{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:21:56Z","timestamp":1758846116366,"version":"3.44.0"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University Grant Commission","award":["CP-4029"],"award-info":[{"award-number":["CP-4029"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Congenital hypothyroidism (CH), characterized by insufficient thyroid hormone production at birth, is frequently associated with fatigue, particularly in cases with delayed diagnosis. This study employed liquid chromatography\u2013tandem mass spectrometry (LC-MS\/MS) to profile carnitine and acylcarnitines in late-diagnosed congenital hypothyroid patients receiving levothyroxine (LT4) therapy, with the aim of identifying metabolic alterations that may be associated with fatigue symptoms. A total of 56 late-diagnosed congenital hypothyroid patients and 107 age-, sex-, and BMI-matched healthy controls were enrolled. Blood samples were collected in EDTA tubes and as dried blood spots (DBS) on Whatman\u00ae 903 filter paper. LC-MS\/MS was used to quantify free carnitine and 28 acylcarnitines, and plasma triglyceride (TG) levels were measured using a biochemical analyzer. Compared to healthy controls, congenital hypothyroid patients showed higher mean (\u00b1SD) concentrations of free carnitine (45.38\u2009\u00b1\u200912.61 vs. 41.54\u2009\u00b1\u20099.85 \u00b5mol\/L; P\u2009=\u20090.049), total carnitines (67.33\u2009\u00b1\u200918.27 vs. 62.51\u2009\u00b1\u200914.13 \u00b5mol\/L), and total acylcarnitines (21.95\u2009\u00b1\u20097.66 vs. 20.96\u2009\u00b1\u20095.61 \u00b5mol\/L), although only free carnitine levels were statistically significant. Long-chain acylcarnitines were significantly lower in congenital hypothyroid patients (2.67\u2009\u00b1\u20090.87 \u00b5mol\/L) compared to controls (3.15\u2009\u00b1\u20090.93 \u00b5mol\/L; P\u2009=\u20090.0014). The \u03b2-oxidation ratio C0\/(C16\u2009+\u2009C18), a proxy for Carnitine Palmitoyltransferase I (CPT-I) activity, was significantly elevated in patients compared to healthy controls (34.55\u2009\u00b1\u200914.88 vs. 25.73\u2009\u00b1\u20096.87; P\u2009&lt;\u20090.0001). Plasma TG levels were also significantly higher in patients (88.92\u2009\u00b1\u200959.54\u2009mg\/dL) than in controls (58.33\u2009\u00b1\u200915.79\u2009mg\/dL; P\u2009=\u20090.02). Metabolic profiling in congenital hypothyroid patients revealed impaired long-chain fatty acid oxidation and elevated triglyceride levels. These metabolic changes may contribute to fatigue symptoms and are potentially associated with reduced CPT-I activity, which is essential for mitochondrial \u03b2-oxidation. Additionally, mutations in the <jats:italic>TPO<\/jats:italic> and <jats:italic>TSHR<\/jats:italic> genes identified within this cohort may be linked to the observed metabolic alterations. Collectively, these findings suggest a possible interplay between genetic variants, disrupted lipid metabolism, and clinical features of congenital hypothyroidism.<\/jats:p>","DOI":"10.1371\/journal.pone.0331474","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T17:24:37Z","timestamp":1758821077000},"page":"e0331474","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Altered carnitine-acylcarnitine profiles in levothyroxine-treated congenital hypothyroid patients with fatigue: An LC-MS\/MS-based study from Bangladesh"],"prefix":"10.1371","volume":"20","author":[{"given":"Mst. Noorjahan","family":"Begum","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suprovath Kumar","family":"Sarker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Md Tarikul","family":"Islam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Golam Sarower","family":"Bhuyan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rumana","family":"Mahtarin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad Hridoy","family":"Patwary","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tasnia Kawsar","family":"Konika","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Syeda Kashfi","family":"Qadri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tasnuva","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hurjahan","family":"Banu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nusrat","family":"Sultana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5271-7853","authenticated-orcid":true,"given":"Asifuzzaman","family":"Rahat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohinoor Jahan","family":"Shyamaly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taufiqur Rahman","family":"Bhuiyan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mizanul","family":"Hasan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad A.","family":"Hasanat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1710-9865","authenticated-orcid":true,"given":"Abu A.","family":"Sajib","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abul B.M.M.K.","family":"Islam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaiissar","family":"Mannoor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharif","family":"Akhteruzzaman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8459-304X","authenticated-orcid":true,"given":"Firdausi","family":"Qadri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"issue":"1","key":"pone.0331474.ref001","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1750-1172-5-17","article-title":"Congenital hypothyroidism","volume":"5","author":"MV Rastogi","year":"2010","journal-title":"Orphanet J Rare Dis"},{"issue":"5","key":"pone.0331474.ref002","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S0022-3476(83)80228-5","article-title":"Second international conference on neonatalthyroid screening: progress report","volume":"102","author":"DA Fisher","year":"1983","journal-title":"J Pediatr"},{"key":"pone.0331474.ref003","first-page":"162","article-title":"Screening for congenital hypothyroidism--a new era in Bangladesh","author":"M Hasan","year":"2003","journal-title":"Southeast Asian J Trop Med Public Health"},{"issue":"5","key":"pone.0331474.ref004","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1046\/j.1365-2265.2002.01654.x","article-title":"Psychological well\u2010being in patients on \u2018adequate\u2019doses of l\u2010thyroxine: results of a large, controlled community\u2010based questionnaire study","volume":"57","author":"P Saravanan","year":"2002","journal-title":"Clin Endocrinol"},{"issue":"6","key":"pone.0331474.ref005","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1530\/eje.1.02025","article-title":"Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism","volume":"153","author":"EM Wekking","year":"2005","journal-title":"Eur J Endocrinol"},{"issue":"2","key":"pone.0331474.ref006","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000339444","article-title":"2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism","volume":"1","author":"WM Wiersinga","year":"2012","journal-title":"Eur Thyroid J"},{"issue":"1","key":"pone.0331474.ref007","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/j.1365-2796.2010.02341.x","article-title":"Long-chain acylcarnitine deficiency in patients with chronic fatigue syndrome. Potential involvement of altered carnitine palmitoyltransferase-I activity","volume":"270","author":"SE Reuter","year":"2011","journal-title":"J Intern Med"},{"issue":"1","key":"pone.0331474.ref008","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1146\/annurev.bi.57.070188.001401","article-title":"Carnitine","volume":"57","author":"L Bieber","year":"1988","journal-title":"Annu Rev Biochem"},{"key":"pone.0331474.ref009","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/978-1-4615-6005-0_6","article-title":"Carnitine deficiency: primary and secondary syndromes","volume-title":"Carnitine Today","author":"G Famularo","year":"1997"},{"key":"pone.0331474.ref010","doi-asserted-by":"crossref","DOI":"10.1177\/0883073895010002S03","article-title":"Primary and secondary carnitine deficiency syndromes","volume":"10","author":"R Pons","year":"1995","journal-title":"J Child Neurol"},{"issue":"5","key":"pone.0331474.ref011","first-page":"351","article-title":"Primary carnitine deficiency","volume":"28","author":"HR Scholte","year":"1990","journal-title":"J Clin Chem Clin Biochem"},{"issue":"11","key":"pone.0331474.ref012","doi-asserted-by":"crossref","first-page":"3211","DOI":"10.1093\/ndt\/gfl356","article-title":"Effects of L-carnitine infusions on inflammatory and nutritional markers in haemodialysis patients","volume":"21","author":"M Duranay","year":"2006","journal-title":"Nephrol Dial Transplant"},{"key":"pone.0331474.ref013","doi-asserted-by":"crossref","DOI":"10.1067\/mhj.2000.103917","article-title":"Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration","volume":"139","author":"I Rizos","year":"2000","journal-title":"Am Heart J"},{"issue":"4","key":"pone.0331474.ref014","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1161\/01.CIR.77.4.767","article-title":"Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study","volume":"77","author":"G Brevetti","year":"1988","journal-title":"Circulation"},{"issue":"4","key":"pone.0331474.ref015","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0293570","article-title":"High-resolution melt curve analysis: An approach for variant detection in the TPO gene of congenital hypothyroid patients in Bangladesh","volume":"19","author":"MN Begum","year":"2024","journal-title":"PLoS One"},{"key":"pone.0331474.ref016","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.jare.2018.04.002","article-title":"Impaired acylcarnitine profile in transfusion-dependent beta-thalassemia major patients in Bangladesh","volume":"12","author":"S Kumar Sarker","year":"2018","journal-title":"J Adv Res"},{"issue":"2","key":"pone.0331474.ref017","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0167-4781(96)00069-3","article-title":"Isolation and characterization of cDNA and genomic clones encoding human muscle type carnitine palmitoyltransferase I","volume":"1307","author":"N Yamazaki","year":"1996","journal-title":"Biochim Biophys Acta"},{"issue":"6","key":"pone.0331474.ref018","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.1073\/pnas.92.6.1984","article-title":"Human liver mitochondrial carnitine palmitoyltransferase I: characterization of its cDNA and chromosomal localization and partial analysis of the gene","volume":"92","author":"CH Britton","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pone.0331474.ref019","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0022-3476(05)81641-5","article-title":"Growth in children with congenital hypothyroidism detected by neonatal screening","volume":"116","author":"R Aronson","year":"1990","journal-title":"J Pediatr"},{"issue":"5","key":"pone.0331474.ref020","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/S0022-3476(87)80005-7","article-title":"Intellectual outcome in children with fetal hypothyroidism","volume":"110","author":"J Rovet","year":"1987","journal-title":"J Pediatr"},{"key":"pone.0331474.ref021","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1750-1172-5-17","article-title":"Congenital hypothyroidism","volume":"5","author":"MV Rastogi","year":"2010","journal-title":"Orphanet J Rare Dis"},{"issue":"2","key":"pone.0331474.ref022","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1542\/peds.63.2.180","article-title":"Neonatal hypothyroidism detected by the Northwest Regional Screening Program","volume":"63","author":"SH LaFranchi","year":"1979","journal-title":"Pediatrics"},{"issue":"1","key":"pone.0331474.ref023","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1136\/adc.67.1.87","article-title":"Congenital hypothyroidism detected by neonatal screening: relationship between biochemical severity and early clinical features","volume":"67","author":"DB Grant","year":"1992","journal-title":"Arch Dis Child"},{"issue":"6453","key":"pone.0331474.ref024","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1136\/bmj.289.6453.1171","article-title":"Incidence of congenital hypothyroidism: retrospective study of neonatal laboratory screening versus clinical symptoms as indicators leading to diagnosis","volume":"289","author":"J Alm","year":"1984","journal-title":"Br Med J (Clin Res Ed)"},{"key":"pone.0331474.ref025","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.clinbiochem.2012.10.006","article-title":"Acylcarnitine profile in thyroid disease","volume":"46","author":"S Wong","year":"2013","journal-title":"Clin Biochem"},{"issue":"3","key":"pone.0331474.ref026","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1007\/s00018-002-8445-3","article-title":"Thyroid hormone controls carnitine status through modifications of gamma-butyrobetaine hydroxylase activity and gene expression","volume":"59","author":"S Galland","year":"2002","journal-title":"Cell Mol Life Sci"},{"issue":"3","key":"pone.0331474.ref027","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/0005-2760(80)90002-8","article-title":"Clofibrate enhancement of mitochondrial carnitine transport system of rat liver and augmentation of liver carnitine and gamma-butyrobetaine hydroxylase activity by thyroxine","volume":"617","author":"SV Pande","year":"1980","journal-title":"Biochim Biophys Acta"},{"issue":"8","key":"pone.0331474.ref028","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1172\/JCI105439","article-title":"The effect of thyroxine on lipid and carbohdrate metabolism in the heart","volume":"45","author":"R Bressler","year":"1966","journal-title":"J Clin Invest"},{"issue":"4","key":"pone.0331474.ref029","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0026-0495(77)90101-9","article-title":"Urinary excretion of carnitine in patients with hyperthyroidism and hypothyroidism: augmentation by thyroid hormone","volume":"26","author":"M Maebashi","year":"1977","journal-title":"Metabolism"},{"key":"pone.0331474.ref030","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.cccn.2005.04.029","article-title":"Plasma and urinary carnitine and acylcarnitines in chronic fatigue syndrome","volume":"360","author":"MG Jones","year":"2005","journal-title":"Clin Chim Acta"},{"issue":"10","key":"pone.0331474.ref031","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1507\/endocrj.EJ16-0109","article-title":"L-carnitine supplementation for the management of fatigue in patients with hypothyroidism on levothyroxine treatment: a randomized, double-blind, placebo-controlled trial","volume":"63","author":"JH An","year":"2016","journal-title":"Endocr J"},{"issue":"6","key":"pone.0331474.ref032","first-page":"349","article-title":"Evaluation of carnitine\u2014an antagonist of thyroid hormone","volume":"6","author":"SG Gilgore","year":"1966","journal-title":"J Clin Pharmacol"},{"issue":"6","key":"pone.0331474.ref033","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1177\/009127006600600607","article-title":"The antagonistic effect of carnitine in hyperthyroidism. Preliminary report","volume":"6","author":"SL DeFelice","year":"1966","journal-title":"J New Drugs"},{"issue":"12","key":"pone.0331474.ref034","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1089\/thy.2000.10.1043","article-title":"Carnitine is a naturally occurring inhibitor of thyroid hormone nuclear uptake","volume":"10","author":"S Benvenga","year":"2000","journal-title":"Thyroid"},{"issue":"2","key":"pone.0331474.ref035","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1006\/bbrc.1994.1791","article-title":"Changes in carnitine palmitoyltransferase-I mRNA abundance produced by hyperthyroidism and hypothyroidism parallel changes in activity","volume":"201","author":"RL Mynatt","year":"1994","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0331474.ref036","article-title":"Hyperlipidemia in patients with primary and secondary hypothyroidism","author":"T O\u2019Brien","year":"1993","journal-title":"Mayo Clin Proc"},{"issue":"2","key":"pone.0331474.ref037","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1530\/EJE-10-0312","article-title":"TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects","volume":"163","author":"J Gardu\u00f1o-Garcia J de","year":"2010","journal-title":"Eur J Endocrinol"},{"issue":"2","key":"pone.0331474.ref038","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1530\/eje.1.02333","article-title":"The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT Study","volume":"156","author":"BO Asvold","year":"2007","journal-title":"Eur J Endocrinol"},{"issue":"2","key":"pone.0331474.ref039","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1210\/jc.2011-2532","article-title":"Update in lipid alterations in subclinical hypothyroidism","volume":"97","author":"EN Pearce","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"pone.0331474.ref040","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.jhep.2012.02.027","article-title":"Non-alcoholic fatty liver disease across the spectrum of hypothyroidism","volume":"57","author":"GE Chung","year":"2012","journal-title":"J Hepatol"},{"issue":"12","key":"pone.0331474.ref041","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1111\/jgh.12998","article-title":"Thyroid function is associated with non-alcoholic fatty liver disease in chronic hepatitis B-infected subjects","volume":"30","author":"W-J Ding","year":"2015","journal-title":"J Gastroenterol Hepatol"},{"issue":"25","key":"pone.0331474.ref042","doi-asserted-by":"crossref","first-page":"8102","DOI":"10.3748\/wjg.v20.i25.8102","article-title":"Non-alcoholic fatty liver disease and thyroid dysfunction: a systematic review","volume":"20","author":"A Eshraghian","year":"2014","journal-title":"World J Gastroenterol"},{"issue":"4","key":"pone.0331474.ref043","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1159\/000454920","article-title":"Nonalcoholic fatty liver disease is not associated with thyroid hormone levels and hypothyroidism: a systematic review and meta-analysis","volume":"6","author":"V Jaruvongvanich","year":"2017","journal-title":"Eur Thyroid J"},{"issue":"5","key":"pone.0331474.ref044","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1203\/01.PDR.0000059220.39578.3D","article-title":"Neonatal blood carnitine concentrations: normative data by electrospray tandem mass spectometry","volume":"53","author":"DH Chace","year":"2003","journal-title":"Pediatr Res"},{"issue":"7","key":"pone.0331474.ref045","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1203\/00006450-198307000-00012","article-title":"Carnitine status at birth of newborn infants of varying gestation","volume":"17","author":"JP Shenai","year":"1983","journal-title":"Pediatr Res"},{"key":"pone.0331474.ref046","doi-asserted-by":"crossref","unstructured":"Begum M, Islam MT, Hossain SR, Bhuyan GS, Halim MA, Shahriar I. Mutation spectrum in TPO gene of Bangladeshi patients with thyroid dyshormonogenesis and analysis of the effects of different mutations on the structural features and functions of TPO protein through in silico approach. 2019.","DOI":"10.1155\/2019\/9218903"},{"key":"pone.0331474.ref047","doi-asserted-by":"crossref","unstructured":"Begum MN, Mahtarin R, Ahmed S, Shahriar I, Hossain SR, Mia MW. Investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer. 2023;18(9):e0291386.","DOI":"10.1371\/journal.pone.0291386"},{"issue":"8","key":"pone.0331474.ref048","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0282553","article-title":"Molecular investigation of TSHR gene in Bangladeshi congenital hypothyroid patients","volume":"18","author":"MN Begum","year":"2023","journal-title":"PLoS One"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0331474","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T17:24:47Z","timestamp":1758821087000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0331474"}},"subtitle":[],"editor":[{"given":"Xiaosheng","family":"Tan","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,9,25]]},"references-count":48,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0331474","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,25]]}}}