medRxiv : the preprint server for health sciences最新文献

{"title":"Dementia Risk and Machine Learning-Derived Brain Age Index from Sleep Electroencephalography: A Pooled Cohort Analysis of Over 7,000 Individuals Across Five Community Cohorts.","authors":"Haoqi Sun, Sasha Milton, Yi Fang, Hash Brown Taha, Shreya Shiju, Robert J Thomas, Wolfgang Ganglberger, Matthew P Pase, Timothy Hughes, Shaun Purcell, Susan Redline, Katie L Stone, Kristine Yaffe, M Brandon Westover, Yue Leng","doi":"10.1101/2025.09.21.25336255","DOIUrl":"10.1101/2025.09.21.25336255","url":null,"abstract":"<p><strong>Importance: </strong>Sleep electroencephalographic (EEG) microstructures are closely related to cognition and undergo age-dependent changes. However, their multidimensional nature makes them challenging to interpret using conventional approaches. Machine learning-computed EEG brain age index (BAI) represents the difference between the sleep EEG-based brain age and chronological age, quantifying deviations in sleep EEG microstructures from normative patterns.</p><p><strong>Objective: </strong>To determine the association between sleep BAI and incident dementia in community-dwelling populations.</p><p><strong>Design: </strong>Five individual cohorts and random-effects meta-analysis.</p><p><strong>Setting: </strong>This study pooled data from five community-based, methodologically consistent, longitudinal cohorts: MESA, ARIC, FHS-OS, MrOS, and SOF. We used Fine-Gray models to assess the association between BAI and incident dementia within each cohort, accounting for death as a competing risk. Cohort-specific estimates were then pooled using random-effects meta-analyses.</p><p><strong>Participants: </strong>7,071 participants (MESA 54-94 years old, ARIC 52-75, FHS-OS 40-81, MrOS 67-96, SOF 79-93) without dementia at the time of polysomnography were included.</p><p><strong>Exposure: </strong>The sleep EEG-based BAI was computed using interpretable machine learning, incorporating 13 age-dependent features extracted from central EEG channels in overnight, home-based sleep polysomnography.</p><p><strong>Main outcomes and measures: </strong>Incident dementia or probable dementia was determined in each cohort, with death as a competing risk.</p><p><strong>Results: </strong>Across the five cohorts, dementia incidence ranged from 6.6% to 34.3% over a median follow-up of 3.5 to 17.0 years. Across cohorts, each 10-year increase in BAI was associated with a 39% increased risk of incident dementia (hazard ratio: 1.39 [95% confidence interval=1.21-1.59], p<0.001) after adjustment for age, sex, race, education, body mass index, current smoking, sleep medications, and physical activity level. The top feature underlying BAI was waveform kurtosis in N2 with a negative association with incident dementia (p<0.001). The associations remained after additional adjustment for multiple comorbidities, APOE e4 status, and apnea-hypopnea index, and were consistent across sex and age groups.</p><p><strong>Conclusions and relevance: </strong>A higher sleep EEG-based BAI was associated with a higher risk of incident dementia across five community-based longitudinal cohorts. Future studies are warranted to evaluate the predictive value of BAI as a non-invasive digital biomarker for the early detection of dementia in community settings.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214882","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":"Evaluation of Care Quality for Atrial Fibrillation Across Non-Interoperable Electronic Health Record Data using a Retrieval-Augmented Generation-enabled Large Language Model.","authors":"Philip Adejumo, Phyllis M Thangaraj, Lovedeep S Dhingra, Dhruva Biswas, Arya Aminorroaya, Sumukh Vasisht Shankar, Aline F Pedroso, Philip M Croon, Rohan Khera","doi":"10.1101/2024.09.19.24313992","DOIUrl":"10.1101/2024.09.19.24313992","url":null,"abstract":"<p><strong>Importance: </strong>Standardized assessment of clinical quality measures from electronic health records (EHRs) is challenging because information is fragmented across structured and unstructured data, and due to low interoperability across systems. Traditionally, extracting this information requires manual EHR abstraction, a time-consuming and expensive process that also limits real-time care quality improvement. <b>Objective:</b> To evaluate whether a data format-agnostic retrieval-augmented generation-enabled large language model (RAG-LLM) can accurately abstract clinical variables from heterogeneous structured and unstructured EHR data.</p><p><strong>Design setting and participants: </strong>Retrospective cross-sectional study assessing stroke and bleeding risk in patients with atrial fibrillation (AF) from two health systems. We developed a RAG-LLM model to extract CHA DS-VASc and HAS-BLED risk factors from tabular data and clinical documentation.The framework was validated on 300 expert-annotated patient records (200 from Yale New Haven Health System [YNHHS] and 100 from the Medical Information Mart for Intensive Care [MIMIC-IV]). The system was deployed on two large cohorts: 104,204 patients with AF from YNHHS (2013-2024) and 13,117 from MIMIC-IV (2008-2022). We compared anticoagulation recommendations derived from RAG-LLM with those based on traditional structured data abstraction.</p><p><strong>Exposures: </strong>Use of a RAG-LLM model to abstract stroke and bleeding risk factors from structured and unstructured EHR data.</p><p><strong>Main outcomes and measures: </strong>Accuracy of RAG-LLM-based risk factor abstraction against expert annotation. Secondary outcomes included efficiency, cross-cohort generalizability, and impact on anticoagulation eligibility based on risk stratification.</p><p><strong>Results: </strong>In the validation cohort (mean age 74.8 years, 42.7% female), RAG-LLM demonstrated superior performance across all metrics compared with structural data abstraction. For individual CHA DS-VASc components, accuracy ranged from 0.94-1.00 (YNHHS) and 0.89-1.00 (MIMIC-IV) versus 0.66-0.92 (YNHHS) and 0.44-0.97 (MIMIC-IV) for structured data, which was similar for HAS-BLED (0.94-1.00 and 0.89-1.00 vs 0.66-0.94 and 0.44-0.97). In the deployment study, among 3,207 patients classified as low/intermediate stroke risk with structured data, 62.1% (1,993) were reclassified as high risk with RAG-LLM and would become eligible for anticoagulation. Similarly, 5.5% of those classified as low bleeding risk by structured data were reclassified as high risk, substantially refining contraindication assessment.</p><p><strong>Conclusions: </strong>A multimodal RAG-LLM accurately abstracts clinical variables from structured and unstructured EHR data to improve stroke and bleeding risk assessments in patients with AF, enhancing identification of appropriate anticoagulation candidates.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11451809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383166","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":"Polygenic Risk Factors for Comorbid Diagnoses in Individuals with Substance Use Disorders: A Phenome-Wide Survival Analysis.","authors":"Peter B Barr, Zoe E Neale, Tim B Bigdeli, Chris Chatzinakos, Philip D Harvey, Roseann E Peterson, Jacquelyn L Meyers","doi":"10.1101/2024.12.13.24319000","DOIUrl":"10.1101/2024.12.13.24319000","url":null,"abstract":"<p><strong>Objective: </strong>Persons with substance use disorders (SUD) often suffer from additional comorbidities. Researchers have explored this overlap via phenome wide association studies (PheWAS). However, PheWAS are largely cross-sectional, limiting our understanding of whether diagnoses predate development of an SUD. We characterize whether polygenic scores (PGS) are associated with time to comorbid diagnoses in electronic health records (EHR) after the first documented SUD diagnosis.</p><p><strong>Methods: </strong>Using data from All of Us (N = 393,596), we explored: 1) whether social determinants of health (SDoH) are associated with lifetime risk of SUD (N cases = 42,568) and 2) within a subset those with a diagnosed SUD and available genetic data SUD (N = 21,357), whether PGS for alcohol use disorders, cannabis use disorders, depression, externalizing, post-traumatic stress disorder, and schizophrenia were associated with subsequent diagnoses via a phenome-wide survival analysis.</p><p><strong>Results: </strong>Multiple SDoH were associated with lifetime SUD diagnosis, with annual household income having the largest overall associations (e.g., <$10K annually vs $100K-$150K annually: OR = 3.89, 95% CI = 3.66, 4.13). There were 101 phenome-wide significant PGS associations with subsequent diagnoses across various bodily systems. PGSs for alcohol use disorders, post-traumatic stress disorder, and schizophrenia were each associated with time to their respective diagnoses.</p><p><strong>Conclusions: </strong>Social determinants, especially those related to income, have profound associations with lifetime SUD risk. Additionally, PGS for psychiatric conditions are associated with multiple post-SUD diagnoses within those with a SUD, suggesting PGS may capture information beyond lifetime risk, including timing and severity of comorbidities related to SUD.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879426","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":"Scalable Deep Learning of Histology Images Reveals Genetic and Phenotypic Determinants of Adipocyte Hypertrophy.","authors":"Emil Jørsboe, Phil Kubitz, Julius Honecker, Andrea Flaccus, Dagmar Mvondo, Matthias Raggi, Craig A Glastonbury, Torben Hansen, Matthias Blüher, Aleksander Krag, Hans Hauner, Philip D Charles, Cecilia M Lindgren, Christoffer Nellåker, Melina Claussnitzer","doi":"10.1101/2025.02.11.25322053","DOIUrl":"10.1101/2025.02.11.25322053","url":null,"abstract":"<p><strong>Background: </strong>White adipose tissue dysfunction has emerged as a critical factor in cardiometabolic disease development, yet the cellular microstructure and genetic architecture of adipocyte morphology remain poorly explored.</p><p><strong>Methods: </strong>We introduce Adipocyte U-Net 2.0, an advanced deep learning method for the semantic segmentation of adipose tissue histology, enabling analysis of over 27 million adipocytes from 2,667 individuals.</p><p><strong>Findings: </strong>Our approach revealed that adipocyte hypertrophy associates with metabolic dysfunction, including increased fasting glucose, glycated hemoglobin, leptin, and triglycerides, with decreased adiponectin and HDL cholesterol levels. Through the largest genome-wide association study of adipocyte size to date (N _Subcutaneous = 2,066, N _Visceral = 1,878), we identified four genome-wide significant loci: two in sex-combined analysis (rs73184721 in <i>NAALADL2</i> and rs200047724 in <i>NRXN3</i> ) and two female-specific variants (rs140503338 and rs11656704 in <i>ULK2</i> ). Notably, these genetic associations showed congruent relationships with cardiometabolic traits, suggesting shared biological mechanisms.</p><p><strong>Interpretation: </strong>Our findings demonstrate the utility of deep learning for adipocyte phenotyping at scale and provide novel insights into the genetic basis of adipocyte morphology and its relationship to metabolic disease.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484913","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":"Parental Socio-economic Class and Obesity in Hispanic and non-Hispanic Individuals with First Episode Psychosis.","authors":"Santiago Vega-Ramos, Santiago Alvarez-Lesmes, Krisha Arora-Guevara, Kelly García-Bohórquez, Mauricio Tohen, Todd Lencz, Anil K Malhotra, Juan A Gallego","doi":"10.1101/2025.09.22.25336105","DOIUrl":"https://doi.org/10.1101/2025.09.22.25336105","url":null,"abstract":"<p><strong>Introduction: </strong>Obesity is a significant public health issue in the United States (U.S.), with rates of obesity increasing for the past few years, particularly in Hispanics. Individuals with schizophrenia have additional risks for obesity due to the metabolic burden associated with antipsychotic (AP) medications, limited physical activity due to negative symptoms, and poor eating habits. There are no published studies that have compared obesity rates between Hispanics and non-Hispanics with first episode psychosis (FEP). We aimed to explore the relationship between ethnicity and obesity in FEP patients prior to the initiation of AP treatment, to eliminate the potential effects of AP treatment on weight.</p><p><strong>Methods: </strong>Baseline data from 145 individuals with FEP enrolled in a FEP research study was used. Demographic, education, occupation and Body Mass Index (BMI) data for FEP participants was stratified by ethnicity (Hispanic vs. non-Hispanic) and BMI (< 25 or ≥ 25). Variables with a p-value < 0.1 were entered into a multivariate linear regression model using a manual backwards elimination approach, using BMI as a continuous measure as the outcome and ethnicity as our predictor of interest.</p><p><strong>Results: </strong>Twenty-four Hispanics, and 121 non-Hispanics were included. Baseline characteristics were not significantly different between ethnicity groups, except for BMI which was significantly higher in Hispanics (mean = 25.3, SD = 6.0, p = 0.037) than non-Hispanics (mean = 23.0, SD = 4.5). Data stratified by BMI showed that age, ethnicity, mother's occupation, and socioeconomic status (SES) were associated with BMI. Multivariate linear regression showed that Hispanic ethnicity (B = 3.04, SE = 1.32, p = 0.024) and age (B = 0.36, SE = 0.09, p < 0.001) were statistically significantly associated with higher BMI scores while adjusting for sex (B = - 0.67, SE = 1.04, p = 0.521).</p><p><strong>Discussion: </strong>Hispanic individuals with FEP present with higher BMI scores compared to non-Hispanics, even before the initiation of antipsychotic treatment. Therefore, in addition to exercise and healthy eating habits, the use of AP medications with less metabolic burden is advisable along with using the lowest effective dose.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214936","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":"Multimodal Neuroimaging Signature of Sleep Problems Predicts Preadolescent Mental Health Trajectories.","authors":"Yulin Wang, Masoud Tahmasian, Sarah Genon, Fateme Samea, Zhihui He, Xinyi Liu, Xu Lei, Simon B Eickhoff, Debo Dong","doi":"10.1101/2025.09.22.25336312","DOIUrl":"https://doi.org/10.1101/2025.09.22.25336312","url":null,"abstract":"<p><p>Sleep-related problems (SRP) in childhood are common and clinically relevant yet their underlying neural mechanisms and links to future mental health outcomes remain poorly understood. Here, we investigated how distinct dimensions of SRP relate to multimodal brain structure and function in preadolescents, and whether these neural signatures predict trajectories of mental health difficulties. We employed multivariate mapping to investigate the relationship between structural and functional brain network patterns and various dimensions of SRP in the Adolescent Brain Cognitive Development (ABCD) dataset. Moreover, we explored whether and how the identified multimodal brain signatures could predict the trajectory of internalizing and externalizing behavior difficulties over a two-year follow-up. Our multivariate analysis revealed two robust dimensions of SRP: a general sleep disturbance dimension and a hypersomnolence and parasomnia dimension. Each was associated with partially distinct patterns of brain morphology and functional connectivity, consistent with their differential alignment along the hierarchical organization of cortical neurodevelopment maps. However, both dimensions shared common disruptions in the somatosensory, attention, and default mode networks. We further observed that only these neural patterns associated with the general sleep disturbance dimension predict the longitudinal trajectories of internalizing/externalizing symptoms. Our findings enhance the understanding of the neurobiological mechanisms underlying dimensions of SRP in preadolescence and could inform brain-based intervention and treatment programs to improve sleep-related and mental health-related outcomes across development.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214781","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":"Early-life gut microbiome is associated with immune response to the oral rotavirus vaccine in healthy infants in the US.","authors":"Janiret Narváez Miranda, Michael B Sohn, Daniel Velasquez-Portocarrero, Kelechi Ejiofor, Ann L Gill, Robert Beblavy, Xing Qiu, Nathan Laniewski, Jessica Brunner, Meghan Best, Alena Leger, Allison Macomber, Sarah L Caddy, Baoming Jiang, Tom O'Connor, Steven R Gill, Kristin Scheible","doi":"10.1101/2025.09.22.25336338","DOIUrl":"https://doi.org/10.1101/2025.09.22.25336338","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Rotavirus remains a leading cause of childhood mortality worldwide, despite the widespread introduction of oral rotavirus vaccines (ORVs). While emerging evidence supports a link between microbiome and vaccine response, findings have been inconsistent, especially across geographic and socioeconomic contexts, and none have been conducted in a US-based cohort. This study investigates the development of the infant gut microbiome and its association with immunogenicity following RotaTeq administration in U.S. infants.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We conducted a longitudinal analysis of infants in Rochester, New York, using 16S rRNA sequencing data to assess microbiome composition. We used rotavirus-specific immunoglobulin A (Rotavirus-IgA) titers at the sixth-month study visit (M6) in plasma to determine the seroresponse to vaccination. Clinical metadata were used to evaluate the influence of different factors on microbial diversity over the first year of life and Rotavirus-IgA titers at the M6 visit. Microbiome data from the M1 visit and Rotavirus-IgA at the M6 visit were used to assess the relationship between the infant gut microbiome and ORV immune responses.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;The infant gut microbiome followed characteristic developmental patterns during the first year (N=264). At the M6 visit, 65 infants had a Rotavirus-IgA geometric mean titer of 455, 95% CI:[272-761]. In a sub-cohort that included the complete dataset of immunogenicity and microbiome (N=47), higher alpha diversity at the month 1 (M1) visit was significantly associated with higher Rotavirus-IgA titers at the M6 visit (ß= 2.151, 95% CI:[0.31-3.99], p=0.023). Specific taxa present at the M1 visit, including &lt;i&gt;Collinsella&lt;/i&gt; (ß: 0.243, 95% CI:[0.076, 0.392], q= 0.037), &lt;i&gt;Atopobium&lt;/i&gt; (ß: 0.262, 95% CI:[0.066, 0.458], q= 0.062), and &lt;i&gt;Schaalia radingae&lt;/i&gt; (ß: 0.28, 95% CI:[0.116, 0.458], q=0.018), were positively associated with Rotavirus-IgA titers. In contrast, &lt;i&gt;Bifidobacterium&lt;/i&gt; (ß: -0.204,95% CI:[-0.323, -0.085], q=0.012), &lt;i&gt;Lactobacillus&lt;/i&gt; (ß: -0.17, 95% CI:[- 0.314, -0.035], q= 0.087), &lt;i&gt;Klebsiella&lt;/i&gt; (ß: -0.195, 95% CI:[-0.331, -0.058], q= 0.042), &lt;i&gt;Escherichia-Shigella&lt;/i&gt; (ß: - 0.128, 95% CI:[-0.245, -0.012], q= 0.162), &lt;i&gt;Streptococcus salivarius&lt;/i&gt; (ß: -0.229, 95% CI:[-0.359, -0.098], q= 0.012), and &lt;i&gt;Peptostreptococcus anaerobius&lt;/i&gt; (ß: -0.176, 95% CI:[-0.338, -0.014], q= 0.162) were negatively associated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;In a healthy U.S.-infant cohort, we report a significant association between the early-life infant gut microbiome and RotaTeq-vaccinated infants' Rotavirus-IgA titers. This study contributes to a clearer understanding of microbiome-vaccine interactions, particularly in high-income settings where existing evidence has been limited.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;Office of the Director of the National Institutes of Health, National Institute of Mental Health of ","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214949","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":"Metal Mixtures Mediate the Socioeconomic Gradient in Blood Pressure: A Four-Way Decomposition in a Prospective Rural Bangladeshi Cohort.","authors":"Juwel Rana, Mohammad Hasan Shahriar, Syed Emdadul Haque, Samar Kumar Hore, Tariqul Islam, Golam Sarwar, Muhammad Yunus, Maria Argos, Habibul Ahsan, Jay S Kaufman","doi":"10.1101/2025.09.22.25336372","DOIUrl":"https://doi.org/10.1101/2025.09.22.25336372","url":null,"abstract":"<p><strong>Background: </strong>The causal mechanisms by which socioeconomic status (SES) affects blood pressure (BP) in low- and middle-income countries (LMICs) remain poorly understood. We examined the effects of SES on BP, and the extent to which disparities in metal mixture exposures mediate these effects among rural Bangladeshi adults.</p><p><strong>Methods: </strong>This study included 5923 participants from the Bangladesh Vitamin E and Selenium Trial (BEST), a prospective cohort followed for six years with repeated BP assessments at baseline and three biennial follow-ups. Baseline exposures included SES indicators: education and agricultural land ownership (socioeconomic position, SEP), and metal mixtures: blood arsenic, lead, selenium, and urinary arsenic. We applied the parametric and mediational g-formula, along with generalized weighted quantile sum regression, to estimate total, direct, and indirect effects of SES on BP outcomes and conduct causal mediation analysis with four-way decomposition.</p><p><strong>Results: </strong>Higher education increased BP, whereas SEP decreased the elevation of BP. Both higher education and SEP lowered metal exposures. Metal mixtures mediated the effects of SES on BP. For example, higher education increased systolic blood pressure (SBP) by 3.53 mmHg (95% CI: 2.23, 4.82), while the pure natural indirect effect showed a protective pathway of -0.44 mmHg (95% CI: -0.62, -0.27) through reduced metals. For SEP, nearly 42% of its protective effect on SBP was mediated by lower metal exposures.</p><p><strong>Conclusions: </strong>Socioeconomic differentials in BP outcomes in rural Bangladesh are partly explained by inequalities in metal mixture exposures. Reducing metal exposures may mitigate SES-related disparities in BP measures in LMICS.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214788","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":"Human Applications of Transcranial Temporal Interference Stimulation: A Systematic Review.","authors":"Ilya Demchenko, Ishaan Tailor, Sina Chegini, Haochen Yu, Fatemeh Gholamali Nezhad, Alice Rueda, Anne Kever, Sridhar Krishnan, Abhishek Datta, Jed A Meltzer, Simon J Graham, Tom A Schweizer, Sumientra Rampersad, Edward S Boyden, Ines R Violante, Robert Chen, Andres M Lozano, Venkat Bhat","doi":"10.1101/2025.05.16.25327804","DOIUrl":"10.1101/2025.05.16.25327804","url":null,"abstract":"<p><strong>Background: </strong>Many neurological and psychiatric disorders involve dysregulation of subcortical structures. Transcranial temporal interference stimulation (tTIS) is a novel, non-invasive method developed to selectively modulate deep brain regions and associated neural circuits.</p><p><strong>Methods: </strong>A systematic review was conducted to evaluate human applications of tTIS (PROSPERO ID: CRD42024559678). MEDLINE, Embase, APA PsycINFO, CENTRAL, ClinicalTrials.gov , and WHO ICTRP were searched up to December 12, 2024. Studies involving human applications of tTIS were eligible. Methodological quality was appraised using the NIH and modified Oxford Centre for Evidence-Based Medicine tools.</p><p><strong>Results: </strong>Forty-eight records were reviewed (20 published studies, 28 ongoing trials). Of published studies, 16 single-session and 4 multi-session studies assessed safety, mechanistic outcomes, or therapeutic effects of tTIS in 820 participants. Stimulation was most commonly delivered at beta (20 Hz) or gamma (30-130 Hz) envelope frequencies. Neuroimaging studies support target engagement of the motor cortex, basal ganglia, and hippocampus in humans, particularly when stimulation is paired with behavioural tasks. Preliminary clinical findings in small samples demonstrated acute symptom improvements in bradykinesia and tremor within 60 minutes following a single tTIS session in Parkinson's disease and essential tremor. Reported adverse events across studies were mild (e.g., tingling, itching). Emerging trials increasingly utilize multi-session protocols (2-40 sessions) and are extending tTIS to patients with neurological and psychiatric disorders, particularly epilepsy and depression.</p><p><strong>Conclusions: </strong>Phase 1 studies demonstrate that tTIS is safe, well-tolerated, and capable of engaging deep brain targets in humans. Well-controlled Phase 2 trials are needed to assess its therapeutic potential in patient populations.</p><p><strong>Highlights: </strong>tTIS engages the motor cortex, basal ganglia, and hippocampus across human studies20 studies show tTIS is safe and well-tolerated in healthy and clinical cohortsOne tTIS session improves bradykinesia and tremor in Parkinsonism within 1 hourMulti-session trials now test tTIS in epilepsy, depression, and other disordersRobust Phase 2 trials are needed to study the efficacy of tTIS in patient populations.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12132165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144218051","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":"The role of language in social-emotional, educational, and vocational outcomes in autism and in individuals who have lost the diagnosis.","authors":"Caroline Larson, Elise Taverna, Anusha Mohan, Teresa Girolamo, Deborah Fein, Inge-Marie Eigsti","doi":"10.1101/2025.09.10.25335495","DOIUrl":"https://doi.org/10.1101/2025.09.10.25335495","url":null,"abstract":"<p><strong>Background: </strong>There is striking heterogeneity in long-term outcomes associated with an autism diagnosis, and the role of language in outcomes has not been sufficiently characterized. This study characterized the roles of structural language ability and early language milestones in long-term social-emotional, educational, and vocational outcomes in individuals with autism and individuals who have lost the autism diagnosis (LAD) relative to neurotypical (NT) peers, over and above the potential confounding role of social skills.</p><p><strong>Methods: </strong>Participants were individuals with autism ( <i>n</i> = 39) or LAD ( <i>n</i> = 32) and NT peers ( <i>n</i> = 38) age 12-39 years. Participants completed standardized and survey-based measures of social-emotional functioning and educational and vocational attainment. Language measures were an experimental structural language task (grammaticality judgement) and caregiver-report of early language milestones. Linear and generalized linear models tested how groups differed in the association between language and outcomes.</p><p><strong>Results: </strong>Language was associated with certain outcomes for all groups, though there were group differences in the nature of these associations. In autism relative to LAD and NT peers, structural language was differentially associated with anxiety/depression, and language milestones were differentially associated with social relationships, quality of life, educational attainment, and full-time employment status.</p><p><strong>Conclusions: </strong>Findings suggest unique pathways of influence between language and outcomes in individuals with autism versus LAD and NT peers. This evidence suggests that current language and early language development must be considered in social-emotional functioning and in educational and vocational supports from childhood <i>through</i> adulthood for individuals diagnosed with autism in childhood.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214832","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}