{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T04:18:32Z","timestamp":1747196312311,"version":"3.40.5"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T00:00:00Z","timestamp":1666224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Objectives<\/jats:title>\n<jats:p>To determine if the electrical heart axis in different types of congenital heart defects (CHD) differs from that of a healthy cohort at mid-gestation.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Non-invasive fetal electrocardiography (NI-fECG) was performed in singleton pregnancies with suspected CHD between 16 and 30 weeks of gestation. The mean electrical heart axis (MEHA) was determined from the fetal vectorcardiogram after correction for fetal orientation. Descriptive statistics were used to determine the MEHA with corresponding 95% confidence intervals (CI) in the frontal plane of all fetuses with CHD and the following subgroups: conotruncal anomalies (CTA), atrioventricular septal defects (AVSD) and hypoplastic right heart syndrome (HRHS). The MEHA of the CHD fetuses as well as the subgroups was compared to the healthy control group using a spherically projected multivariate linear regression analysis. Discriminant analysis was applied to calculate the sensitivity and specificity of the electrical heart axis for CHD detection.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>The MEHA was determined in 127 fetuses. The MEHA was 83.0\u00b0 (95% CI: 6.7\u00b0; 159.3\u00b0) in the total CHD group, and not significantly different from the control group (122.7\u00b0 (95% CI: 101.7\u00b0; 143.6\u00b0). The MEHA was 105.6\u00b0 (95% CI: 46.8\u00b0; 164.4\u00b0) in the CTA group (n = 54), -27.4\u00b0 (95% CI: -118.6\u00b0; 63.9\u00b0) in the AVSD group (n = 9) and 26.0\u00b0 (95% CI: -34.1\u00b0; 86.1\u00b0) in the HRHS group (n = 5). The MEHA of the AVSD and the HRHS subgroups were significantly different from the control group (resp. p = 0.04 and p = 0.02).<\/jats:p>\n<jats:p>The sensitivity and specificity of the MEHA for the diagnosis of CHD was 50.6% (95% CI 47.5% - 53.7%) and 60.1% (95% CI 57.1% - 63.1%) respectively.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>The MEHA alone does not discriminate between healthy fetuses and fetuses with CHD. However, the left-oriented electrical heart axis in fetuses with AVSD and HRHS was significantly different from the control group suggesting altered cardiac conduction along with the structural defect.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Trial registration<\/jats:title>\n<jats:p><jats:bold>Clinical trial registration number:<\/jats:bold> <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.google.com\/search?client=firefox-b-d&amp;q=NL48535.015.14\" xlink:type=\"simple\">NL48535.015.14<\/jats:ext-link>.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0275802","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T18:13:28Z","timestamp":1666289608000},"page":"e0275802","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["The electrical heart axis in fetuses with congenital heart disease, measured with non-invasive fetal electrocardiography"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4894-0873","authenticated-orcid":true,"given":"L.","family":"Noben","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Lempersz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E. R.","family":"van den Heuvel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Z.","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F. P. H. A.","family":"Vandenbussche","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. B. C.","family":"Coumans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. C.","family":"Haak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Vullings","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. G.","family":"Oei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. A. B.","family":"Clur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. O. E. H.","family":"van Laar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,10,20]]},"reference":[{"issue":"21","key":"pone.0275802.ref001","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1016\/j.jacc.2011.08.025","article-title":"Birth prevalence of congenital heart disease worldwide: A systematic review and meta-analysis","volume":"58","author":"D Van Der Linde","year":"2011","journal-title":"J Am Coll Cardiol"},{"issue":"8","key":"pone.0275802.ref002","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1161\/CIRCULATIONAHA.110.958405","article-title":"Congenital heart defects in Europe: Prevalence and perinatal mortality, 2000 to 2005","volume":"123","author":"H Dolk","year":"2011","journal-title":"Circulation"},{"issue":"3","key":"pone.0275802.ref003","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.ahj.2003.05.003","article-title":"Prevalence of congenital heart disease","volume":"147","author":"JIE Hoffman","year":"2004","journal-title":"Am Heart J"},{"issue":"12","key":"pone.0275802.ref004","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1016\/S0735-1097(02)01886-7","article-title":"The incidence of congenital heart disease","volume":"39","author":"JIE Hoffman","year":"2002","journal-title":"J Am Coll Cardiol"},{"issue":"4","key":"pone.0275802.ref005","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s00246-006-1291-6","article-title":"The impact of fetal echocardiography on the prevalence of liveborn congenital heart disease","volume":"27","author":"I Germanakis","year":"2006","journal-title":"Pediatr Cardiol"},{"issue":"1","key":"pone.0275802.ref006","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1542\/peds.2004-0516","article-title":"Trends in prenatal diagnosis, pregnancy termination, and perinatal mortality of newborns with congenital heart disease in France, 1983\u20132000: a population-based evaluation","volume":"115","author":"B Khoshnood","year":"2005","journal-title":"Pediatrics"},{"issue":"3","key":"pone.0275802.ref007","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1007\/s00246-012-0526-y","article-title":"Improved prenatal detection of congenital heart disease in an integrated health care system","volume":"34","author":"DJ Levy","year":"2013","journal-title":"Pediatr Cardiol"},{"issue":"3","key":"pone.0275802.ref008","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/1471-0528.13274","article-title":"Prenatal detection of congenital heart disease-results of a national screening programme","volume":"123","author":"C van Velzen","year":"2016","journal-title":"BJOG An Int J Obstet Gynaecol"},{"issue":"2","key":"pone.0275802.ref009","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1136\/hrt.2010.206623","article-title":"Prenatal ultrasound screening of congenital heart disease in an unselected national population: a 21-year experience","volume":"97","author":"J Marek","year":"2011","journal-title":"Heart"},{"key":"pone.0275802.ref010","unstructured":"EUROCAT. Prevalence tables. http:\/\/www.eurocat-network.eu\/accessprevalencedata\/prevalencetables. Accessed August 23, 2018."},{"issue":"11","key":"pone.0275802.ref011","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1093\/eurheartj\/ehn194","article-title":"Foetal echocardiographic assessment of tetralogy of Fallot and post-natal outcome","volume":"29","author":"F Kaguelidou","year":"2008","journal-title":"Eur Heart J"},{"issue":"7","key":"pone.0275802.ref012","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1161\/01.CIR.99.7.916","article-title":"Detection of transposition of the great arteries in fetuses reduces neonatal morbidity and mortality","volume":"99","author":"D Bonnet","year":"1999","journal-title":"Circulation"},{"issue":"6","key":"pone.0275802.ref013","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1542\/peds.107.6.1277","article-title":"Impact of prenatal diagnosis on survival and early neurologic morbidity in neonates with the hypoplastic left heart syndrome","volume":"107","author":"WT Mahle","year":"2001","journal-title":"Pediatrics"},{"issue":"1","key":"pone.0275802.ref014","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1136\/heart.87.1.67","article-title":"Prenatal diagnosis of coarctation of the aorta improves survival and reduces morbidity","volume":"87","author":"O Franklin","year":"2002","journal-title":"Heart"},{"issue":"11","key":"pone.0275802.ref015","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1161\/CIRCULATIONAHA.105.588194","article-title":"Fetal aortic valve stenosis and the evolution of hypoplastic left heart syndrome: patient selection for fetal intervention","volume":"113","author":"K Makikallio","year":"2006","journal-title":"Circulation"},{"issue":"2","key":"pone.0275802.ref016","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ijgo.2016.05.010","article-title":"A systematic review of prenatal screening for congenital heart disease by fetal electrocardiography","volume":"135","author":"KMJ Verdurmen","year":"2016","journal-title":"Int J Gynaecol Obstet"},{"issue":"3","key":"pone.0275802.ref017","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1002\/uog.14689","article-title":"Prenatal detection of transposition of the great arteries reduces mortality and morbidity.","volume":"45","author":"CL van Velzen","year":"2015","journal-title":"Ultrasound Obstet Gynecol"},{"issue":"4","key":"pone.0275802.ref018","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1002\/pd.4525","article-title":"Prenatal detection of congenital heart disease in a low risk population undergoing first and second trimester screening","volume":"35","author":"DES J\u00f8rgensen","year":"2015","journal-title":"Prenat Diagn"},{"issue":"4","key":"pone.0275802.ref019","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1159\/000322519","article-title":"Prenatal detection of congenital heart defects: A survey on clinical practice in Spain.","volume":"29","author":"A Galindo","year":"2011","journal-title":"Fetal Diagn Ther"},{"issue":"4","key":"pone.0275802.ref020","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1002\/uog.10116","article-title":"Barriers to prenatal detection of congenital heart disease: A population-based study","volume":"40","author":"NM Pinto","year":"2012","journal-title":"Ultrasound Obstet Gynecol"},{"issue":"7","key":"pone.0275802.ref021","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.cjca.2013.04.028","article-title":"Effectiveness of Prenatal Screening for Congenital Heart Disease: Assessment in a Jurisdiction With Universal Access to Health Care","volume":"29","author":"J Trines","year":"2013","journal-title":"Can J Cardiol"},{"issue":"2","key":"pone.0275802.ref022","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/ijgo.12373","article-title":"Systematic review and meta-analysis of the performance of second-trimester screening for prenatal detection of congenital heart defects","volume":"140","author":"CL van Velzen","year":"2018","journal-title":"Int J Gynecol Obstet"},{"issue":"12","key":"pone.0275802.ref023","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1002\/pd.5347","article-title":"The effect of the introduction of the three-vessel view on the detection rate of transposition of the great arteries and tetralogy of Fallot","volume":"38","author":"SMP Everwijn","year":"2018","journal-title":"Prenat Diagn"},{"issue":"9","key":"pone.0275802.ref024","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/jp.2016.23","article-title":"Three- and four-dimensional ultrasound in fetal echocardiography: an up-to-date overview.","volume":"36","author":"BME Adriaanse","year":"2016","journal-title":"J Perinatol"},{"issue":"2","key":"pone.0275802.ref025","doi-asserted-by":"crossref","first-page":"189","DOI":"10.2217\/fca.12.15","article-title":"Fetal cardiac screening and variation in prenatal detection rates of congenital heart disease: why bother with screening at all?","volume":"8","author":"G. Sharland","year":"2012","journal-title":"Future Cardiol."},{"key":"pone.0275802.ref026","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.ejogrb.2016.10.030","article-title":"Orientation of the electrical heart axis in mid-term pregnancy","volume":"207","author":"KMJ Verdurmen","year":"2016","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"pone.0275802.ref027","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1186\/s12884-016-1021-x","article-title":"Normal ranges for fetal electrocardiogram values for the healthy fetus of 18\u201324 weeks of gestation: a prospective cohort study.","volume":"16","author":"KMJ Verdurmen","year":"2016","journal-title":"BMC Pregnancy Childbirth"},{"issue":"12","key":"pone.0275802.ref028","doi-asserted-by":"crossref","first-page":"e0256115","DOI":"10.1371\/journal.pone.0256115","article-title":"The electrical heart axis of the fetus between 18 and 24 weeks of gestation: A cohort study.","volume":"16","author":"C Lempersz","year":"2021","journal-title":"PLoS One"},{"issue":"4","key":"pone.0275802.ref029","doi-asserted-by":"crossref","first-page":"e0232606","DOI":"10.1371\/journal.pone.0232606","article-title":"The standardized 12-lead fetal electrocardiogram of the healthy fetus in mid-pregnancy: A cross-sectional study.","volume":"15","author":"C Lempersz","year":"2020","journal-title":"PLoS One"},{"issue":"3","key":"pone.0275802.ref030","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1088\/0967-3334\/30\/3\/005","article-title":"Dynamic segmentation and linear prediction for maternal ECG removal in antenatal abdominal recordings.","volume":"30","author":"R Vullings","year":"2009","journal-title":"Physiol Meas"},{"issue":"3","key":"pone.0275802.ref031","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1109\/TBME.2009.2033664","article-title":"Bayesian approach to patient-tailored vectorcardiography","volume":"57","author":"R Vullings","year":"2010","journal-title":"IEEE Trans Biomed Eng"},{"issue":"5","key":"pone.0275802.ref032","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/0002-8703(58)90006-1","article-title":"The mean manifest electrical axis of the ventricular activation process (AQRS) in congenital heart disease: a new approach in electrocardiographic diagnosis.","volume":"55","author":"D Sodi-Pallares","year":"1958","journal-title":"Am Heart J"},{"issue":"6","key":"pone.0275802.ref033","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/0028-2243(83)90205-8","article-title":"The significance of indirect electrocardiography in fetal cardiac arrhythmias.","volume":"14","author":"B Brambati","year":"1983","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"issue":"5","key":"pone.0275802.ref034","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1111\/j.1447-0756.2010.01367.x","article-title":"Understanding congenital heart defects through abdominal fetal electrocardiography: case reports and clinical implications","volume":"37","author":"C Velayo","year":"2011","journal-title":"J Obstet Gynaecol Res"},{"journal-title":"Bootstrap Methods and Their Application","author":"AC Davison","key":"pone.0275802.ref035"},{"key":"pone.0275802.ref036","volume-title":"Directional Statistics","author":"KV Mardia","year":"2000","edition":"2"},{"key":"pone.0275802.ref037","article-title":"Spherical regression models with general covariates and anisotropic errors.","author":"PJ Paine","year":"2019","journal-title":"Stat Comput. April"},{"issue":"443","key":"pone.0275802.ref038","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1080\/01621459.1998.10473768","article-title":"Projected Multivariate Linear Models for Directional Data","volume":"93","author":"B Presnell","year":"1998","journal-title":"J Am Stat Assoc"},{"key":"pone.0275802.ref039","first-page":"335","volume-title":"Biometrika","author":"JE Morris","year":"1974"},{"issue":"June","key":"pone.0275802.ref040","first-page":"89","article-title":"Paediatric electrocardiography.","volume":"324","author":"S Goodacre","year":"2002","journal-title":"BMJ"},{"issue":"1","key":"pone.0275802.ref041","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/0002-9378(65)90585-5","article-title":"Estimation of the electrical axis of the fetal heart","volume":"91","author":"S. Larks","journal-title":"Am J Obstet Gynecol"},{"issue":"6","key":"pone.0275802.ref042","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s002469900502","article-title":"Congenital heart disease among 815,569 children born between 1980 and 1990 and their 15-year survival: a prospective Bohemia survival study.","volume":"20","author":"M Samanek","year":"1999","journal-title":"Pediatr Cardiol."},{"issue":"5","key":"pone.0275802.ref043","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1046\/j.1469-0705.1995.06050313.x","article-title":"Fetal heart screening in low-risk pregnancies","volume":"6","author":"MA Rustico","year":"1995","journal-title":"Ultrasound Obstet Gynecol"},{"issue":"2","key":"pone.0275802.ref044","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/S0002-9378(99)70577-6","article-title":"The performance of routine ultrasonographic screening of pregnancies in the Eurofetus Study.","volume":"181","author":"H Grandjean","year":"1999","journal-title":"Am J Obstet Gynecol"},{"issue":"1","key":"pone.0275802.ref045","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1542\/peds.2004-0516","article-title":"Trends in Prenatal Diagnosis, Pregnancy Termination, and Perinatal Mortality of Newborns With Congenital Heart Disease in France, 1983\u20132000: A Population-Based Evaluation","volume":"115","author":"B Khoshnood","year":"2005","journal-title":"Pediatrics"},{"issue":"1","key":"pone.0275802.ref046","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.ejogrb.2009.04.032","article-title":"Conotruncal anomalies in fetal life: accuracy of diagnosis, associated defects and outcome.","volume":"146","author":"A Galindo","year":"2009","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"issue":"6","key":"pone.0275802.ref047","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1016\/S0735-1097(99)00049-2","article-title":"Accuracy of prenatal echocardiographic diagnosis and prognosis of fetuses with conotruncal anomalies","volume":"33","author":"AJ Tometzki","year":"1999","journal-title":"J Am Coll Cardiol"},{"issue":"4","key":"pone.0275802.ref048","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1046\/j.1469-0705.1996.08040241.x","article-title":"Conotruncal anomalies in prenatal life.","volume":"8","author":"D Paladini","year":"1996","journal-title":"Ultrasound Obstet Gynecol"},{"issue":"4","key":"pone.0275802.ref049","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1055\/s-2006-939535","article-title":"Prenatal diagnosis of conotruncal malformations: diagnostic accuracy, outcome, chromosomal abnormalities, and extracardiac anomalies.","volume":"23","author":"S Sivanandam","year":"2006","journal-title":"Am J Perinatol."},{"issue":"6","key":"pone.0275802.ref050","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1016\/0735-1097(94)90391-3","article-title":"Prospective diagnosis of 1,006 consecutive cases of congenital heart disease in the fetus","volume":"23","author":"LD Allan","year":"1994","journal-title":"J Am Coll Cardiol"},{"key":"pone.0275802.ref051","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1017\/S1047951118002147","article-title":"Emerging trends in the prenatal diagnosis of complex CHD and its influence on infant mortality in this cohort","volume":"29","author":"SR Gorla","year":"2019","journal-title":"Cardiol Young"},{"issue":"4","key":"pone.0275802.ref052","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1161\/01.CIR.13.4.499","article-title":"The persistent ostium primum atrial septal defect","volume":"13","author":"OJ Balchum","year":"1956","journal-title":"Circulation"},{"issue":"12","key":"pone.0275802.ref053","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/j.jcmg.2009.08.009","article-title":"Electroanatomic relationships in patients with primum atrioventricular septal defect.","volume":"2","author":"N Hakacova","year":"2009","journal-title":"JACC Cardiovasc Imaging"},{"journal-title":"Park\u2019s Pediatric Cardiology for Practitioners.","year":"2014","author":"MK Park","key":"pone.0275802.ref054"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0275802","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T18:14:25Z","timestamp":1666289665000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0275802"}},"subtitle":[],"editor":[{"given":"Linglin","family":"Xie","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,10,20]]},"references-count":54,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0275802","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2022,10,20]]}}}