{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T11:12:14Z","timestamp":1784113934722,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,13]]},"group-title":"Cardiovascular Medicine","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,13]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Clonal hematopoiesis (CH) is associated with increased risks of diverse cardiovascular diseases, hematologic malignancies and mortality, yet no preventive therapies are approved. As emerging data implicate lipid pathways in CH pathogenesis, we investigated the association of statin use and genetically proxied inhibition of HMG-CoA reductase (HMGCR) with CH risk, and validated findings using primary peripheral blood mononuclear cells (PBMCs).<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We performed an observational analysis of 416,118 UK Biobank participants of European ancestry using multivariable logistic regression to compare CH prevalence among statin users and nonusers. Mendelian randomization (MR) analyses evaluated the causal association of genetically proxied lowering of low-density lipoprotein cholesterol (LDL-C) with risk of CH using two instruments; (i) the lead\n HMGCR<\/jats:italic>\n variant (rs12916) which proxied LDL-C lowering by statins, and, (ii) 303 genome-wide LDL-C-lowering variants representing polygenic mechanisms. Summary statistics were obtained from the Global Lipid Genetics Consortium genome-wide association study (N = 842,634). Experimentally, primary PBMCs from a\n DNMT3A<\/jats:italic>\n R882<\/jats:sup>\n hotspot mutation carrier were cultured in methylcellulose with pravastatin or vehicle control to evaluate colony-forming dynamics.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 416,118 individuals, 20,488 had CH, including 11,550 with single\n DNMT3A<\/jats:italic>\n -mutant and 4,375 with single\n TET2<\/jats:italic>\n -mutant CH. Pre-recruitment statin users had reduced odds of\n DNMT3A<\/jats:italic>\n -mutant CH (OR=0.93; 95% CI:0.88-0.98;\n P<\/jats:italic>\n =0.009), driven primarily by associations with\n DNMT3A<\/jats:italic>\n R882<\/jats:sup>\n \u2013mutant (OR=0.78; 95% CI:0.66-0.92;\n P<\/jats:italic>\n =0.003), but not\n TET2<\/jats:italic>\n -mutant CH (OR=1.05; 95% CI:0.97-1.14;\n P<\/jats:italic>\n =0.20). Similarly, genetically predicted HMG-CoA-reductase inhibition equivalent to a 1 SD reduction in circulating LDL-C levels was associated with lower odds of\n DNMT3A<\/jats:italic>\n -mutant CH (OR=0.66; 95% CI:0.45-0.95;\n P<\/jats:italic>\n =0.03) but not\n TET2<\/jats:italic>\n -mutant CH (OR=1.34; 95% CI:0.76-2.36;\n P<\/jats:italic>\n = 0.31). By contrast, polygenic estimation of LDL-C lowering was not associated with\n DNMT3A<\/jats:italic>\n -mutant CH (OR=1.05; 95% CI:0.97-1.14;\n P<\/jats:italic>\n =0.20), suggesting protective effects were independent of LDL-C lowering per se. Genetically predicted HMG-CoA reductase inhibition had wide effects on blood cell counts and indices, suggesting effects on bone marrow cell dynamics.\n In vitro<\/jats:italic>\n , pravastatin selectively suppressed colony formation of primary human\n DNMT3A<\/jats:italic>\n R882<\/jats:sup>\n \u2013mutant relative to wild-type cells (P=0.031).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Statin therapy and genetically predicted lifelong inhibition of HMG-CoA reductase were significantly associated with reduced risk of\n DNMT3A<\/jats:italic>\n -mutant CH, likely via LDL-C-independent mechanisms, which may be specific to\n DNMT3A<\/jats:italic>\n -mutant CH. This provides a strong rationale for prospective trials evaluating the effect of statins on risk of developing\n DNMT3A<\/jats:italic>\n -mutant CH, subsequent clonal expansion, and associated clinical sequelae.\n <\/jats:p>\n <\/jats:sec>\n \n Clinical Perspectives<\/jats:title>\n \n What is new?<\/jats:title>\n \n \n \n This study provides the first evidence that statins may protect against\n DNMT3A<\/jats:italic>\n -mutant clonal hematopoiesis (CH), with convergent findings of observational analysis of statin users and genetic epidemiology utilizing Mendelian randomization to proxy lifelong HMG-CoA reductase inhibition.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Observational analyses suggest the protective effect may be strongest against\n DNMT3A<\/jats:italic>\n R882<\/jats:sup>\n \u2013mutant CH.\n <\/jats:p>\n <\/jats:list-item>\n \n \n We provide evidence that pravastatin selectively suppresses colony formation of primary human\n DNMT3A<\/jats:italic>\n R882<\/jats:sup>\n \u2013mutant primary peripheral blood mononuclear cells\n in vitro<\/jats:italic>\n , suggesting a possible effect on clonal expansion.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:sec>\n \n What are the clinical implications?<\/jats:title>\n \n \n \n Although\n DNMT3A<\/jats:italic>\n -mutant CH is associated with diverse cardiovascular diseases, hematological malignancies and mortality, no preventive treatments are currently established; this study provides a viable avenue for future interventional studies.\n <\/jats:p>\n <\/jats:list-item>\n \n \n These data establish a strong rationale for prospective trials evaluating whether statins prevent the development or expansion of\n DNMT3A<\/jats:italic>\n -mutant CH and its cardiovascular consequences.\n <\/jats:p>\n <\/jats:list-item>\n \n Given that statins are widely used with established safety profiles, affordable and have proven cardiovascular benefit, such trials are readily implementable.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:sec>\n <\/jats:sec>","DOI":"10.64898\/2026.07.08.26357595","type":"posted-content","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T19:35:11Z","timestamp":1783971311000},"source":"Crossref","is-referenced-by-count":0,"title":["Statin Use and Genetically Predicted HMG-CoA Reductase Inhibition in Relation to Clonal Hematopoiesis"],"prefix":"10.64898","author":[{"given":"Paul R","family":"Carter","sequence":"first","affiliation":[{"name":"The Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Gozdecka","sequence":"additional","affiliation":[{"name":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom"},{"name":"Department of Haematology, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Haematology, University of Cambridge, Cambridge, United Kingdom"},{"name":"Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals Research and Development, AstraZeneca, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7793-6291","authenticated-orcid":false,"given":"Pedro M.","family":"Quir\u00f3s","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Instituto Universitario de Oncolog\u00eda, Universidad de Oviedo, Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, ISPA, Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2092-4350","authenticated-orcid":false,"given":"Samuel M.","family":"Lockhart","sequence":"additional","affiliation":[{"name":"MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom"},{"name":"Wellcome-Wolfson Institute for Experimental Medicine, Queen\u2019s University Belfast, Belfast, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Dudek","sequence":"additional","affiliation":[{"name":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom"},{"name":"Department of Haematology, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Bond","sequence":"additional","affiliation":[{"name":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom"},{"name":"Department of Haematology, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Richenberg","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom"},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0118-0341","authenticated-orcid":false,"given":"Susanna C.","family":"Larsson","sequence":"additional","affiliation":[{"name":"Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden"},{"name":"Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4243-5964","authenticated-orcid":false,"given":"Daniel","family":"Bromage","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Medicine and Sciences, King\u2019s College London British Heart Foundation Centre of Excellence, James Black Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals Research and Development, AstraZeneca, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0312-161X","authenticated-orcid":false,"given":"Brian","family":"Huntly","sequence":"additional","affiliation":[{"name":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom"},{"name":"Department of Haematology, University of Cambridge, Cambridge, United Kingdom"},{"name":"Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1502-502X","authenticated-orcid":false,"given":"Peter","family":"Libby","sequence":"additional","affiliation":[{"name":"Heart and Vascular Institute, Mass General Brigham and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murray C. H.","family":"Clarke","sequence":"additional","affiliation":[{"name":"The Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarete","family":"Fabre","sequence":"additional","affiliation":[{"name":"Department of Haematology, University of Cambridge, Cambridge, United Kingdom"},{"name":"Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals Research and Development, AstraZeneca, Cambridge, United Kingdom"},{"name":"Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4337-8022","authenticated-orcid":false,"given":"George S.","family":"Vassiliou","sequence":"additional","affiliation":[{"name":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom"},{"name":"Department of Haematology, University of Cambridge, Cambridge, United Kingdom"},{"name":"Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5365-8760","authenticated-orcid":false,"given":"Stephen","family":"Burgess","sequence":"additional","affiliation":[{"name":"The Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, United Kingdom"},{"name":"MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2314-1426","authenticated-orcid":false,"given":"Siddhartha P.","family":"Kar","sequence":"additional","affiliation":[{"name":"The Li Ka Shing Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071504000900000_2026.07.08.26357595v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408617"},{"key":"2026071504000900000_2026.07.08.26357595v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01121-z"},{"key":"2026071504000900000_2026.07.08.26357595v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1701719"},{"key":"2026071504000900000_2026.07.08.26357595v1.4","doi-asserted-by":"publisher","DOI":"10.1136\/openhrt-2025-003602"},{"key":"2026071504000900000_2026.07.08.26357595v1.5","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehad869"},{"key":"2026071504000900000_2026.07.08.26357595v1.6","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2018.3965"},{"key":"2026071504000900000_2026.07.08.26357595v1.7","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313225"},{"key":"2026071504000900000_2026.07.08.26357595v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-023-00326-7"},{"key":"2026071504000900000_2026.07.08.26357595v1.9","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.45.120403.095748"},{"key":"2026071504000900000_2026.07.08.26357595v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/343425a0"},{"issue":"6","key":"2026071504000900000_2026.07.08.26357595v1.11","first-page":"6","article-title":"Statins have biphasic effects on angiogenesis","volume":"105","year":"2002","journal-title":"Circulation"},{"issue":"8","key":"2026071504000900000_2026.07.08.26357595v1.12","first-page":"8","article-title":"In vivo anti-inflammatory effect of statins is mediated by nonsterol mevalonate products","volume":"21","year":"2001","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026071504000900000_2026.07.08.26357595v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2020.11.008"},{"key":"2026071504000900000_2026.07.08.26357595v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-019-0018-6"},{"key":"2026071504000900000_2026.07.08.26357595v1.15","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.57191"},{"key":"2026071504000900000_2026.07.08.26357595v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2018.04.002"},{"key":"2026071504000900000_2026.07.08.26357595v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-025-02822-0"},{"key":"2026071504000900000_2026.07.08.26357595v1.18","doi-asserted-by":"publisher","DOI":"10.1182\/BLOOD.V93.4.1308"},{"issue":"2","key":"2026071504000900000_2026.07.08.26357595v1.19","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1182\/bloodadvances.2021006047","article-title":"Vesicular trafficking is a key determinant of the statin response in acute myeloid leukemia","volume":"6","year":"2022","journal-title":"Blood Adv"},{"key":"2026071504000900000_2026.07.08.26357595v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2018.01.021"},{"key":"2026071504000900000_2026.07.08.26357595v1.21","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-08-044446"},{"key":"2026071504000900000_2026.07.08.26357595v1.22","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023009784"},{"key":"2026071504000900000_2026.07.08.26357595v1.23","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023009818"},{"key":"2026071504000900000_2026.07.08.26357595v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08980-6"},{"key":"2026071504000900000_2026.07.08.26357595v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-025-02085-6"},{"key":"2026071504000900000_2026.07.08.26357595v1.26","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022018825"},{"key":"2026071504000900000_2026.07.08.26357595v1.27","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwt084"},{"key":"2026071504000900000_2026.07.08.26357595v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04064-3"},{"key":"2026071504000900000_2026.07.08.26357595v1.29","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.034942"},{"key":"2026071504000900000_2026.07.08.26357595v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61183-1"},{"key":"2026071504000900000_2026.07.08.26357595v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.12.060"},{"key":"2026071504000900000_2026.07.08.26357595v1.32","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2017.4293"},{"key":"2026071504000900000_2026.07.08.26357595v1.33","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-021-02013-5"},{"key":"2026071504000900000_2026.07.08.26357595v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05448-9"},{"key":"2026071504000900000_2026.07.08.26357595v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-021-04103-Z"},{"key":"2026071504000900000_2026.07.08.26357595v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0579-z"},{"key":"2026071504000900000_2026.07.08.26357595v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.008"},{"key":"2026071504000900000_2026.07.08.26357595v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.06.045"},{"issue":"7","key":"2026071504000900000_2026.07.08.26357595v1.39","first-page":"7","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","year":"2013","journal-title":"Genet Epidemiol"},{"key":"2026071504000900000_2026.07.08.26357595v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0291-9"},{"key":"2026071504000900000_2026.07.08.26357595v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00944-6"},{"key":"2026071504000900000_2026.07.08.26357595v1.42","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.18236"},{"key":"2026071504000900000_2026.07.08.26357595v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.intell.2004.11.005"},{"key":"2026071504000900000_2026.07.08.26357595v1.44","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2026019625"},{"key":"2026071504000900000_2026.07.08.26357595v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05806-1"},{"key":"2026071504000900000_2026.07.08.26357595v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04785-z"},{"key":"2026071504000900000_2026.07.08.26357595v1.47","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-3033"},{"key":"2026071504000900000_2026.07.08.26357595v1.48","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a030320"},{"key":"2026071504000900000_2026.07.08.26357595v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3895"},{"key":"2026071504000900000_2026.07.08.26357595v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01472-1"},{"key":"2026071504000900000_2026.07.08.26357595v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2402196"},{"key":"2026071504000900000_2026.07.08.26357595v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1901"},{"key":"2026071504000900000_2026.07.08.26357595v1.53","doi-asserted-by":"publisher","DOI":"10.1126\/science.aba9304"},{"issue":"22","key":"2026071504000900000_2026.07.08.26357595v1.54","first-page":"22","article-title":"Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes","volume":"375","year":"2016","journal-title":"N Engl J Med"},{"key":"2026071504000900000_2026.07.08.26357595v1.55","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.14568"},{"key":"2026071504000900000_2026.07.08.26357595v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.09.017"},{"key":"2026071504000900000_2026.07.08.26357595v1.57","doi-asserted-by":"crossref","first-page":"103953","DOI":"10.1016\/j.ebiom.2022.103953","article-title":"Lipid traits and type 2 diabetes risk in African ancestry individuals: A Mendelian Randomization study","volume":"78","year":"2022","journal-title":"EBioMedicine"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.08.26357595","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T11:00:17Z","timestamp":1784113217000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.07.08.26357595"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":57,"URL":"https:\/\/doi.org\/10.64898\/2026.07.08.26357595","relation":{},"subject":[],"published":{"date-parts":[[2026,7,13]]},"subtype":"preprint"}}