medRxiv : the preprint server for health sciences最新文献

{"title":"Structural Evaluation of <i>RYR2</i> -CPVT Missense Variants and Continuous Bayesian Estimates of their Penetrance.","authors":"Kohei Yamauchi, Matthew Ku, Devyn W Mitchell, Alex Shen, Kundivy Dauda, Loren Vanags, Jeffrey Schmeckpeper, Bjorn C Knollmann, Matthew J O'Neill, Brett M Kroncke","doi":"10.1101/2025.03.20.25324327","DOIUrl":"https://doi.org/10.1101/2025.03.20.25324327","url":null,"abstract":"<p><strong>Background: </strong>Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is strongly associated with rare missense variants in <i>RYR2</i> , the gene encoding the intracellular calcium release channel RyR2. Precision medicine is complicated by incomplete penetrance, particularly in the case of <i>RYR2</i> -CPVT variants.</p><p><strong>Objective: </strong>To improve structural understanding and clinical actionability of <i>RYR2-</i> CPVT incomplete penetrance.</p><p><strong>Methods: </strong>We curated 179 manuscripts reviewed by three individuals to extrapolate <i>RYR2</i> -CPVT missense variant genotype-phenotype relationships. Purportedly neutral control variants were ascertained from <i>RYR2</i> missense variants observed in gnomAD and ClinVar. We performed an <i>RYR2</i> -CPVT Bayesian penetrance analysis by conditioning a CPVT penetrance prior on variant-specific features ( <i>in silico</i> and structural) calibrated by heterozygote phenotypes. We compared the calibration of our Bayesian penetrance estimates and our previous described structural density metric with <i>in silico</i> predictors REVEL, AlphaMissense and ClinVar annotations, using Spearman rank-order correlations, and Brier Scores. Penetrance estimates were superimposed upon a cryo-EM structure of RyR2 to investigate 'hot-spot' heterogeneity.</p><p><strong>Results: </strong>From the literature and gnomAD, we identified 1,014 affected missense <i>RYR2</i> heterozygotes (468 unique variants) among a total of 622,575 heterozygotes (5,181 unique variants). Among the predictors, our Bayesian prior score had the highest Spearman rank-order and lowest Brier scores, respectively (0.19; 0.0090), compared to ClinVar (0.083; 0.019), REVEL (0.16; 0.018), or AlphaMissense (0.18; 0.018). Penetrance estimates for all <i>RYR2</i> missense variants are prospectively hosted at our Variant Browser website.</p><p><strong>Conclusions: </strong>Bayesian penetrance scores outperform current tools in evaluating variant penetrance. We provide prospective CPVT penetrance values for 29,242 <i>RYR2</i> missense variants at our online Variant Browser.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757137","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":"Increased sensorimotor and superior parietal activation correlate with reduced writing dysfluency in writer's cramp dystonia.","authors":"Noreen Bukhari-Parlakturk, Patrick J Mulcahey, Michael Fei, Michael W Lutz, James T Voyvodic, Simon W Davis, Andrew M Michael","doi":"10.1101/2025.03.20.25324331","DOIUrl":"https://doi.org/10.1101/2025.03.20.25324331","url":null,"abstract":"<p><p>Writer's cramp (WC) dystonia is a disabling brain disorder characterized by abnormal postures during writing tasks. Although abnormalities were identified in the sensorimotor, parietal, basal ganglia, and cerebellum, the network-level interactions between these brain regions and dystonia symptoms are not well understood. This study investigated the relationship between peak accelerations, an objective measure of writing dysfluency, and functional network (FN) activation in WC and healthy volunteers (HVs). Twenty WC and 22 HV performed a writing task using a kinematic software outside an MRI scanner and repeated it during functional MRI. Group independent component analysis identified 21 FNs, with left sensorimotor, superior parietal, cerebellum, and basal ganglia FNs selected for further analysis. These FNs were activated during writing and no group differences in FN activity were observed. Correlational analysis between FN activity and peak acceleration behavior revealed that reduced activity in left sensorimotor and superior parietal FNs correlated with greater writing dysfluency in WC, a pattern distinct from HVs. These findings suggest that enhanced activation of the left sensorimotor and superior parietal networks may mitigate writing dysfluency in WC. This study provides a mechanistic hypothesis to guide the development of network-based neuromodulation therapies for WC dystonia.</p><p><strong>Author’s summary: </strong>A critical barrier to advancing clinical therapies for writer's cramp (WC) dystonia is the limited understanding of how brain activation patterns associate with worsening disease severity. Our study addressed this gap by integrating an objective behavioral measure of WC dystonia symptom with changes in functional network activity, revealing the direction of brain activity associated with increased symptom severity. We showed that reduced activity in the left sensorimotor and superior parietal cortices correlated with greater writing dysfluency. These findings suggested that neuromodulation strategies aimed at increasing activity in these cortical regions may offer a promising avenue for developing network-based therapies for WC dystonia.</p><p><strong>Conflict of interest: </strong>All authors report no financial disclosures or conflicts of interest relevant to this research.</p><p><strong>Authors’ roles: </strong>NBP: conceptualization, data collection, data analysis, statistical analysis, and manuscript writing. PJM: data analysis, and manuscript writing. MF: data analysis. MWL: statistical analysis and manuscript review. JV: study design. SWD: data analysis advice and manuscript critique. AMM: conceptualization, data analysis critique, manuscript writing and critique.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756983","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":"Feature Extraction Tool Using Temporal Landmarks in Arterial Blood Pressure and Photoplethysmography Waveforms.","authors":"Ravi Pal, Akos Rudas, Tiffany Williams, Jeffrey N Chiang, Anna Barney, Maxime Cannesson","doi":"10.1101/2025.03.20.25324325","DOIUrl":"https://doi.org/10.1101/2025.03.20.25324325","url":null,"abstract":"<p><p>Arterial blood pressure (ABP) and photoplethysmography (PPG) waveforms both contain vital physiological information for the prevention and treatment of cardiovascular diseases. Extracted features from these waveforms have diverse clinical applications, including predicting hyper- and hypo-tension, estimating cardiac output from ABP, and monitoring blood pressure and nociception from PPG. However, the lack of standardized tools for feature extraction limits their exploration and clinical utilization. In this study, we propose an automatic feature extraction tool that first detects temporal location of landmarks within each cardiac cycle of ABP and PPG waveforms, including the systolic phase onset, systolic phase peak, dicrotic notch, and diastolic phase peak using the iterative envelope mean method. Then, based on these landmarks, extracts 852 features per cardiac cycle, encompassing time-, statistical-, and frequency-domains. The tool's ability to detect landmarks was evaluated using ABP and PPG waveforms from a large perioperative dataset (MLORD dataset) comprising 17,327 patients. We analyzed 34,267 cardiac cycles of ABP waveforms and 33,792 cardiac cycles of PPG waveforms. Additionally, to assess the tool's real-time landmark detection capability, we retrospectively analyzed 3,000 cardiac cycles of both ABP and PPG waveforms, collected from a Philips IntelliVue MX800 patient monitor. The tool's detection performance was assessed against markings by an experienced researcher, achieving average F1-scores and error rates for ABP and PPG as follows: (1) On MLORD dataset: systolic phase onset (99.77 %, 0.35 % and 99.52 %, 0.75 %), systolic phase peak (99.80 %, 0.30 % and 99.56 %, 0.70 %), dicrotic notch (98.24 %, 2.63 % and 98.72 %, 1.96 %), and diastolic phase peak (98.59 %, 2.11 % and 98.88 %, 1.73 %); (2) On real time data: systolic phase onset (98.18 %, 3.03 % and 97.94 %, 3.43 %), systolic phase peak (98.22 %, 2.97 % and 97.74 %, 3.77 %), dicrotic notch (97.72 %, 3.80 % and 98.16 %, 3.07 %), and diastolic phase peak (98.04 %, 3.27 % and 98.08 %, 3.20 %). This tool has significant potential for supporting clinical utilization of ABP and PPG waveform features and for facilitating feature-based machine learning models for various clinical applications where features derived from these waveforms play a critical role.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757060","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":"Increased L-type calcium current causes action potential prolongation in Jervell and Lange-Nielsen syndrome and is a drug target.","authors":"Yuko Wada, Marcia A Blair, Teresa L Strickland, Julie A Laudeman, Kyungsoo Kim, M Lorena Harvey, Joseph F Solus, Darlene F Fountain, Bjorn C Knollmann, M Benjamin Shoemaker, Prince J Kannankeril, Dan M Roden","doi":"10.1101/2025.03.20.25324224","DOIUrl":"https://doi.org/10.1101/2025.03.20.25324224","url":null,"abstract":"<p><strong>Background: </strong><i>KCNQ1</i> loss of function variants are thought to cause type 1 long QT syndrome by reducing <i>I</i> _Ks . However, we have recently reported that pharmacologic block of <i>I</i> _Ks in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) produced minimal increases in action potential duration at 90% repolarization (APD ₉₀ ), while genetic loss of <i>KCNQ1</i> markedly prolonged APD ₉₀ . We sought here to define mechanisms underlying APD prolongation by genetic loss of <i>KCNQ1</i> .</p><p><strong>Methods: </strong>We studied iPSC-CMs from population controls, an isogenic <i>KCNQ1</i> knock out (KO) line created by a homozygous edit for the R518X loss of function variant, and 2 unrelated patients with the Jervell and Lange-Nielsen syndrome (JLN) due to compound heterozygosity for loss of function <i>KCNQ1</i> variants.</p><p><strong>Results: </strong>In both JLN and the KCNQ1-KO lines, <i>I</i> _Ks was absent, APD ₉₀ was markedly prolonged, and L-type Ca channel (LTCC) current ( <i>I</i> _Ca-L ) was significantly increased, 2-3-fold, compared to the control cells with no change in kinetics or gating. RNA-sequencing identified 298 and 584 genes that were up- and down-regulated, respectively, by KCNQ1-KO compared to the isogenic control cells. Gene ontology analysis identified down-regulation of 6 Ca ²⁺ channel negative regulatory genes (p=0.0002, FDR=0.02), and in knockdown experiments in wild-type iPSC-CMs, three of these, <i>CBARP</i> , <i>FKBP1B</i> , and <i>RRAD</i> , increased <i>I</i> _Ca-L , and <i>RRAD</i> increased APD ₉₀ . A therapeutic low concentration (1 μM) of the Ca channel antagonist diltiazem significantly shortened APD ₉₀ in the two JLN cell lines and in KCNQ1-KO cells. A single low dose of intravenous diltiazem in one of the JLN patients shortened QTc.</p><p><strong>Conclusions: </strong>These data further support the concept that delayed repolarization in JLN cannot be explained solely by loss of <i>I</i> _Ks . Our findings demonstrate that <i>KCNQ1</i> mutations lead to down-regulation of Ca ²⁺ channel inhibitory genes, with resultant increased <i>I</i> _Ca-L that underlies delayed repolarization in JLN. We further propose that diltiazem can be repurposed for treatment of patients with JLN.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756979","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":"Determinants of Qigong, Tai Chi, and Yoga Use for Health Conditions: A Systematic Review Protocol.","authors":"Ryan S Wexler, Christopher Joyce, Rocky Reichman, Cora Pereira, Emma Fanuele, Emily Hurstak, Lance Laird, Helen Lavretsky, Chenchen Wang, Rob Saper, Karen S Alcorn, Brian S Mittman, Eric J Roseen","doi":"10.1101/2025.03.18.25324204","DOIUrl":"https://doi.org/10.1101/2025.03.18.25324204","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Mind-body movement interventions such as qi gong, tai chi, and yoga are recommended in clinical practice guidelines to improve outcomes for several health conditions. However, use of these interventions for health conditions, or the integration of these interventions within healthcare settings, is low. A systematic synthesis of implementation determinants (i.e., barriers and facilitators) is needed to increase adoption. Similarly, determinants may influence other implementation outcomes, such as scalability or sustainability of these interventions in a healthcare system or community organization. Thus, in conducting this review we aim to identify determinants of qi gong, tai chi, and yoga use for health conditions. The secondary aim is to evaluate whether barriers and facilitators differ by intervention type, health condition, implementation setting, or implementation outcome.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods and analysis: &lt;/strong&gt;We conducted a comprehensive search of electronic databases (MEDLINE, EMBASE, Web of Science, CINAHL, PsycInfo) through May 2024 and a grey literature search (Google Scholar, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov , the WHO Clinical Trials database) through March 2025. We will include original research articles in English that identify barriers and facilitators to adoption of qi gong, tai chi, and yoga by adults with health conditions. Study quality will be assessed using the Mixed Methods Appraisal Tool. We will code each article using a codebook informed by the Consolidated Framework for Implementation Research (CFIR), a comprehensive taxonomy of implementation determinants. Findings will be presented as a narrative synthesis. We will report on how barriers and facilitators may relate to intervention type (qi gong, tai chi, yoga), health condition (e.g., low back pain, fall prevention), implementation settings (e.g., primary care clinic, community organization) or implementation outcome (e.g., adoption, sustainability).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Ethics and dissemination: &lt;/strong&gt;Ethics approval will not be obtained for this review of published, publicly accessible data. The results from this systematic review will be disseminated through conference presentations and journal publications.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Strengths and limitations of this study: &lt;/strong&gt;There are no prior comprehensive reviews of the determinants (i.e., barriers and facilitators) of qi gong, tai chi and yoga use. This review will examine whether barriers and/or facilitators vary by type of mind-body movement intervention, health condition, implementation setting, or implementation outcome.Our search has been guided by librarians with expertise in systematic review methodology and informed by the PEER Review of Electronic Search Strategies (PRESS) guidelines. Reporting of results will be informed by the PRISMA-P checklist for systematic reviews.We will use the updated version of the Consolidated Framework for Imple","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757129","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":"Leveraging tissue-resident memory T cells for non-invasive immune monitoring via microneedle skin patches.","authors":"Sasan Jalili, Ryan R Hosn, Wei-Che Ko, Khashayar Afshari, Ashok Kumar Dhinakaran, Namit Chaudhary, Laura Maiorino, Nazgol Haddadi, Anusha Nathan, Matthew A Getz, Gaurav D Gaiha, Mehdi Rashighi, John E Harris, Paula T Hammond, Darrell J Irvine","doi":"10.1101/2025.03.17.25324099","DOIUrl":"https://doi.org/10.1101/2025.03.17.25324099","url":null,"abstract":"<p><p>Detecting antigen-specific lymphocytes is crucial for immune monitoring in the setting of vaccination, infectious disease, cancer, and autoimmunity. However, their low frequency and dispersed distribution across lymphoid organs, peripheral tissues, and blood pose challenges for reliable detection. To address this issue, we developed a strategy exploiting the functions of tissue-resident memory T cells (T _rm s) to concentrate target circulating immune cells in the skin and then sample these cells non-invasively using a microneedle (MN) skin patch. T _rm s were first induced at a selected skin site through initial sensitization with a selected antigen. Subsequently, these T _rm s were restimulated by intradermal inoculation of a small quantity of the same antigen to trigger the \"alarm\" and immune recruitment functions of these cells, leading to accumulation of antigen-specific T cells from the circulation over several days. In mouse models of vaccination, we show that application of MN patches coated with an optimized hydrogel layer for cell and fluid sampling to this skin site allowed effective isolation of thousands of live antigen-specific lymphocytes as well as innate immune cells. In a human subject with allergic contact dermatitis, stimulation of T _rm s with allergen followed by MN patch application allowed the recovery of diverse lymphocyte populations that were absent from untreated skin sites. These results suggest that T _rm restimulation coupled with microneedle patch sampling can be used to obtain a window into both local and systemic antigen-specific immune cell populations in a noninvasive manner that could be readily applied to a wide range of disease or vaccination settings.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757105","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":"Tuberculosis disease severity assessment using clinical variables and radiology enabled by artificial intelligence.","authors":"Marwan Ghanem, Ratnam Srivastava, Yasha Ektefaie, Drew Hoppes, Gabriel Rosenfeld, Ziv Yaniv, Alina Grinev, Ava Y Xu, Eunsol Yang, Gustavo E Velásquez, Linda Harrison, Alex Rosenthal, Radojka M Savic, Karen R Jacobson, Maha R Farhat","doi":"10.1101/2024.08.19.24311411","DOIUrl":"10.1101/2024.08.19.24311411","url":null,"abstract":"<p><p>Radiology can define tuberculosis (TB) severity and may guide duration of treatment, however the optimal radiological metric to use and which clinical variables to combine it with in the real-world is unclear. We systematically associated baseline chest X-rays (CXR) metrics with TB treatment outcome using real-world data from diverse TB clinical settings. We used logistic regression to associate 10 radiological metrics including percent of lung involved in disease (PLI), cavitation, and Timika score, alone or with other clinical characteristics, stratifying by drug resistance and HIV (n = 2,809). We fine-tuned convolutional neural nets (CNN) to automate PLI measurement from the CXR DICOM images (n = 5,261). PLI is the only CXR finding associated with unfavorable outcome across drug resistance and HIV subgroups [rifampicin-susceptible disease without HIV, adjusted odds ratio 1·11 (1·01, 1·22), P-value 0·025]. The most informed model of baseline characteristics tested predicts outcome with a validation mean area under the curve (AUC) of 0·769. PLI alone predicts unfavorable outcomes equally or better than Timika or cavitary information (AUC PLI 0·656 vs. Timika 0·655 and cavitation best 0·591). PLI>25% provides a better separation of favorable and unfavorable outcomes compared to PLI>50% currently used in some clinical trials. The best performing ensemble of CNNs has an AUC 0·850 for PLI>25% and mean absolute error of 11·7% for the PLI value. PLI is better than cavitation, is accurately predicted with CNNs, and is optimally combined with age, sex, and smear grade for predicting unfavorable treatment outcome in pulmonary TB in real-world settings.</p><p><strong>Significance statement: </strong>A systematic evaluation of specific CXR findings in combination with clinical variables and their association with unfavorable outcomes in real-world settings is currently lacking. Stratification by severity of pulmonary TB can support personalized treatment, including the identification of patient groups that can be cured reliably with a shortened treatment regimen. Shorter regimens can minimize drug side effects, improve adherence and reduce costs of care. With the wider use of digital CXR and the increased adoption of AI for computer assisted diagnosis, radiology has the potential to be leveraged for multiple uses in the treatment and monitoring of TB disease, including contributing to a more individualized approach to TB treatment.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127848","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, Psychopathology, and Personalized Functional Brain Network Topography in Adolescence.","authors":"Kevin Y Sun, J Eric Schmitt, Tyler M Moore, Ran Barzilay, Laura Almasy, Laura M Schultz, Allyson P Mackey, Eren Kafadar, Zhiqiang Sha, Jakob Seidlitz, Travis T Mallard, Zaixu Cui, Hongming Li, Yong Fan, Damien A Fair, Theodore D Satterthwaite, Arielle S Keller, Aaron Alexander-Bloch","doi":"10.1101/2024.09.20.24314007","DOIUrl":"10.1101/2024.09.20.24314007","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Functional brain networks are associated with both behavior and genetic factors. To uncover biological mechanisms of psychopathology, it is critical to define how the spatial organization of these networks relates to genetic risk during development.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To determine the relationships among transdiagnostic polygenic risk scores (PRSs), personalized functional brain networks (PFNs), and overall psychopathology (p-factor) during early adolescence.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design: &lt;/strong&gt;The Adolescent Brain Cognitive Development (ABCD) Study &lt;sup&gt;⍰&lt;/sup&gt; is an ongoing longitudinal cohort study of 21 collection sites across the United States. Here, we conduct a cross-sectional analysis of ABCD baseline data, collected 2017-2018.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Setting: &lt;/strong&gt;The ABCD Study &lt;b&gt;&lt;sup&gt;®&lt;/sup&gt;&lt;/b&gt; is a multi-site community-based study.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants: &lt;/strong&gt;The sample is largely recruited through school systems. Exclusion criteria included severe sensory, intellectual, medical, or neurological issues that interfere with protocol and scanner contraindications. Split-half subsets were used for cross-validation, matched on age, ethnicity, family structure, handedness, parental education, site, sex, and anesthesia exposure.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Exposures: &lt;/strong&gt;Polygenic risk scores of transdiagnostic genetic factors F1 (PRS-F1) and F2 (PRS-F2) derived from adults in Psychiatric Genomic Consortium and UK Biobanks datasets. PRS-F1 indexes liability for common psychiatric symptoms and disorders related to mood disturbance; PRS-F2 indexes liability for rarer forms of mental illness characterized by mania and psychosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main outcomes and measures: &lt;/strong&gt;(1) P-factor derived from bifactor models of youth- and parent-reported mental health assessments. (2) Person-specific functional brain network topography derived from functional magnetic resonance imaging (fMRI) scans.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Total participants included 11,873 youths ages 9-10 years old; 5,678 (47.8%) were female, and the mean (SD) age was 9.92 (0.62) years. PFN topography was found to be heritable ( &lt;i&gt;N&lt;/i&gt; =7,459, 57.1% of vertices &lt;i&gt;h&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt; &lt;i&gt;p &lt;sub&gt;FDR&lt;/sub&gt;&lt;/i&gt; &lt;0.05, mean &lt;i&gt;h&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt; =0.35). PRS-F1 was associated with p-factor ( &lt;i&gt;N&lt;/i&gt; =5,815, &lt;i&gt;r&lt;/i&gt; =0.12, 95% CI [0.09-0.15], p&lt;0.001). Interindividual differences in functional network topography were associated with p-factor ( &lt;i&gt;N&lt;/i&gt; =7,459, mean &lt;i&gt;r&lt;/i&gt; =0.12), PRS-F1 ( &lt;i&gt;N&lt;/i&gt; =3,982, mean &lt;i&gt;r&lt;/i&gt; =0.05), and PRS-F2 ( &lt;i&gt;N&lt;/i&gt; =3,982, mean &lt;i&gt;r&lt;/i&gt; =0.08). Cortical maps of p-factor and PRS-F1 regression coefficients were highly correlated ( &lt;i&gt;r&lt;/i&gt; =0.7, &lt;i&gt;p&lt;/i&gt; =0.003).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions and relevance: &lt;/strong&gt;Polygenic risk for transdiagnostic adulthood psychopathology is associated with both p-factor and heritable PFN topography during early adolescence. These results advance our understanding of the d","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11469391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484950","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":"NutriRAG: Unleashing the Power of Large Language Models for Food Identification and Classification through Retrieval Methods.","authors":"Huixue Zhou, Lisa S Chow, Lisa Harnack, Satchidananda Panda, Emily N C Manoogian, Minchen Li, Yongkang Xiao, Rui Zhang","doi":"10.1101/2025.03.19.25324268","DOIUrl":"https://doi.org/10.1101/2025.03.19.25324268","url":null,"abstract":"<p><strong>Objective: </strong>This study explores the use of advanced Natural Language Processing (NLP) techniques to enhance food classification and dietary analysis using raw text input from a diet tracking app.</p><p><strong>Materials and methods: </strong>The study was conducted in three stages: data collection, framework development, and application. Data were collected via the myCircadianClock app, where participants logged their meals in free-text format. Only de-identified food-related entries were used. We developed the NutriRAG framework, an NLP framework utilizing a Retrieval-Augmented Generation (RAG) approach to retrieve examples and incorporating large language models such as GPT-4 and Llama-2-70b. NutriRAG was designed to identify and classify user-recorded food items into predefined categories and analyzed dietary patterns from free-text entries in a 12-week randomized clinical trial (RCT: NCT04259632 ). The RCT compared three groups of obese participants: those following time-restricted eating (TRE, 8-hour eating window), caloric restriction (CR, 15% reduction), and unrestricted eating (UR).</p><p><strong>Results: </strong>NutriRAG significantly enhanced classification accuracy and effectively identified nutritional content and analyzed dietary patterns, as noted by the retrieval-augmented GPT-4 model achieving a Micro F1 score of 82.24. Both interventions showed dietary alterations: CR participants ate fewer snacks and sugary foods, while TRE participants reduced nighttime eating.</p><p><strong>Conclusion: </strong>By using AI, NutriRAG marks a substantial advancement in food classification and dietary analysis of nutritional assessments. The findings highlight NLP's potential to personalize nutrition and manage diet-related health issues, suggesting further research to expand these models for wider use.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756689","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":"Genome-wide association study of dry eye disease reveals shared heritability with systemic comorbidities.","authors":"Bryan R Gorman, Jaxon J Huang, Peter B Barr, Christopher W Halladay, Cari L Nealon, Chris Chatzinakos, Michael Francis, Chen Jiang, Million Veteran Program, Paul B Greenberg, Wen-Chih Wu, Saiju Pyarajan, Hélène Choquet, Tim B Bigdeli, Sudha K Iyengar, Neal S Peachey, Anat Galor","doi":"10.1101/2025.03.18.25324218","DOIUrl":"https://doi.org/10.1101/2025.03.18.25324218","url":null,"abstract":"<p><p>Dry eye disease (DED) affects up to 25% of the adult population, with chronic symptoms of pain and dryness often negatively impacting quality of life. The genetic architecture of DED is largely unknown. Here, we develop and validate an algorithm for DED in the Million Veteran Program using a combination of diagnosis codes and prescription records, resulting in 132,657 cases and 352,201 controls. In a multi-ancestry genome-wide association study, we identify ten significant loci in nine susceptibility regions with largely consistent effects across ancestries, including loci linked to synapse maintenance ( <i>EPHA5</i> , <i>GRIA1</i> , <i>SYNGAP1</i> ) and autoimmunity ( <i>BLK</i> ). Phenome-wide scans for genetic pleiotropy indicate substantial genetic correlations of DED with comorbidities, including fibromyalgia, post-traumatic stress disorder, and Sjögren's disease. Finally, applying genomic structural equation modeling, we derive a latent factor underlying DED and other chronic pain traits which accounts for 51% of the genetic variance of DED.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756561","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}