medRxiv : the preprint server for health sciences最新文献

{"title":"Altered oscillatory coupling reflects possible inhibitory interneuron dysfunction in Rett syndrome.","authors":"Devorah Kranz, Yael Braverman, Michelle McCarthy, Claire Mackay, Karen Sabol, Tim A Benke, David Lieberman, Eric D Marsh, Jeffrey L Neul, Fleming Peck, Alan K Percy, Joni Saby, Nancy Kopell, Charles A Nelson, April R Levin, Michela Fagiolini","doi":"10.1101/2025.07.21.25331927","DOIUrl":"10.1101/2025.07.21.25331927","url":null,"abstract":"<p><p>Rett syndrome is a rare neurodevelopmental disorder caused primarily by pathogenic variants in the MECP2 gene, leading to lifelong cognitive impairments. To understand the broad neural disruptions in Rett syndrome, it is essential to examine large-scale brain dynamics at the level of neural oscillations. Phase-amplitude coupling, a form of cross-frequency interaction that supports information integration across temporal and spatial scales, is a promising candidate measure for capturing such widespread neural dysfunction. Phase-amplitude coupling depends on the coordinated activity of specific neuronal subtypes, and while multiple subtypes are implicated in different aspects of the Rett syndrome phenotype, their role in shaping large-scale oscillatory dynamics in Rett syndrome is not well understood. To investigate this, we utilized a multi-level approach, combining EEG recordings with computational modeling to identify alterations in phase-amplitude coupling in Rett syndrome and probe their underlying cellular and circuit-level mechanisms. We recorded resting-state EEG from 38 individuals with Rett syndrome and 30 age- and sex-matched typically developing individuals. Phase-amplitude coupling was quantified: modulation index was obtained to determine coupling strength, and phase bias was assessed to examine the preferred phase of coupling. We characterized phase-amplitude coupling across all low and high frequency combinations and electrodes, as well as within canonical theta-gamma and alpha-gamma frequency pairs across four predefined cortical regions. Finally, we modeled a biophysically-constrained Layer 4 cortical network to propose a possible mechanism underlying changes to oscillatory dynamics. We found significantly stronger phase-amplitude coupling in Rett syndrome across widespread cortical regions and frequency pairs, with a pronounced increase in theta-gamma and alpha-gamma coupling in anterior, posterior, and whole-brain regions (P < 0.05). Individuals with Rett syndrome also exhibited a more positive alpha-gamma phase bias in anterior and whole-brain regions (P < 0.05). Biophysically constrained modelling demonstrated that reduced VIP-expressing interneuron activity alone could recapitulate the pattern of increased theta-gamma and alpha-gamma phase-amplitude coupling observed in Rett syndrome (P < 0.001). These findings identify alterations in awake-state phase-amplitude coupling in Rett syndrome and propose a mechanistic link to VIP+ interneuron dysfunction. Elevated phase-amplitude coupling may serve as a promising biomarker of cortical dysfunction and a translational bridge from neural circuitry to clinically observable EEG signatures. By implicating VIP+ interneurons, our results open new avenues for testing interventions in preclinical models to identify potential novel therapeutic targets for individuals with Rett syndrome.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144801408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intravenous Thrombolysis for Acute Central Retinal Artery Occlusion: Protocol For a Systematic Review and Individual Participant Data Meta-Analysis of Randomized Controlled Trials.","authors":"Brian Mac Grory, Cecile Preterre, Pierre Lebranchu, Stephen James Ryan, Oystein Kalsnes Jorstad, Carstens Moe, Johannes Tuennnerhoff, Martin Spitzer, Carsten Grohmann, Oana M Dumitrascu, Valerie Biousse, Benoit Guillon, Anne Hege Aamodt, Sven Poli, Matthew S Schrag","doi":"10.1101/2025.09.24.25336565","DOIUrl":"10.1101/2025.09.24.25336565","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Central retinal artery occlusion (CRAO) is a disabling subtype of acute ischemic stroke. It is not known whether intravenous (IV) thrombolysis delivered within 4.5 hours of time last known well (LKW) improves visual outcomes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Study design: &lt;/strong&gt;Systematic review and individual participant data meta-analysis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;The objective of this study is to determine whether IV thrombolysis improves visual outcomes among patients with acute non-arteritic CRAO when administered within 4.5 hours of time LKW compared with placebo, no IV thrombolysis, and/or anti-thrombotic therapy. Evidence Review Plan: This study will be prospectively registered through PROSPERO. We will include randomized controlled trials (RCTs) that enroll patients with non-arteritic CRAO presenting within 4.5 hours of time LKW. We will not include non-controlled interventional studies or retrospective studies. We will search MEDLINE, Embase, the Cochrane Library, Web of Science, and the ClinicalTrials.gov registry from inception through the date of commencement of the systematic review. We will assess the risk of bias using the Cochrane Risk of Bias Tool 2.0. We will contact the corresponding author(s) of any studies identified that meet the study selection criteria. We will inspect, harmonize, and collate trial datasets. The primary end point will be attainment of a final best corrected visual acuity (BCVA) equal to or better than 20/63 (logarithm of the minimum angle of resolution [logMAR] of ≤0.5). Secondary end points will include shift analyses of key visual acuity outcome categories according to the World Health Organization (WHO) International Classification of Disease (ICD)-11, final BCVA considered as a continuous variable, final BCVA equal to or better than 20/100 (logMAR of ≤0.7), final BCVA equal to or better than 20/200 (logMAR of ≤1), a quantitative measure of visual field function (where available), global disability (modified Rankin Scale score [mRS]), and key safety end points (including symptomatic intracranial hemorrhage [sICH] and other systemic hemorrhage). We will fit a series of mixed logistic and linear regression models with trial, and trial by treatment interaction terms as random effects. To probe for sources of heterogeneity, we will pursue a series of subgroup and sensitivity analyses. Finally, a GRADE assessment will be presented.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions and relevance: &lt;/strong&gt;Completion of the proposed study will permit a synopsis of the interventional literature on IV thrombolysis for CRAO, generate a pooled estimate of the treatment effect, and allow exploration of sources of heterogeneity. Such results may be of interest to healthcare professionals, guideline development bodies, policymakers, payors, and future patients with CRAO.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding source: &lt;/strong&gt;An application for federal support from the US National Institutes of Health is planned.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Regi","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Appendix300: A multi-institutional laparoscopic appendectomy video dataset for computational modeling tasks.","authors":"Fiona R Kolbinger, Max Kirchner, Kevin Pfeiffer, Sebastian Bodenstedt, Alexander C Jenke, Julia Barthel, Matthias Carstens, Karolin Dehlke, Sophia Dietz, Sotirios Emmanouilidis, Guido Fitze, Martin Freitag, Fabian Holderried, Thorsten Jacobi, Weam Kanjo, Linda Leitermann, Sören Torge Mees, Steffen Pistorius, Conrad Prudlo, Astrid Seiberth, Jurek Schultz, Karolin Thiel, Daniel Ziehn, Stefanie Speidel, Jürgen Weitz, Jakob Nikolas Kather, Marius Distler, Oliver Lester Saldanha","doi":"10.1101/2025.09.05.25335174","DOIUrl":"10.1101/2025.09.05.25335174","url":null,"abstract":"<p><strong>Background: </strong>The limited availability of diverse and representative training data poses a critical barrier to the development of clinically relevant computational tools for intraoperative surgical decision support. Surgical procedures are not routinely recorded, and annotation requires domain expertise, resulting in a scarcity of open-access surgical video datasets with high-quality annotations. Existing datasets are typically limited to single institutions and specific procedures, such as cholecystectomy, and rarely comprise patient-level metadata like demographic characteristics, disease history, or laboratory parameters.</p><p><strong>Methods: </strong>The Appendix300 dataset comprises 330 laparoscopic surgery recordings, including 325 full-length laparoscopic appendectomies and 5 control recordings from non-appendectomy procedures in pediatric and adult patients treated at five German centers. The dataset includes patient-level clinical metadata (demographics, medical history, clinical symptoms, laboratory parameters, and histopathological findings), as well as standardized expert annotations of the laparoscopic grade of appendicitis.</p><p><strong>Results: </strong>Appendix300 currently represents the largest publicly available collection of surgical video data with patient metadata and the first curated dataset of laparoscopic appendectomies. It enables novel validation tasks for computer vision in surgery, including the classification of appendicitis severity and the detection of appendiceal perforation. Technical validation of the laparoscopic appendicitis grade annotations showed substantial interrater agreement (weighted Cohen's κ = 0.615).</p><p><strong>Conclusion: </strong>The Appendix300 dataset expands the scope of surgical data science by integrating video data with clinical and pathological metadata across institutions. It enables new and clinically relevant patient-level validation tasks for computer vision in laparoscopic surgery and facilitates decentralized learning approaches, overall enhancing the breadth and translational relevance of AI-based surgical video analysis.</p><p><strong>Dataset description: </strong>Appendix300 is a multi-institutional dataset comprising 330 laparoscopic surgery recordings, including 325 appendectomies and 5 control cases, detailed patient-level metadata (demographics, medical history, clinical symptoms, laboratory parameters, and histopathological findings), and expert annotations of appendicitis severity. It enables novel validation tasks for surgical AI, such as inflammation grading and perforation detection, and supports decentralized learning across diverse patient populations.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abnormal Meibum Is Associated With SREBF1 Mutation And IFAP Syndrome-2.","authors":"Igor A Butovich, Martha Schatz, Ujwala Saboo, Jadwiga C Wojtowicz, Daniel A Johnson","doi":"10.1101/2025.07.25.25332204","DOIUrl":"10.1101/2025.07.25.25332204","url":null,"abstract":"<p><p>The X-linked Ichthyosis Follicularis, Alopecia, and Photophobia syndrome type-2 (IFAP-2), is a condition that has been linked to a c.1579C>T mutation in the SREBF1 gene. However, the molecular implications of the mutation in Meibomian glands (MG) remain unknown. The goals of our project were to elucidate the biochemical factors associated with IFAP-2 and develop approaches for unbiased diagnosing this condition. Meibum samples were collected from normal subjects and a patient with IFAP-2-like signs and symptoms. Genetic analysis of the IFAP-2 subject revealed a c.1579C>T (p.Arg527Cys) mutation in the SREBF-1 gene that was previously associated with IFAP-2. The meibum samples were analyzed using liquid chromatography-mass spectrometry (LC-MS), and the data were compared using multivariate statistical approaches. The LC-MS provided detailed information on the differences between the Meibomian lipid profiles of normal subjects and the IFAP-2 patient, specifically in saturated and unsaturated wax esters (SWE and UWE). Our data showed that IFAP-2 meibum was enriched with SWE which increased the SWE/UWE ratio to highly abnormal levels. The higher melting temperature of SWE compared to that of UWE correlated well with poor expressibility and abnormal thickness of IFAP-2 meibum. Thus, our study demonstrated possible links between the p.Arg527Cys mutation in SREBP1 protein, upregulation of SWE in the IFAP-2 meibum, and MG Dysfunction. It also showed that LC-MS can be used as a sensitive and informative tool to reveal minute differences in the Meibomian lipidomes of the subjects with MG Dysfunction, and identify molecular markers of the conditions.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144801407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type-2 immune skewing in patients with disseminated coccidioidomycosis.","authors":"Timothy J Thauland, Smriti S Nagarajan, Alexis V Stephens, Samantha L Jensen, Anviksha Srivastava, Miguel A Moreno Lastre, Terrie S Ahn, Chantana Bun, Michael T Trump, Royce H Johnson, George R Thompson, Maria I Garcia-Lloret, Valerie A Arboleda, Manish J Butte","doi":"10.1101/2025.09.26.25336729","DOIUrl":"10.1101/2025.09.26.25336729","url":null,"abstract":"<p><strong>Background: </strong>Disseminated coccidioidomycosis (DCM) is an often fatal and otherwise intractable condition requiring lifelong antifungal treatment. We have previously shown that a deranged polarization of CD4 ⁺ T cells toward a Type-2 phenotype can exist in the context of DCM. Here we studied a large population of subjects to determine the frequency of abnormal Type-2 skewing of CD4 ⁺ T cells in patients with coccidioidomycosis and to identify underlying genetic mechanisms supporting this skew.</p><p><strong>Methods: </strong>We collected peripheral blood mononuclear cells from 204 patients with coccidioidomycosis, including 96 patients with disseminated disease. We measured immune phenotypes and cytokine production by CD4 ⁺ T cells from patients and healthy controls, and comparisons between groups were made based on disease severity and demographics. Whole genome sequencing was conducted on 149 individuals who also had cytokine profiling.</p><p><strong>Results: </strong>We found that ~20% of DCM patients had a CD4 ⁺ T-cell compartment that was abnormally skewed toward a Type-2 (IFN-γ-IL-4+) phenotype. Type-2 skewing was highly correlated with male sex, with 80% of moderately skewed (Th2:Th1 ratio > 1.5) and 100% of severely skewed (Th2:Th1 ratio > 2) patients being male. Co-culture of T cells with the IL4R/IL13R-blocking antibody dupilumab rectified their Th1/Th2 skewing. Sequencing revealed rare variants in genes involved in the IL-12-IFN-γ axis in several Type-2 skewed patients, and we validated one such variant in <i>IFNGR1</i> as hypomorphic.</p><p><strong>Conclusion: </strong>Patients with DCM, especially those who are male, should be screened for Type-2 skewing of CD4 ⁺ T cells. Patients with Type-2 skewing should be additionally screened for genetic defects in the IL-12-IFN-γ axis. Our findings give a mechanistic rationale for exploring blockade of IL4R as a treatment option in Type-2 skewed patients with refractory coccidioidomycosis.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vivo Mechanical Assessment of Cortical Bone Rigidity Enhances Fracture Discrimination Beyond DXA in Postmenopausal Women.","authors":"Brian C Clark, Todd M Manini, Janet E Simon, Leatha A Clark, Charalampos Lyssikatos, Stuart J Warden","doi":"10.1101/2025.08.28.25334655","DOIUrl":"10.1101/2025.08.28.25334655","url":null,"abstract":"<p><p>Dual-energy x-ray absorptiometry (DXA)-derived areal bone mineral density (BMD) remains the clinical standard for assessing osteoporosis risk, yet it fails to identify over 75% of individuals who sustain fragility fractures. Direct in vivo mechanical assessment of cortical bone strength may address this diagnostic gap by capturing structural and material properties that govern whole-bone strength but are not reflected by BMD. We conducted a multicenter case-control study with cross-sectional assessment to compare ulna flexural rigidity, a biomechanical property correlated with whole-bone strength (R² ≈ 0.99), estimated using Cortical Bone Mechanics Technology (CBMT), with DXA-derived BMD for discriminating prior fragility fractures in postmenopausal women. A total of 372 women aged 50-80 years (109 with low-trauma fractures, 263 matched controls) were enrolled across four U.S. sites. Ulna flexural rigidity was assessed by dynamic vibrational analysis; BMD was measured at the spine, hip, and 1/3 radius. Women with prior fractures had significantly lower flexural rigidity than controls (absolute: 20.0 vs. 24.8 N·m²; 21% lower; weight-normalized: 0.29 vs. 0.36 N·m²/kg; 22% lower; both P < .001). CBMT demonstrated strong discriminatory accuracy (AUC = 0.80 normalized; 0.76 absolute) versus poor DXA performance (AUC ≤ 0.63) for discriminating all fragility fractures. In multivariable models including CBMT, DXA-derived BMD, age, and BMI, CBMT remained independently associated with fracture status, whereas BMD did not. Subgroup analyses showed CBMT retained strong performance in treatment-naïve women (AUC = 0.85) and in those with non-osteoporotic BMD (AUC = 0.80). Exploratory fracture-site analyses demonstrated that ulna EI discriminated upper and lower extremity fractures, including hip, whereas DXA-derived BMD generally showed modest or nonsignificant discrimination. These findings demonstrate that in vivo mechanical assessment of cortical bone rigidity provides clinically relevant information beyond areal BMD, including women not classified high risk. Direct in vivo assessment of cortical bone rigidity may enhance fracture risk stratification and enhance osteoporosis screening.</p><p><strong>Lay summary: </strong>Most people who break a bone from a simple fall do not meet the standard definition of osteoporosis based on a bone density scan (DXA). This means many at risk are not identified or treated. Our study tested a new, noninvasive technology that directly measures how strong a bone is by assessing how much it resists bending. We found that this measure, called flexural rigidity, more accurately identified women with past fractures than DXA did, even in women whose bone density was \"normal\". It also showed strong performance across different types of fractures, including hip fractures. Directly testing bone strength may help doctors better identify who needs treatment to prevent fractures.</p><p><strong>Abstract figure: </strong></p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PregMedNet: Multifaceted Maternal Medication Impacts on Neonatal Complications.","authors":"Yeasul Kim, Ivana Maric, Chloe Kashiwagi, Lichy Han, Philip Chung, Jonathan Reiss, Lindsay D Butcher, Kaitlin J Caoili, Eloise Berson, Lei Xue, Camilo Espinosa, Tomin James, Sayane Shome, Feng Xie, Marc Ghanem, David Seong, Alan Chang, Momsen Reincke, Samson Mataraso, Chi-Hung Shu, Davide De Francesco, Martin Becker, Wasan Kumar, Ron Wong, Brice Gaudilliere, Martin Angst, Gary M Shaw, Brian Bateman, David Stevenson, Lance Prince, Nima Aghaeepour","doi":"10.1101/2025.02.13.25322242","DOIUrl":"10.1101/2025.02.13.25322242","url":null,"abstract":"<p><p>While medication use is common among pregnant women, medication safety remains insufficiently characterized because studies in pregnant women are challenging due to safety concerns. The recent digitization of healthcare databases and advances in computational methods have created new opportunities for large-scale, retrospective drug safety evaluations. Here, we present PregMedNet, a platform that characterizes multifaceted maternal medication effects on neonatal outcomes during pregnancy, covering more than 27,000 drug-disease pairs across 1,152 medications and 24 outcomes. These results encompass known and novel odds ratios (ORs), adjusted ORs, and drug-drug interactions, systematically analyzed using nationwide claims data and an advanced machine learning pipeline. Notably, one of the newly discovered associations was experimentally validated in vivo. This supports the reliability of PregMedNet findings and demonstrates the utility of claims data and machine learning for perinatal medication safety studies. Additionally, potential biological mechanisms underlying the associations were explored using a graph learning method, providing candidate pathways for future mechanistic investigations. We expect that PregMedNet will contribute to advancing maternal medication safety and improving neonatal outcomes by providing extensive, multifaceted drug safety information on this previously underrepresented population.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-ancestry genome-wide and transcriptome-wide association analyses identified new risk loci and genes for inflammatory bowel disease.","authors":"Xingyi Guo, Linshuoshuo Lyu, Qing Li, Chao Li, Ghadeer K Dawwas, You Chen, Ran Tao, Qi Liu, Wanqing Wen, Xiao-Ou Shu, Kay Washington, David A Schwartz, Wei Zheng, Zhijun Yin, Ken S Lau","doi":"10.1101/2025.09.23.25336483","DOIUrl":"https://doi.org/10.1101/2025.09.23.25336483","url":null,"abstract":"<p><p>To advance genetic understanding of inflammatory bowel disease (IBD), we conducted genome-wide association meta-analyses of 63,415 IBD cases of European and East Asian descendants and identified 90 previously unknown risk loci. Integrating multi-ancestry transcriptome-wide association studies (TWAS), cell type-specific TWAS, alternative splicing (AS-WAS), and alternative polyadenylation (APA-WAS) analyses using RNA-seq data from normal colon tissues of 707 European and 364 East Asian individuals, we uncovered 506 high-confidence IBD risk genes, including 384 not previously reported. These genes converge on immune regulation, microbial interaction, and other pathways central to IBD pathogenesis, with over half showing transcriptional dysregulation supported by single-cell and spatial omics analyses. Notably, 46 risk genes are targeted by 225 drugs that have been approved or in Phase II/III trials, including sulfasalazine already used in IBD therapy. Our study findings deepen the understanding of IBD genetics and support the development of precision medicine for its prevention and treatment.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations between plasma proteins and psychological wellbeing: evidence from over 20 years of the English Longitudinal Study of Ageing.","authors":"Jessica Gong, Shaun Scholes, Steven Cole, Paola Zaninotto, Andrew Steptoe","doi":"10.1101/2025.02.05.25321715","DOIUrl":"10.1101/2025.02.05.25321715","url":null,"abstract":"<p><p>A deeper understanding of the molecular processes involved in psychological wellbeing in older adults is essential for advancing knowledge of underlying biological mechanisms. Leveraging proteomics data from 3,262 older adults (mean age=63.5 years, 55% female) of the English Longitudinal Study of Ageing (ELSA), we investigated the cross-sectional and longitudinal associations (before and after protein measurement) between 276 proteins and eudaimonic wellbeing, hedonic wellbeing, life satisfaction, and depressive symptoms, over 20-year span. For positive wellbeing, two proteins (DEFB4A and ECE1) were longitudinally associated with subsequent eudaimonic wellbeing trajectory. We further identified higher concentrations of 7, 8, and 2 proteins were linked to subsequent lower eudaimonic wellbeing, hedonic wellbeing, and life satisfaction, respectively. Sex differences in XCL1 and SLAMF7 were observed, associated with lower eudaimonic and hedonic wellbeing in males. These findings link human psychological wellbeing to regulation of several biological pathways, particularly involving cytokine regulation, neurotrophic signaling, inflammatory and immune systems.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11838684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Classifying Obsessive-Compulsive Disorder from Resting-State EEG using Convolutional Neural Networks: A Pilot Study.","authors":"Brian A Zaboski, Sarah Kathryn Fineberg, Patrick D Skosnik, Stephen Kichuk, Madison Fitzpatrick, Christopher Pittenger","doi":"10.1101/2025.05.06.25327094","DOIUrl":"10.1101/2025.05.06.25327094","url":null,"abstract":"<p><p><b>Objective:</b> Identifying obsessive-compulsive disorder (OCD) using brain data remains challenging. Resting-state electroencephalography (EEG) offers an affordable and noninvasive approach, but identifying predictive signals in EEG data has met with little success, even with the application of traditional machine learning methods. We explored whether convolutional neural networks (CNNs) applied to EEG time-frequency representations can distinguish individuals with OCD from healthy controls. <b>Method:</b> We collected resting-state EEG data from 20 unmedicated participants (10 with OCD, 10 healthy controls). Four-second EEG segments were transformed into time-frequency representations. We then trained a 2D CNN using a leave-one-subject-out cross-validation framework to perform subject-level classification and compared its performance to a more traditional support vector machine (SVM) approach. Next, using multimodal fusion, we examined whether adding clinical and demographic information improved classification. <b>Results:</b> The CNN classifier achieved high subject-level performance, distinguishing individuals with an accuracy of 85.0% and an area under the curve (AUC) of 0.88. This significantly outperformed the SVM baseline, which performed no better than chance (45.0% accuracy, AUC: 0.47). A subsequent multimodal analysis revealed that clinical and demographic variables did not contribute any additional independent information. <b>Conclusion:</b> CNNs applied to resting-state EEG show promise for identifying OCD, outperforming traditional machine learning methods. These findings highlight the potential of deep learning to uncover complex, diagnostically relevant patterns in neural data. While limited by sample size, this work supports further investigation into multimodal models for psychiatric classification, warranting replication in larger, more diverse samples.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144096328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}