medRxiv : the preprint server for health sciences最新文献

{"title":"The Circulating Lipidome In Severe Obesity.","authors":"Mohammad Yaser Anwar, Heather M Highland, Alexandra B Palmer, Thy Duong, Zhaotong Lin, Wanying Zhu, Jessica Sprinkles, Daeeun Kim, Kristin L Young, Hung-Hsin Chen, Mohanraj Krishnan, Absalon Gutierrez, Rashedeh Roshani, Elizabeth G Frankel, Joshua Landman, Penny Gordon-Larsen, Miryoung Lee, Susan P Fisher-Hoch, Joseph B McCormick, Joanne Curran, John Blangero, Peter J Meikle, Corey Giles, Jennifer E Below, Kari E North, Mariaelisa Graff","doi":"10.1101/2025.06.11.25329456","DOIUrl":"10.1101/2025.06.11.25329456","url":null,"abstract":"<p><strong>Background: </strong>Severe obesity (SevO; BMI ≥40 kg/m²) is rapidly increasing globally and disproportionately affects minority populations. However, it remains understudied in mechanistic and omics literature. Lipid metabolism plays a central role in obesity-related cardiometabolic disease (CMD), but the relationship between molecular lipid species and SevO is poorly understood, particularly in high-risk groups.</p><p><strong>Methods: </strong>We analyzed 578 participants from the Cameron County Hispanic Cohort (CCHC) with fasting plasma lipidomic and genetic data, comparing those living with SevO (n=185) to non-obese controls (n=393). A total of 830 circulating lipid species across 49 classes were quantified. Associations between individual lipids and SevO were assessed using logistic regression and orthogonal projections to latent structures discriminant analysis (OPLS-DA). Potential causal links were assessed using network deconvolution mendelian randomization (NDMR), and influential lipids were correlated with CMD traits and DXA-derived body composition.</p><p><strong>Results: </strong>Participants with SevO exhibited statistically significantly more adverse cardiometabolic risk factors than controls. Lipidomic profiling revealed broad alterations: shorter, saturated, and monounsaturated triacylglycerols were markedly elevated, while lysophospholipids, plasmalogens, cholesteryl esters, and long-chain lipids were reduced in individuals with SevO when compared to controls (BMI ≥ 18.5 and > 25 kg/m²). OPLS-DA identified over 300 influential lipid species predictive of SevO status. NDMR analyses implicated specific triacylglycerol species as potentially causally linked with SevO status. Influential lipids correlated with insulin resistance, liver steatosis, body fat measures, and HDL-C (absolute value ranges 0.2-0.4).</p><p><strong>Conclusions: </strong>Our findings reveal that SevO is marked by extensive and lipid class-specific dysregulation of the circulating lipidome, with strong links to cardiometabolic risk. Notably, triacylglycerols containing shorter length acyl chains emerged as a distinctive lipid signature of SevO-consistently elevated, strongly discriminative of SevO status, and uniquely exhibiting a consistent causal relationship. Our results provide compelling evidence for a novel lipidomic pathway underpinning severe obesity and underscore critical avenues for future research into its genetic, dietary, and mechanistic determinants.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532263","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 Ethnic/Racial Variations of Intracerebral Hemorrhage Genetics (ERICH-GENE) Study Protocol.","authors":"Guido J Falcone, Stacey Q Wolfe, Marialuisa Zedde, Rosario Pascarella, Jordi Jimenez-Conde, Marta Vallverdu Prats, Joan Jimenez-Balado, Alessandro Pezzini, Sandra Rossi, Rustam Al-Shahi Salman, Neshika Samarasekera, Ramin Zand, Jinag Li, Christina Jern, Daniel Strbian, Liisa Tomppo, Hanne Sallinen, Mar Hernandez Guillamon, Magdy Selim, Mayowa Owolabi, Rufus Akinyemi, Gregory Fakunle, Tsong-Hai Lee, David Werring, Isabel C Hostettler, Henry Houlden, Pankaj Sharma, Isaac John, Gie Ken-Dror, Wendy Jenkins, Kevin N Sheth, Lauren H Sansing, Dharambir K Sanghera, Evgeny Sidorov, Israel Fernandez-Cadenas, Jara Cárcel-Márquez, Ching-Jen Chen, Andrea Becerril-Gaitan, Keon-Joo Lee, Hee-Joon Bae, Martin Dichgans, Rainer Malik, Stephanie Debette, Aniket Mishra, Guillaume Pare, Michael Chong, Yoichiro Kamatani, Zhengming Chen, Robin G Walters, Sudha Seshadri, Myriam Fornage, Catherine Sudlow, Lee A Gilkerson, Vivek J Khandwala, Thomas C Maloney, Stacie Demel, Livia Parodi, Ramin Zand, Paul Nyquist, Wendy Ziai, Bradford Worrall, Vagal M Achala, Carl D Langefeld, Jonathan Rosand, Christopher D Anderson, Daniel Woo","doi":"10.1101/2025.06.11.25329301","DOIUrl":"https://doi.org/10.1101/2025.06.11.25329301","url":null,"abstract":"<p><strong>Background: </strong>Spontaneous, non-traumatic intracranial hemorrhage (ICH) is highly heritable disease. However, the identification of the genetic risk factors driving this high genetic predisposition has been limited by small sample sizes and underrepresentation of non-European populations. The ERICH-GENE study will gather and harmonize clinical, neuroimaging and genomic data on the largest and more diverse collection of ICH cases assembled to date.</p><p><strong>Methods: </strong>ERICH-GENE is an NIH-funded, multi-center, international, genetic and neuroimaging study that aims to achieve the necessary sample size and diversity required to accurately describe the genetic architecture and trans-ethnic variation of ICH. ERICH-GENE will collect and harmonize clinical, neuroimaging and genomic data at least 10,000 multi-ethnic ICH cases. These data will be aggregated with 20,000 existing ICH cases and 600,000 ICH-free controls available through completed studies by the International Stroke Genetics Consortium. To ensure validity, data will undergo extensive harmonization, including expert review of neuroimages to ensure spontaneous etiology and hemorrhage location. We will conduct genome-wide association studies of risk, severity and outcome of ICH, testing for effect modification by race/ethnicity, sex and hemorrhage location. We will also conduct pathway, polygenic risk score and Mendelian randomization analyses.</p><p><strong>Results: </strong>This study will include whole genome sequencing data from 10,850 spontaneous ICH samples, including clinical and radiographic phenotypic data to ensure reliability of true non-traumatic, non-lesional ICH and lobar vs nonlobar location. Of these, 1,497 have already been genotyped using genome-wide arrays, 3,753 have undergone whole genome sequencing, and 5,600 will undergo genome-wide genotyping through ERICH-GENE. There are currently 42 contributing sites exceeding study milestone enrollments. 16,175 radiographic studies from 4,974 patients have been uploaded for harmonization to date, including 26% lobar and 64% nonlobar hemorrhages. Neuroimaging assessment will also include grading for white matter hyperintensities, cerebral atrophy, and presence and severity of IVH. Nearly 6,000 ICH cases will complete genotyping by August 2025. Data/material transfer agreements for summary statistics as well as additional samples are on target to meet the study's objectives.</p><p><strong>Conclusion: </strong>ERICH-GENE is the largest trans-ethnic genetic study of ICH conducted to date. Combining a diverse patient population with expert adjudication of neuroimaging data, ERICH-GENE will identify genetic risk loci that drive the high heritability observed for this disease and make a significant contribution to the understanding of the trans-ethnic variation of its genetic architecture.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532281","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":"Proton pump inhibitors and upper gastrointestinal cancer: a matched case-control study addressing confounding by indication.","authors":"Ibrahim O Sawaid, Zohar Din, Efrat Golan, Eytan Ruppin, Avivit Golan-Cohen, Ilan Green, Eugene Merzon, Shlomo Vinker, Abraham O Samson, Ariel Israel","doi":"10.1101/2025.06.13.25329558","DOIUrl":"https://doi.org/10.1101/2025.06.13.25329558","url":null,"abstract":"<p><strong>Objectives: </strong>To assess the association between proton pump inhibitor (PPI) use and upper gastrointestinal (GI) cancer while addressing potential confounding by indication.</p><p><strong>Design: </strong>Matched case-control study using multivariable conditional logistic regression.</p><p><strong>Setting: </strong>Electronic health records from a national health provider.</p><p><strong>Participants: </strong>Patients diagnosed with upper GI cancer (n=875), each matched with 10 cancer-free controls (n=8750) by age, sex, and ethnic group.</p><p><strong>Main outcome measures: </strong>Adjusted odds ratios (aORs) for upper GI cancer associated with prior exposure to PPIs, H2 receptor antagonists, or antacids, with medication exposure modelled as multiple binary variables corresponding to distinct time windows before the index date. Additional models adjusted for GI-related diagnoses recorded prior to the index date (e.g., gastritis, gastroesophageal reflux disease, peptic ulcer disease).</p><p><strong>Results: </strong>PPI use in the five years before the index date was initially associated with increased odds of upper GI malignancy (e.g., esomeprazole aOR 3.90 [95% CI 3.14 to 4.84]; omeprazole aOR 2.60 [2.22 to 3.06]). However, when exposure was modelled as separate binary variables for each time window, the association was strongest for use within six months of diagnosis and was not observed-or reversed-for more remote exposures. After excluding the final year before diagnosis and adjusting for symptom-related diagnoses, no positive association remained. Remote PPI use was associated with reduced risk (e.g., omeprazole more than 3 years before the index date: aOR 0.62 [0.51 to 0.75]).</p><p><strong>Conclusions and relevance: </strong>The association between PPI use and upper GI malignancy appears to reflect confounding by indication, with PPIs prescribed in response to early symptoms associated with increased cancer risk. After accounting for timing of use and underlying GI diagnoses, no harmful association remained. These findings suggest that new-onset upper GI symptoms warrant investigation for malignancy, rather than attribution of risk to acid-suppressive therapy.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12191108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500050","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":"Whole genome sequence association analysis of brain structural volume measures in the NHLBI TOPMed Program highlights novel loci in diverse participants.","authors":"Lincoln Mp Shade, Mohsen Sharifitabar, Alexa Beiser, Claudia L Satizabal, Thomas H Mosley, Joanne E Curran, Jan Bressler, Susan R Heckbert, Timothy M Hughes, Thomas R Austin, Ilya M Nasrallah, Lenore J Launer, Lisa R Yanek, Joshua C Bis, Harsha Doddapaneni, Richard A Gibbs, Stacey Gabriel, Namrata Gupta, Karine A Viaud-Martinez, Albert V Smith, Lauren A Opsasnick, Farrah Ammous, Jennifer A Smith, Donna K Arnett, Sharon L R Kardia, Bruce M Psaty, W T Longstreth, Rasika A Mathias, Paul Nyquist, Stephen S Rich, Jerome I Rotter, Eric Boerwinkle, Charles S DeCarli, David C Glahn, John Blangero, Myriam Fornage, David W Fardo, Sudha Seshadri, Chloé Sarnowski","doi":"10.1101/2025.06.11.25329426","DOIUrl":"10.1101/2025.06.11.25329426","url":null,"abstract":"<p><p>Brain structural volumes are highly heritable and are linked to multiple neuropsychological outcomes, including Alzheimer's disease (AD). Genome-wide association studies have successfully identified genetic variants associated with intracranial volume (ICV), total brain volume (TBV), hippocampal volume (HV), and lateral ventricular volume (LVV). However, these studies mostly focused on common genetic variants with minor allele frequencies (MAF) > 1%, and individuals included in most of these studies were of predominantly European ancestry. Here, we performed whole-genome sequence (WGS) association studies of MRI brain volumes in 7,674 individuals of diverse race and ethnicity from the Trans-Omics for Precision Medicine (TOPMed) program. We identified novel genetic loci on chromosomes 13 and 16 near <i>LINC00598</i> and <i>CACNG3</i> associated with HV and TBV, respectively (lead variants rs115674829, <i>P</i>-value = 1.7×10^-9 in pooled analysis and rs150440001, <i>P</i>-value = 6.6×10^-9 in black participants). Both lead variant minor A alleles are rarer in white participants (MAF = 0.14% and 0.03%) and in Hispanic participants (MAF = 1.5% and 0.17%) but more common in black participants (MAF = 13% and 1.5%). Rare variant aggregated analyses identified <i>RIPK1,</i> a gene encoding a kinase involved in neuroinflammation and promising target for AD treatment, suggestively associated with LVV (<i>P</i>-value=5×10^-6). This study provides new insights into the genetic correlates of brain structural volumes and illustrates the importance of leveraging WGS data and cohorts of diverse race and ethnicity to better characterize the genetic architecture of complex polygenic traits.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12191100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500027","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":"Transspinal stimulation preceding assisted step training reorganizes neuronal excitability and function of inhibitory networks in spinal cord injury: A randomized controlled trial.","authors":"Abdullah M Sayed Ahmad, Morad Zaaya, Noam Y Harel, Maria Knikou","doi":"10.1101/2025.06.11.25329338","DOIUrl":"https://doi.org/10.1101/2025.06.11.25329338","url":null,"abstract":"<p><strong>Introduction: </strong>In this pilot randomized sham-controlled clinical trial, we characterized the spinal neuronal and network excitability in human spinal cord injury (SCI) when transspinal stimulation preceded locomotor training within the same session.</p><p><strong>Methods: </strong>Fourteen participants with chronic SCI received an average of 40 sessions with 30 Hz transspinal stimulation delivered for 30 minutes during standing (active: n= 4; sham: n= 5) or supine (active: n= 5) followed by 30-minutes of robotic assisted step training. Before and 1-2 days after completion of all training sessions, we assessed the soleus H-reflex homosynaptic depression and soleus H-reflex recruitment curve, and the amount of reciprocal and presynaptic inhibition following conditioning stimulation of the antagonistic common peroneal nerve.</p><p><strong>Results: </strong>Transspinal stimulation administered before locomotor training increased the amount of homosynaptic depression in the active-standing and active-supine groups, while presynaptic inhibition exerted on Ia afferent terminals increased in all study groups. Reciprocal Ia inhibition improved in the sham-standing and active-supine groups while in all groups the excitability threshold of muscle group Ia afferents was decreased in all groups.</p><p><strong>Conclusion: </strong>This study demonstrated that transspinal stimulation preceding locomotor training partially restores natural spinal inhibition and produces network reorganization in chronic SCI. Noninvasive transspinal stimulation can increase the benefits of locomotor training, bringing spinal neuronal networks to a more functional state in chronic SCI.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532284","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":"Striatal Dopamine and Skeletal Muscle Energy Metabolism in Older Adults.","authors":"Caterina Rosano, Nico I Bohnen, Brian LoPresti, Lana M Chahine, Haley N Barnes, Stephanie L Studenski, Nancy W Glynn, Anne B Newman, David J Marcinek, Russell T Hepple, Paul Coen","doi":"10.1101/2025.06.12.25329490","DOIUrl":"10.1101/2025.06.12.25329490","url":null,"abstract":"<p><p>Dopamine (DA) in the central nervous system is considered a master regulator of mobility performance and vigor, but its mechanistic relationship with skeletal muscle energetics is unclear. We tested the cross-sectional association of striatal DA and skeletal muscle mitochondrial function in 146 older adults participating in the Study of Muscle, Mobility and Aging (75.4 years old, 54% women). Striatal DA was measured using (+)-a-[¹¹C] dihydrotetrabenazine (DTBZ) PET imaging for the limbic, sensorimotor, and executive control subregions. Mitochondrial capacity to produce ATP (ATP_max, mM ATP/s) was measured in vivo using ³¹P magnetic resonance spectroscopy after repeated voluntary muscle contractions. Ex-<i>vivo</i> respirometry assays from biopsies of resting muscle captured complementary aspects of mitochondrial function under optimal conditions. In multivariable linear regression models, [¹¹C]DTBZ in the limbic striatum, but not other subregions, was positively associated with greater ATPmax <i>in vivo</i>, independent of demographics, muscle volume, leg power, white matter hyperintensities, gray matter atrophy, moderate-to-vigorous physical activity and diabetes (β = 0.275, standard error 0.108, p=0.019). [¹¹C]DTBZ was not associated with the ex-vivo mitochondrial respiration markers (p>0.2). The role of striatal limbic DA and the energetic capacity of skeletal muscles should be further investigated in older adults.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532258","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":"Attention-based deep learning for analysis of pathology images and gene expression data in lung squamous premalignant lesions.","authors":"Lingyi Xu, Yohana Kefella, Yichi Zhang, Regan D Conrad, Kelley E Anderson, Kostyantyn Krysan, Gang Liu, Erin Kane, Adam Pennycuick, Sam M Janes, Mary E Reid, Eric J Burks, Ehab Billatos, Sarah A Mazzilli, Vijaya B Kolachalama, Jennifer E Beane","doi":"10.1101/2025.06.06.25328492","DOIUrl":"https://doi.org/10.1101/2025.06.06.25328492","url":null,"abstract":"<p><p>Molecular and cellular alterations to the normal pseudostratified columnar bronchial epithelium results in the development of bronchial premalignant lesions representing a spectrum of histology from normal to hyperplasia, metaplasia, dysplasia (mild, moderate, and severe), carcinoma in situ and invasive carcinoma. Several studies have identified molecular alterations associated with lesion histology and progression. The broad and continuous spectrum of histologic and molecular changes makes reproducible stratification of lesions across multiple studies challenging. Here we propose a transformer-based framework that flexibly utilizes transcriptomic and histologic patterns to distinguish lesions with bronchial dysplasia or worse from normal, hyperplasia, and metaplasia. We leveraged H&E whole slide images (WSIs) of endobronchial biopsies and bulk gene expression data (GE) from previously published studies and on-going lung precancer atlas efforts obtained from patients as high-risk for lung cancer. Models trained using both WSIs and GE compared to a single data modality had higher performance. On an external testing dataset of WSIs, the area under the ROC curve (AUROC) of the model trained on WSIs plus GE was 0.761±0.015 compared to 0.690±0.027 for model trained on WSIs. On external testing datasets of GE, the AUROC of the model trained on WSIs plus GE was 0.890±0.023 versus 0.816±0.032 for a model trained on GE. Based on these results, we leveraged data across 4 studies to train a flexible fusion model that allows one or both data modalities to be used in training. The model achieved an AUROC of 0.809±0.036 on external testing WSIs data and 0.903±0.022 on external testing GE data. Despite model training on a binary label, model probabilities are associated with histologic grade and the model identifies gene expression alterations associated with bronchial dysplasia across multiple studies. This framework maps bronchial premalignant lesions that contain at least one data modality into a spectrum of disease. In the future, a framework trained on multiple data modalities may be useful in predicting premalignant disease severity, progression, and interception agent efficacy.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532245","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":"Wearable-Echo-FM: An ECG-echo foundation model for single lead electrocardiography.","authors":"Elizabeth Knight, Evangelos K Oikonomou, Arya Aminorroaya, Aline F Pedroso, Rohan Khera","doi":"10.1101/2025.06.10.25329163","DOIUrl":"https://doi.org/10.1101/2025.06.10.25329163","url":null,"abstract":"<p><p>Artificial intelligence (AI) models can now detect patterns of structural heart diseases (SHDs) from electrocardiograms (ECGs), though scaling them requires the broader use of single-lead ECGs that are now ubiquitous in wearable and portable devices. However, model development for these devices is limited by a lack of diagnostic labels for SHDs for wearable ECGs. Here, we present Wearable-Echo-FM, a foundation model that encodes single-lead ECGs with information from echocardiographic text reports. Using 274,057 single-lead ECG-echo pairs from 77,378 adults (2015-2019), we contrastively pre-trained convolutional neural network (CNN) and RoBERTa encoders. The ECG encoder was fine-tuned on a distinct progressively larger ECG set (250 to 250,260 ECGs) to detect different cardiac disorders (i) left-ventricular systolic dysfunction (LVSD), (ii) diastolic dysfunction, and (iii) a composite SHD. This was compared with a randomly initialized CNN, with both approaches evaluated in an independent held-out test set. With the full training set, Wearable-Echo-FM matched the baseline CNN (AUROC 0.894 vs 0.884 for LVSD; 0.849 vs 0.843 diastolic dysfunction; 0.887 vs 0.869 composite). With only 0.5% (~1000 ECGs) of data, it markedly outperformed baseline (0.855 vs 0.548; 0.819 vs 0.582; 0.863 vs 0.496, respectively). Contrastive pre-training of single-lead ECGs on echocardiographic text reduces label requirements for SHD screening on wearable and portable devices.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532353","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 Genetic Evolution of Driver Mutations in Uveal Melanoma.","authors":"James J Dollar, Christina L Decatur, Ezekiel Weis, Amy C Schefler, Miguel A Materin, Timothy S Fuller, Alison H Skalet, David A Reichstein, Ivana Kim, Kisha D Piggott, Hakan Demirci, Thomas A Aaberg, Prithvi Mruthyunjaya, Basil K Williams, Eugene Shildkrot, Scott C N Oliver, Devron H Char, Antonio Capone, John Mason, Scott D Walter, Michael Altaweel, Jill Wells, Dan S Gombos, Jay Duker, Peter Hovland, Tony Tsai, Cameron Javid, Michael A Durante, Kyle R Covington, Song Zhang, Zelia M Correa, J William Harbour","doi":"10.1101/2025.06.10.25329358","DOIUrl":"https://doi.org/10.1101/2025.06.10.25329358","url":null,"abstract":"<p><p>Uveal melanoma (UM) is an aggressive cancer of the eye that frequently results in metastatic death. UMs are most likely to metastasize when they are small, at a time when they are difficult to distinguish from benign nevi and often observed without treatment. Unfortunately, little is known about the early genetic evolution of UM or potential biomarkers to indicate small tumors undergoing malignant transformation. Here, we performed targeted next generation sequencing for the 7 canonical UM driver mutations in 1140 primary UMs, including 131 small early-stage tumors. We found that the evolutionary burst of genetic aberrations that determines the archetypal UM subtypes and metastatic propensity has already occurred by the time most small tumors are biopsied, although a significantly larger proportion of small tumors are still evolving compared to larger tumors. We found that the 15-gene expression profile (15-GEP) support vector machine discriminant score was the best indicator of tumors in transition from low-risk Class 1 to high-risk Class 2 signature. While <i>BAP1</i> , <i>SF3B1</i> and <i>EIF1AX</i> mutations were associated with poor, intermediate and good prognosis, respectively, mutation analysis was inferior to the prospectively validated 15-GEP + <i>PRAME</i> expression classifier for predicting metastasis-free and overall survival. These results provide a more complete picture of genetic evolution in UM, and they move us closer to a molecular definition of malignant transformation in this cancer type.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532295","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":"Diverse Genomes, Shared Health: Insights from a Health System Biobank.","authors":"Roni Haas, Michael P Margolis, Angela Wei, Takafumi N Yamaguchi, Jeffrey Feng, Thai Tran, Veronica Tozzo, Katelyn J Queen, Mohammed Faizal Eeman Mootor, Vishakha Patil, Michael E Broudy, Paul Tung, Shafiul Alam, Danielle B Martinez, Yash Patel, Nicole Zeltser, Rupert Hugh-White, Jaron Arbet, Christa Caggiano, Ruhollah Shemirani, Mao Tian, Prapti Thapaliya, Lora Eloyan, Lawrence O Chen, Maryam Ariannejad, Clara Lajonchere, Bogdan Pasaniuc, Alex Bui, Valerie A Arboleda, Timothy S Chang, Noah Zaitlen, Paul T Spellman, Paul C Boutros, Daniel H Geschwind","doi":"10.1101/2025.06.11.25329386","DOIUrl":"10.1101/2025.06.11.25329386","url":null,"abstract":"<p><p>Coupling genetic profiling with electronic health records from hospital biobanks is a foundational resource for precision medicine. However, lack of ancestral heterogeneity limits discovery and generalizability. We leveraged the UCLA ATLAS Community Health Initiative, a diverse biobank with >35% non-European participants in a single health system, to inform disease prevalence and genetic risk across five continental and 36 fine-scale ancestry groups. Analyzing clinical and genetic data for 93,937 individuals, 61,797 with whole-exome sequencing (WES), we identified novel associations between genetic variants and phenotypes, including <i>STARD7</i> with asthma risk in Mexican Americans and <i>FN3K</i> with intestinal disaccharidase deficiency across Europeans and Admixed Americans. Top decile polygenic scores (PGS) predicted patient status for many common diseases (40% of patients with Type 1 diabetes); an effect markedly diminished in non-Europeans. Exploring the distribution of ACMG ClinGen rare variants across populations demonstrated European bias in curated clinical variants. Mitigating this bias using computationally predicted deleterious variants, we identified new gene-disease associations, including <i>EXOC1L</i> and blood glucose level in East Asians. We identified <i>PTPRU</i> as a modulator of semaglutide's effects on weight loss, and additionally found variability across ancestries and a relationship with type-2-diabetes PGS. We provide an interactive web portal for accessing cross-ancestry associations at atlas-phewas.mednet.ucla.edu. Collectively, our findings support the value of ancestral diversity in advancing precision health across a broad spectrum of populations.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532294","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}