{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T18:07:48Z","timestamp":1788890868475,"version":"build-2803163510"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["INV-001822"],"award-info":[{"award-number":["INV-001822"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Long-term opioid use is common in critically ill children and can cause withdrawal symptoms at discontinuation. To avoid withdrawal, short-acting opioids are usually converted into a long-acting drug, such as methadone, which is then carefully tapered. However, the exact conversion ratio and the optimal tapering protocol are unknown. This study aimed to design optimized conversion and tapering schedules of morphine and fentanyl to methadone for pediatric intensive care unit patients using physiologically-based pharmacokinetic (PBPK) modeling and expert panel decision-making. PBPK models of fentanyl, morphine, and methadone were verified with published pharmacokinetic data and opioid conversion ratios and relevant tapering protocols identified through literature review. Then, plasma concentration-time curves of opioid infusions (1 \u00b5g\/kg\/h fentanyl, 10 \u00b5g\/kg\/h morphine), several opioid-methadone conversion ratios, and different methadone tapering protocols were simulated. Predicted methadone plasma concentrations were compared to minimal therapeutic concentrations (i.e., 1 ng\/mL for fentanyl, 4 ng\/mL for morphine, and 60 ng\/mL for methadone). These simulations were reviewed by the expert panel consisting of pediatric intensivists and hospital pharmacists to establish recommendations. Simulations showed that a conversion ratio of 1:10 for fentanyl and 1:1 for morphine resulted in therapeutic methadone concentrations. Most previously established tapering recommendations resulted in equal maximum methadone concentrations, except for the low-risk tapering schedules of two of the three protocols. The robustness of these findings is reinforced by both a target attainment analysis and a sensitivity analysis employing the therapeutic target of methadone. The panel established consensus-based Dutch recommendations for conversion and tapering. These findings demonstrate that PBPK models can support dosing decisions by simulating clinical scenarios. The resulting recommendations have been implemented in the Dutch Pediatric Formulary, ensuring that the model-informed recommendations are directly applied in clinical practice.<\/jats:p>","DOI":"10.1371\/journal.pone.0356917","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:24:36Z","timestamp":1788888276000},"page":"e0356917","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Supporting clinical guidelines for opioid conversion to methadone and tapering to prevent withdrawal in critically ill children using physiology based pharmacokinetic modeling and simulation"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1923-2111","authenticated-orcid":true,"given":"Marika A.","family":"de Hoop-Sommen","sequence":"first","affiliation":[{"name":"Pharmacology and Toxicology, Radboud university medical center","place":["Nijmegen, The Netherlands"],"department":["Department of Pharmacy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0732-7012","authenticated-orcid":true,"given":"Sahar","family":"Alozai","sequence":"additional","affiliation":[{"name":"Royal Dutch Pharmacy Association (KNMP), Medicines Information Centre (GIC)","place":["The Hague, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3144-9359","authenticated-orcid":true,"given":"Violette M. G. J.","family":"Gijsen","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology, Radboud university medical center","place":["Nijmegen, The Netherlands"],"department":["Department of Pharmacy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tjitske M.","family":"van der Zanden","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology, Radboud university medical center","place":["Nijmegen, The Netherlands"],"department":["Department of Pharmacy"]},{"name":"Dutch Knowledge Centre Pharmacotherapy for Children","place":["Rotterdam, The Netherlands"]},{"name":"Erasmus MC-Sophia Children\u2019s Hospital","place":["Rotterdam, The Netherlands"],"department":["Department of Neonatal and Pediatric Intensive Care, Division of Pediatric Intensive care"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry T.","family":"Akinbi","sequence":"additional","affiliation":[{"name":"Perinatal Institute, Cincinnati Children's Hospital Medical Center","place":["Cincinnati, Ohio, United States of America"],"department":["Division of Neonatology"]},{"name":"University of Cincinnati College of Medicine","place":["Cincinnati, Ohio, United States of America"],"department":["Department of Pediatrics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Mizuno","sequence":"additional","affiliation":[{"name":"University of Cincinnati College of Medicine","place":["Cincinnati, Ohio, United States of America"],"department":["Department of Pediatrics"]},{"name":"Cincinnati Children's Hospital Medical Center","place":["Cincinnati, Ohio, United States of America"],"department":["Division of Translational and Clinical Pharmacology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A.","family":"Vinks","sequence":"additional","affiliation":[{"name":"University of Cincinnati College of Medicine","place":["Cincinnati, Ohio, United States of America"],"department":["Department of Pediatrics"]},{"name":"Cincinnati Children's Hospital Medical Center","place":["Cincinnati, Ohio, United States of America"],"department":["Division of Translational and Clinical Pharmacology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick","family":"Greupink","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology, Radboud university medical center","place":["Nijmegen, The Netherlands"],"department":["Department of Pharmacy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0502-0647","authenticated-orcid":true,"given":"Saskia N.","family":"de Wildt","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology, Radboud university medical center","place":["Nijmegen, The Netherlands"],"department":["Department of Pharmacy"]},{"name":"Dutch Knowledge Centre Pharmacotherapy for Children","place":["Rotterdam, The Netherlands"]},{"name":"Erasmus MC-Sophia Children\u2019s Hospital","place":["Rotterdam, The Netherlands"],"department":["Department of Neonatal and Pediatric Intensive Care, Division of Pediatric Intensive care"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"issue":"3","key":"pone.0356917.ref001","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1111\/pan.13056","article-title":"The use of methadone to facilitate opioid weaning in pediatric critical care patients: a systematic review of the literature and meta-analysis","volume":"27","author":"LA Dervan","year":"2017","journal-title":"Paediatr Anaesth"},{"issue":"11","key":"pone.0356917.ref002","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1542\/hpeds.2021-006306","article-title":"Implementation of an opioid weaning protocol at a tertiary care children\u2019s hospital","volume":"12","author":"J Ford","year":"2022","journal-title":"Hosp Pediatr"},{"issue":"1","key":"pone.0356917.ref003","first-page":"42","article-title":"Exposure-based methadone and lorazepam weaning protocol reduces wean length in children","volume":"26","author":"AK Wilson","year":"2021","journal-title":"J Pediatr Pharmacol Ther"},{"issue":"3","key":"pone.0356917.ref004","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1177\/0897190019875613","article-title":"Iatrogenic opiate withdrawal in pediatric patients: implementation of a standardized methadone weaning protocol and withdrawal assessment tool","volume":"34","author":"RA Walters","year":"2021","journal-title":"J Pharm Pract"},{"key":"pone.0356917.ref005","doi-asserted-by":"crossref","first-page":"592204","DOI":"10.3389\/fphar.2020.592204","article-title":"A new framework to implement model-informed dosing in clinical guidelines: piperacillin and amikacin as proof of concept","volume":"11","author":"SJF Hartman","year":"2020","journal-title":"Front Pharmacol"},{"issue":"3","key":"pone.0356917.ref006","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1002\/cpt.3510","article-title":"Barriers and facilitators for bringing model-informed precision dosing to the patient\u2019s bedside: a systematic review","volume":"117","author":"AC Dibbets","year":"2025","journal-title":"Clin Pharmacol Ther"},{"issue":"5","key":"pone.0356917.ref007","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1002\/cpt.3023","article-title":"Physiologically-based pharmacokinetic modeling for drug dosing in pediatric patients: a tutorial for a pragmatic approach in clinical care","volume":"114","author":"JEM van der Heijden","year":"2023","journal-title":"Clin Pharmacol Ther"},{"key":"pone.0356917.ref008","doi-asserted-by":"crossref","first-page":"1288376","DOI":"10.3389\/fped.2023.1288376","article-title":"Pragmatic physiologically-based pharmacokinetic modeling to support clinical implementation of optimized gentamicin dosing in term neonates and infants: proof-of-concept","volume":"11","author":"MA de Hoop-Sommen","year":"2023","journal-title":"Front Pediatr"},{"key":"pone.0356917.ref009","unstructured":"Erasmus MC. Sedativa\/opiaten, afbouwen bij kinderen. 2016."},{"issue":"9","key":"pone.0356917.ref010","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1046\/j.1460-9592.2003.01153.x","article-title":"Methadone dosage for prevention of opioid withdrawal in children","volume":"13","author":"R Siddappa","year":"2003","journal-title":"Paediatr Anaesth"},{"issue":"2","key":"pone.0356917.ref011","doi-asserted-by":"crossref","first-page":"110","DOI":"10.5409\/wjcp.v6.i2.110","article-title":"Conversion from prolonged intravenous fentanyl infusion to enteral methadone in critically ill children","volume":"6","author":"V Srinivasan","year":"2017","journal-title":"World J Clin Pediatr"},{"issue":"5","key":"pone.0356917.ref012","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1177\/088506669601100504","article-title":"Outpatient therapy of iatrogenic drug dependency following prolonged sedation in the pediatric intensive care unit","volume":"11","author":"JD Tobias","year":"1996","journal-title":"Intensive Care Med"},{"issue":"6","key":"pone.0356917.ref013","doi-asserted-by":"crossref","first-page":"451","DOI":"10.5005\/jp-journals-10071-23465","article-title":"Protocolized sedative weaning vs usual care in pediatric critically Ill patients: a pilot randomized controlled trial","volume":"24","author":"D Tiacharoen","year":"2020","journal-title":"Indian J Crit Care Med"},{"issue":"9","key":"pone.0356917.ref014","doi-asserted-by":"crossref","DOI":"10.1097\/PCC.0000000000002492","article-title":"Methadone\u2019s effect on cardiac repolarization: safety in the PICU","volume":"21","author":"SD Friedman","year":"2020","journal-title":"Pediatr Crit Care Med"},{"issue":"2","key":"pone.0356917.ref015","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1097\/00130478-200010000-00005","article-title":"Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients","volume":"1","author":"RC Robertson","year":"2000","journal-title":"Pediatr Crit Care Med"},{"key":"pone.0356917.ref016","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.pedn.2019.08.001","article-title":"Effect of a sedation weaning protocol on safety and medication use among hospitalized children post critical illness","volume":"49","author":"JC Solodiuk","year":"2019","journal-title":"J Pediatr Nurs"},{"issue":"4","key":"pone.0356917.ref017","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1001\/jama.2014.18399","article-title":"Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: a randomized clinical trial","volume":"313","author":"MAQ Curley","year":"2015","journal-title":"JAMA"},{"issue":"1","key":"pone.0356917.ref018","first-page":"54","article-title":"Impact of a standardized treatment guideline for pediatric iatrogenic opioid dependence: a quality improvement initiative","volume":"21","author":"R Abdouni","year":"2016","journal-title":"J Pediatr Pharmacol Ther"},{"issue":"2","key":"pone.0356917.ref019","doi-asserted-by":"crossref","first-page":"123","DOI":"10.5055\/jom.2016.0324","article-title":"Methadone conversion in infants and children: retrospective cohort study of 199 pediatric inpatients","volume":"12","author":"A Fife","year":"2016","journal-title":"J Opioid Manag"},{"issue":"1","key":"pone.0356917.ref020","doi-asserted-by":"crossref","first-page":"12","DOI":"10.4212\/cjhp.v65i1.1098","article-title":"Use of methadone for prevention of opioid withdrawal in critically ill children","volume":"65","author":"SA Jeffries","year":"2012","journal-title":"Can J Hosp Pharm"},{"issue":"5","key":"pone.0356917.ref021","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1097\/PCC.0b013e3181fe38f5","article-title":"A trial of methadone tapering schedules in pediatric intensive care unit patients exposed to prolonged sedative infusions","volume":"12","author":"CD Bowens","year":"2011","journal-title":"Pediatr Crit Care Med"},{"issue":"4","key":"pone.0356917.ref022","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1097\/00130478-200110000-00009","article-title":"Efficacy of an enteral 10-day methadone wean to prevent opioid withdrawal in fentanyl-tolerant pediatric intensive care unit patients","volume":"2","author":"MM Meyer","year":"2001","journal-title":"Pediatr Crit Care Med"},{"issue":"7","key":"pone.0356917.ref023","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1007\/BF01711905","article-title":"Outpatient therapy of iatrogenic drug dependency following prolonged sedation in the pediatric intensive care unit","volume":"20","author":"JD Tobias","year":"1994","journal-title":"Intensive Care Med"},{"issue":"10","key":"pone.0356917.ref024","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1007\/s40262-016-0398-z","article-title":"Pharmacodynamic analysis of morphine time-to-remedication events in infants and young children after congenital heart surgery","volume":"55","author":"MH Elkomy","year":"2016","journal-title":"Clin Pharmacokinet"},{"issue":"4","key":"pone.0356917.ref025","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1002\/phar.2515","article-title":"Analysis of fentanyl pharmacokinetics, and its sedative effects and tolerance in critically ill children","volume":"41","author":"SY Lim","year":"2021","journal-title":"Pharmacotherapy"},{"issue":"6","key":"pone.0356917.ref026","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/S0022-3476(76)81074-8","article-title":"Pharmacologic observations on the neonatal withdrawal syndrome","volume":"88","author":"TS Rosen","year":"1976","journal-title":"J Pediatr"},{"issue":"1","key":"pone.0356917.ref027","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1097\/00000542-198407000-00005","article-title":"Postoperative pain control with methadone: influence of supplementary methadone doses and blood concentration--response relationships","volume":"61","author":"GK Gourlay","year":"1984","journal-title":"Anesthesiology"},{"issue":"6","key":"pone.0356917.ref028","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s40262-014-0135-4","article-title":"Evidence-based morphine dosing for postoperative neonates and infants","volume":"53","author":"EHJ Krekels","year":"2014","journal-title":"Clin Pharmacokinet"},{"key":"pone.0356917.ref029","unstructured":"Dutch Knowledge Centre Pharmacotherapy for Children. Pediatric formularies. http:\/\/www.kinderformularium.nl\/internationaal"},{"issue":"10","key":"pone.0356917.ref030","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1007\/s40263-019-00660-0","article-title":"Opioid-induced tolerance and hyperalgesia","volume":"33","author":"S Mercadante","year":"2019","journal-title":"CNS Drugs"},{"issue":"5","key":"pone.0356917.ref031","doi-asserted-by":"crossref","DOI":"10.1136\/archdischild-2012-301728.2","article-title":"Methadone toxicity in children","volume":"97","author":"N Alotaibi","year":"2012","journal-title":"Arch Dis Child"},{"issue":"5","key":"pone.0356917.ref032","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3941\/jrcr.v13i5.3658","article-title":"Methadone-induced toxic encephalopathy in pediatric patients: two case reports","volume":"13","author":"SC Tiong","year":"2019","journal-title":"J Radiol Case Rep"},{"issue":"2","key":"pone.0356917.ref033","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1213\/ANE.0000000000005366","article-title":"A novel perioperative multidose methadone-based multimodal analgesic strategy in children achieved safe and low analgesic blood methadone levels enabling opioid-sparing sustained analgesia with minimal adverse effects","volume":"133","author":"S Sadhasivam","year":"2021","journal-title":"Anesth Analg"},{"issue":"4","key":"pone.0356917.ref034","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/clpt.1987.47","article-title":"Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain","volume":"41","author":"CE Inturrisi","year":"1987","journal-title":"Clin Pharmacol Ther"},{"issue":"5","key":"pone.0356917.ref035","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/clpt.1990.77","article-title":"Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain","volume":"47","author":"CE Inturrisi","year":"1990","journal-title":"Clin Pharmacol Ther"},{"issue":"1","key":"pone.0356917.ref036","article-title":"Population pharmacokinetics to support intravenous and enteral methadone dosing in children","volume":"66","author":"KM Watt","year":"2026","journal-title":"J Clin Pharmacol"},{"issue":"2","key":"pone.0356917.ref037","doi-asserted-by":"crossref","first-page":"58","DOI":"10.12968\/bjon.2023.32.2.58","article-title":"The pathophysiology, assessment, and management of acute pain","volume":"32","author":"L Mears","year":"2023","journal-title":"Br J Nurs"},{"issue":"9","key":"pone.0356917.ref038","article-title":"Understanding cancer-related pain: pathophysiology, classification, and treatment modalities","volume":"17","author":"J Murari","year":"2025","journal-title":"Cureus"},{"issue":"1","key":"pone.0356917.ref039","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s12929-014-0062-6","article-title":"Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain","volume":"21","author":"HF Miranda","year":"2014","journal-title":"J Biomed Sci"},{"issue":"6","key":"pone.0356917.ref040","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1111\/pan.12385","article-title":"The pharmacokinetics of methadone and its metabolites in neonates, infants, and children","volume":"24","author":"RM Ward","year":"2014","journal-title":"Paediatr Anaesth"},{"key":"pone.0356917.ref041","unstructured":"Aurobindo Pharma BV. Summary of Product Characteristics Methadon. 2023. Accessed 2025 June 24."},{"key":"pone.0356917.ref042","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.drugalcdep.2014.10.014","article-title":"Ethnic and genetic factors in methadone pharmacokinetics: a population pharmacokinetic study","volume":"145","author":"G Bart","year":"2014","journal-title":"Drug Alcohol Depend"},{"issue":"4","key":"pone.0356917.ref043","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1111\/j.1369-1600.2011.00349.x","article-title":"CYP2B6 SNPs are associated with methadone dose required for effective treatment of opioid addiction","volume":"18","author":"O Levran","year":"2013","journal-title":"Addict Biol"},{"issue":"1","key":"pone.0356917.ref044","doi-asserted-by":"crossref","first-page":"20250010","DOI":"10.2478\/bjmg-2025-0010","article-title":"Association of CYP2B6 and OPRM1 genotypes with methadone dose requirements and serum concentrations in a vietnamese cohorts","volume":"28","author":"QG Nguyen","year":"2025","journal-title":"Balkan J Med Genet"},{"issue":"2","key":"pone.0356917.ref045","first-page":"145","article-title":"Pharmacogenomics biomarkers for personalized methadone maintenance treatment: the mechanism and its potential use","volume":"21","author":"FF Ramli","year":"2021","journal-title":"Bosn J Basic Med Sci"},{"issue":"4","key":"pone.0356917.ref046","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0231467","article-title":"Toward precision prescribing for methadone: determinants of methadone deposition","volume":"15","author":"AH Talal","year":"2020","journal-title":"PLoS One"},{"issue":"6","key":"pone.0356917.ref047","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1007\/s11010-023-04810-3","article-title":"Molecular mechanisms of morphine tolerance and dependence; novel insights and future perspectives","volume":"479","author":"I Badshah","year":"2024","journal-title":"Mol Cell Biochem"},{"key":"pone.0356917.ref048","unstructured":"Diana D. Opioid equivalencies. 2026. https:\/\/www.pharmguides.com\/clinical-notes\/opioid-equianalgesics\/"},{"issue":"6","key":"pone.0356917.ref049","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1007\/s40262-025-01477-5","article-title":"Scoping review of paediatric population pharmacokinetic models of morphine","volume":"64","author":"MA Stokes","year":"2025","journal-title":"Clin Pharmacokinet"},{"issue":"3","key":"pone.0356917.ref050","article-title":"Physiologically based pharmacokinetic\/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children","volume":"17","author":"LFM Verscheijden","year":"2021","journal-title":"PLoS Comput Biol"},{"key":"pone.0356917.ref051","doi-asserted-by":"crossref","first-page":"1416440","DOI":"10.3389\/fped.2024.1416440","article-title":"Getting the dose right using physiologically-based pharmacokinetic modeling: dexamethasone to prevent post-extubation stridor in children as proof of concept","volume":"12","author":"JEM van der Heijden","year":"2024","journal-title":"Front Pediatr"},{"issue":"2","key":"pone.0356917.ref052","article-title":"Optimization of the betamethasone and dexamethasone dosing regimen during pregnancy: a combined placenta perfusion and pregnancy physiologically based pharmacokinetic modeling approach","volume":"232","author":"JEM Van Der Heijden","year":"2025","journal-title":"Am J Obstet Gynecol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0356917","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:24:46Z","timestamp":1788888286000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0356917"}},"subtitle":[],"editor":[{"given":"Wenyu","family":"Lin","sequence":"first","affiliation":[{"name":"Harvard Medical School","place":["UNITED STATES OF AMERICA"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":52,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0356917","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]}}}