{"author_name":"William Bishai","author_inst":"Johns Hopkins School of Medicine"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Monoclonal nephritic factors reveal insights into C3 convertase dynamics and dysregulation","rel_doi":"10.64898\/2026.06.11.731599","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731599","rel_abs":"C3- and C5-nephritic factors are potent but poorly understood autoantibodies that dysregulate complement convertases. To date, their underlying mechanisms of action, epitopes, and sequences remain unknown. To address this knowledge gap, we immune profiled B cells from a nephritic factor-positive C3 glomerulopathy patient and identified the first monoclonal C3- and C5-nephritic factors. We present the structure of a C3-nephritic factor bound to a C3 convertase with the convertase protease domain unexpectedly rotated and inhibited. This rotation advances our understanding of complement convertase progression and decay, explains disease-associated convertase variants, and reveals the molecular mechanism by which nephritic factors can either activate or inhibit convertase activity. We also detail heterogeneity within and between C3- and C5-nephritic factors in terms of convertase binding, stabilizing capacity, regulator inhibition, fluid-phase activation, and disease contribution. These findings improve stratification of patients with C3 glomerulopathy, redefine basic C3 convertase dynamics, and provide insights into antibody-mediated modulation of the complement system.","rel_num_authors":26,"rel_authors":[{"author_name":"Seth J Welsh","author_inst":"University of Iowa"},{"author_name":"Christopher T Culek","author_inst":"University of Iowa"},{"author_name":"Zhen Xu","author_inst":"University of Iowa"},{"author_name":"Hector Martin Merinero","author_inst":"University of Iowa"},{"author_name":"Jannik Sichau","author_inst":"University of Ulm Medical Centre"},{"author_name":"Daniel Walls","author_inst":"University of Iowa"},{"author_name":"Renee Goodfellow","author_inst":"University of Iowa"},{"author_name":"Dingwu Shao","author_inst":"University of Iowa"},{"author_name":"Cobey Donelson","author_inst":"University of Iowa"},{"author_name":"Kameron Kruger","author_inst":"University of Iowa"},{"author_name":"Sarah Roberts","author_inst":"University of Iowa"},{"author_name":"Nicole C Meyer","author_inst":"University of Iowa"},{"author_name":"Angela F.M. Nelson","author_inst":"University of Iowa"},{"author_name":"Anna R Carmen","author_inst":"University of Iowa"},{"author_name":"Sydney S Jellison","author_inst":"University of Iowa"},{"author_name":"Stephanie N Cook","author_inst":"University of Iowa"},{"author_name":"Monica D Hall","author_inst":"University of Iowa"},{"author_name":"Rebecca Franklin","author_inst":"University of Iowa"},{"author_name":"Tina Liu","author_inst":"University of Iowa"},{"author_name":"Jill Hall","author_inst":"University of Iowa"},{"author_name":"Lauren O Fergus","author_inst":"University of Iowa"},{"author_name":"Nicholas J Schnicker","author_inst":"University of Iowa"},{"author_name":"Christoph Q Schmidt","author_inst":"University of Ulm Medical Centre"},{"author_name":"Yuzhou Zhang","author_inst":"University of Iowa"},{"author_name":"Carla M Nester","author_inst":"University of Iowa"},{"author_name":"Richard J.H. Smith","author_inst":"University of Iowa"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Effects of Left Atrial Wall Thickness on Myocardial Mechanics and Blood Dynamics using Multiscale Modeling","rel_doi":"10.64898\/2026.06.09.731221","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731221","rel_abs":"Purpose: Patient-specific models of left atrial (LA) mechanics often assume uniform left atrial wall thickness (LAWT), but the effect of LAWT on the mechanics and hemodynamics remains less quantified. Methods: Four LA myocardium models were built from gated CTA images: a baseline variable thickness (VT#0), two reduced-dilation variants, and a 2 mm uniform thickness model. Multiscale mechanics and blood flow simulations were performed across all the thickness variants using model parameters personalized on the baseline model. Predicted displacements, wall stresses and strains, and hemodynamics were compared. Results: Across all LAWT variants, myocardial volume spanned 14.4--19.9 mL (38%), while cavity volume remained mostly within 5% of image data throughout the cardiac cycle. Circulatory system output, myocardial displacements, and strains varied by 5--6% relative to the baseline model. Instantaneous stresses increased by up to 19% in the thinner variable thickness models and decreased by up to 16% in the uniformly thick case. Globally, the area under low time-averaged wall shear stress (TAWSS) varied between 23% and 30% across all thickness variants, while LA exposed to elevated oscillatory shear index (OSI) increased from nearly 6% to 19%. Over 90% of LAA was exposed to low shear, but the high-OSI area increased from 7% in VT#0 to over 30% in Uniform. Conclusion: A personalized multiscale modeling framework was leveraged to demonstrate that the left atrial myocardial stresses and oscillatory shear had a greater sensitivity to local wall thickness representation compared to cavity volumes, tissue displacements, strains, and mean blood shear.","rel_num_authors":4,"rel_authors":[{"author_name":"Boyang Gan","author_inst":"Columbia University"},{"author_name":"Lei Shi","author_inst":"Kennesaw State University"},{"author_name":"Ian Y. Chen","author_inst":"Stanford University School of Medicine"},{"author_name":"Vijay Vedula","author_inst":"Columbia University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Co-Expressed MicroRNAs Identify Potential Mechanisms Underlying Risk for Multimorbid Depression and Type 2 Diabetes in Midlife Women","rel_doi":"10.64898\/2026.06.10.731370","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731370","rel_abs":"Background Women are disproportionately affected by multimorbid depression and type 2 diabetes (T2D), with prevalence peaking during midlife (40-64 years), a biologically dynamic timeframe due to changes associated with reproductive aging. Yet, phenotypic and mechanistic factors contributing to midlife women's disproportionate risk for co-occurrence remain poorly defined. We previously identified co-expressed microRNAs (miRs) in midlife women with prediabetes that increased odds of assignment to a high psychometabolic risk phenotype. Here, we extend these findings by characterizing putative mRNA targets of these co-expressed miRs and pathways overrepresented among mRNAs, providing insights into potential mechanisms underlying psychometabolic risk in midlife women. Methods This study included baseline data from midlife women (ages 40-64 years) with prediabetes who participated in the Diabetes Prevention Program (DPP) (n = 603). In silico analyses were performed using miRTarBase to identify mRNAs regulated by 3 or more of the miRs that most prominently loaded a principal component previously identified to increase odds of assignment to a high psychometabolic risk phenotype defined in this sample. Pathway enrichment analysis was conducted to assess for overrepresentation of KEGG pathways among predicted mRNA targets. To enhance interpretability, pathways were thematically clustered based on their evidenced role in human physiology. Results We identified a total of 13 mRNAs targeted by co-expressed miRs associated with increased odds of assignment to a high psychometabolic risk phenotype in midlife women with prediabetes. Pathway enrichment analysis revealed a total of 71 KEGG pathways with overrepresentation of identified mRNA targets. Four overarching biological themes emerged, reflecting involvement of metabolic, inflammatory, endocrine, and stress\/biological weathering-related processes. Conclusions Experimentally validated mRNA targets related biological pathways were identified, providing multisystem insights into potential mechanisms underlying risk for multimorbid depression and T2D in midlife women. Findings offer mechanistic targets for experimental validation and future precision health research focused on this high-risk population. Overall, this work positions the utility of miRs as context-sensitive biomarkers in the characterization of risk for complex, multimorbid conditions in women during biologically dynamic timeframes. Keywords: biomarkers, depression, type 2 diabetes, multimorbidity risk, women's health","rel_num_authors":7,"rel_authors":[{"author_name":"Kayla  D. D. Longoria","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Benjamin Stroebel","author_inst":"University of California, San Francisco"},{"author_name":"Meghana Gadgil","author_inst":"University of California, San Francisco"},{"author_name":"Sandra Weiss","author_inst":"University of California, San Francisco"},{"author_name":"Kimberly A. Lewis","author_inst":"UCLA Health"},{"author_name":"Nicole Perez","author_inst":"New York University"},{"author_name":"Elena Flowers","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"LizardLens: A Two-Stage Deep Learning Pipeline for Detecting and Classifying Similar Species in Visually Complex Environments","rel_doi":"10.64898\/2026.06.10.731342","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731342","rel_abs":"Community science platforms like iNaturalist generate unprecedented volumes of biodiversity data, but their scientific utility depends critically on accurate species identification--a persistent challenge when contributors often lack taxonomic expertise. We developed \"LizardLens\", a two-stage machine learning pipeline that decouples object detection from species classification to enable fine-grained identification of morphologically similar organisms in visually complex field photographs. Using 10,000 verified iNaturalist images of five Anolis lizard species in Florida, we trained specialized YOLO-based detection and Swin Transformer classification models and compared performance against state-of-the-art single-stage architectures. Our two-stage pipeline achieved 83.0% Top-1 accuracy and a macro-averaged F1-score of 89.0%, indicating strong precision-recall performance across species and outperforming single-stage YOLOv8 and YOLOv12 models across all evaluation metrics for all species, with relative improvements ranging from 10.5% to 13.2%. Gradient-weighted Class Activation Mapping (Grad-CAM) indicated that the models predictions were consistently associated with regions corresponding to diagnostic morphological (e.g., head shape, feet, and limb lengths) and pattern features (e.g., ocular rings and body patterning), providing evidence that LizardLens leverages biologically relevant visual cues consistent with those used by expert taxonomists. Error analysis identified partial occlusion and multiple proximate individuals as primary sources of missed detections, while spurious detections of lizard-like environmental features (e.g., sticks, bark) represented the dominant false positive error mode. We deployed LizardLens as an accessible web application featuring interactive bounding box correction, ranked species predictions with confidence scores, directly supporting the \"Lizards on the Loose\" middle school community science initiative. By combining technical advances in fine-grained visual classification with user-centered design, LizardLens demonstrates how machine learning can simultaneously enhance data quality for biodiversity monitoring and provide authentic scientific experiences for student participants. Our approach is generalizable to other small-bodied organisms in complex habitats and provides a framework for translating computer vision advances into practical tools for community science and conservation.","rel_num_authors":8,"rel_authors":[{"author_name":"Wen Han Chia","author_inst":"Georgia Institute of Technology"},{"author_name":"Ilia Jahanshahi","author_inst":"Iowa State University"},{"author_name":"Le Yang Loh","author_inst":"Georgia Institute of Technology"},{"author_name":"Anqi Zheng","author_inst":"Georgia Institute of Technology"},{"author_name":"Niral Verma","author_inst":"Georgia Institute of Technology"},{"author_name":"Stephen Mussman","author_inst":"Georgia Institute of Technology"},{"author_name":"Breanna Shi","author_inst":"Georgia Institute of Technology"},{"author_name":"James T. Stroud","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"LizardLens: A Two-Stage Deep Learning Pipeline for Detecting and Classifying Similar Species in Visually Complex Environments","rel_doi":"10.64898\/2026.06.10.731342","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731342","rel_abs":"Community science platforms like iNaturalist generate unprecedented volumes of biodiversity data, but their scientific utility depends critically on accurate species identification--a persistent challenge when contributors often lack taxonomic expertise. We developed \"LizardLens\", a two-stage machine learning pipeline that decouples object detection from species classification to enable fine-grained identification of morphologically similar organisms in visually complex field photographs. Using 10,000 verified iNaturalist images of five Anolis lizard species in Florida, we trained specialized YOLO-based detection and Swin Transformer classification models and compared performance against state-of-the-art single-stage architectures. Our two-stage pipeline achieved 83.0% Top-1 accuracy and a macro-averaged F1-score of 89.0%, indicating strong precision-recall performance across species and outperforming single-stage YOLOv8 and YOLOv12 models across all evaluation metrics for all species, with relative improvements ranging from 10.5% to 13.2%. Gradient-weighted Class Activation Mapping (Grad-CAM) indicated that the models predictions were consistently associated with regions corresponding to diagnostic morphological (e.g., head shape, feet, and limb lengths) and pattern features (e.g., ocular rings and body patterning), providing evidence that LizardLens leverages biologically relevant visual cues consistent with those used by expert taxonomists. Error analysis identified partial occlusion and multiple proximate individuals as primary sources of missed detections, while spurious detections of lizard-like environmental features (e.g., sticks, bark) represented the dominant false positive error mode. We deployed LizardLens as an accessible web application featuring interactive bounding box correction, ranked species predictions with confidence scores, directly supporting the \"Lizards on the Loose\" middle school community science initiative. By combining technical advances in fine-grained visual classification with user-centered design, LizardLens demonstrates how machine learning can simultaneously enhance data quality for biodiversity monitoring and provide authentic scientific experiences for student participants. Our approach is generalizable to other small-bodied organisms in complex habitats and provides a framework for translating computer vision advances into practical tools for community science and conservation.","rel_num_authors":8,"rel_authors":[{"author_name":"Wen Han Chia","author_inst":"Georgia Institute of Technology"},{"author_name":"Ilia Jahanshahi","author_inst":"Iowa State University"},{"author_name":"Le Yang Loh","author_inst":"Georgia Institute of Technology"},{"author_name":"Anqi Zheng","author_inst":"Georgia Institute of Technology"},{"author_name":"Niral Verma","author_inst":"Georgia Institute of Technology"},{"author_name":"Stephen Mussman","author_inst":"Georgia Institute of Technology"},{"author_name":"Breanna Shi","author_inst":"Georgia Institute of Technology"},{"author_name":"James T. Stroud","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells","rel_doi":"10.64898\/2026.06.11.731694","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731694","rel_abs":"Cytokine production is a core function of effector T cells, yet the mechanisms that regulate cytokine output during an immune response remain incompletely understood. Here, we identify citrate compartmentalization as a cellular mechanism by which CD8+ T cells couple cytokine production to glucose availability. Under glucose-replete conditions, citrate transport from the mitochondria to the cytosol by the citrate carrier SLC25A1 suppresses calcium-dependent transcription factor activity in effector T cells. Either reducing glucose availability or blocking the exchange of citrate across the mitochondrial membrane raises free cytosolic calcium, thereby driving nuclear localization of Nuclear Factor of Activated T cells (NFAT)-family transcription factors and sustaining cytokine production. As a calcium-chelating metabolite, we show that citrate buffers free cytosolic calcium, thereby linking calcium-dependent signaling to mitochondrial fuel oxidation. We also identify signatures of this regulatory mechanism across hundreds of human cancer cell lines, where there are negative associations between citrate-derived metabolites and calcium-dependent transcriptional programs, and within the spatial organization of human tumors. These findings identify cytosolic citrate as a broadly conserved metabolic rheostat coupling glucose availability to calcium signaling. By adding calcium signaling to the known functions regulated by SLC25A1, our work reveals a mechanism by which mitochondria adaptively tune cytokine expression and other calcium-dependent programs in response to local metabolic conditions, such as nutrients that are available within a tissue or tumor.","rel_num_authors":7,"rel_authors":[{"author_name":"Andrea L. Cote","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Claire L. McIntyre","author_inst":"Ragon Institute of Mass General Brigham, MIT, and Harvard"},{"author_name":"Joshua A. Acklin","author_inst":"Ragon Institute of Mass General Brigham, MIT, and Harvard"},{"author_name":"Lillian R. Delacruz","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Yunping Qiu","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Irwin J. Kurland","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Alison E. Ringel","author_inst":"Ragon Institute of Mass General Brigham, MIT, and Harvard"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"PN6047 Demonstrates Broad Preclinical Efficacy in Headache Models as a Novel Delta-Opioid Receptor Agonist","rel_doi":"10.64898\/2026.06.09.729278","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.729278","rel_abs":"BackgroundThe Delta-opioid receptor (DOR) has gained attention as a promising target for the treatment of migraine and headache disorders. This is largely attributed to its unique pharmacological profile, which suggests that DOR-targeting treatment offers effective therapeutic benefit with a lower risk of medication overuse headache (MOH), reduced abuse liability, and minimal potential for physical dependence. These advantages have driven the development of a novel DOR agonist PN6047 (3-[[4-(dimethylcarbamoyl) phenyl]-[1-(thiazol-5-ylmethyl)-4-piperidylidene] methyl]benzamide), which has completed Phase I clinical trial and showed a favorable safety and tolerability profile. Although PN6047 has shown promising effects in neuropathic pain models, its efficacy in preclinical models of headache-associated pain remains to be evaluated. Here, we investigated the effects of PN6047 in models of migraine-associated pain and aura as well as post-traumatic headache (PTH) and MOH.\n\nMethodsC57BL6\/J mice were used to examine the effects of PN6047 in the following migraine models: chronic intermittent nitroglycerin (NTG)-induced migraine-associated pain, PTH, KCl-induced cortical spreading depression (CSD), and optogenetic evoked CSD in a freely behaving transgenic mice expressing ChR2-eYFP. In addition, we tested whether chronic PN6047 induced MOH and whether it could prevent the development of MOH induced by sumatriptan.\n\nResultsA single injection of PN6047 blocked chronic cephalic allodynia established by chronic intermittent NTG and PTH. Moreover, chronic PN6047 treatment prevented the development of MOH induced by sumatriptan, without causing MOH itself. In addition, PN6047 significantly reduced the number of CSD events in the KCl-induced CSD model, and delayed CSD onset triggered in freely behaving mice along with subsequent CSD-evoked allodynia.\n\nConclusionPN6047, a novel DOR agonist, strikingly blocks headache-associated mechanism and symptoms in preclinical models of chronic migraine, migraine aura, PTH, and MOH. Importantly, prolonged PN6047 treatment did not induce MOH or analgesic tolerance. Together, these data demonstrate that despite the distinct mechanisms underlying migraine and headache disorder, PN6047 exhibits robust efficacy without inducing MOH, and displays a favorable safety and tolerability profile.","rel_num_authors":11,"rel_authors":[{"author_name":"Yaseen Awad-Igbaria","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Yanping Zhang","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Mattin Aframian","author_inst":"University of California Los Angeles"},{"author_name":"Guido  C. Faas","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Andrew Charles","author_inst":"University of California Los Angeles"},{"author_name":"Serapio M Baca","author_inst":"University of Virginia"},{"author_name":"Emily Jutkiewicz","author_inst":"University of Michigan"},{"author_name":"Bengt von Mentzer","author_inst":"Pharmnovo"},{"author_name":"John Traynor","author_inst":"University of Michigan"},{"author_name":"David Kendall","author_inst":"Pharmnovo"},{"author_name":"Amynah A Pradhan","author_inst":"Washington University School of Medicine in St. Louis"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Evaluating cell type annotations in single-cell omics in the absence of ground truth","rel_doi":"10.64898\/2026.06.10.731285","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731285","rel_abs":"Accurate cell type annotation is essential for single-cell transcriptomics, directly shaping downstream analyses and biological interpretations. Yet, objective evaluation of annotation quality remains a major challenge. Here, we argue that a cell type or cell state label has practical utility only if it captures a molecular pattern that is reproducible across biological replicates. Based on this principle, we introduce inter-sample consistency (ISC), a quantitative framework to assess annotation quality in single-cell RNA-seq datasets. Unlike existing cluster validation approaches, ISC distinguishes annotations that generalize across samples and individuals from those driven by technical or unwanted variation, thereby providing principled criteria for annotation quality and transferability. When applied to published single-cell atlases, ISC reveals widespread reproducibility gaps and provides actionable guidance for repairing inconsistent annotations. Notably, ISC enables benchmarking of automated cell type annotation tools even when ground-truth labels are unavailable, providing interpretable metrics to guide their development and evaluation. Implemented as the scTypeEval Bioconductor package, this framework offers a broadly applicable resource for evaluating and improving cell type annotations in single-cell RNA-seq experiments.","rel_num_authors":3,"rel_authors":[{"author_name":"Josep Garnica","author_inst":"University of Geneva"},{"author_name":"Massimo Andreatta","author_inst":"University of Geneva"},{"author_name":"Santiago J Carmona","author_inst":"University of Geneva"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"LizardMorph: A generalizable machine learning framework for automated anatomical landmark detection in digital images","rel_doi":"10.64898\/2026.06.10.731351","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731351","rel_abs":"Morphological measurements underpin a wide range of ecological and evolutionary research, yet the manual landmarking workflows on which most morphometric studies depend remain a persistent bottleneck that limits both the pace and scale of biological research. Machine learning offers compelling solutions, but most automated landmarking tools require substantial computational expertise, creating a gap between technical capability and practical adoption by biologists. Here, we present LizardMorph, an integrated machine learning pipeline and web-based interface for semi-automated anatomical landmark detection on biological images. LizardMorph couples a fine-tuned ML-Morph shape predictor with an accessible, browser-based interface that enables researchers to upload images, review automated landmark predictions, interactively correct outliers through point-and-click editing, and export results in standard morphometric formats--all without programming expertise or local software installation. Using dorsal X-ray radiographs of Anolis lizards with 34 anatomical landmarks as a proof-of-concept, we show that the ML-Morph model achieves high predictive accuracy, with landmarks on well-defined skeletal structures predicted with 100% accuracy within a 1 mm tolerance threshold. A controlled user study comparing LizardMorph against traditional manual landmarking (TpsDig2) demonstrated significant efficiency gains: experienced annotators completed LizardMorph landmark verification 37.5% faster than manual annotation. Extrapolated to batch processing 1,000 lizards, LizardMorph saves experienced researchers approximately 6.5 hours of manual processing time. Critically, LizardMorph implements a human-in-the-loop design in which automated predictions serve as editable starting points, preserving researcher oversight and enabling correction of the occasional large-error outliers that would be unacceptable in fully automated workflows. LizardMorph is freely available as an open-source tool and provides a replicable framework for developing ML-assisted annotation tools that can democratize access to high-quality morphometric analysis across diverse biological research communities.","rel_num_authors":8,"rel_authors":[{"author_name":"Mercedes Quintana","author_inst":"Georgia Institute of Technology"},{"author_name":"Le Yang Loh","author_inst":"Georgia Institute of Technology"},{"author_name":"Ayush Parikh","author_inst":"Georgia Institute of Technology"},{"author_name":"Jonathan J. Suh","author_inst":"Georgia Institute of Technology"},{"author_name":"Victoria Chavez","author_inst":"Northwestern University"},{"author_name":"Arthur Porto","author_inst":"University of Florida"},{"author_name":"Breanna Shi","author_inst":"Georgia Institute of Technology"},{"author_name":"James T. Stroud","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Connectome wiring shapes population-level neural geometry in the Drosophila visual system","rel_doi":"10.64898\/2026.06.10.731214","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731214","rel_abs":"What does biological wiring actually contribute to neural computation? Behavioral experiments can test whether a model produces the right outputs, but they cannot determine whether its internal representations are biologically faithful. Brunton et al. (2026) made this concrete: a C. elegans worm connectome trained with deep reinforcement learning produces realistic Drosophila fly walking -- yet the model is biologically meaningless, because behavioral fidelity is achievable without biological fidelity. We need a population-level metric that discriminates real biological wiring from arbitrary wiring, without requiring a behavioral decoder. We propose representational geometry as that metric. Representational geometry -- the structure of pairwise distances between population responses to different stimuli -- captures how a neural circuit organizes its representational space, independently of what behavior it drives. We apply representational similarity analysis (RSA) and centered kernel alignment (CKA) to the Flyvis pretrained Drosophila melanogaster visual system ensemble (Lappalainen et al. 2024): 50 networks whose architecture is fixed to the FlyWire connectome, compared against stability-constrained random baselines (sign-preserving weight shuffles, rejection-sampled for dynamic stability, n = 50). Connectome-constrained networks produce a smooth circular direction geometry that random networks cannot replicate: RSA Spearman r = 0.686 (p < 0.0001) for ON edge stimuli and r = 0.846 (p < 0.0001) for ON+OFF edge stimuli, corroborated by CKA (p < 0.05 in both experiments). The geometry also tracks biological T4\/T5 direction tuning recorded in living flies (Maisak et al. 2013): connectome-constrained geometry matches biology substantially better than random geometry (r = 0.930 vs. r = 0.603, gap {Delta}r = 0.327, p < 0.0001). Within each stimulus polarity, the ON pathway encodes direction with stronger geometric separation than the OFF pathway ({Delta}r = 0.138, 95% CI [0.091, 0.236]), consistent with known T4\/T5 asymmetries in direction selectivity strength. These results establish representational geometry as a candidate fidelity metric that discriminates biological from arbitrary wiring at the population level. The framework requires no behavioral decoder and no single-unit recordings -- only population responses to a structured stimulus set -- suggesting a practical path toward verifiable fidelity metrics for connectome-scale emulations as they scale toward mammalian cortex.","rel_num_authors":2,"rel_authors":[{"author_name":"Michael George Zhou","author_inst":"Georgia Institute of Technology"},{"author_name":"Jennifer Olson Hasler","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"The Geometry of Allostery: A Laplacian Minor Hierarchy for Many-Body Protein Communication","rel_doi":"10.64898\/2026.06.10.731266","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731266","rel_abs":"Quantifying how cooperative, many-body relationships drive allostery in protein networks remains a major challenge. To address this, we develop the Laplacian minor hierarchy, a mathematical framework that characterizes the geometric invariants of a protein network. Lower-order minors yield standard metrics including the partition function and effective distances, whereas higher-order minors define novel topological measures: cooperation indices, each bounded between zero and one, that characterize pathway correlations at increasing levels of complexity, the third-order minor determines whether allosteric pathways are correlated or uncorrelated, and the fourth-order minor quantifies how distinct pathways communicate through intermediary residues. We apply this framework to analyze the evolutionary adaptation of the PSD95pdz3 domain from Class I to Class II ligand specificity via mutations G330T and H372A. The cooperation index demonstrates a distinct evolutionary hierarchy: the G330T mutation establishes distributed pathway couplings that the H372A mutation subsequently exploits, whereas H372A alone produces minimal global changes. Furthermore, the fourth-order analysis identifies His317 as a critical intermediary node bridging the class-switching (330-372) and class-bridging (330-400) allosteric pathways. These results demonstrate that allosteric dependencies emerge only when mutations accumulate in specific combinations, with a hierarchical organization of pathways structured around position 330 and intermediary nodes His317 and Phe400. Rather than predicting allosteric mechanisms, this framework provides a mechanistic explanation for why and how allostery emerges during protein evolution.","rel_num_authors":2,"rel_authors":[{"author_name":"Fatma Senguler Ciftci","author_inst":"Koc University"},{"author_name":"Burak Erman","author_inst":"Koc University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Generalisable tissue-wide molecular reconstruction from histology","rel_doi":"10.64898\/2026.06.09.731252","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731252","rel_abs":"Spatial transcriptomics technologies measure gene expression within intact tissues but remain difficult to scale across large tissue sections and patient cohorts. Consequently, many studies rely on tissue microarrays (TMAs) or sparse spatial profiling designs, where molecular measurements are available for only limited tissue regions and are often generated using heterogeneous gene panels. Existing H&E to spatial gene expression prediction methods remain challenged by sparse molecular measurements, partially overlapping gene panels and tissue-wide reconstruction across heterogeneous spatial datasets. Here, we present GHIST+, a framework for tissue-wide reconstruction of single-cell molecular states from H&E histology. GHIST+ integrates cellular morphology, local tissue context and shared tissue representations to extend sparse molecular measurements into tissue-wide molecular maps across heterogeneous spatial datasets. Across multiple cancer types and GTEx breast tissues, GHIST+ reconstructs biologically meaningful tissue-wide molecular organisation from sparse TMA-derived measurements while preserving spatial tissue structure, cell-type organisation and age-associated tissue states across cancer and non-cancer settings. GHIST+ establishes a scalable framework for transforming sparse spatial profiling experiments into tissue-wide molecular maps, enabling cohort-scale molecular reconstruction from routine histology under heterogeneous spatial transcriptomic settings.","rel_num_authors":13,"rel_authors":[{"author_name":"Andrew Zhang","author_inst":"University of Sydney"},{"author_name":"Lijia Yu","author_inst":"The University of Sydney"},{"author_name":"Beilei Bian","author_inst":"University of Sydney"},{"author_name":"Yue Cao","author_inst":"The University of Sydney"},{"author_name":"Shuchang Ye","author_inst":"University of Sydney"},{"author_name":"Ethan Han","author_inst":"University of Sydney"},{"author_name":"Harry Robertson","author_inst":"University of Sydney"},{"author_name":"Yuhao Dong","author_inst":"National University of Singapore"},{"author_name":"Yixiao Mao","author_inst":"National University of Singapore"},{"author_name":"Boxiang Liu","author_inst":"National University of Singapore"},{"author_name":"Ellis Patrick","author_inst":"University of Sydney"},{"author_name":"Jinman Kim","author_inst":"University of Sydney"},{"author_name":"Jean Yee Hwa Yang","author_inst":"University of Sydney"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Nutrient currencies and P resorption greatly amplify the perceived costs of reproductive allocation in perennial heath shrubs","rel_doi":"10.64898\/2026.06.10.731282","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731282","rel_abs":"-In woody perennials, reproductive allocation considered as a fraction of NPP (RA) has been rarely quantified, especially tracked across plant lifetimes, measured in biologically meaningful currencies, and separated from standing biomass. -We addressed this gap by measuring dry mass, nitrogen, and phosphorus for every aboveground tissue type for 14 iteroparous perennial shrubs tracked across their full lifetimes, calculating RA using four accounting schemes and three currencies. -RA was substantially higher by mid-life than typical estimates from ecosystem-scale studies. Distinguishing standing biomass from yearly production further revised RA upwards. Using a nutrient currency (especially P) increased the perceived costs of reproduction. Propagules were highly nutrient-enriched and reproductive accessory costs consumed more nutrients than did the propagules themselves. Considering N and P resorption from senescing leaves and wood shrank the effective vegetative nutrient budget, further concentrating net annual nutrient demand in reproductive tissues. -Our results highlight high investment in RA for woody perennials, especially using nutrient currencies. Broadly similar allocation patterns were observed across species with different functional traits and lifespans, suggesting generality that may apply across biomes. Widespread underestimation of RA in forest growth models likely overestimates the proportion of NPP available for vegetative growth, leading to substantial errors in predictions.","rel_num_authors":4,"rel_authors":[{"author_name":"Elizabeth Wenk","author_inst":"University of New South Wales"},{"author_name":"Daniel S Falster","author_inst":"University of New South Wales"},{"author_name":"Ian J Wright","author_inst":"Western Sydney University"},{"author_name":"Mark Westoby","author_inst":"Macquarie University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Nutrient currencies and P resorption greatly amplify the perceived costs of reproductive allocation in perennial heath shrubs","rel_doi":"10.64898\/2026.06.10.731282","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731282","rel_abs":"-In woody perennials, reproductive allocation considered as a fraction of NPP (RA) has been rarely quantified, especially tracked across plant lifetimes, measured in biologically meaningful currencies, and separated from standing biomass. -We addressed this gap by measuring dry mass, nitrogen, and phosphorus for every aboveground tissue type for 14 iteroparous perennial shrubs tracked across their full lifetimes, calculating RA using four accounting schemes and three currencies. -RA was substantially higher by mid-life than typical estimates from ecosystem-scale studies. Distinguishing standing biomass from yearly production further revised RA upwards. Using a nutrient currency (especially P) increased the perceived costs of reproduction. Propagules were highly nutrient-enriched and reproductive accessory costs consumed more nutrients than did the propagules themselves. Considering N and P resorption from senescing leaves and wood shrank the effective vegetative nutrient budget, further concentrating net annual nutrient demand in reproductive tissues. -Our results highlight high investment in RA for woody perennials, especially using nutrient currencies. Broadly similar allocation patterns were observed across species with different functional traits and lifespans, suggesting generality that may apply across biomes. Widespread underestimation of RA in forest growth models likely overestimates the proportion of NPP available for vegetative growth, leading to substantial errors in predictions.","rel_num_authors":4,"rel_authors":[{"author_name":"Elizabeth Wenk","author_inst":"University of New South Wales"},{"author_name":"Daniel S Falster","author_inst":"University of New South Wales"},{"author_name":"Ian J Wright","author_inst":"Western Sydney University"},{"author_name":"Mark Westoby","author_inst":"Macquarie University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Why do we seek information about the future? On the origins of subjective value without instrumental value","rel_doi":"10.64898\/2026.06.09.731206","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731206","rel_abs":"Why do we want to know the future? Humans and many animals pay for information to predict uncertain rewards, even when they cannot control them. The reason for this conserved yet seemingly paradoxical preference - \"subjective value without instrumental value\" - remains unknown. Here we develop a normative framework to explain the origins of such preferences, their persistence across species, and their contributions to survival. We formalize and evaluate theories that explain subjective value as originating from an adaptive estimate of advantage for solving core computational problems in naturalistic environments. We show that human and animal subjective values are remarkably well suited to solve these problems, accomplishing the goals of multiple theories simultaneously. We derive novel forms of information to enable existing theories to be dissociated, and show that pooling their subjective values improves performance across diverse environments. Thus, organisms may value information because it pays diverse dividends in nature.","rel_num_authors":3,"rel_authors":[{"author_name":"Ethan S Bromberg-Martin","author_inst":"Johns Hopkins University"},{"author_name":"Josh Merel","author_inst":"Fauna Robotics"},{"author_name":"Ilya E Monosov","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Automated Segmentation of Brainstem and Subcortical White Matter: Mapping the Deep Tegmental Core with BundleParc","rel_doi":"10.64898\/2026.06.09.731210","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731210","rel_abs":"Diffusion MRI enables noninvasive mapping of human white matter pathways, but automated segmentation methods have largely focused on large association, projection, and commissural bundles. Brainstem and subcortical pathways supporting basal ganglia, cerebellar, limbic\/reward, sensory, and homeostatic functions remain underrepresented in large-scale connectomic analyses. To address this gap, we adapted BundleParc, a recently introduced bundle-parcellation architecture, into an automated pipeline for direct segmentation and along-tract parcellation of 97 subcortical and brainstem white matter pathways. The model was trained on a curated reference dataset derived from Human Connectome Project diffusion MRI using anatomy-guided tractography, explicit inclusion and exclusion criteria, automated outlier filtering, and manual quality assurance. Operating directly on native-space fiber orientation distributions, the algorithm successfully recovers these intricate anatomical trajectories and ordered parcellations. We show the model generalizes to diverse external datasets spanning development, aging, and neurodegenerative disease cohorts, maintaining robust performance across variations in spatial resolution and angular sampling. The released container, trained model, population atlas, reference streamlines, and quality assurance outputs provide a resource for studying deep brainstem and subcortical pathways in development, aging, disease, and neuromodulation-relevant anatomy.","rel_num_authors":19,"rel_authors":[{"author_name":"Kurt G. Schilling","author_inst":"Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Radiology and Radiological"},{"author_name":"Gaurav Rudravaram","author_inst":"Department of Electrical Engineering, Vanderbilt University, Nashville, TN, United States"},{"author_name":"Antoine Theberge","author_inst":"Sherbrooke Connectivity Imaging Lab (SCIL), Universite de Sherbrooke, Quebec, Canada."},{"author_name":"Matthew Amandola","author_inst":"Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Radiology and Radiological"},{"author_name":"Michael E. Kim","author_inst":"Department of Computer Science, Vanderbilt University, Nashville, TN, United States"},{"author_name":"Kathryn L. Humphreys","author_inst":"Vanderbilt University, Department of Psychology and Human Development, Nashville, TN, USA"},{"author_name":"Laurie Cutting","author_inst":"Vanderbilt University, Vanderbilt Brain Institute, Nashville, TN, USA; Peabody College of Education and Human Development, Department of Special Education, Nash"},{"author_name":"Derek Archer","author_inst":"Vanderbilt University, Vanderbilt Brain Institute, Nashville, TN, USA; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University School of Medicine, Nashv"},{"author_name":"Timothy J. Hohman","author_inst":"Vanderbilt Memory and Alzheimers Center, Vanderbilt University School of Medicine, Nashville, TN, United States; Vanderbilt University Medical Center, Vanderbil"},{"author_name":"Angela L. Jefferson","author_inst":"Vanderbilt Memory and Alzheimers Center, Vanderbilt University School of Medicine, Nashville, TN, United States; Vanderbilt University Medical Center, Departmen"},{"author_name":"Lori L. Beason Held","author_inst":"Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA"},{"author_name":"Murat Bilgel","author_inst":"Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA"},{"author_name":"- Alzheimers Disease Neuroimaging Initiative","author_inst":"Alzheimers Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu)"},{"author_name":"- The BIOCARD Study Team","author_inst":"BIOCARD study, supported by grant U19AG033655 from the National Institute on Aging"},{"author_name":"Maxime Chamberland","author_inst":"Department of Mathematics and Computer Science, Eindhoven University of Technology, The Netherlands"},{"author_name":"Maxime Descoteaux","author_inst":"Sherbrooke Connectivity Imaging Lab (SCIL), Universite de Sherbrooke, Quebec, Canada."},{"author_name":"Laurent Petit","author_inst":"IRP\/LIA OpTeam, CNRS Biologie et Universite de Bordeaux, France - Universite de Sherbrooke, Sherbrooke, Canada; Universite Bordeaux, CNRS, CEA, IMN, GIN, UMR 52"},{"author_name":"Francois Rheault","author_inst":"Sherbrooke Connectivity Imaging Lab (SCIL), Universite de Sherbrooke, Quebec, Canada."},{"author_name":"Bennett A. Landman","author_inst":"Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Radiology and Radiological"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Unified comparison of spinal locomotion control architectures in neuromechanical simulations","rel_doi":"10.64898\/2026.06.09.731213","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731213","rel_abs":"Neuromechanical simulations provide a powerful framework for investigating how neural control architectures generate and regulate human locomotion. Numerous biologically inspired locomotion controllers have been proposed, including reflex-based, central pattern generator (CPG)-based, and muscle synergy-based models. However, direct comparison across studies remains difficult because of differences in musculoskeletal models, optimization methods, and evaluation protocols. Here, we implemented four representative locomotion control architectures, reflex-based, CPG-reflex-based, muscle synergy-based, and CPG-reflex-synergy-based controllers, within a unified neuromechanical simulation framework to enable controlled comparisons under shared biomechanical and computational conditions. Performance was assessed in terms of (1) agreement with experimentally observed gait characteristics, including kinematics, kinetics, muscle activations, and biomechanical trends across speeds and slopes, and (2) locomotor versatility across speed-slope conditions. The reflex-based and CPG-reflex-synergy-based controllers most closely reproduced experimentally observed gait characteristics, while the CPG-reflex-synergy controller achieved the broadest range of stable walking behaviors across speeds and slopes, followed closely by the reflex-based controller. These findings should be interpreted as comparisons of specific model implementations rather than definitive evaluations of the underlying biological hypotheses. Moreover, because the investigated controllers primarily focused on spinal-level mechanisms for nominal steady-state locomotion, the limited versatility observed in some of the models across broader speed and slope conditions suggests the importance of integrating spinal locomotor mechanisms with supraspinal modulation when modeling locomotion beyond nominal steady gait. To facilitate further investigation, we publicly share the simulation framework and controller implementations.","rel_num_authors":2,"rel_authors":[{"author_name":"Vincent Ton","author_inst":"Northeastern University"},{"author_name":"Seungmoon Song","author_inst":"Northeastern University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Biological Aging of the Cardiopulmonary System","rel_doi":"10.64898\/2026.06.09.731192","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731192","rel_abs":"Age-related stiffening of large arteries is a predictor of cardiovascular morbidity and mortality, yet how pulmonary vascular stiffening integrates with right ventricular (RV) and lung functional decline--and how best to quantify \"biological\" cardiopulmonary aging--remains unclear. Here we map cardiopulmonary aging across the adult murine lifespan by integrating RV, proximal pulmonary artery (PA), and lung biomechanics with single-cell transcriptomics. Using ex vivo biaxial testing of the proximal PA, in vivo echocardiography, and lung mechanics, we find that cardiopulmonary aging is phase-dependent: PA circumferential stiffening and reduced distensibility progress largely linearly with age; whereas, RV remodeling and lung mechanical changes exhibit non-linear trajectories. This is consistent with early intrinsic functional decline of cells and organs followed by later, extrinsic load-dependent structural adaptation. To quantify organ-level biological aging, we apply principal component analysis to PA, RV, and lung feature sets to derive physiology-based aging scores that summarize coordinated variance within and across organs. Anchoring differential gene expression in PA single-cell RNA-seq to these continuous biological aging scores rather than chronological age reveals extensive, cell-type-specific remodeling programs (13,636 genes) that are sparse or non-informative when modeled by chronologic age. Biological aging associates across endothelia, smooth muscle cells, fibroblasts, and perivascular macrophages with increased oxidative phosphorylation signatures alongside suppression of adaptive\/regulatory pathways, including impaired endothelial mechanotransduction, reduced smooth muscle Wnt signaling, altered extracellular matrix remodeling programs, and erosion of macrophage innate immune and TGF{beta}\/NF-{kappa}B signaling nodes. These findings support a model in which pulmonary arterial stiffening is not merely a marker but an active contributor to cardiopulmonary aging via a biomechanical-metabolic-inflammatory uncoupling that diminishes vasoactive and mechano-adaptive reserve and promotes a positive feedback loop. Together, our work establishes physiology-derived biological aging as a powerful framework for interpreting vascular single-cell aging trajectories and identifies mechanistic pathways to target pulmonary vascular stiffening and preserve cardiopulmonary function with age.","rel_num_authors":15,"rel_authors":[{"author_name":"Dongnan Liu","author_inst":"Yale School of Medicine"},{"author_name":"Pramath Doddaballapur","author_inst":"University of California, Santa Barbara"},{"author_name":"Zhongyu Cai","author_inst":"Yale School of Medicine"},{"author_name":"Rira Choi","author_inst":"Yale School of Medicine"},{"author_name":"Jack Di Palo","author_inst":"Yale School of Medicine"},{"author_name":"Nicole Guerrera","author_inst":"Yale School of Medicine"},{"author_name":"Nebal Abu Hussein","author_inst":"Yale School of Medicine"},{"author_name":"Meredith S. Gwin","author_inst":"Yale School of Medicine"},{"author_name":"Liqin Lin","author_inst":"Yale School of Medicine"},{"author_name":"Siming Zheng","author_inst":"Yale School of Medicine"},{"author_name":"Yuening Zhang","author_inst":"Yale School of Medicine"},{"author_name":"Aurelien Justet","author_inst":"Yale University School of Medicine"},{"author_name":"Abhay B. Ramachandra","author_inst":"Iowa State University"},{"author_name":"Xiting Yan","author_inst":"Yale University School of Medicine"},{"author_name":"Edward P. Manning","author_inst":"VA, Yale"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Biological Aging of the Cardiopulmonary System","rel_doi":"10.64898\/2026.06.09.731192","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731192","rel_abs":"Age-related stiffening of large arteries is a predictor of cardiovascular morbidity and mortality, yet how pulmonary vascular stiffening integrates with right ventricular (RV) and lung functional decline--and how best to quantify \"biological\" cardiopulmonary aging--remains unclear. Here we map cardiopulmonary aging across the adult murine lifespan by integrating RV, proximal pulmonary artery (PA), and lung biomechanics with single-cell transcriptomics. Using ex vivo biaxial testing of the proximal PA, in vivo echocardiography, and lung mechanics, we find that cardiopulmonary aging is phase-dependent: PA circumferential stiffening and reduced distensibility progress largely linearly with age; whereas, RV remodeling and lung mechanical changes exhibit non-linear trajectories. This is consistent with early intrinsic functional decline of cells and organs followed by later, extrinsic load-dependent structural adaptation. To quantify organ-level biological aging, we apply principal component analysis to PA, RV, and lung feature sets to derive physiology-based aging scores that summarize coordinated variance within and across organs. Anchoring differential gene expression in PA single-cell RNA-seq to these continuous biological aging scores rather than chronological age reveals extensive, cell-type-specific remodeling programs (13,636 genes) that are sparse or non-informative when modeled by chronologic age. Biological aging associates across endothelia, smooth muscle cells, fibroblasts, and perivascular macrophages with increased oxidative phosphorylation signatures alongside suppression of adaptive\/regulatory pathways, including impaired endothelial mechanotransduction, reduced smooth muscle Wnt signaling, altered extracellular matrix remodeling programs, and erosion of macrophage innate immune and TGF{beta}\/NF-{kappa}B signaling nodes. These findings support a model in which pulmonary arterial stiffening is not merely a marker but an active contributor to cardiopulmonary aging via a biomechanical-metabolic-inflammatory uncoupling that diminishes vasoactive and mechano-adaptive reserve and promotes a positive feedback loop. Together, our work establishes physiology-derived biological aging as a powerful framework for interpreting vascular single-cell aging trajectories and identifies mechanistic pathways to target pulmonary vascular stiffening and preserve cardiopulmonary function with age.","rel_num_authors":15,"rel_authors":[{"author_name":"Dongnan Liu","author_inst":"Yale School of Medicine"},{"author_name":"Pramath Doddaballapur","author_inst":"University of California, Santa Barbara"},{"author_name":"Zhongyu Cai","author_inst":"Yale School of Medicine"},{"author_name":"Rira Choi","author_inst":"Yale School of Medicine"},{"author_name":"Jack Di Palo","author_inst":"Yale School of Medicine"},{"author_name":"Nicole Guerrera","author_inst":"Yale School of Medicine"},{"author_name":"Nebal Abu Hussein","author_inst":"Yale School of Medicine"},{"author_name":"Meredith S. Gwin","author_inst":"Yale School of Medicine"},{"author_name":"Liqin Lin","author_inst":"Yale School of Medicine"},{"author_name":"Siming Zheng","author_inst":"Yale School of Medicine"},{"author_name":"Yuening Zhang","author_inst":"Yale School of Medicine"},{"author_name":"Aurelien Justet","author_inst":"Yale University School of Medicine"},{"author_name":"Abhay B. Ramachandra","author_inst":"Iowa State University"},{"author_name":"Xiting Yan","author_inst":"Yale University School of Medicine"},{"author_name":"Edward P. Manning","author_inst":"VA, Yale"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"A multi-omics map of diabetic nephropathy links c-Jun activation to tubular injury and metabolic stress","rel_doi":"10.64898\/2026.06.09.731164","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731164","rel_abs":"Diabetic nephropathy (DN) is a major cause of end-stage renal disease, yet the molecular mechanisms driving tubular injury and fibrosis remain poorly defined. Here, we integrated single-cell multiplexed protein imaging, spatial transcriptomics, single-nucleus and single-cell RNA sequencing and chromatin accessibility profiling to comprehensively characterize human DN pathology. Our multi-modal analysis precisely maps kidney cell types and their spatial distributions, immune-fibrotic interactions, and key transcriptional regulators. We identified eight distinct cellular neighborhoods defining the immune-fibrotic microenvironment and uncovered molecular networks driving tubular injury and fibrosis. JUN (encoding c-Jun) emerged as a central regulator of transcriptional reprogramming during tubular injury and fibrogenic remodeling. In a diabetic mouse model, c-Jun is activated in injured proximal tubules. Using an inducible c-Jun mouse model, we demonstrated that tubular-specific c-Jun activation alone is sufficient to induce tubular injury, chronic inflammation, progressive fibrosis, and systemic metabolic alterations, including impaired glucose homeostasis. We also observed reduced expression of SLC4A4, a bicarbonate transporter essential for proximal tubular function, in injured tubules. Together, our findings establish a spatially resolved framework for understanding DN pathogenesis and identify c-Jun as a key mediator of tubular injury and fibrosis in diabetic kidney disease.","rel_num_authors":11,"rel_authors":[{"author_name":"Qiwen Deng","author_inst":"Department of Pathology, Stanford School of Medicine"},{"author_name":"Yu Liu","author_inst":"Cardiovascular Institute, Stanford School of Medicine"},{"author_name":"Nathan Bracey","author_inst":"Stanford Institute for Immunology, Transplantation and Infection, Stanford University"},{"author_name":"Yi-Chuan Wang","author_inst":"Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"},{"author_name":"Paul Wadsworth","author_inst":"Department of Pathology, Stanford School of Medicine"},{"author_name":"Marjia Afrin","author_inst":"Department of Pathology, Stanford School of Medicine"},{"author_name":"Matteo Santoro","author_inst":"Department of Pathology, Stanford School of Medicine"},{"author_name":"Shih-Yu Chen","author_inst":"Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"},{"author_name":"Joseph Wu","author_inst":"Cardiovascular Institute, Stanford School of Medicine"},{"author_name":"Vivek Charu","author_inst":"Department of Pathology, Stanford School of Medicine"},{"author_name":"Gerlinde Wernig","author_inst":"Department of Pathology, Stanford School of Medicine"}],"rel_date":"2026-06-12","rel_site":"biorxiv"}]}