medRxiv : the preprint server for health sciences最新文献

{"title":"Subjective Response to Opioids Predicts Risk for Opioid Use Disorder.","authors":"Jean Gonzalez, Vinh Tran, John Meredith, Ivonne Xu, Ritviksiddha Penchala, Laura Vilar Ribo, Natasia S Courchesne-Krak, Daniel Zoleikhaeian, Matt McIntyre, Pierre Fontanillas, Katelyn Kukar Bond, Eric Otto Johnson, Alvin Jeffery, James MacKillop, Carla Marienfeld, Harriet de Wit, Abraham A Palmer, Sandra Sanchez-Roige","doi":"10.1101/2025.03.21.25324409","DOIUrl":"https://doi.org/10.1101/2025.03.21.25324409","url":null,"abstract":"<p><p>Exposure to prescription opioids can lead to opioid use disorder (OUD) in some individuals, but we lack scalable tools to predict who is at risk. We collected retrospective data on the initial subjective effects of prescription opioids from 117,508 research participants, 5.3% of whom self-reported OUD. Positive subjective effects, particularly \"Like Overall\", \"Euphoric\", and \"Energized\", were the strongest predictors of OUD. For example, the odds-ratio for individuals responding \"Extremely\" for \"Like Overall\" was 36.2. The sensitivity and specificity of this single question was excellent (ROC=0.87). Negative effects and analgesic effects were much less predictive. We present a two-step decision tree that can identify a small high-risk subset with 77.4% prevalence of OUD and a much larger low-risk subset with 1.7% prevalence of OUD. Our results demonstrate that positive subjective responses are predictive of future misuse and suggest that vulnerable individuals may be identified and targeted for preventative interventions.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757145","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":"Network-based Molecular Constraints on in vivo Synaptic Density Alterations in Schizophrenia.","authors":"Sidhant Chopra, Patrick D Worhunsky, Mika Naganawa, Xi-Han Zhang, Ashlea Segal, Edwina Orchard, Vanessa Cropley, Stephen Wood, Gustavo A Angarita, Kelly Cosgrove, David Matuskey, Nabeel B Nabulsi, Yiyun Huang, Richard E Carson, Irina Esterlis, Patrick D Skosnik, Deepak C D'Souza, Avram J Holmes, Rajiv Radhakrishnan","doi":"10.1101/2025.03.22.25324465","DOIUrl":"https://doi.org/10.1101/2025.03.22.25324465","url":null,"abstract":"<p><p>Converging neuroimaging, genetic, and post-mortem evidence show a fundamental role of synaptic deficits in schizophrenia pathogenesis. However, the underlying molecular and cellular mechanisms that drive the onset and progression of synaptic pathology remain to be established. Here, we used synaptic density positron emission tomography (PET) imaging using the [11C]UCB-J radiotracer to reveal a prominent widespread pattern (p_FWE<0.05) of lower synaptic density in individuals with schizophrenia (n=29), compared to a large sample of healthy controls (n=93). We found that the spatial pattern of lower synaptic density in schizophrenia is spatially aligned (r_cca = 0.67; p<0.001) with higher normative distributions of GABAA/BZ, 5HT1B, 5HT2A, and 5HT6, and lower levels of CB1 and 5HT1A. Competing neighborhood deformation network models revealed that regional synaptic pathology strongly correlated with estimates predicted using a model constrained by both interregional structural connectivity and molecular similarity (.42 < r < .61; p_FWE<0.05). These data suggest that synaptic pathology in schizophrenia is jointly constrained by both global axonal connectivity and local molecular vulnerability. Simulation-based network diffusion models were used to identify regions that may represent the initial sources of pathology, nominating left prefrontal areas (p_FWE<0.05) as potential foci from which synaptic pathology initiates and propagates to molecularly similar areas. Overall, our findings provide in vivo evidence for widespread deficit in synaptic density in schizophrenia that is jointly constrained by axonal connectivity and molecular similarity between regions, and that synaptic deficits spread from initial source regions to axonally connected and molecularly similar territories.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757146","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":"HIV seroprevalence, incidence, and viral suppression among Ugandan males with bar or sex worker partners: a population-based study.","authors":"Xinyi Feng, Kate Grabowski, Fred Nalugoda, Godfrey Kigozi, Larry W Chang, Andrea Wirtz, Caitlin E Kennedy, Gertrude Nakigozi, Eshan U Patel, Anthony Ndyanabo, Hadijja Nakawooya, Thomas C Quinn, Ronald M Galiwango, David Serwadda, Victor Ssempijja, Steven J Reynolds, Aaron A R Tobian, Robert Ssekubugu","doi":"10.1101/2025.03.22.25324410","DOIUrl":"https://doi.org/10.1101/2025.03.22.25324410","url":null,"abstract":"<p><strong>Background: </strong>Female bar or sex workers (FBSWs) in Eastern Africa experience a high burden of HIV. However, there is limited population-level data on HIV seroprevalence, incidence, and viral suppression among their male partners.</p><p><strong>Methods: </strong>Men who had sex with FBSWs in the past year were identified through longitudinal population-based HIV surveillance in southern Uganda between 2013 and 2020. Surveillance was conducted over four surveys in four Lake Victoria fishing communities (HIV seroprevalence∼40%) and 37 inland agricultural and trading communities (∼12%). Primary outcomes included laboratory-confirmed HIV seropositivity, incident infection, and viral suppression (<200 copies/mL). Prevalence and incidence rate ratios (PR, IRR) were estimated using univariable and multivariable Poisson regressions with 95% confidence intervals (95%CIs).</p><p><strong>Findings: </strong>17,438 male participants contributed 35,273 visits, with 2,420 (13.9%) reporting FBSW partners at ≥1 study visit. Men with FBSW partners tended to be older, have less education and lower incomes, and be previously married compared to those without. HIV seroprevalence was significantly higher among men with FBSW partners (vs. without FBSW partners) in both inland (21.0%vs.7.5%; PR=2.79,95%CI=2.41-3.23) and fishing communities (38.6%vs.23.0%; PR=1.67,95%CI=1.53-1.84). Overall, 154 HIV incident events occurred over 27,396 years of participant follow-up. HIV incidence was also higher among men with FBSW partners than those without (1.93vs.0.44/100 person-years; IRR=4.37,95%CI=3.04-6.16). Among men with HIV, viral suppression was similar among those with and without FBSW partners. However, the population prevalence of HIV viremia was 1.6 times higher (95%CI=1.41-1.84) among men with FBSW partners due to a higher background seroprevalence of HIV.</p><p><strong>Interpretation: </strong>Men in Uganda frequently report sex with FBSWs, which is associated with a significantly higher risk of HIV acquisition. Tailored HIV prevention strategies, including the promotion and uptake of PrEP, are essential to reduce the HIV burden in this population.</p><p><strong>Funding: </strong>National Institute of Allergy and Infectious Diseases, National Institutes of Health.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756843","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":"HIV seroprevalence, incidence, and viral suppression among Ugandan female bar workers: a population-based study.","authors":"Xinyi Feng, Gertrude Nakigozi, Eshan U Patel, Caitlin E Kennedy, Slisha Shrestha, Fred Nalugoda, Godfrey Kigozi, Robert Ssekubugu, Larry W Chang, Andrea L Wirtz, Hadijja Nakawooya, Grace Kigozi, Ronald M Galiwango, Steven J Reynolds, Joseph Kagaayi, Aaron A R Tobian, M Kate Grabowski","doi":"10.1101/2025.03.22.25324404","DOIUrl":"https://doi.org/10.1101/2025.03.22.25324404","url":null,"abstract":"<p><strong>Background: </strong>Prior studies have linked female bar and sex work in Africa. However, population-level data on HIV burden among female bar workers (FBWs) in African settings are rare.</p><p><strong>Methods: </strong>We used five survey rounds of data collected between 2011 and 2020 from the Rakai Community Cohort Study, a population-based HIV surveillance cohort in 36 inland agrarian and trading communities (HIV prevalence ~12%) and four Lake Victoria fishing communities (~36%) in southern Uganda. Women reporting bar work as a primary or secondary occupation were identified and compared to non-FBWs. Primary outcomes included laboratory-confirmed HIV seropositivity, incident infection, viral suppression (<200 copies/ml) among women with HIV, and population prevalence of viremia. Prevalence ratios (PRs) and incidence rate ratios (IRRs) were estimated using Poisson regression models with 95% confidence intervals (95%CI).</p><p><strong>Findings: </strong>A total of 23,556 female participants contributed 52,708 person visits. Overall, 1,205 (5.1%) women self-identified as FBWs. FBWs had significantly higher baseline HIV seroprevalence compared to non-FBWs (51.9% vs. 18.5%,PR=2.81, 95%CI=2.64-2.95). 356 HIV incident events occurred over 39,228 years of participant follow-up. Incidence among FBWs was 2.49/100 person-years versus 0.87/100 person-years among non-FBWs (age-adjusted IRR=3.64,95%CI=2.33-5.42). While HIV viral suppression was similar among participants living with HIV regardless of FBW status, the population prevalence of HIV viremia among FBWs was 1.69 times higher compared to non-FBWs, adjusting for age and community type (95%CI=1.38-2.08). Among 179 HIV seronegative FBWs surveyed in 2018-20, 79.9% (143/179) were aware of PrEP, while only 13.4% (24/179) had ever used it, and just 2.8% (5/179) were current users.</p><p><strong>Interpretation: </strong>FBWs in Uganda experience substantially higher HIV burden and acquisition risk compared to the general population. Tailored prevention strategies like prioritizing their HIV service delivery may reduce HIV incidence among FBWs and their partners.</p><p><strong>Funding: </strong>National Institute of Allergy and Infectious Diseases, National Institutes of Health.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756835","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":"Peripheral blood somatic mosaicism and clonal hematopoiesis across ancestry backgrounds.","authors":"Christelle Colin-Leitzinger, Yi-Han Tang, Mingxiang Teng, Nancy Gillis","doi":"10.1101/2025.03.21.25324408","DOIUrl":"https://doi.org/10.1101/2025.03.21.25324408","url":null,"abstract":"<p><p>Somatic mosaicism (SM), the presence of somatic mutations, is classified as clonal hematopoiesis (CH) when it occurs in hematopoietic cells at an age-related rate. CH is associated with risk for hematologic malignancies and cardiovascular disease, but most studies are predominately based on individuals of European ancestry. Using peripheral blood whole exome sequencing data from 125,748 individuals of diverse genetic ancestries, we cataloged 503,703 SM mutations based on low variant allele frequency distributions and 89,361 CH variants based on age-skewing. We examined CH prevalence across ancestry groups, including commonly recognized pathogenic variants in myeloid (M-CHIP) and lymphoid (L-CHIP) malignancies. CH and M-CHIP variants had the highest prevalence in the European non-Finnish ancestry group, and males trended toward more M-CHIP variants. Ancestry differences in CH included more mutations in <i>NF1</i> in African/African American, <i>TP53</i> in European, and <i>CUX1</i> in Asian and Latino/Admixed American ancestry groups. Linking the identified CH variants to a cancer database, CH was detected in 14% (55,190/391,102) of patient tumors. Prevalence of CH variants in some solid tumors ranged from 25% - 40%. M-CHIP variants in solid tumors were associated with younger age (61 vs 63, p <0.001), while M-CHIP in hematologic malignancies were linked to older age (60 vs 50, p <0.001), suggesting differences in disease biology. This study provides a catalog of SM, CH, and CHIP variants across diverse ancestry groups, highlighting differences that are important to inform clinical care, drug discovery, and study design to maximize generalizability across individuals.</p><p><strong>Key points: </strong>Establish a large-scale catalog of somatic mosaicism and clonal hematopoiesis mutations across genetic ancestry groups.Mutation occurrences within clonal hematopoiesis genes vary across ancestry groups, with age, and across tumor types.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756927","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":"A comparative analysis of dengue, chikungunya, and Zika manifestations in a pediatric cohort over 18 years.","authors":"Fausto Andres Bustos Carrillo, Sergio Ojeda, Nery Sanchez, Miguel Plazaola, Damaris Collado, Tatiana Miranda, Saira Saborio, Brenda Lopez Mercado, Jairo Carey Monterrey, Sonia Arguello, Lora Campredon, Zijin Chu, Colin J Carlson, Aubree Gordon, Angel Balmaseda, Guillermina Kuan, Eva Harris","doi":"10.1101/2025.01.06.25320089","DOIUrl":"10.1101/2025.01.06.25320089","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Dengue, chikungunya, and Zika are diseases of major human concern. Differential diagnosis is complicated in children and adolescents by their overlapping clinical features (signs, symptoms, and complete blood count results). Few studies have directly compared the three diseases. We aimed to identify distinguishing pediatric characteristics of each disease.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Data were derived from laboratory-confirmed cases aged 2-17 years enrolled in a longitudinal cohort study in Managua, Nicaragua, and attending a primary health care center from January 2006 through December 2023. We collected clinical records and laboratory results across the first 10 days of illness. Data were analyzed with generalized additive models, generalized linear mixed models, and machine learning models.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;We characterized 1,405 dengue, 517 chikungunya, and 522 Zika pediatric cases. The prevalence of many clinical features exhibited by dengue, chikungunya, and Zika cases differed substantially overall, by age, and by day of illness. Dengue cases were differentiated most by abdominal pain, leukopenia, nausea, vomiting, and basophilia; chikungunya cases were differentiated most by arthralgia and the absence of leukopenia and papular rash; and Zika cases were differentiated most by rash and the lack of fever and lymphocytopenia. Dengue and chikungunya cases exhibited similar temperature dynamics during acute illness, and their temperatures were higher than Zika cases. Sixty-two laboratory-confirmed afebrile dengue cases, which would not be captured by any widely used international case definition, presented very similarly to afebrile Zika cases, though some exhibited warning signs of disease severity. The presence of arthralgia, the presence of basophilia, and the absence of fever were the most important model-based distinguishing predictors of chikungunya, dengue, and Zika, respectively.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretations: &lt;/strong&gt;These findings substantially update our understanding of dengue, chikungunya, and Zika in children while identifying various clinical features that could improve differential diagnoses. The occurrence of afebrile dengue warrants reconsideration of current case definitions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;US National Institutes of Health R01AI099631, P01AI106695, U01AI153416, U19AI118610.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Research in context: &lt;/strong&gt;&lt;b&gt;Evidence before this study:&lt;/b&gt; Dengue, chikungunya, and Zika co-occur in tropical and subtropical settings and cause fever, rash, and other clinical features. We reviewed widely used international case definitions for the three diseases; the Pan American Health Organization's (PAHO) 2022 report on differential diagnosis of the diseases; and the 80 studies underlying PAHO's diagnostic recommendations. On March 15, 2025, we queried PubMed without restrictions for \"pediatric cohort\" AND \"dengue\" AND \"chikungunya\" AND \"Zika,\" revealing that no ","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143019413","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":"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}