medRxiv : the preprint server for health sciences最新文献

{"title":"Plasma acellular transcriptome contains Parkinson's disease signatures that can inform clinical diagnosis.","authors":"Aleksandra Beric, Alejandro Cisterna-García, Charissa Martin, Ravindra Kumar, Isabel Alfradique-Dunham, Kevin Boyer, Ibrahim Olabayode Saliu, Shinnosuke Yamada, Jessie Sanford, Daniel Western, Menghan Liu, Ignacio Alvarez, Joel S Perlmutter, Scott A Norris, Pau Pastor, Guoyan Zhao, Juan Botia, Laura Ibanez","doi":"10.1101/2024.10.18.24315717","DOIUrl":"10.1101/2024.10.18.24315717","url":null,"abstract":"<p><p>We aimed to identify plasma cell-free transcripts (cfRNA) associated with Parkinson's disease (PD) that also have a high predictive value to differentiate PD from healthy controls. Leveraging two independent populations from two different movement disorder centers we identified 2,188 differentially expressed cfRNAs after meta-analysis. The identified transcripts were enriched in PD relevant pathways, such as PD (p=9.26×10^-4), ubiquitin-mediated proteolysis (p=7.41×10^-5) and endocytosis (p=4.21×10^-6). Utilizing in-house and publicly available brain, whole blood, and acellular plasma transcriptomic and proteomic PD datasets, we found significant overlap across dysregulated biological species in the different tissues and the different biological layers. We developed three predictive models containing increasing number of transcripts that can distinguish PD from healthy control with an area under the ROC Curve (AUC) ≥0.85. Finally, we showed that several of the predictive transcripts significantly correlate with symptom severity measured by UPDRS-III. Overall, we have demonstrated that cfRNA contains pathological signatures and has the potential to be utilized as biomarker to aid in PD diagnostics and monitoring.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559976","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":"Humoral waning kinetics against SARS-CoV-2 is dictated by disease severity and vaccine platform.","authors":"Xin Tong, Benjamin Kellman, Maria-Jose Avendano, Maanasa Mendu, Jeff C Hsiao, Eileen Serrano, Tamara Garcia-Salum, Nicolas Muena, Catalina Pardo-Roa, Mauricio Morales, Jorge Levican, Erick Salinas, Simone Cardenas-Cáceres, Arnoldo Riquelme, Nicole D Tischler, Douglas A Lauffenburger, Galit Alter, Ryan P McNamara, Rafael A Medina","doi":"10.1101/2024.10.17.24315607","DOIUrl":"10.1101/2024.10.17.24315607","url":null,"abstract":"<p><p>SARS-CoV-2 vaccine-acquired immunity provides robust cross-variant recognition, while infection-acquired immunity can be heterogenous, with disease severity often modulating post-recovery responses. We assessed antibody waning dynamics between infection- and vaccination-acquired immunity across variants of concern (VOC). mRNA vaccination induced potent, cross-VOC Spike recognition and functional responses, but waned more rapidly for Omicron Spike. Hospitalized individuals developed more durable functional responses with lower peaks compared to mRNA vaccination, while outpatients exhibited slower decay than inactivated vaccine recipients. Humoral decay for the receptor binding domain tracked with neutralizing antibody titers, while S2-directed responses tracked with antibody-dependent myeloid cellular phagocytosis. Boosting the recovered patients with mRNA or inactivated vaccines expanded humoral breadth, durability, and restored functional responses, eliminating the severity- and platform-associated decay differences. Therefore, post-recovery hybrid immunization compensates for this distinction and broadens humoral breadth, highlighting the value of boosting immunity in previously infected individuals.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559968","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":"Detecting Glaucoma Worsening Using Optical Coherence Tomography Derived Visual Field Estimates.","authors":"Alex T Pham, Chris Bradley, Kaihua Hou, Patrick Herbert, Mathias Unberath, Pradeep Y Ramulu, Jithin Yohannan","doi":"10.1101/2024.10.17.24315710","DOIUrl":"10.1101/2024.10.17.24315710","url":null,"abstract":"<p><strong>Objective: </strong>Multiple studies have attempted to generate visual field (VF) mean deviation (MD) estimates using cross-sectional optical coherence tomography (OCT) data. However, whether such models offer any value in detecting longitudinal VF progression is unclear. We address this by developing a machine learning (ML) model to convert OCT data to MD and assessing its ability to detect longitudinal worsening.</p><p><strong>Design: </strong>Retrospective, longitudinal study.</p><p><strong>Participants: </strong>A model dataset of 70,575 paired OCT/VFs to train an ML model converting OCT to VF-MD. A separate progression dataset of 4,044 eyes with ≥ 5 paired OCT/VFs to assess the ability of OCT-derived MD to detect worsening. Progression dataset eyes had two additional unpaired VFs (≥ 7 total) to establish a \"ground truth\" rate of progression defined by MD slope.</p><p><strong>Methods: </strong>We trained an ML model using paired VF/OCT data to estimate MD measurements for each OCT scan (OCT-MD). We used this ML model to generate longitudinal OCT-MD estimates for progression dataset eyes. We calculated MD slopes after substituting/supplementing VF-MD with OCT-MD and measured the ability to detect progression. We labeled true progressors using a ground truth MD slope <0.5 dB/year calculated from ≥ 7 VF-MD measurements. We compared the area under the curve (AUC) of MD slopes calculated using both VF-MD (with <7 measurements) and OCT-MD. Because we found OCT-MD substitution had a statistically inferior AUC to VF-MD, we simulated the effect of reducing OCT-MD mean absolute error (MAE) on the ability to detect worsening.</p><p><strong>Main outcome measures: </strong>AUC.</p><p><strong>Results: </strong>OCT-MD estimates had an MAE of 1.62 dB. AUC of MD slopes with partial OCT-MD substitution was significantly worse than the VF-MD slope. Supplementing VF-MD with OCT-MD also did not improve AUC, regardless of MAE. OCT-MD estimates needed an MAE ≤ 1.00 dB before AUC was statistically similar to VF-MD alone.</p><p><strong>Conclusion: </strong>ML models converting OCT data to VF-MD with error levels lower than published in prior work (MAE: 1.62 dB) were inferior to VF-MD data for detecting trend-based VF progression. Models converting OCT data to VF-MD must achieve better prediction errors (MAE ≤ 1 dB) to be clinically valuable at detecting VF worsening.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559950","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":"Effects of the COVID-19 pandemic on TB outcomes in the United States: a Bayesian analysis.","authors":"Nicole A Swartwood, Ted Cohen, Suzanne M Marks, Andrew N Hill, Garrett R Beeler Asay, Julie Self, Pei-Jean I Feng, C Robert Horsburgh, Joshua A Salomon, Nicolas A Menzies","doi":"10.1101/2024.10.17.24315683","DOIUrl":"10.1101/2024.10.17.24315683","url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis (TB) cases and deaths in the United States fluctuated substantially during the COVID-19 pandemic. We analyzed multiple data sources to understand the factors contributing to these changes and estimated future TB trends.</p><p><strong>Methods: </strong>We identified four mechanisms potentially contributing to observed TB trends during 2020-2023: immigration, respiratory contact rates, rates of accurate diagnosis and treatment initiation, and mortality rates for persons with TB disease. We employed a Bayesian approach to synthesize evidence on how these mechanisms changed during the pandemic and how they might have combined to produce observed 2020-2023 TB data, using a transmission-dynamic model to link mechanisms to TB outcomes. We also simulated a no-pandemic counterfactual scenario that assumed mechanisms followed pre-pandemic trends. We estimated TB outcomes associated with the pandemic until 2035 to capture lagged effects. We evaluated additional scenarios to estimate the individual effect of each mechanism.</p><p><strong>Results: </strong>Over the 2020-2035 study period, we estimate an additional 2,784 (95% uncertainty interval: 2,164-3,461) TB cases and 1,138 (1,076-1,201) TB deaths in the United States associated with changes occurring during the COVID-19 pandemic. The four mechanisms had offsetting effects - decreases in TB diagnosis rates and increases in TB mortality rates led to more TB deaths, while reductions in contact rates reduced TB deaths. Immigration changes initially reduced TB deaths, but increased deaths over time.</p><p><strong>Discussion: </strong>While the direct impacts of the COVID-19 pandemic occurred between 2020-2023, these changes may continue to influence TB incidence and mortality in future years.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559952","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":"Safety and implementation of a phase 1 randomized GLA-SE-adjuvanted CH505TF gp120 HIV vaccine trial in newborns.","authors":"Avy Violari, Kennedy Otwombe, William Hahn, Shiyu Chen, Deirdre Josipovic, Vuyelwa Baba, Asimenia Angelidou, Kinga K Smolen, Ofer Levy, Nonhlanhla N Mkhize, Amanda S Woodward, Troy M Martin, Bart Haynes, Wilton B Williams, Zachary K Sagawa, James Kublin, Laura Polakowski, Margaret Brewinski Isaacs, Catherine Yen, Georgia Tomaras, Lawrence Corey, Holly Janes, Glenda Gray","doi":"10.1101/2024.10.15.24315548","DOIUrl":"10.1101/2024.10.15.24315548","url":null,"abstract":"<p><strong>Background: </strong>The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a novel glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV.</p><p><strong>Methods: </strong>HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo. Healthy infants in South Africa aged ≤5 days, born to mothers living with HIV but HIV nucleic acid negative at birth were randomized to five doses of CH505TF + GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks.</p><p><strong>Results: </strong>38 infants (median age = 4 days; interquartile range 4, 4.75 days) were enrolled November 2020 to January 2022. Among 28 (10) infants assigned to receive CH505TF + GLA-SE (placebo), most (32/38) completed the 5-dose immunization series and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) vs. placebo recipients (1, 10% local, p = 0.25; 4, 40.0% systemic, p = 0.38). All events were Grade 1 except two Grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded.</p><p><strong>Conclusions: </strong>This study illustrates the feasibility of conducting trials of novel adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF + GLA-SE vaccine was reassuring.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov NCT04607408.</p><p><strong>Funding: </strong>National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH).</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559980","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":"Assessing Retrieval-Augmented Large Language Model Performance in Emergency Department ICD-10-CM Coding Compared to Human Coders.","authors":"Eyal Klang, Idit Tessler, Donald U Apakama, Ethan Abbott, Benjamin S Glicksberg, Monique Arnold, Akini Moses, Ankit Sakhuja, Ali Soroush, Alexander W Charney, David L Reich, Jolion McGreevy, Nicholas Gavin, Brendan Carr, Robert Freeman, Girish N Nadkarni","doi":"10.1101/2024.10.15.24315526","DOIUrl":"10.1101/2024.10.15.24315526","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Accurate medical coding is essential for clinical and administrative purposes but complicated, time-consuming, and biased. This study compares Retrieval-Augmented Generation (RAG)-enhanced LLMs to provider-assigned codes in producing ICD-10-CM codes from emergency department (ED) clinical records.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Retrospective cohort study using 500 ED visits randomly selected from the Mount Sinai Health System between January and April 2024. The RAG system integrated past 1,038,066 ED visits data (2021-2023) into the LLMs' predictions to improve coding accuracy. Nine commercial and open-source LLMs were evaluated. The primary outcome was a head-to-head comparison of the ICD-10-CM codes generated by the RAG-enhanced LLMs and those assigned by the original providers. A panel of four physicians and two LLMs blindly reviewed the codes, comparing the RAG-enhanced LLM and provider-assigned codes on accuracy and specificity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;RAG-enhanced LLMs demonstrated superior performance to provider coders in both the accuracy and specificity of code assignments. In a targeted evaluation of 200 cases where discrepancies existed between GPT-4 and provider-assigned codes, human reviewers favored GPT-4 for accuracy in 447 instances, compared to 277 instances where providers' codes were preferred (p&lt;0.001). Similarly, GPT-4 was selected for its superior specificity in 509 cases, whereas human coders were preferred in only 181 cases (p&lt;0.001). Smaller open-access models, such as Llama-3.1-70B, also demonstrated substantial scalability when enhanced with RAG, with 218 instances of accuracy preference compared to 90 for providers' codes. Furthermore, across all models, the exact match rate between LLM-generated and provider-assigned codes significantly improved following RAG integration, with Qwen-2-7B increasing from 0.8% to 17.6% and Gemma-2-9b-it improving from 7.2% to 26.4%.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;RAG-enhanced LLMs improve medical coding accuracy in EDs, suggesting clinical workflow applications. These findings show that generative AI can improve clinical outcomes and reduce administrative burdens.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;This work was supported in part through the computational and data resources and staff expertise provided by Scientific Computing and Data at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (CTSA) grant UL1TR004419 from the National Center for Advancing Translational Sciences. Research reported in this publication was also supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD026880 and S10OD030463. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders played no role in study design, data collection, analysis and interpretation","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559941","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":"Imaging, Pulmonary Function, and Histopathologic Findings of Persistent Fibrosis in a Longitudinal Cohort Three Years after Severe COVID-19 Infection.","authors":"Scarlett O Murphy, Claire F McGroder, Mary M Salvatore, Belinda M D'Souza, Kathleen M Capaccione, Anjali Saqi, Faisal Shaikh, Shannon Benesh, David Zhang, Matthew R Baldwin, Christine Kim Garcia","doi":"10.1101/2024.10.16.24315602","DOIUrl":"10.1101/2024.10.16.24315602","url":null,"abstract":"<p><p>Fibrotic-like abnormalities are present in 60% of a single-center, longitudinal, multi-ethnic cohort 3-years after severe COVID-19. They are independently associated with male sex, low BMI, shorter telomere length, increased severity of illness, and mechanical ventilation; Black race and asthma are protective. Participants with fibrotic-like abnormalities are more likely to have reduced diffusion capacity and 6-minute walk distance. Fibrotic-like abnormalities persist but modestly improve over time. Transbronchial biopsies show small airways histopathology, consistent with high prevalence of air trapping in expiration, and infrequent interstitial thickening. This study highlights the need for continued monitoring of patients with persistent fibrosis after severe COVID-19.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559970","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":"5-hydroxymethylcytosine sequencing in plasma cell-free DNA identifies unique epigenomic features in prostate cancer patients resistant to androgen deprivation therapies.","authors":"Qianxia Li, Chiang-Ching Huang, Shane Huang, Yijun Tian, Jinyong Huang, Amirreza Bitaraf, Xiaowei Dong, Marja T Nevalanen, Manishkumar Patel, Jodie Wong, Jingsong Zhang, Brandon J Manley, Jong Y Park, Manish Kohli, Elizabeth M Gore, Deepak Kilari, Liang Wang","doi":"10.1101/2023.10.13.23296758","DOIUrl":"10.1101/2023.10.13.23296758","url":null,"abstract":"<p><strong>Background: </strong>Currently, no biomarkers are available to identify resistance to androgen-deprivation therapies (ADT) in men with hormone-naive prostate cancer. Since 5-hydroxymethylcytosines (5hmC) in gene body are associated with gene activation, in this study, we evaluated whether 5hmC signatures in cell-free DNA (cfDNA) predicts early resistance to ADT.</p><p><strong>Results: </strong>We collected a total of 139 serial plasma samples from 55 prostate cancer patients receiving ADT at three time points including baseline (prior to initiating ADT, N=55), 3-month (after initiating ADT, N=55), and disease progression (N=15) within 24 months or 24-month if no progression was detected (N=14). To quantify 5hmC abundance across the genome, we used selective chemical labeling sequencing and mapped sequence reads to individual genes. Differential methylation analysis in baseline samples identified significant 5hmC difference in 1,642 of 23,433 genes between patients with and without progression (false discovery rate, FDR<0.1). Patients with disease progression showed significant 5hmC enrichments in multiple hallmark gene sets with androgen responses as top enriched gene set (FDR=1.19E-13). Interestingly, this enrichment was driven by a subgroup of patients featuring a significant 5hmC hypermethylation in the gene sets involving <i>AR</i> , <i>FOXA1</i> and <i>GRHL2</i> . To quantify overall activities of these gene sets, we developed a gene set activity scoring algorithm and observed significant association of high activity scores with poor progression-free survival (P<0.05). Longitudinal analysis showed that the high activity scores were significantly reduced after 3-months of initiating ADT (P<0.0001) but returned to higher levels when the disease was progressed (P<0.05).</p><p><strong>Conclusions: </strong>This study demonstrates that 5hmC-based activity scores from gene sets involved in <i>AR</i> , <i>FOXA1</i> and <i>GRHL2</i> may be used as biomarkers to determine early treatment resistance, monitor disease progression, and potentially identify patients who would benefit from upfront treatment intensification.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10615016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71416383","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":"GLP-1 Receptor Agonists and Risk of Paralytic Ileus: A drug-target Mendelian Randomization Study.","authors":"Pingjian Ding, Zhenxiang Gao, Maria P Gorenflo, Rong Xu","doi":"10.1101/2024.10.17.24315627","DOIUrl":"10.1101/2024.10.17.24315627","url":null,"abstract":"<p><strong>Background: </strong>Paralytic ileus (PI), a condition characterized by reduced bowel motor activity without physical obstruction, can be affected by complications from type 2 diabetes (T2D) and anti-diabetic medications. It is unclear of the causal associations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with the risk of PI in the context of T2D management.</p><p><strong>Methods: </strong>To investigate the causal relationship of GLP-1RAs with PI, we conducted a 2-sample mendelian randomization (MR) study based on summary statistics from genome-wide association studies (GWAS). Genetic variants in the GLP1R were identified as genetical proxies of GLP-1RAs by the glycemic control therapy, based on genetic associations with glycated hemoglobin (GWAS n=344,182) and T2D (n_{cases/controls}=228,499/1,178,783). The effects of GLP-1RAs were estimated for PI risk (n_{cases/controls}=517/182,423) using GWAS data from the FinnGen project.</p><p><strong>Results: </strong>Based on MR analysis, GLP-1RAs are causally associated with a decreased risk of PI (OR per 1 mmol/mol decrease in glycated hemoglobin: 0.21; 95% confidence interval [CI]=0.06-0.69). The magnitude of these benefit exceeded those expected from improved glycemic control more generally.</p><p><strong>Conclusions: </strong>Our study's findings show that GLP-1RAs are causally associated with a lower risk for PI, which provides information to guide clinicians in the selection of appropriate therapies for individuals with T2D while mitigating the risk of developing PI. Investigating the underlying mechanisms that contribute to the lower PI risk associated with GLP-1RAs is essential for a deeper understanding of these associations.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559965","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":"Isolated prolapse of the posterior mitral valve leaflet: phenotypic refinement, heritability and genetic etiology.","authors":"Antoine Rimbert, Damien Duval, Daniel Trujillano, Florence Kyndt, Antoine Jobbe-Duval, Pierre Lindenbaum, Nathan Tucker, Simon Lecointe, Pauline Labbé, Claire Toquet, Matilde Karakachoff, Jean-Christian Roussel, Christophe Baufreton, Patrick Bruneval, Caroline Cueff, Erwan Donal, Richard Redon, Robert Olaso, Anne Boland, Jean-François Deleuze, Xavier Estivill, Susan Slaugenhaupt, Roger R Markwald, Russel A Norris, Jean-Philippe Verhoye, Vincent Probst, Albert Hagège, Robert Levine, Xavier Jeunemaitre, Hervé Le Marec, Romain Capoulade, Nabila Bouatia-Naji, Christian Dina, David Milan, Stephan Ossowski, Jean-Jacques Schott, Jean Mérot, Solena Le Scouarnec, Thierry Le Tourneau","doi":"10.1101/2024.10.16.24315096","DOIUrl":"10.1101/2024.10.16.24315096","url":null,"abstract":"<p><strong>Background: </strong>Isolated posterior leaflet mitral valve prolapse (PostMVP), a common form of MVP, often referred as fibroelastic deficiency, is considered a degenerative disease. PostMVP patients are usually asymptomatic and often undiagnosed until chordal rupture. The present study aims to characterize familial PostMVP phenotype and familial recurrence, its genetic background, and the pathophysiological processes involved.</p><p><strong>Methods: </strong>We prospectively enrolled 284 unrelated MVP probands, of whom 178 (63%) had bi-leaflet MVP and 106 had PostMVP (37%). Familial screening within PostMVP patients allowed the identification of 20 families with inherited forms of PostMVP for whom whole genome sequencing was carried out in probands. Functional <i>in vivo</i> and <i>in vitro</i> investigations were performed in zebrafishand in Hek293T cells.</p><p><strong>Results: </strong>In the 20 families with inherited form of PostMVP, 38.8% of relatives had a MVP/prodromal form, mainly of the posterior leaflet, with transmission consistent with an autosomal dominant mode of inheritance. Compared with control relatives, PostMVP family patients have clear posterior leaflet dystrophy on echocardiography. Patients with PostMVP present a burden of rare genetic variants in <i>ARHGAP24. ARHGAP24</i> encodes the filamin A binding RhoGTPase-activating protein FilGAP and its silencing in zebrafish leads to atrioventricular regurgitation. <i>In vitro</i> functional studies showed that variants of FilGAP, found in PostMVP families, are <i>loss-of-function</i> variants impairing cellular adhesion and mechano-transduction capacities.</p><p><strong>Conclusions: </strong>PostMVP should not only be considered an isolated degenerative pathology but as a specific heritable phenotypic trait with genetic and functional pathophysiological origins. The identification of <i>loss-of-function</i> variants in <i>ARHGAP24</i> further reinforces the pivotal role of mechano-transduction pathways in the pathogenesis of MVP.</p><p><strong>Clinical perspective: </strong>Isolated posterior mitral valve prolapse (PostMVP), often called fibro-elastic deficiency MVP, is at least in some patients, a specific inherited phenotypic traitPostMVP has both genetic and functional pathophysiological origins Genetic variants in the <i>ARHGAP24</i> gene, which encodes for the FilGAP protein, cause progressive Post MVP in familial cases, and impair cell adhesion and mechano-transduction capacities.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559957","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}