medRxiv : the preprint server for health sciences最新文献

{"title":"<i>NUBP2</i> deficiency disrupts the centrosome-check point in the brain and causes primary microcephaly.","authors":"Rebekah Rushforth, Hanan E Shamseldin, Nicole Costantino, Jes-Rite Michaels, Sarah L Sawyer, Matthew Osmond, Wesam Kurdi, Firdous Abdulwahab, Andrew DiStasio, Kym M Boycott, Fowzan S Alkuraya, Rolf W Stottmann","doi":"10.1101/2025.01.16.25320041","DOIUrl":"https://doi.org/10.1101/2025.01.16.25320041","url":null,"abstract":"<p><p>Microcephaly affects 1 in 2,500 babies per year. Primary microcephaly results from aberrant neurogenesis leading to a small brain at birth. This is due to altered patterns of proliferation and/or early differentiation of neurons. Premature differentiation of neurons is associated with defects in the centrosome and/or primary cilia. In this study, we report on the first patients identified with <i>NUBP2</i> -deficiency and utilize a conditional mouse model to ascertain the molecular mechanisms associated with <i>NUBP2</i> -deficient primary microcephaly. We identified homozygous <i>NUBP2</i> variants in these patients who displayed profound primary microcephaly in addition to intrauterine growth restriction, cervical kyphosis, severe contractures of joints, and facial dysmorphia. We then generated a mouse model using <i>Emx1-Cre</i> to ablate <i>Nubp2</i> from the forebrain. The mice presented with severe microcephaly starting at E18.5. Neurospheres generated from the forebrain of <i>Emx1-Cre; Nubp2 ^flox/flox</i> conditional deletion mice were used to support the pathogenicity of the patient variants. We show that loss of <i>Nubp2</i> increases both canonical and non-canonical cell death, but that loss of <i>p53</i> fails to rescue microcephaly in the mouse model. Examination of neurogenesis in <i>Emx1-Cre; Nubp2 ^flox/flox</i> mice revealed distinct alterations in proliferation and cellular migration accompanied by supernumerary centrosomes and cilia. We therefore propose that <i>NUBP2</i> is a novel primary microcephaly-related gene and that the role of <i>Nubp2</i> in centrosome and cilia regulation is crucial for proper neurogenesis.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048478","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 clinical algorithm to identify people with the glucose-6-phosphate dehydrogenase p.Val68Met variant at risk for diabetes undertreatment.","authors":"Yash Pershad, Joseph H Breeyear, Robert W Corty, Jonathan D Mosley, Ayush Giri, Dan M Roden, Todd L Edwards, Alexander G Bick","doi":"10.1101/2025.01.17.25320736","DOIUrl":"https://doi.org/10.1101/2025.01.17.25320736","url":null,"abstract":"<p><strong>Purpose: </strong>To develop an algorithm using routine clinical laboratory measurements to identify people at risk for systematic underestimation of glycated hemoglobin (HbA1c) due to p.Val68Met glucose-6-phosphate dehydrogenase (G6PD) deficiency.</p><p><strong>Methods: </strong>We analyzed 122,307 participants of self-identified Black race across four large cohorts with blood glucose, HbA1c, and red cell distribution width measurements from a single blood draw. In UK Biobank, we used recursive partitioning to develop criteria for possible and likely G6PD deficiency. We validated the algorithm in NIH All of Us, Vanderbilt BioVU, and the Million Veterans Program. In Vanderbilt's Synthetic Derivative, we created a cohort of 48,031 participants with type 2 diabetes and no genetic data to test whether predicted risk for G6PD deficiency was associated with incident diabetic retinopathy.</p><p><strong>Results: </strong>G6PD deficiency predictions in hemizygous males showed precision/recall of 31%/81% for possible and 81%/10% for likely deficiency. In homozygous females, precision/recall was 6%/76% for possible and 34%/13% for likely deficiency. Diabetic patients with predicted possible deficiency demonstrated 1.4-fold higher 20-year retinopathy rates (14.3% vs 11.2%, P=0.003).</p><p><strong>Conclusion: </strong>We report a simple clinical algorithm that enables healthcare systems to identify people who may benefit from G6PD genotyping and glucose-based diabetes monitoring.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048630","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":"Eye Tracking during Passage Reading Supports Precise Oculomotor Assessment in Ataxias.","authors":"Brandon Oubre, Faye Yang, Anna C Luddy, Rohin Manohar, Nancy N Soja, Christopher D Stephen, Jeremy D Schmahmann, Divya Kulkarni, Lawrence White, Siddharth Patel, Anoopum S Gupta","doi":"10.1101/2025.01.13.25320487","DOIUrl":"10.1101/2025.01.13.25320487","url":null,"abstract":"<p><p>Abnormal eye movements occur early in the course of disease in many ataxias. However, clinical assessments of oculomotor function lack precision, limiting sensitivity for measuring progression and the ability to detect subtle early signs. Quantitative assessment of eye movements during everyday behaviors such as reading has potential to overcome these limitations and produce functionally relevant measures. In this study, we analyze eye movements in individuals with ataxia during passage reading. Binocular gaze sampled at 1000 Hz was collected from 102 individuals with ataxia diagnoses (including 36 spinocerebellar ataxias, 12 Friedreich's ataxia, and 5 multiple system atrophy among other conditions) and 70 healthy controls participating in the Neurobooth study. Longitudinal data were available for 26 participants with ataxia. Saccades were categorized as progressive (rightward) saccades, regressive saccades, or sweeps (large displacement saccades primarily generated when scanning to the beginning of the next line) based on their direction and displacement. Saccade and fixation kinematics were summarized using 28 statistical features. A linear model was trained to estimate clinician-performed ataxia rating scale scores. Model scores were reliable (ICC=0.96, p<0.001) and demonstrated convergent validity with Brief Ataxia Rating Scale total (r=0.82, p<0.001), oculomotor (r=0.52, p<0.001), and speech (r=0.73, p<0.001) scores, as well as patient surveys. The scores were also sensitive to disease progression (d=0.36, p=0.03), demonstrated strong separability between healthy controls and participants with ataxias (AUC=0.89, p<0.001), and showed evidence of the ability to detect subclinical oculomotor patterns (AUC=0.69, p=0.02). Several kinematic saccade and fixation features demonstrated strong differences across disease severity groups. Notable features included the mean angular displacement of fixations (<i>η</i> ²=0.44, p<0.001), the number (<i>η</i> ²=0.27, p<0.001) and frequency of saccades (<i>η</i> ²=0.25, p<0.001), and the proportion of regressive saccades (<i>η</i> ²=0.11, p<0.001). Quantitative assessment of eye movements during passage reading were highly informative of ataxia severity, were sensitive to disease progression, and enabled detection of subclinical signs. These properties support the inclusion of video-oculography-based measures of reading in natural history studies and clinical trials. Furthermore, this study demonstrates the feasibility of integration of oculomotor assessments in clinical workflows.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049235","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":"What is the best brain state to predict autistic traits?","authors":"Corey Horien, Francesca Mandino, Abigail S Greene, Xilin Shen, Kelly Powell, Angelina Vernetti, David O'Connor, James C McPartland, Fred R Volkmar, Marvin Chun, Katarzyna Chawarska, Evelyn M R Lake, Monica D Rosenberg, Theodore Satterthwaite, Dustin Scheinost, Emily Finn, R Todd Constable","doi":"10.1101/2025.01.14.24319457","DOIUrl":"10.1101/2025.01.14.24319457","url":null,"abstract":"<p><p>Autism is a heterogeneous condition, and functional magnetic resonance imaging-based studies have advanced understanding of neurobiological correlates of autistic features. Nevertheless, little work has focused on the optimal brain states to reveal brain-phenotype relationships. In addition, there is a need to better understand the relevance of attentional abilities in mediating autistic features. Using connectome-based predictive modelling, we interrogate three datasets to determine scanning conditions that can boost prediction of clinically relevant phenotypes and assess generalizability. In dataset one, a sample of youth with autism and neurotypical participants, we find that a sustained attention task (the gradual onset continuous performance task) results in high prediction performance of autistic traits compared to a free-viewing social attention task and a resting-state condition. In dataset two, we observe the predictive network model of autistic traits generated from the sustained attention task generalizes to predict measures of attention in neurotypical adults. In dataset three, we show the same predictive network model of autistic traits from dataset one further generalizes to predict measures of social responsiveness in data from the Autism Brain Imaging Data Exchange. In sum, our data suggest that an in-scanner sustained attention challenge can help delineate robust markers of autistic traits and support the continued investigation of the optimal brain states under which to predict phenotypes in psychiatric conditions.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049399","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":"Large language models outperform traditional structured data-based approaches in identifying immunosuppressed patients.","authors":"Vijeeth Guggilla, Mengjia Kang, Melissa J Bak, Steven D Tran, Anna Pawlowski, Prasanth Nannapaneni, Luke V Rasmussen, Daniel Schneider, Helen Donnelly, Ankit Agrawal, David Liebovitz, Alexander V Misharin, Gr Scott Budinger, Richard G Wunderink, Theresa L Walunas, Catherine A Gao","doi":"10.1101/2025.01.16.25320564","DOIUrl":"10.1101/2025.01.16.25320564","url":null,"abstract":"<p><p>Identifying immunosuppressed patients using structured data can be challenging. Large language models effectively extract structured concepts from unstructured clinical text. Here we show that GPT-4o outperforms traditional approaches in identifying immunosuppressive conditions and medication use by processing hospital admission notes. We also demonstrate the extensibility of our approach in an external dataset. Cost-effective models like GPT-4o mini and Llama 3.1 also perform well, but not as well as GPT-4o.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048505","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":"Rare Variant Analyses in Ancestrally Diverse Cohorts Reveal Novel ADHD Risk Genes.","authors":"Seulgi Jung, Madison Caballero, Emily Olfson, Jeffrey H Newcorn, Thomas V Fernandez, Behrang Mahjani","doi":"10.1101/2025.01.14.25320294","DOIUrl":"10.1101/2025.01.14.25320294","url":null,"abstract":"<p><p>Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, but its genetic architecture remains incompletely characterized. Rare coding variants, which can profoundly impact gene function, represent an underexplored dimension of ADHD risk. In this study, we analyzed large-scale DNA sequencing datasets from ancestrally diverse cohorts and observed significant enrichment of rare protein-truncating and deleterious missense variants in highly evolutionarily constrained genes. This analysis identified 15 high-confidence ADHD risk genes, including the previously implicated <i>KDM5B</i>. Integrating these findings with genome-wide association study (GWAS) data revealed nine enriched pathways, with strong involvement in synapse organization, neuronal development, and chromatin regulation. Protein-protein interaction analyses identified chromatin regulators as central network hubs, and single-cell transcriptomic profiling confirmed their expression in neurons and glial cells, with distinct patterns in oligodendrocyte subtypes. These findings advance our understanding of the genetic architecture of ADHD, uncover core molecular mechanisms, and provide promising directions for future therapeutic development.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049244","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 Comparison of In-Person and Telehealth Treatment Modalities using the SpeechVive Device.","authors":"Renee Covert, Sandy Snyder, Ashleigh Lambert, Mary Spremulli, Brianna Blandford, Kaitlyn Dwenger, Georgia Malandraki, Meghan McDonough, Françoise Brosseau-Lapre, Jessica E Huber","doi":"10.1101/2025.01.16.25320611","DOIUrl":"https://doi.org/10.1101/2025.01.16.25320611","url":null,"abstract":"<p><p>Telehealth is increasing popular as a treatment option for people with Parkinson disease (PD). The SpeechVive device is a wearable device that uses the Lombard effect to help patients speak more loudly, slowly, and clearly. This study sought to examine the effectiveness of the device to improve communication in people with PD, delivered over a telehealth modality as compared to in-person, using implementation science design. 66 people with PD were enrolled for 12 weeks with 34 choosing the in-person group and 32 in the telehealth group. Participants were assessed pre-, mid-, and post-treatment. Participants produced continuous speech samples on and off the device at each timepoint. Sound pressure level (SPL), utterance length, pause frequency, and total pause duration were measured. Psychosocial surveys were administered to evaluate the effects of treatment on depression, self-efficacy, and participation. The in-person group increased SPL when wearing the device while the telehealth group did not. Both groups paused less often while wearing the device. Utterance length increased post-treatment for the telehealth group, but not for the in-person group. An increase in communication participation ratings in the telehealth group, but not the in-person group, was the only significant change in the psychosocial metrics. The in-person group showed similar treatment effects as previous studies. The device was not as effective in the telehealth group. One limitation was data loss due to recording issues that impacted the telehealth group more than the in-person group.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049124","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":"Abdominal Myosteatosis and Cognitive Decline in a Biracial Cohort: Insights from CARDIA Study.","authors":"Adrianna Acevedo-Fontánez, Caterina Rosano, Kristine Yaffe, J Jeffrey Carr, James G Terry, Sangeeta Nair, Emma Barinas-Mitchell, Ryan K Cvejkus, Iva Miljkovic","doi":"10.1101/2025.01.17.25320741","DOIUrl":"https://doi.org/10.1101/2025.01.17.25320741","url":null,"abstract":"<p><strong>Objective: </strong>Skeletal muscle fat infiltration (myosteatosis) increases with age and is an emerging risk factor for dementia. We aimed to determine the association between myosteatosis and cognitive decline among middle-aged White and Black Americans.</p><p><strong>Methods: </strong>Data were on men (n=1,080; 41.9% Black) and women (n=1,432; 49.0% Black) from the CARDIA study. CT-measured abdominal intermuscular fat (IMAT) volume was assessed at baseline. Cognition was assessed by Digit Symbol Substitution (DSST), Rey Auditory Verbal Learning (RAVLT), and Stroop Test at baseline and 5-year follow-up. Multivariable linear regression was used to assess associations of IMAT with cognitive change.</p><p><strong>Results: </strong>Participants were aged 50.2 (3.6) years and had IMAT of 2.3 (1.6) cm ³ , 5-year change in DSST of -2.8% (21.8), RAVLT 2.8% (17.5) and Stroop 6.5% (49.5). Greater IMAT was associated with steeper DSST decline (β =-0.52 points per SD, p-value=0.035), but not with Stroop or RAVLT. Stratified by race, greater IMAT predicted DSST decline among White (β =-0.73, p =0.044), but not Black (β =-0.44, p =0.195), participants.</p><p><strong>Conclusions: </strong>Abdominal myosteatosis may be a novel risk factor for decline in psychomotor speed, especially in middle-aged Whites. Further research on mechanisms, including metabolic mediators, is warranted to understand myosteatosis's role in mid-life cognitive decline.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049129","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":"Understanding Data Differences across the ENACT Federated Research Network.","authors":"Taowei D Wang, Darren W Henderson, Griffin M Weber, Michele Morris, Eugene M Sadhu, Shawn N Murphy, Shyam Visweswaran, Jeff G Klann","doi":"10.1101/2025.01.17.25320686","DOIUrl":"10.1101/2025.01.17.25320686","url":null,"abstract":"<p><strong>Objective: </strong>Federated research networks, like Evolve to Next-Gen Accrual of patients to Clinical Trials (ENACT), aim to facilitate medical research by exchanging electronic health record (EHR) data. However, poor data quality can hinder this goal. While networks typically set guidelines and standards to address this problem, we developed an organically evolving, data-centric method using patient counts to identify data quality issues, applicable even to sites not yet in the network.</p><p><strong>Materials and methods: </strong>We distribute high-performance patient counting scripts as part of Integrating Biology at the Bedside (i2b2), which all ENACT sites operate. They produce counts of patients associated with ENACT ontology terms for each site. At the ENACT Hub, our pipeline aggregates site-contributed counts to produce network statistics, which our self-service web application, Data Quality Explorer (DQE), ingests to help sites conduct data quality investigation relative to the network.</p><p><strong>Results: </strong>Thirteen ENACT sites have contributed their patient counts, and currently seven sites have signed up to use DQE to analyze data quality issues. We announced a call to all ENACT sites to contribute additional patient counts.</p><p><strong>Discussion: </strong>Identifying site data quality problems relative to the network is novel. Using a metric based on evolving network statistics complements rigid data quality checks. It is adaptable to any network and has low barriers of entry, with patient counting being the sole requirement.</p><p><strong>Conclusion: </strong>We implemented a metric for conducting data quality investigation in ENACT using patient counting and network statistics. Our end-to-end pipeline is privacy-preserving and the underlying design is generalizable.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049396","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":"Atypical hyperendemicity of Rift Valley fever in Southwestern Uganda associated with the rapidly evolving lineage C viruses.","authors":"Barnabas Bakamutumaho, John Juma, Erin Clancey, Luke Nyakarahuka, Silvia Situma, Raymond Odinoh, Jeanette Dawa, Carolyne Nasimiyu, Evan A Eskew, Stephen Balinandi, Sophia Mulei, John Kayiwa, John D Klena, Trevor R Shoemaker, Shannon L M Whitmer, Joel M Montgomery, John Schieffelin, Julius Lutwama, Allan Muruta, Henry Kyobe Bosa, Scott L Nuismer, Samuel O Oyola, Robert F Breiman, M Kariuki Njenga","doi":"10.1101/2025.01.14.25320317","DOIUrl":"https://doi.org/10.1101/2025.01.14.25320317","url":null,"abstract":"<p><strong>Introduction: </strong>Recent Rift Valley fever (RVF) epidemiology in eastern Africa region is characterized by widening geographic range and increasing frequency of small disease clusters. Here we conducted studies in southwestern (SW) Uganda region that has since 2016 reported increasing RVF activities.</p><p><strong>Methods: </strong>A 22-month long hospital-based study in three districts of SW Uganda targeting patients with acute febrile illness (AFI) or unexplained bleeding was followed by a cross-sectional population-based human-animal survey. We then estimated RVFV force of infection (FOI) and yearly cases using the age-structured seroprevalence data and conducted genomic phylodynamic modelling of RVFV isolates.</p><p><strong>Results: </strong>Overall RVF prevalence was 10.5% (205 of 1,968) among febrile or hemorrhagic cases, including 5% with acute (PCR or IgM positive) infection, averaging 5 cases per month. Community-based serosurvey recorded prevalence of 11.8% (88 of 743) among humans and 14.6% (347 of 2,383) in livestock. Expected yearly human RVF cases were 314-2,111 per 1,369 km <i>²</i> in SW Uganda versus 0-711 in comparable regions of Kenya and Tanzania. Viral genomic studies identified RVFV lineage C, sub-clade C.2.2, as the circulating strain in SW Uganda since 2019. Lineage C strain has undergone recent rapid evolution and clonal expansion resulting in four sub-clades, C.1.1, C.1.2, C.2.1, and C.2.2, that are more adept at establishing endemicity in new territories.</p><p><strong>Conclusions: </strong>We demonstrate an atypical RVF hyperendemic region in SW Uganda characterized by sustained human clinical RVF cases, unusually high population prevalence, and high number of expected yearly human cases, associated in part with emergence of new RVFV sub-lineages.</p><p><strong>Key points: </strong>Rift Valley fever (RVF) studies in SW Uganda found atypical sustained human cases averaging 5 cases/month, >10% population prevalence, and expected yearly cases >3-fold higher (314-2,111 vs 0-711) than comparable regions in East Africa, associated with emerging RVFV sub-lineages.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049047","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}