{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:30:54Z","timestamp":1790037054785,"version":"4.0.1"},"reference-count":57,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T00:00:00Z","timestamp":1665532800000},"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>Background<\/jats:title>\n<jats:p>Tuberculosis (TB) remains the leading cause of death among human immunodeficiency virus (HIV) infected individuals in South Africa. Despite the implementation of HIV\/TB integration services at primary healthcare facility level, the effect of HIV on TB treatment outcomes has not been well investigated. To provide evidence base for TB treatment outcome improvement to meet End TB Strategy goal, we assessed the effect of HIV status on treatment outcomes of TB patients at a rural clinic in the Ugu Health District, South Africa.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We reviewed medical records involving a cohort of 508 TB patients registered for treatment between 1 January 2013 and 31 December 2015 at rural public sector clinic in KwaZulu-Natal province, South Africa. Data were extracted from National TB Programme clinic cards and the TB case registers routinely maintained at study sites. The effect of HIV status on TB treatment outcomes was determined by using multinomial logistic regression. Estimates used were relative risk ratio (RRR) at 95% confidence intervals (95%CI).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>A total of 506 patients were included in the analysis. Majority of the patients (88%) were new TB cases, 70% had pulmonary TB and 59% were co-infected with HIV. Most of HIV positive patients were on antiretroviral therapy (ART) (90% (n = 268)). About 82% had successful treatment outcome (cured 39.1% (n = 198) and completed treatment (42.9% (n = 217)), 7% (n = 39) died 0.6% (n = 3) failed treatment, 3.9% (n = 20) defaulted treatment and the rest (6.6% (n = 33)) were transferred out of the facility. Furthermore, HIV positive patients had a higher mortality rate (9.67%) than HIV negative patients (2.91%)\u201d. Using completed treatment as reference, HIV positive patients not on ART relative to negative patients were more likely to have unsuccessful outcomes [RRR, 5.41; 95%CI, 2.11\u201313.86].<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>When compared between HIV status, HIV positive TB patients were more likely to have unsuccessful treatment outcome in rural primary care. Antiretroviral treatment seems to have had no effect on the likelihood of TB treatment success in rural primary care. The TB mortality rate in HIV positive patients, on the other hand, was higher than in HIV negative patients emphasizing the need for enhanced integrated management of HIV\/TB in rural South Africa through active screening of TB among HIV positive individuals and early access to ART among HIV positive TB cases.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0274549","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T17:30:24Z","timestamp":1665595824000},"page":"e0274549","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Effect of HIV status and antiretroviral treatment on treatment outcomes of tuberculosis patients in a rural primary healthcare clinic in South Africa"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2757-0663","authenticated-orcid":true,"given":"Peter S.","family":"Nyasulu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emery","family":"Ngasama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1070-1962","authenticated-orcid":true,"given":"Jacques L.","family":"Tamuzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lovemore N.","family":"Sigwadhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lovelyn U.","family":"Ozougwu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruvimbo B. C.","family":"Nhandara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birhanu T.","family":"Ayele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teye","family":"Umanah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jabulani","family":"Ncayiyana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,10,12]]},"reference":[{"key":"pone.0274549.ref001","unstructured":"World Health Organization. Global tuberculosis report, 2020. https:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/336069\/9789240013131-eng.pdf."},{"key":"pone.0274549.ref002","unstructured":"Department of Health (Republic of South Africa). National Tuberculosis Management Guidelines, 2009. https:\/\/www.tbonline.info\/media\/uploads\/documents\/south_african_national_tuberculosis_management_guidelines_%282009%29.pdf"},{"issue":"4","key":"pone.0274549.ref003","doi-asserted-by":"crossref","first-page":"373","DOI":"10.2174\/156652407780831557","article-title":"Current strategies in TB immunotherapy","volume":"7","author":"E Roy","year":"2007","journal-title":"Curr Mol Med"},{"issue":"6","key":"pone.0274549.ref004","doi-asserted-by":"crossref","first-page":"e0253848","DOI":"10.1371\/journal.pone.0253848","article-title":"Predictors of mortality in patients with drug-resistant tuberculosis: A systematic review and meta-analysis","volume":"16","author":"A Alemu","year":"2021","journal-title":"PLoS One"},{"issue":"1","key":"pone.0274549.ref005","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.4102\/phcfm.v11i1.1831","article-title":"Health system challenges affecting HIV and tuberculosis integration at primary healthcare clinics in Durban, South Africa","volume":"11","author":"D Kalonji","year":"2019","journal-title":"Afr J Prim Health Care Fam Med"},{"key":"pone.0274549.ref006","unstructured":"World Health Organization. HIV-Associated Tuberculosis, 2019. https:\/\/www.who.int\/tb\/areas-of-work\/tb-hiv\/tbhiv_factsheet.pdf?ua=1."},{"issue":"1","key":"pone.0274549.ref007","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s13012-017-0661-1","article-title":"Addressing challenges in scaling up TB and HIV treatment integration in rural primary healthcare clinics in South Africa (SUTHI): a cluster randomized controlled trial protocol","volume":"12","author":"K Naidoo","year":"2017","journal-title":"Implement Sci"},{"issue":"1","key":"pone.0274549.ref008","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12981-016-0106-y","article-title":"Integrated therapy for HIV and tuberculosis","volume":"13","author":"W Manosuthi","year":"2016","journal-title":"AIDS Res Ther"},{"key":"pone.0274549.ref009","first-page":"806","article-title":"Tuberculosis in children dying with HIV-related lung disease: clinical-pathological correlations","volume":"6","author":"WP Rennert","year":"2002","journal-title":"Int J Tuberc Lung Dis"},{"issue":"10","key":"pone.0274549.ref010","doi-asserted-by":"crossref","first-page":"e47542","DOI":"10.1371\/journal.pone.0047542","article-title":"Causes of death on antiretroviral therapy: a post-mortem study from South Africa","volume":"7","author":"EB Wong","year":"2012","journal-title":"PLoS One"},{"issue":"15","key":"pone.0274549.ref011","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1097\/QAD.0000000000000802","article-title":"Prevalence of tuberculosis in post-mortem studies of HIV-infected adults and children in resource-limited settings: a systematic review and meta-analysis","volume":"29","author":"K Gupta Rishi","year":"2015","journal-title":"AIDS (London, England)"},{"issue":"1","key":"pone.0274549.ref012","first-page":"55","article-title":"Pathology and causes of death in a group of 128 predominantly HIV-positive patients in Botswana, 1997\u20131998","volume":"6","author":"NA Ansari","year":"2002","journal-title":"Int J Tuberc Lung Dis"},{"key":"pone.0274549.ref013","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1136\/adc.76.2.124","article-title":"Pulmonary manifestations in HIV seropositivity and malnutrition in Zimbabwe","volume":"76","author":"MO Ikeogu","year":"1997","journal-title":"Arch Dis Child"},{"issue":"1","key":"pone.0274549.ref014","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0035-9203(01)90325-6","article-title":"Fatal Pneumocystis carinii pneumonia in HIV-seropositive infants in Harare, Zimbabwe","volume":"95","author":"KJ Nathoo","year":"2001","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"pone.0274549.ref015","first-page":"1","article-title":"Causes of death in HIV\/AIDS patients in Maputo Central Hospital: a retrospective study from 2011","volume":"61","author":"C Carrilho","year":"2012","journal-title":"Histopathology"},{"issue":"3","key":"pone.0274549.ref016","doi-asserted-by":"crossref","first-page":"e33685","DOI":"10.1371\/journal.pone.0033685","article-title":"An autopsy study describing causes of death and comparing clinico-pathological findings among hospitalized patients in Kampala, Uganda","volume":"7","author":"JA Cox","year":"2012","journal-title":"PLoS One"},{"issue":"2","key":"pone.0274549.ref017","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1179\/027249302125000841","article-title":"The post-mortem pathology of HIV-1-infected African children","volume":"22","author":"R Chakraborty","year":"2002","journal-title":"Ann Trop Paediatr"},{"key":"pone.0274549.ref018","unstructured":"Stats sa. TB tops leading causes of death in SA in 2018. http:\/\/www.statssa.gov.za\/?p=14435."},{"issue":"9","key":"pone.0274549.ref019","doi-asserted-by":"crossref","first-page":"e851","DOI":"10.1016\/S2214-109X(17)30304-2","article-title":"Mortality, and socioeconomic status: the vicious cycle between poverty and ill health","volume":"5","author":"V Pillay-van Wyk","year":"2017","journal-title":"Lancet Glob Health"},{"key":"pone.0274549.ref020","unstructured":"Statistic South Africa. Mid-year population estimates, 2019. https:\/\/www.statssa.gov.za\/publications\/P0302\/P03022019.pdf."},{"issue":"9","key":"pone.0274549.ref021","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/S1473-3099(15)00147-4","article-title":"Nationwide and regional incidence of microbiologically confirmed pulmonary tuberculosis in South Africa, 2004\u201312: a time series analysis","volume":"15","author":"A Nanoo","year":"2015","journal-title":"Lancet Infect Dis"},{"issue":"8","key":"pone.0274549.ref022","first-page":"12370","article-title":"On Behalf of The Desmond Tutu TB Centre-Working Group Data Analysis and Modelling FM. Variation in HIV prevalence and the population-level effects of antiretroviral therapy in reducing tuberculosis incidence in South Africa","volume":"108","author":"R Sloot","journal-title":"S Afr Med J."},{"issue":"1","key":"pone.0274549.ref023","doi-asserted-by":"crossref","first-page":"10724","DOI":"10.1038\/s41598-019-46455-7","article-title":"Space-time clustering of recently diagnosed tuberculosis and impact of ART scale-up: Evidence from an HIV hyper-endemic rural South African population","volume":"9","author":"A Tomita","year":"2019","journal-title":"Sci Rep"},{"key":"pone.0274549.ref024","unstructured":"Health System Trust. Durban. District Health Barometer 2015\/16. https:\/\/www.hst.org.za\/publications\/District%20Health%20Barometers\/District%20Health%20Barometer%202015_16.pdf"},{"key":"pone.0274549.ref025","unstructured":"Health Systems Trust. Tuberculosis, 2015. https:\/\/www.hst.org.za\/publications\/District%20Health%20Barometers\/9%20(Section%20A)%20Tuberculosis.pdf"},{"key":"pone.0274549.ref026","unstructured":"UNAIDS. UNAIDS data 2019. https:\/\/www.unaids.org\/sites\/default\/files\/media_asset\/2019-UNAIDS-data_en.pdf"},{"issue":"1","key":"pone.0274549.ref027","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1097\/QAI.0000000000000684","article-title":"Brief Report: The Effect of Antiretroviral Therapy and CD4 Count on Markers of Infectiousness in HIV-Associated Tuberculosis","volume":"70","author":"CL van Halsema","year":"2015","journal-title":"J Acquir Immune Defic Syndr"},{"issue":"11","key":"pone.0274549.ref028","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.5588\/ijtld.17.0162","article-title":"Does antiretroviral treatment increase the infectiousness of smear-positive pulmonary tuberculosis?","volume":"21","author":"PY Khan","year":"2017","journal-title":"Int J Tuberc Lung Dis"},{"issue":"16","key":"pone.0274549.ref029","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1056\/NEJMoa1014181","article-title":"Integration of antiretroviral therapy with tuberculosis treatment","volume":"365","author":"SS Abdool Karim","year":"2011","journal-title":"N Engl J Med"},{"issue":"16","key":"pone.0274549.ref030","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1056\/NEJMoa1013911","article-title":"Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis","volume":"365","author":"CAMELIA (ANRS 1295\u2013CIPRA KH001) Study Team","year":"2011","journal-title":"N Engl J Med"},{"issue":"16","key":"pone.0274549.ref031","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1056\/NEJMoa1013607","article-title":"AIDS Clinical Trials Group Study A5221. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis","volume":"365","author":"DV Havlir","year":"2011","journal-title":"N Engl J Med"},{"key":"pone.0274549.ref032","unstructured":"World Health Organization. WHO Global Tuberculosis Report\u2014South Africa profile, 2019. file:\/\/\/D:\/Files\/The%20burden%20of%20TB-COVID-19%20in%20Sub-Saharan%20Africa\/2019%20WHO%20Global%20Tuberculosis%20Report%20-%20South%20Africa%20profile.pdf"},{"key":"pone.0274549.ref033","doi-asserted-by":"crossref","unstructured":"Scott V, Sanders D. Evaluation of how integrated HIV and TB programs are implemented in South Africa and the implications for rural-urban equity 2013. http:\/\/repository.uwc.ac.za\/handle\/10566\/1111","DOI":"10.22605\/RRH2165"},{"key":"pone.0274549.ref034","unstructured":"World Health Organization. Global tuberculosis report (executive summary), 2018. https:\/\/www.who.int\/tb\/publications\/global_report\/tb18_ExecSum_web_4Oct18."},{"issue":"2","key":"pone.0274549.ref035","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1128\/CMR.00042-10","article-title":"HIV and tuberculosis: a deadly human syndemic","volume":"24","author":"CK Kwan","year":"2011","journal-title":"Clin MicrobiolRev"},{"key":"pone.0274549.ref036","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1471-2334-10-23","article-title":"The tuberculosis challenge in a rural South African HIV programme","volume":"10","author":"CF Houlihan","year":"2010","journal-title":"BMC Infect Dis"},{"key":"pone.0274549.ref037","unstructured":"Department of Health Province\/KwaZulu Natal. District Health Plan 2015\/2016. UGU KwaZulu-Natal, 2015. http:\/\/www.kznhealth.gov.za\/Strategic\/DHP\/2015-16\/ethekwini.pdf"},{"key":"pone.0274549.ref038","unstructured":"World Health Organization. Treatment of tuberculosis: guidelines, 2010. https:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/44165\/9789241547833_eng.pdf"},{"key":"pone.0274549.ref039","unstructured":"World Health Organization. Global Tuberculosis 2018 report, 2018. https:\/\/www.who.int\/tb\/publications\/global_report\/gtbr2018_main_text_28Feb2019.pdf"},{"key":"pone.0274549.ref040","doi-asserted-by":"crossref","first-page":"206","DOI":"10.11604\/pamj.2019.32.206.18673","article-title":"Effect of HIV infection on TB treatment outcomes and time to mortality in two urban hospitals in Ghana-a retrospective cohort study","volume":"32","author":"L Ogyiri","year":"2019","journal-title":"Pan Afr Med J"},{"issue":"3","key":"pone.0274549.ref041","doi-asserted-by":"crossref","first-page":"e0229875","DOI":"10.1371\/journal.pone.0229875","article-title":"KIULARCO Study Group. Extrapulmonary tuberculosis in HIV-infected patients in rural Tanzania: The prospective Kilombero and Ulanga antiretroviral cohort","volume":"15","author":"A Arpagaus","year":"2020","journal-title":"PloS One"},{"issue":"1","key":"pone.0274549.ref042","doi-asserted-by":"crossref","first-page":"36","DOI":"10.5588\/pha.14.0092","article-title":"Integrating tuberculosis and HIV services in rural Kenya: uptake and outcomes","volume":"5","author":"P Owiti","year":"2015","journal-title":"Public Health Action"},{"issue":"4","key":"pone.0274549.ref043","doi-asserted-by":"crossref","first-page":"849","DOI":"10.4314\/ahs.v14i4.12","article-title":"Mortality associated with tuberculosis\/HIV co-infection among patients on TB treatment in the Limpopo province, South Africa","volume":"14","author":"TE Mabunda","year":"2014","journal-title":"Afr Health Sci"},{"issue":"3","key":"pone.0274549.ref044","doi-asserted-by":"crossref","first-page":"212","DOI":"10.5588\/pha.17.0024","article-title":"Age-stratified tuberculosis treatment outcomes in Zimbabwe: are we paying attention to the most vulnerable?","volume":"7","author":"RT Ncube","year":"2017","journal-title":"Public health action"},{"key":"pone.0274549.ref045","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ijid.2014.11.018","article-title":"Tuberculosis among older adults\u2014time to take notice","volume":"32","author":"J Negin","year":"2015","journal-title":"Int J Infect Dis"},{"key":"pone.0274549.ref046","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1378\/chest.114.5.1244","article-title":"The impact of comorbidity on mortality following in-hospital diagnosis of tuberculosis","volume":"114","author":"VK Rao","year":"1998","journal-title":"Chest"},{"issue":"1","key":"pone.0274549.ref047","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1183\/09031936.00198012","article-title":"Sputum induction to aid diagnosis of smear-negative or sputum-scarce tuberculosis in adults in HIV-endemic settings","volume":"43","author":"JG Peter","year":"2014","journal-title":"Eur Respir J"},{"issue":"10","key":"pone.0274549.ref048","first-page":"1049","article-title":"Tobacco, and tuberculosis: a qualitative systematic review and meta-analysis","volume":"11","author":"K Slama","year":"2007","journal-title":"Int J Tuberc Lung Dis"},{"issue":"9","key":"pone.0274549.ref049","doi-asserted-by":"crossref","first-page":"e0239333","DOI":"10.1371\/journal.pone.0239333","article-title":"Effect of smoking on tuberculosis treatment outcomes: A systematic review and meta-analysis","volume":"15","author":"A Burusie","year":"2020","journal-title":"PLoS One"},{"issue":"1","key":"pone.0274549.ref050","doi-asserted-by":"crossref","first-page":"268","DOI":"10.18632\/oncotarget.13613","article-title":"Impacts of cigarette smoking on immune responsiveness: Up and down or upside down?","volume":"8","author":"F Qiu","year":"2017","journal-title":"Oncotarget"},{"issue":"11","key":"pone.0274549.ref051","first-page":"942","article-title":"Smoking and tuberculosis an association overlooked","volume":"6","author":"V Maurya","year":"2002","journal-title":"The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease"},{"issue":"4","key":"pone.0274549.ref052","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1001\/archinte.167.4.335","article-title":"Risk of tuberculosis from exposure to tobacco smoke: a systematic review and meta-analysis","volume":"167","author":"MN Bates","year":"2007","journal-title":"Archives of internal medicine"},{"issue":"4","key":"pone.0274549.ref053","doi-asserted-by":"crossref","first-page":"347","DOI":"10.4103\/ijmy.ijmy_140_18","article-title":"Associated factors with unsuccessful tuberculosis treatment outcomes among tuberculosis\/HIV coinfected patients with drug-resistant tuberculosis","volume":"7","author":"A Azeez","year":"2018","journal-title":"International Journal of Mycobacteriology"},{"issue":"12","key":"pone.0274549.ref054","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.7196\/SAMJ.2021.v111i12.15822","article-title":"Effect of COVID-19 on HIV, tuberculosis, and prevention of mother-to-child transmission of HIV indicators in Mopani district, South Africa","volume":"111","author":"C Mutyambizi","year":"2021","journal-title":"S Afr Med J"},{"issue":"12","key":"pone.0274549.ref055","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.7196\/SAMJ.2020.v110i12.15126","article-title":"For The National TB Think Tank \u2019Optimising Tb Treatment Outcomes\u2019 Task Team K. Opportunities from a new disease for an old threat: Extending COVID-19 efforts to address tuberculosis in South Africa","volume":"110","author":"M Loveday","year":"2020","journal-title":"S Afr Med J"},{"issue":"8","key":"pone.0274549.ref056","doi-asserted-by":"crossref","first-page":"714","DOI":"10.7196\/SAMJ.2021.v111i8.15786","article-title":"Impact of COVID-19 on routine primary healthcare services in South Africa","volume":"111","author":"Y Pillay","year":"2021","journal-title":"S Afr Med J"},{"key":"pone.0274549.ref057"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0274549","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T17:31:13Z","timestamp":1665595873000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0274549"}},"subtitle":[],"editor":[{"given":"Janet E","family":"Rosenbaum","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,10,12]]},"references-count":57,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10,12]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0274549","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,12]]}}}