{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T07:32:15Z","timestamp":1793345535593,"version":"4.5.0"},"reference-count":60,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"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\"><jats:title>Objectives<\/jats:title><jats:p>The general anesthetic sevoflurane is being repurposed as a topical analgesic for painful chronic wounds. We conducted a Bayesian cost-effectiveness analysis (CEA) comparing the addition of domiciliary topical sevoflurane to conventional analgesics (SEVOFLURANE, n = 38) versus conventional analgesics alone (CONVENTIONAL, n = 26) for the treatment of nonrevascularizable painful leg ulcers in an outpatient Pain Clinic of a Spanish tertiary hospital.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>We used real-world data collected from charts to conduct this CEA from a public healthcare perspective and with a one-year time horizon. Costs of analgesics, visits and admissions were considered, expressed in \u20ac2016. Analgesic effectiveness was measured with SPID (Sum of Pain Intensity Difference). A Bayesian regression model was constructed, including \u201ctreatment\u201d and baseline characteristics for patients (\u201carterial hypertension\u201d) and ulcers (\u201cduration\u201d, \u201cnumber\u201d, \u201cdepth\u201d, \u201cpain\u201d) as covariates. The findings were summarized as a cost-effectiveness plane and a cost-effectiveness acceptability curve. One-way sensitivity analyses, a re-analysis excluding those patients who died or suffered from leg amputation, and an extreme scenario analysis were conducted to reduce uncertainty.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p>Compared to CONVENTIONAL, SEVOFLURANE was associated with a 46% reduction in costs, and the mean incremental effectiveness (28.15\u00b13.70 effectiveness units) was favorable to SEVOFLURANE. The estimated probability for SEVOFLURANE being dominant was 99%. The regression model showed that costs were barely influenced by any covariate, whereas effectiveness was noticeably influenced by \u201ctreatment\u201d. All sensitivity analyses showed the robustness of the model, even in the extreme scenario analysis against SEVOFLURANE.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Conclusions<\/jats:title><jats:p>SEVOFLURANE was dominant over CONVENTIONAL as it was less expensive and much more effective.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0257494","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T17:59:33Z","timestamp":1632160773000},"page":"e0257494","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cost-effectiveness analysis of domiciliary topical sevoflurane for painful leg ulcers"],"prefix":"10.1371","volume":"16","author":[{"given":"Carmen","family":"Selva-Sevilla","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. D\u00e1maso","family":"Fern\u00e1ndez-Gin\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Corti\u00f1as-S\u00e1enz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9911-7572","authenticated-orcid":true,"given":"Manuel","family":"Ger\u00f3nimo-Pardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,9,20]]},"reference":[{"key":"pone.0257494.ref001","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.annepidem.2018.10.005","article-title":"Prevalence of chronic wounds in the general population: systematic review and meta-analysis of observational studies","volume":"29","author":"L Martinengo","year":"2019","journal-title":"Ann Epidemiol"},{"key":"pone.0257494.ref002","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.12968\/jowc.2017.26.Sup4.S4","article-title":"Cost-of-illness studies in chronic ulcers: a systematic review","volume":"26","author":"B Chan","year":"2017","journal-title":"J Wound Care"},{"key":"pone.0257494.ref003","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1111\/wrr.12683","article-title":"The humanistic and economic burden of chronic wounds: A systematic review","volume":"27","author":"M Olsson","year":"2019","journal-title":"Wound Repair Regen"},{"key":"pone.0257494.ref004","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jval.2017.07.007","article-title":"An economic evaluation of the impact, cost, and medicare policy implications of chronic nonhealing wounds","volume":"21","author":"SR Nussbaum","year":"2018","journal-title":"Value Health"},{"key":"pone.0257494.ref005","doi-asserted-by":"crossref","first-page":"601","DOI":"10.12968\/jowc.2014.23.12.601","article-title":"The impact of chronic venous leg ulcers: a systematic review","volume":"23","author":"J Green","year":"2014","journal-title":"J Wound Care"},{"key":"pone.0257494.ref006","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1136\/bmjspcare-2017-001359","article-title":"Systematic review of pharmacological therapies for the management of ischaemic pain in patients with non-reconstructable critical limb ischaemia","volume":"8","author":"\u00c1N Laoire","year":"2018","journal-title":"BMJ Support Palliat Care"},{"key":"pone.0257494.ref007","first-page":"423","article-title":"Identifying and prioritising adverse episodes and failures related to patient safety in Pain Treatment Units [in Spanish].","volume":"59","author":"JJ P\u00e9rez L\u00e1zaro","year":"2012","journal-title":"Rev Esp Anestesiol Reanim."},{"key":"pone.0257494.ref008","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.mayocp.2012.11.015","article-title":"Topical Analgesics in the Management of Acute and Chronic Pain","volume":"88","author":"CE Argoff","year":"2013","journal-title":"Mayo Clin Proc"},{"key":"pone.0257494.ref009","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1055\/s-0037-1621757","article-title":"Analgesic effect of topical sevoflurane on venous leg ulcer with intractable pain","volume":"40","author":"M Ger\u00f3nimo-Pardo","year":"2011","journal-title":"Phlebologie"},{"key":"pone.0257494.ref010","first-page":"46","article-title":"Analgesic effect of topical sevoflurane on ischaemic wound in a patient with ischaemic cardiopathy and respiratory failure secondary to morphine [in Spanish]","volume":"6","author":"A Mart\u00ednez-Monsalve","year":"2011","journal-title":"Heridas y Cicatrizaci\u00f3n"},{"key":"pone.0257494.ref011","first-page":"16","article-title":"The analgesic effect of topical sevoflurane on painful varicose ulcers in ambulatory patients [in Spanish]","volume":"1","author":"A Mart\u00ednez-Monsalve","year":"2013","journal-title":"Heridas y Cicatrizaci\u00f3n"},{"key":"pone.0257494.ref012","doi-asserted-by":"crossref","first-page":"e176","DOI":"10.2146\/ajhp151008","article-title":"Efficacy and safety of topical sevoflurane in the treatment of chronic skin ulcers","volume":"74","author":"F D\u00e1maso Fern\u00e1ndez-Gin\u00e9s","year":"2017","journal-title":"Am J Heal Pharm"},{"key":"pone.0257494.ref013","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ejvssr.2017.08.001","article-title":"Pain, quality of life, and functional capacity with topical sevoflurane application for chronic venous ulcers: a retrospective clinical study","volume":"36","author":"A Imbernon-Moya","year":"2017","journal-title":"EJVES Short Reports"},{"key":"pone.0257494.ref014","first-page":"138","article-title":"Topical sevoflurane for rescue analgesia in refractory pain due to chronic venous ulcers [in Spanish]","volume":"30","author":"P Amores Valenciano","year":"2018","journal-title":"Emergencias"},{"key":"pone.0257494.ref015","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1016\/j.jvs.2018.08.175","article-title":"Analgesic effectiveness of topical sevoflurane to perform sharp debridement of painful wounds","volume":"69","author":"A Mart\u00ednez-Monsalve","year":"2019","journal-title":"J Vasc Surg"},{"key":"pone.0257494.ref016","article-title":"Sevoflurane topical analgesia for intractable pain with suicidal ideation","author":"FD Fern\u00e1ndez-Gin\u00e9s","year":"2020","journal-title":"BMJ Support Palliat Care"},{"key":"pone.0257494.ref017","first-page":"141","article-title":"Topical sevoflurane as rescue therapy in a frail patient suffering from leg ulcers causing refractory pain and superinfected by methicillin-resistant Staphylococcus aureus and sensitive Pseudomonas aeruginosa. A case report [in Spanish]","volume":"27","author":"J Pinar S\u00e1nchez","year":"2020","journal-title":"Med Paliativa"},{"key":"pone.0257494.ref018","first-page":"45","article-title":"Efects of topical sevoflurane in the treatment of vascular ulcers. Report of a clinical case [in Spanish].","volume":"4","author":"GA Navarro-Buend\u00eda","year":"2020","journal-title":"Hosp a Domic"},{"key":"pone.0257494.ref019","first-page":"253","article-title":"Painful diabetic foot ulcer amputation avoided thanks to topical sevoflurane [in Spanish]","volume":"26","author":"M Padilla del Rey","year":"2019","journal-title":"Rev Soc Esp Dolor"},{"key":"pone.0257494.ref020","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1136\/ejhpharm-2017-001421","article-title":"Palliative analgesia with topical sevoflurane in cancer-related skin ulcers: a case report","volume":"26","author":"FD Fern\u00e1ndez-Gin\u00e9s","year":"2019","journal-title":"Eur J Hosp Pharm"},{"key":"pone.0257494.ref021","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/iwj.13235","article-title":"Pain reduction of topical sevoflurane vs intravenous opioids in pressure ulcers","volume":"17","author":"FD Fern\u00e1ndez\u2010Gin\u00e9s","year":"2020","journal-title":"Int Wound J"},{"key":"pone.0257494.ref022","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s12916-015-0326-3","article-title":"A systematic review of cost-effectiveness analyses of complex wound interventions reveals optimal treatments for specific wound types","volume":"13","author":"AC Tricco","year":"2015","journal-title":"BMC Med"},{"key":"pone.0257494.ref023","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/s40258-014-0094-9","article-title":"Economic evaluations of guideline-based or strategic interventions for the prevention or treatment of chronic wounds","volume":"12","author":"MJ Carter","year":"2014","journal-title":"Appl Health Econ Health Policy"},{"key":"pone.0257494.ref024","doi-asserted-by":"crossref","first-page":"348","DOI":"10.12968\/jowc.2006.15.8.26942","article-title":"A cost-effectiveness analysis of two community models of care for patients with venous leg ulcers","volume":"15","author":"L Gordon","year":"2006","journal-title":"J Wound Care"},{"key":"pone.0257494.ref025","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1097\/00003643-199805000-00009","article-title":"Pharmaco-economic evaluation of a disposable patient-controlled analgesia device and intramuscular analgesia in surgical patients","volume":"15","author":"Vanlersberghe D\u2019Haese","year":"1998","journal-title":"Eur J Anaesthesiol"},{"key":"pone.0257494.ref026","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1002\/pds.3945","article-title":"A synthesis of oral morphine equivalents (OME) for opioid utilisation studies","volume":"25","author":"S Nielsen","year":"2016","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"pone.0257494.ref027","unstructured":"Instituto Nacional de Estad\u00edstica. [cited 2 Jun 2019]. Available: https:\/\/www.ine.es\/jaxiT3\/Tabla.htm?t=22350"},{"key":"pone.0257494.ref028","unstructured":"Servicio Andaluz de Salud: Retribuciones del personal de Centros e Instituciones Sanitarias. Ejercicio 2012. [cited 2 Jun 2019]. Available: https:\/\/www.sspa.juntadeandalucia.es\/servicioandaluzdesalud\/sites\/default\/files\/sincfiles\/wsas-media-sas_normativa_mediafile\/2019\/Resoluci\u00f3n00022012.pdf"},{"key":"pone.0257494.ref029","unstructured":"Servicio Andaluz de Salud: Retribuciones del personal de Centros e Instituciones Sanitarias. Ejercicio 2015. [cited 2 Jun 2019]. Available: https:\/\/www.sspa.juntadeandalucia.es\/servicioandaluzdesalud\/sites\/default\/files\/sincfiles\/wsas-media-sas_normativa_mediafile\/2019\/ResolucionSSA_00182015.pdf"},{"key":"pone.0257494.ref030","unstructured":"Servicio Andaluz de Salud: Retribuciones del personal de Centros e Instituciones Sanitarias. Ejercicio 2016. [cited 2 Jun 2019]. Available: https:\/\/www.sspa.juntadeandalucia.es\/servicioandaluzdesalud\/sites\/default\/files\/sincfiles\/wsas-media-sas_normativa_mediafile\/2019\/20160418_Resolucion_0136_2016.pdf"},{"key":"pone.0257494.ref031","unstructured":"Servicio Andaluz de Salud: Retribuciones del personal de Centros e Instituciones Sanitarias. Ejercicio 2017. [cited 2 Jun 2019]. Available: https:\/\/www.sspa.juntadeandalucia.es\/servicioandaluzdesalud\/sites\/default\/files\/sincfiles\/wsas-media-sas_normativa_mediafile\/2019\/R_0193_2017.pdf"},{"key":"pone.0257494.ref032","unstructured":"Knowledge Health Bot PLUS. [cited 2 Jun 2019]. Available: https:\/\/botplusweb.portalfarma.com\/"},{"key":"pone.0257494.ref033","unstructured":"Bolet\u00edn Oficial de la Junta de Andaluc\u00eda. [cited 1 Dec 2019]. Available: https:\/\/www.juntadeandalucia.es\/boja\/2005\/210\/28"},{"key":"pone.0257494.ref034","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/(SICI)1099-1050(199905)8:3<257::AID-HEC427>3.0.CO;2-E","article-title":"A Bayesian approach to stochastic cost-effectiveness analysis","volume":"8","author":"AH Briggs","year":"1999","journal-title":"Health Econ"},{"key":"pone.0257494.ref035","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/(SICI)1099-1050(199905)8:3<191::AID-HEC409>3.0.CO;2-R","article-title":"Bayesian estimation of cost-effectiveness ratios from clinical trials","volume":"8","author":"DF Heitjan","year":"1999","journal-title":"Health Econ"},{"key":"pone.0257494.ref036","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1002\/sim.861","article-title":"Bayesian cost-effectiveness analysis from clinical trial data","volume":"20","author":"A O\u2019Hagan","year":"2001","journal-title":"Stat Med"},{"key":"pone.0257494.ref037","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1471-2288-2-5","article-title":"The probability of cost-effectiveness","volume":"2","author":"A O\u2019Hagan","year":"2002","journal-title":"BMC Med Res Methodol"},{"key":"pone.0257494.ref038","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1002\/hec.617","article-title":"A framework for cost-effectiveness analysis from clinical trial data","volume":"10","author":"A O\u2019Hagan","year":"2001","journal-title":"Health Econ"},{"key":"pone.0257494.ref039","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1111\/j.1524-4733.2009.00605.x","article-title":"The ISPOR good practices for quality improvement of cost-effectiveness research Task Force Report","volume":"12","author":"WF McGhan","year":"2009","journal-title":"Value Health"},{"key":"pone.0257494.ref040","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.jval.2013.02.002","article-title":"Consolidated Health Economic Evaluation Reporting Standards (CHEERS)\u2014explanation and elaboration: A report of the ISPOR Health Economic Evaluation Publication Guidelines Good Reporting Practices Task Force.","volume":"16","author":"D Husereau","year":"2013","journal-title":"Value Health"},{"key":"pone.0257494.ref041","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1111\/j.1524-4733.2009.00600.x","article-title":"Good research practices for comparative effectiveness research: defining, reporting and interpreting nonrandomized studies of treatment effects using secondary data sources: the ISPOR good research practices for retrospective database analysis task force","volume":"12","author":"ML Berger","year":"2009","journal-title":"Value Health"},{"key":"pone.0257494.ref042","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/j.jval.2017.08.3019","article-title":"Good practices for real-world data studies of treatment and\/or comparative effectiveness: Recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in health care decision making","volume":"20","author":"ML Berger","year":"2017","journal-title":"Value Health"},{"key":"pone.0257494.ref043","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.jclinepi.2007.11.008","article-title":"The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies","volume":"61","author":"E von Elm","year":"2008","journal-title":"J Clin Epidemiol"},{"key":"pone.0257494.ref044","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/hec.678","article-title":"Something old, something new, something borrowed, something blue: a framework for the marriage of health econometrics and cost-effectiveness analysis","volume":"11","author":"JS Hoch","year":"2002","journal-title":"Health Econ"},{"key":"pone.0257494.ref045","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1002\/hec.843","article-title":"Regression methods for covariate adjustment and subgroup analysis for non-censored cost-effectiveness data","volume":"13","author":"AR Willan","year":"2004","journal-title":"Health Econ"},{"key":"pone.0257494.ref046","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1002\/hec.1008","article-title":"Methods for incorporating covariate adjustment, subgroup analysis and between-centre differences into cost-effectiveness evaluations","volume":"14","author":"RM Nixon","year":"2005","journal-title":"Health Econ"},{"key":"pone.0257494.ref047","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1002\/hec.914","article-title":"Assessing generalisability by location in trial-based cost-effectiveness analysis: the use of multilevel models","volume":"14","author":"A Manca","year":"2005","journal-title":"Health Econ"},{"key":"pone.0257494.ref048","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s10198-004-0256-z","article-title":"Bayesian regression models for cost-effectiveness analysis","volume":"6","author":"FJ V\u00e1zquez-Polo","year":"2005","journal-title":"Eur J Health Econ"},{"key":"pone.0257494.ref049","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1002\/hec.947","article-title":"Using covariates to reduce uncertainty in the economic evaluation of clinical trial data","volume":"14","author":"FJ V\u00e1zquez-Polo","year":"2005","journal-title":"Health Econ"},{"key":"pone.0257494.ref050","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1016\/j.jhealeco.2008.03.005","article-title":"Incorporating model uncertainty in cost-effectiveness analysis: A Bayesian model averaging approach","volume":"27","author":"MA Negr\u00edn","year":"2008","journal-title":"J Health Econ"},{"key":"pone.0257494.ref051","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.3390\/ijerph7041577","article-title":"Bayesian variable selection in cost-effectiveness analysis","volume":"7","author":"MA Negr\u00edn","year":"2010","journal-title":"Int J Environ Res Public Health"},{"key":"pone.0257494.ref052","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1002\/hec.2806","article-title":"Statistical methods for cost-effectiveness analyses that use observational data: A critical appraisal tool and review of current practice","volume":"22","author":"N Kreif","year":"2013","journal-title":"Health Econ (United Kingdom)"},{"key":"pone.0257494.ref053","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1109\/TPAMI.1984.4767596","article-title":"Stochastic relaxation, Gibbs distributions, and the Bayesian restoration of images","volume":"6","author":"S Geman","year":"1984","journal-title":"IEEE Trans Pattern Anal Mach Intell"},{"key":"pone.0257494.ref054","volume-title":"Markov Chain Monte Carlo in practice","author":"W Gilks","year":"1996"},{"key":"pone.0257494.ref055","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/j.1742-481X.2010.00660.x","article-title":"Cost-of-illness of chronic leg ulcers in Germany","volume":"7","author":"S Purwins","year":"2010","journal-title":"Int Wound J"},{"key":"pone.0257494.ref056","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.jvs.2012.02.069","article-title":"Cost-effectiveness in the contemporary management of critical limb ischemia with tissue loss","volume":"56","author":"NR Barshes","year":"2012","journal-title":"J Vasc Surg"},{"key":"pone.0257494.ref057","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1111\/j.1524-4733.2007.00186.x","article-title":"Using real-world data for coverage and payment decisions: The ISPOR Real-World Data Task Force Report","volume":"10","author":"LP Garrison","year":"2007","journal-title":"Value Health"},{"key":"pone.0257494.ref058","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1089\/wound.2018.0817","article-title":"Health economics and outcomes research of wound care: overview of methodology","volume":"7","author":"AM Gilligan","year":"2018","journal-title":"Adv Wound Care"},{"key":"pone.0257494.ref059","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780198526629.001.0001","volume-title":"Decision modelling for health economic evaluation","author":"AH Briggs","year":"2006"},{"key":"pone.0257494.ref060","first-page":"3","article-title":"Handling uncertainty when performing economic evaluation of healthcare interventions","author":"AH Briggs","year":"1999","journal-title":"Health Technol Assess (Rockv)"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0257494","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T02:27:35Z","timestamp":1699496855000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0257494"}},"subtitle":[],"editor":[{"given":"Carlos Alberto","family":"Z\u00faniga-Gonz\u00e1lez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,9,20]]},"references-count":60,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0257494","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,20]]}}}