{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T18:41:07Z","timestamp":1793385667570,"version":"4.5.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Public Health"],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>This study aimed to investigate the prevalence of resistance to first-line anti-tuberculosis (TB) drugs and the molecular mechanisms underlying resistance mutations in patients with culture-positive <jats:italic>Mycobacterium tuberculosis<\/jats:italic> complex (MTBC). The findings provide a data basis for developing more precise and regionally tailored anti-TB treatment regimens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>From 2015 to 2022, a total of 3,605 strains isolated from 10 designated TB medical institutions in the main urban and county\/township areas of Luoyang City, China, were confirmed as MTBC members through polymerase chain reaction (PCR) targeting a specific insertion sequence IS6110. Drug susceptibility testing using the proportional method was performed to analyze resistance patterns to first-line anti-TB drugs, namely, isoniazid (INH), rifampin (RFP), streptomycin (SM), and ethambutol (EMB). Molecular drug susceptibility testing was conducted on resistant strains using multicolor melting curve analysis (MMCA) to determine the mutation mechanisms associated with phenotypic resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among the 3,605 culture-positive MTBC cases, 79.5% (2,866 cases) were male, 64.9% (2,341 cases) resided in county and township areas, and 64.8% (2,336 cases) were younger than 60 years. The resistance rates for first-line anti-TB drugs, from highest to lowest, were SM (16.5%), INH (15.7%), RFP (9.9%), and EMB (6.4%). The overall TB resistance rates were significantly higher in the main urban areas. During the study period, the proportion of mono-resistance tuberculosis (MR-TB), multidrug-resistant tuberculosis (MDR-TB) and polydrug-resistant tuberculosis (PDR-TB) decreased by 59.2% (12.9\u20135.3%), 40.3% (12.4\u20137.4%), and 68.3% (6.9\u20132.2%), respectively. The predominant resistance patterns for MDR-TB and PDR-TB were MDR4 (INH + RIF + EMB + SM) and PDR2 (INH + SM). The significant molecular mutations observed were <jats:italic>rpsL<\/jats:italic>43 for SM resistance (66.2%, 344 cases), <jats:italic>katG<\/jats:italic>315 for INH resistance (70.6%, 361 cases), <jats:italic>rpoB<\/jats:italic>529-533 for RFP resistance (54.0%, 183 cases), and <jats:italic>embB<\/jats:italic>306 for EMB resistance (56.5%, 108 cases). Resistance in MDR-TB and PDR-TB cases frequently involved combinations of hotspot mutations but was not strictly confined to these sites.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Tuberculosis resistance rates have declined over time, with distinct regional variations in resistance patterns. Significant molecular mutations responsible for drug resistance predominantly involve common hotspot mutations, but they are not limited to these.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fpubh.2025.1543647","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T05:29:02Z","timestamp":1747978142000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Resistance characteristics of culture-positive tuberculosis from 2015 to 2022"],"prefix":"10.3389","volume":"13","author":[{"given":"Zhenzhen","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengfei","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinwei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyang","family":"Zu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanqin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/S0140-6736(20)30049-0","article-title":"Challenging the management of drug-resistant tuberculosis","volume":"395","author":"Kim","year":"2020","journal-title":"Lancet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1016\/S0140-6736(19)31882-3","article-title":"Management of drug-resistant tuberculosis","volume":"394","author":"Lange","year":"2019","journal-title":"Lancet."},{"key":"B3","unstructured":"Geneva\n          World Health Organization\n          Definitions and Reporting Framework for Tuberculosis-2013 Revision\n          \n          2013"},{"key":"B4","unstructured":"Geneva\n          World Health Organization\n          Global Tuberculosis Report\n          \n          2023"},{"key":"B5","doi-asserted-by":"crossref","DOI":"10.1016\/S2213-2600(17)30079-6","article-title":"The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis","author":"Dheda","year":"2017","journal-title":"Lancet Respir. Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1016\/S1473-3099(18)30625-X","article-title":"Global, regional, and national burden of tuberculosis, 1990-2016: results from the Global Burden of Diseases, Injuries, and Risk Factors 2016 Study","volume":"18","author":"GBD","year":"2018","journal-title":"Lancet Infect Dis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.ijid.2019.07.001","article-title":"Insight into genetic diversity of Mycobacterium tuberculosis in Kandy, Sri Lanka reveals predominance of the Euro-American lineage","volume":"87","author":"Mendis","year":"2019","journal-title":"Int J Infect Dis."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2161","DOI":"10.1056\/NEJMoa1108789","article-title":"National survey of drug resistant tuberculosis in China","volume":"366","author":"Zhao","year":"2012","journal-title":"N Engl J Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e01096","DOI":"10.1128\/JCM.01096-18","article-title":"Rapid identification of clinically relevant mycobacterium species by multicolor melting curve analysis","volume":"57","author":"Xu","year":"2019","journal-title":"J Clin Microbiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"167954","DOI":"10.1155\/2013\/167954","article-title":"Mutations in the embB gene and their association with ethambutol resistance in multidrug-resistant Mycobacterium tuberculosis clinical isolates from Poland","volume":"2013","author":"Baku\u0142a","year":"2013","journal-title":"Biomed Res Int."},{"key":"B11","doi-asserted-by":"publisher","first-page":"629","DOI":"10.12138\/j.issn.1671-9638.20233646","article-title":"Drug resistance of Mycobacterium tuberculosis in five monitoring sites of Henan Province, 2013-2018","volume":"22","author":"Wang","year":"2023","journal-title":"Chin J Infect Control."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1117101","DOI":"10.3389\/fpubh.2023.1117101","article-title":"Epidemiological characteristics and risk factors of multidrug-resistant tuberculosis in Luoyang, China","volume":"11","author":"Wang","year":"2023","journal-title":"Front in Public Health."},{"key":"B13","doi-asserted-by":"publisher","first-page":"857","DOI":"10.3760\/cma.j.cn112338-20240311-00111","article-title":"Current status of tuberculosis burden in China","volume":"45","author":"Wang","year":"2024","journal-title":"Chin J Epidemiol."},{"key":"B14","unstructured":"Guidelines for Surveillance of Drug Resistance in Tuberculosis\n          \n          2015"},{"key":"B15","doi-asserted-by":"publisher","first-page":"268","DOI":"10.3969\/j.issn.2095-3755.2018.04.009","article-title":"Clinical application of multicolor melting curve analysis in detection of drug resistance of Mycobacterium tuberculosis in sputum samples","volume":"7","author":"Yu","year":"2018","journal-title":"J Tubercul Lung Health."},{"key":"B16","doi-asserted-by":"publisher","first-page":"4133","DOI":"10.2147\/IDR.S277203","article-title":"Primary drug-resistance pattern and trend in elderly tuberculosis patients in Shandong, China, from 2004 to 2019","volume":"13","author":"An","year":"2020","journal-title":"Infect Drug Resist."},{"key":"B17","doi-asserted-by":"publisher","first-page":"281","DOI":"10.3109\/00365540903493723","article-title":"Treatment default and death among tuberculosis patients in Hunan, China","volume":"42","author":"Abuaku","year":"2010","journal-title":"Scand J Infect Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e88290","DOI":"10.1371\/journal.pone.0088290","article-title":"Population aging and migrant workers: bottlenecks in tuberculosis control in rural China","volume":"9","author":"Bele","year":"2014","journal-title":"PLoS ONE."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2057","DOI":"10.1016\/S0140-6736(13)62639-2","article-title":"Tuberculosis prevalence in China, 1990-2010; a longitudinal analysis of national survey data","volume":"383","author":"Wang","year":"2014","journal-title":"Lancet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1007\/978-3-031-35139-6_6","article-title":"Sex and gender differences in tuberculosis pathogenesis and treatment outcomes","volume":"441","author":"Dabitao","year":"2023","journal-title":"Curr Top Microbiol Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2102538","DOI":"10.1183\/13993003.02538-2021","article-title":"Tuberculosis and COVID-19 co-infection: description of the global cohort","volume":"59","author":"TB\/COVID-19","year":"2022","journal-title":"Eur Respir J"},{"key":"B22","doi-asserted-by":"publisher","first-page":"710","DOI":"10.5588\/ijtld.22.0006","article-title":"The COVID-19 and TB syndemic: the way forward","volume":"26","author":"Trajman","year":"2022","journal-title":"Int J Tuberc Lung Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"100899","DOI":"10.1016\/S2666-5247(24)00131-9","article-title":"The catalogue of Mycobacterium tuberculosis mutations associated with drug resistance to 12 drugs in China from a nationwide survey: a genomic analysis","volume":"5","author":"Pei","year":"2024","journal-title":"Lancet Microbe."},{"key":"B24","doi-asserted-by":"publisher","first-page":"170","DOI":"10.3760\/cma.j.cn112147-20241016-00615","article-title":"Annual progress of new drugs and new regimens for anti-tuberculosis treatment 2024","volume":"48","author":"Yao","year":"2025","journal-title":"Chin J Tubercul Respir Dis."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.3969\/j.issn.1000-6621.2019.12.007","article-title":"The status and risk factors of drug resistance tuberculosis in Shanghai, 2013-2017","volume":"12","author":"Wang","year":"2019","journal-title":"Chin J Antitubercul"},{"key":"B26","doi-asserted-by":"publisher","first-page":"945","DOI":"10.3760\/cma.j.issn.0254-6450.2016.07.008","article-title":"Analysis on drug resistance of Mycobacterium tuberculosis and influencing factors in six provinces of China","volume":"37","author":"Song","year":"2016","journal-title":"Chin J Epidemiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"685","DOI":"10.19982\/j.issn.1000-6621.20220028","article-title":"Analysis of monitoring results of tuberculosis drug-resistance in Guangdong Province from 2016 to 2020","volume":"44","author":"Chen","year":"2022","journal-title":"Chin J Antitubercul."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e36242","DOI":"10.2196\/36242","article-title":"Unbalanced risk of pulmonary tuberculosis in China at the subnational scale: spatiotemporal analysis","volume":"8","author":"Hu","year":"2022","journal-title":"JMIR Public Health Surveill"},{"key":"B29","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1177\/10105395231169083","article-title":"Characteristics and treatment outcome of culture-positive tuberculosis patients among rural and urban residents in Jiangxi, China: a retrospective cross-sectional study","volume":"35","author":"Zhan","year":"2023","journal-title":"Asia-Pacific J Public Health."},{"key":"B30","doi-asserted-by":"publisher","first-page":"280","DOI":"10.4269\/ajtmh.13-0717","article-title":"Comparing risk factors for primary multidrug-resistant tuberculosis and primary drug-susceptible tuberculosis in Jiangsu province, China: a matched-pairs case-control study","volume":"92","author":"Li","year":"2015","journal-title":"Am J Trop Med Hyg."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3784\/j.issn.1003-9961.2012.8.003","article-title":"Epidemiological characteristics of 2271 cases of pulmonary tuberculosis in floating population of Wenling, Zhejiang","author":"Lin","year":"2012","journal-title":"Dis Surveill"},{"key":"B32","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/s12941-017-0239-4","article-title":"Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes","volume":"16","author":"Xu","year":"2017","journal-title":"Ann Clin Microbiol Antimicrob."},{"key":"B33","doi-asserted-by":"publisher","first-page":"2913","DOI":"10.1128\/JCM.00560-14","article-title":"Diagnostic accuracy of a molecular drug susceptibility testing method for the antituberculosis drug ethambutol: a systematic review and meta-analysis","volume":"52","author":"Cheng","year":"2014","journal-title":"J Clin Microbiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3214","DOI":"10.1093\/jac\/dkv253","article-title":"Mutation profiling for detection of isoniazid resistance in Mycobacterium tuberculosis clinical isolates","volume":"70","author":"Jagielski","year":"2015","journal-title":"J Antimicrob Chemother."},{"key":"B35","doi-asserted-by":"publisher","first-page":"298","DOI":"10.5603\/ARM.34789","article-title":"Identification and analysis of mutations in the katG gene in multidrug-resistant Mycobacterium tuberculosis clinical isolates","volume":"81","author":"Jagielski","year":"2013","journal-title":"Pneumonol Alergol Pol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"398","DOI":"10.4103\/0255-0857.142245","article-title":"Rapid screening of rpoB and katG mutations in Mycobacterium tuberculosis isolates by high-resolution melting curve analysis","volume":"32","author":"Haeili","year":"2014","journal-title":"Indian J Med Microbiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"227","DOI":"10.4103\/lungindia.lungindia_204_19","article-title":"Pattern of InhA and KatG mutations in isoniazid monoresistant Mycobacterium tuberculosis isolates","volume":"37","author":"Charan","year":"2020","journal-title":"Lung India."},{"key":"B38","doi-asserted-by":"publisher","first-page":"392","DOI":"10.7655\/NYDXBNS20230314","article-title":"Study on the correlation between isoniazid-resistant gene mutations of Mycobacterium tuberculosis and the level of drug resistance","volume":"43","author":"Yang","year":"2023","journal-title":"J Nanjing Med Univ."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.19982\/j.issn.1000-6621.20220224","article-title":"Analysis on characteristic of drug resistance-associated gene mutations and the correlation with genotypes among Mycobacterium tuberculosis isolates in Zhejiang Province","volume":"44","author":"Wu","year":"2022","journal-title":"Chin J Antitubercul."},{"key":"B40","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1186\/s12866-016-0786-4","article-title":"Genotypic characterization of drug resistant Mycobacterium tuberculosis in Quebec, 2002-2012","volume":"16","author":"Spinato","year":"2016","journal-title":"BMC Microbiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1442987","DOI":"10.3389\/fpubh.2025.1442987","article-title":"Genetic diversity and transmission pattern of multidrug-resistant tuberculosis based on whole-genome sequencing in Wuhan, China","volume":"13","author":"Wei","year":"2025","journal-title":"Front Public Health."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2853","DOI":"10.3969\/j.issn.1003-6350.2017.17.031","article-title":"Mechanisms of rifampicin resistance in Mycobacterium tuberculosis and research advances","volume":"28","author":"Xiang","year":"2017","journal-title":"Hainan Med J"},{"key":"B43","doi-asserted-by":"publisher","first-page":"99","DOI":"10.4269\/ajtmh.13-0057","article-title":"High prevalence of rifampin-monoresistant tuberculosis: a retrospective analysis among Iranian pulmonary tuberculosis patients","volume":"90","author":"Velayati","year":"2014","journal-title":"Am J Trop Med Hyg."},{"key":"B44","doi-asserted-by":"publisher","first-page":"534","DOI":"10.13604\/j.cnki.46-1064\/r.2018.06.05","article-title":"Mutation characteristics of streptomycin resistance genes in Mycobacterium tuberculosis","volume":"18","author":"Chen","year":"2018","journal-title":"China Trop Med"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1093\/jac\/dkr173","article-title":"Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical and new drugs","volume":"66","author":"Almeida Da Silva","year":"2011","journal-title":"J Antimicrob Chemother."},{"key":"B46","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1016\/j.jiph.2017.04.008","article-title":"Screening mutations in drug-resistant Mycobacterium tuberculosis strains in Yunnan, China","volume":"10","author":"Li","year":"2017","journal-title":"J Infect Public Health."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.3389\/fmicb.2020.01444","article-title":"Genomic analysis identifies mutations concerning drug-resistance and beijing genotype in multidrug-resistant Mycobacterium tuberculosis isolated from China","volume":"11","author":"Wan","year":"2020","journal-title":"Front Microbiol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"725","DOI":"10.13604\/j.cnki.46-1064\/r.2023.07.09","article-title":"Molecular characterization of mutations associated with resistance among 72 multidrug-resistant strains of Mycobacterium tuberculosis by whole genome sequencing","volume":"23","author":"Mu","year":"2023","journal-title":"China Tropical Medicine."},{"key":"B49","doi-asserted-by":"publisher","first-page":"251","DOI":"10.5588\/ijtld.12.0319","article-title":"Molecular characterisation of drug resistance in Mycobacterium tuberculosis isolates from North India","volume":"17","author":"Yadav","year":"2013","journal-title":"Int J Tuberc Lung Dis."},{"key":"B50","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1007\/s11274-013-1256-x","article-title":"Molecular genetics of Mycobacterium tuberculosis resistant to aminoglycosides and cyclic peptide capreomycin antibiotics in Korea","volume":"29","author":"Jnawali","year":"2013","journal-title":"World J Microbiol Biotechnol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"e100078","DOI":"10.1371\/journal.pone.0100078","article-title":"Screening for streptomycin resistance-conferring mutations in Mycobacterium tuberculosis clinical isolates from Poland","volume":"9","author":"Jagielski","year":"2014","journal-title":"PLoS ONE."},{"key":"B52","doi-asserted-by":"publisher","first-page":"2891","DOI":"10.1128\/AAC.00007-10","article-title":"Mycobacterium tuberculosis embB codon 306 mutations confer moderately increased resistance to ethambutol in vitro and in vivo","volume":"55","author":"Plinke","year":"2011","journal-title":"Antimicrob Agents Chemother."},{"key":"B53","doi-asserted-by":"publisher","first-page":"7295","DOI":"10.1128\/AAC.00532-16","article-title":"Association between embB codon 306 mutations, phenotypic resistance profiles, and genotypic characterization in clinical Mycobacterium tuberculosis isolates from Hebei, China","volume":"60","author":"Li","year":"2016","journal-title":"Antimicrob Agents Chemother."},{"key":"B54","doi-asserted-by":"publisher","first-page":"3810","DOI":"10.1128\/JCM.40.10.3810-3813.2002","article-title":"Detection of embB306 mutations in ethambutol-susceptible clinical isolates of Mycobacterium tuberculosis from Northwestern Russia: implications for genotypic resistance testing","volume":"40","author":"Mokrousov","year":"2002","journal-title":"J Clin Microbiol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"4800","DOI":"10.1128\/AAC.00150-15","article-title":"Molecular analysis of the embCAB locus and embR gene involved in ethambutol resistance in clinical isolates of Mycobacterium tuberculosis in France","volume":"59","author":"Brossier","year":"2015","journal-title":"Antimicrob Agents Chemother."},{"key":"B56","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1186\/s12879-020-05479-5","article-title":"Detection of Beijing strains of MDR M. tuberculosis and their association with drug resistance mutations in katG, rpoB, and embB genes","volume":"20","author":"Gupta","year":"2020","journal-title":"BMC Infect Dis."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1128\/JCM.39.4.1591-1594.2001","article-title":"The susceptibility of Mycobacterium tuberculosis to isoniazid and the Arg \u2192 Leu mutation at codon 463 of katG are not associated","volume":"39","author":"van Doorn","year":"2001","journal-title":"J Clin Microbiol."}],"container-title":["Frontiers in Public Health"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2025.1543647\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T05:29:16Z","timestamp":1747978156000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2025.1543647\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,23]]},"references-count":57,"alternative-id":["10.3389\/fpubh.2025.1543647"],"URL":"https:\/\/doi.org\/10.3389\/fpubh.2025.1543647","relation":{},"ISSN":["2296-2565"],"issn-type":[{"value":"2296-2565","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,23]]},"article-number":"1543647"}}