{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T17:09:06Z","timestamp":1779296946812,"version":"3.51.4"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T00:00:00Z","timestamp":1744588800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T00:00:00Z","timestamp":1744588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"The Nanchong Science and Technology Bureau","award":["22SXQT0293"],"award-info":[{"award-number":["22SXQT0293"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Objective: Remimazolam is a novel benzodiazepine sedative that provides effective sedation, stable haemodynamics, and minimal adverse effects during intravenous general anaesthesia. The aim of this study was to determine the 50% effective dose (ED50) of remimazolam combined with different doses of esketamine for painless gastroscopy and to evaluate the efficacy and safety of this combination. Methods: This was a randomised, double-blind, up-and-down sequential allocation study. Patients undergoing painless gastroscopy who met all the inclusion criteria and did not meet any of the exclusion criteria were randomised in a 1:1:1 ratio into the ES0 group (0\u00a0mg\/kg of esketamine), ES1 group (0.2\u00a0mg\/kg of esketamine), and ES2 group (0.4\u00a0mg\/kg of esketamine). The initial dose of remimazolam was 0.3\u00a0mg\/kg in each group, with the dose increased or decreased by 0.05\u00a0mg\/kg for the subsequent patient based on the success or failure of sedation in the previous patient. The trial was concluded when seven successful failure crossovers were achieved. The ED50 and 95% confidence intervals (CI) of remimazolam were calculated using Probit regression. Haemodynamic parameters, time to induction of anaesthesia, time to gastroscopy, time to awakening from anaesthesia, and adverse events were recorded. Results: A total of 59 patients were included in the final analysis: 19 in the ES0 group, 23 in the ES1 group, and 17 in the ES2 group. The ED50 (95% CI) of remimazolam in the ES0, ES1, and ES2 groups was 0.344 (0.302\u20130.389) mg\/kg, 0.289 (0.249\u20130.328) mg\/kg, and 0.193 (0.145\u20130.239) mg\/kg, respectively. Additionally, the ES1 and ES2 groups exhibited more stable haemodynamics compared to the ES0 group. However, the ES1 and ES2 groups had significantly longer recovery times than the ES0 group. The incidence of hypotension was higher in the ES0 group compared to the ES1 and ES2 groups. Conclusion: The ED50 of remimazolam combined with 0\u00a0mg\/kg, 0.2\u00a0mg\/kg, and 0.4\u00a0mg\/kg of esketamine for induction of anaesthesia during painless gastroscopy was 0.344\u00a0mg\/kg, 0.289\u00a0mg\/kg, and 0.193\u00a0mg\/kg, respectively. Combining esketamine with remimazolam for induction of anaesthesia during painless gastroscopy offers advantages in terms of haemodynamic stability and reduced adverse effects.<\/jats:p>","DOI":"10.1038\/s41598-025-97649-1","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T05:19:51Z","timestamp":1744607991000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The 50% effective dose of remimazolam combined with different doses of esketamine for painless gastroscopy"],"prefix":"10.1038","volume":"15","author":[{"given":"Li","family":"Zhao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuelei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linlin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Mao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiping","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianchun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Longyi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linji","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"key":"97649_CR1","doi-asserted-by":"publisher","unstructured":"Travis, A. C., Pievsky, D. & Saltzman, J. R. Endoscopy in the elderly. Am. J. Gastroenterol. 107, 1495\u2009\u2013\u2009501, 1494, 1502. (2012). https:\/\/doi.org\/10.1038\/ajg.2012.246","DOI":"10.1038\/ajg.2012.246"},{"key":"97649_CR2","doi-asserted-by":"publisher","first-page":"102","DOI":"10.4253\/wjge.v7.i2.102","volume":"7","author":"AO Ferreira","year":"2015","unstructured":"Ferreira, A. O. & Cravo, M. Sedation in Gastrointestinal endoscopy: where are we at in 2014? World J. Gastrointest. Endosc. 7, 102\u2013109. https:\/\/doi.org\/10.4253\/wjge.v7.i2.102 (2015).","journal-title":"World J. Gastrointest. Endosc"},{"key":"97649_CR3","doi-asserted-by":"publisher","first-page":"135","DOI":"10.5946\/ce.2014.47.2.135","volume":"47","author":"S Moon","year":"2014","unstructured":"Moon, S. Sedation regimens for Gastrointestinal endoscopy. Clin. Endosc. 47, 135\u2013140. https:\/\/doi.org\/10.5946\/ce.2014.47.2.135 (2014).","journal-title":"Clin. Endosc"},{"key":"97649_CR4","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1097\/01.mcg.0000225579.65761.b1","volume":"40","author":"M Ristikankare","year":"2006","unstructured":"Ristikankare, M. et al. Sedation, topical pharyngeal anesthesia and cardiorespiratory safety during gastroscopy. J. Clin. Gastroenterol. 40, 899\u2013905 (2006).","journal-title":"J. Clin. Gastroenterol."},{"key":"97649_CR5","doi-asserted-by":"publisher","first-page":"e38120","DOI":"10.1097\/MD.0000000000038120","volume":"103","author":"L Qiu","year":"2024","unstructured":"Qiu, L., Yao, L., Hu, P. & He, T. Analysis of the detection rate and clinical characteristics of early gastric cancer by painless gastroscopy and ordinary gastroscopy. Med. (Baltim). 103, e38120. https:\/\/doi.org\/10.1097\/MD.0000000000038120 (2024).","journal-title":"Med. (Baltim)."},{"key":"97649_CR6","doi-asserted-by":"publisher","first-page":"3558","DOI":"10.3892\/ol.2018.7737","volume":"15","author":"F Men","year":"2018","unstructured":"Men, F. et al. Comparison of the safety of the application of painless gastroscopy and ordinary gastroscopy in chronic hypertension patients combined with early gastric cancer. Oncol. Lett. 15, 3558\u20133561. https:\/\/doi.org\/10.3892\/ol.2018.7737 (2018).","journal-title":"Oncol. Lett."},{"key":"97649_CR7","doi-asserted-by":"publisher","first-page":"2347","DOI":"10.2147\/DDDT.S462607","volume":"18","author":"Y Guo","year":"2024","unstructured":"Guo, Y. et al. Ed50 and ed95 of remimazolam tosilate combined with different doses of Fentanyl in elderly patients for painless gastroscopy. Drug. Des. Devel. Ther. 18, 2347\u20132356. https:\/\/doi.org\/10.2147\/DDDT.S462607 (2024).","journal-title":"Drug. Des. Devel. Ther."},{"key":"97649_CR8","doi-asserted-by":"publisher","first-page":"1392141","DOI":"10.3389\/fmed.2024.1392141","volume":"11","author":"S Tang","year":"2024","unstructured":"Tang, S., Zheng, Y., Li, X., Zhang, Y. & Zhang, Z. Optimizing sedation in gastroscopy: a study on the Etomidate\/propofol mixture ratio. Front. Med. (Lausanne). 11, 1392141. https:\/\/doi.org\/10.3389\/fmed.2024.1392141 (2024).","journal-title":"Front. Med. (Lausanne)"},{"key":"97649_CR9","doi-asserted-by":"publisher","first-page":"639190","DOI":"10.1155\/2012\/639190","volume":"2012","author":"D Garewal","year":"2012","unstructured":"Garewal, D. & Waikar, P. Propofol sedation for Ercp procedures: a Dilemna?? Observations from an anesthesia perspective. Diagn. Therapeutic Endoscopy. 2012, 639190. https:\/\/doi.org\/10.1155\/2012\/639190 (2012).","journal-title":"Diagn. Therapeutic Endoscopy"},{"key":"97649_CR10","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1097\/EJA.0b013e32832c500c","volume":"26","author":"AS Eer","year":"2009","unstructured":"Eer, A. S., Padmanabhan, U. & Leslie, K. Propofol dose and incidence of dreaming during sedation. Eur. J. Anaesthesiol. 26, 833\u2013836. https:\/\/doi.org\/10.1097\/EJA.0b013e32832c500c (2009).","journal-title":"Eur. J. Anaesthesiol."},{"key":"97649_CR11","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1111\/jch.14693","volume":"25","author":"Y Liu","year":"2023","unstructured":"Liu, Y. et al. Sedation with a 1:1 mixture of etomidate and Propofol for gastroscopy in hypertensive elderly patients. J. Clin. Hypertens. (Greenwich Conn. 25, 778\u2013783. https:\/\/doi.org\/10.1111\/jch.14693 (2023).","journal-title":"J. Clin. Hypertens. (Greenwich Conn"},{"key":"97649_CR12","doi-asserted-by":"publisher","unstructured":"Liu, G. & Xiong, Y. Analysis of stress response and analgesic effect of remazolam combined with etomidate in painless gastroenteroscopy. Contrast Media Mol. Imaging 2022 (4863682). https:\/\/doi.org\/10.1155\/2022\/4863682 (2022).","DOI":"10.1155\/2022\/4863682"},{"key":"97649_CR13","doi-asserted-by":"publisher","first-page":"93","DOI":"10.24875\/RIC.23000109","volume":"75","author":"D Albores-Garc\u00eda","year":"2023","unstructured":"Albores-Garc\u00eda, D. & Cruz, S. L. Fentanyl and other new psychoactive synthetic opioids. Challenges to prevention and treatment. Revista De Investigacion Clinica; Organo Del. Hosp. De Enfermedades De La. Nutricion. 75, 93\u2013104. https:\/\/doi.org\/10.24875\/RIC.23000109 (2023).","journal-title":"Revista De Investigacion Clinica; Organo Del. Hosp. De Enfermedades De La. Nutricion"},{"key":"97649_CR14","first-page":"35","volume":"44","author":"D Maciejewski","year":"2012","unstructured":"Maciejewski, D. Sufentanil in anaesthesiology and intensive therapy. Anaesthesiol. Intensive Ther. 44, 35\u201341 (2012).","journal-title":"Anaesthesiol. Intensive Ther."},{"key":"97649_CR15","doi-asserted-by":"publisher","first-page":"39","DOI":"10.6859\/aja.202306_61(2).0001","volume":"61","author":"G Chen","year":"2023","unstructured":"Chen, G., Lin, S., Lin, P., Tseng, W. & Lu, C. A narrative review of remimazolam in procedural sedation. Asian J. Anesthesiology. 61, 39\u201345. https:\/\/doi.org\/10.6859\/aja.202306_61(2).0001 (2023).","journal-title":"Asian J. Anesthesiology"},{"key":"97649_CR16","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1007\/s40265-021-01544-8","volume":"81","author":"A Lee","year":"2021","unstructured":"Lee, A. & Shirley, M. Remimazolam: a review in procedural sedation. Drugs 81, 1193\u20131201. https:\/\/doi.org\/10.1007\/s40265-021-01544-8 (2021).","journal-title":"Drugs"},{"key":"97649_CR17","doi-asserted-by":"publisher","first-page":"e15495","DOI":"10.7717\/peerj.15495","volume":"11","author":"Y Chang","year":"2023","unstructured":"Chang, Y., Huang, Y., Chi, K. & Huang, Y. Remimazolam versus Propofol for procedural sedation: a meta-analysis of randomized controlled trials. Peerj 11, e15495. https:\/\/doi.org\/10.7717\/peerj.15495 (2023).","journal-title":"Peerj"},{"key":"97649_CR18","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.23736\/S0375-9393.22.16817-3","volume":"88","author":"J Zhang","year":"2022","unstructured":"Zhang, J. et al. Remimazolam versus Propofol for procedural sedation and anesthesia: a systemic review and meta-analysis. Minerva Anestesiol. 88, 1035\u20131042. https:\/\/doi.org\/10.23736\/S0375-9393.22.16817-3 (2022).","journal-title":"Minerva Anestesiol"},{"key":"97649_CR19","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1213\/ANE.0000000000006851","volume":"139","author":"G Mion","year":"2024","unstructured":"Mion, G. & Himmelseher, S. Esketamine: less drowsiness, more analgesia. Anesth. Analg. 139, 78\u201391. https:\/\/doi.org\/10.1213\/ANE.0000000000006851 (2024).","journal-title":"Anesth. Analg"},{"key":"97649_CR20","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/ibra.12019","volume":"8","author":"X Zhang","year":"2022","unstructured":"Zhang, X. et al. Research advances in the clinical application of Esketamine. Ibrain 8, 55\u201367. https:\/\/doi.org\/10.1002\/ibra.12019 (2022).","journal-title":"Ibrain"},{"key":"97649_CR21","doi-asserted-by":"publisher","first-page":"1379101","DOI":"10.3389\/fphar.2024.1379101","volume":"15","author":"Y Yu","year":"2024","unstructured":"Yu, Y. et al. Efficacy and safety of Esketamine for pediatric Gastrointestinal endoscopy: a meta-analysis and trial sequential analysis. Front. Pharmacol. 15, 1379101. https:\/\/doi.org\/10.3389\/fphar.2024.1379101 (2024).","journal-title":"Front. Pharmacol."},{"key":"97649_CR22","doi-asserted-by":"publisher","first-page":"e25100","DOI":"10.1016\/j.heliyon.2024.e25100","volume":"10","author":"M Fu","year":"2024","unstructured":"Fu, M. et al. Postoperative Esketamine improves ventilation after video-assisted thoracoscopic lung resection: a double-blinded randomized controlled trial. Heliyon 10, e25100. https:\/\/doi.org\/10.1016\/j.heliyon.2024.e25100 (2024).","journal-title":"Heliyon"},{"key":"97649_CR23","doi-asserted-by":"publisher","first-page":"1298409","DOI":"10.3389\/fphar.2024.1298409","volume":"15","author":"T Chu","year":"2024","unstructured":"Chu, T. et al. Comparison of remimazolam and Propofol combined with low dose Esketamine for pediatric same-day painless bidirectional endoscopy: a randomized, controlled clinical trial. Front. Pharmacol. 15, 1298409. https:\/\/doi.org\/10.3389\/fphar.2024.1298409 (2024).","journal-title":"Front. Pharmacol."},{"key":"97649_CR24","doi-asserted-by":"publisher","first-page":"1124743","DOI":"10.3389\/fmed.2023.1124743","volume":"10","author":"K Zhang","year":"2023","unstructured":"Zhang, K. et al. Effects of opioid-free Propofol or remimazolam balanced anesthesia on hypoxemia incidence in patients with obesity during Gastrointestinal endoscopy: a prospective, randomized clinical trial. Front. Med. (Lausanne). 10, 1124743. https:\/\/doi.org\/10.3389\/fmed.2023.1124743 (2023).","journal-title":"Front. Med. (Lausanne)"},{"key":"97649_CR25","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/S0149-7634(05)80090-9","volume":"15","author":"WJ Dixon","year":"1991","unstructured":"Dixon, W. J. Staircase Bioassay: the up-and-down method. Neurosci. Biobehav Rev. 15, 47\u201350 (1991).","journal-title":"Neurosci. Biobehav Rev."},{"key":"97649_CR26","doi-asserted-by":"publisher","first-page":"1372139","DOI":"10.3389\/fphar.2024.1372139","volume":"15","author":"M Ni","year":"2024","unstructured":"Ni, M. et al. Effective dose of intranasal remimazolam for preoperative sedation in preschool children: a dose-finding study using Dixon\u2019s up-and-down method. Front. Pharmacol. 15, 1372139. https:\/\/doi.org\/10.3389\/fphar.2024.1372139 (2024).","journal-title":"Front. Pharmacol."},{"key":"97649_CR27","doi-asserted-by":"publisher","unstructured":"Bang, J. et al. Impact of remote ischemic preconditioning conducted in living kidney donors on renal function in donors and recipients following living donor kidney transplantation: a randomized clinical trial. J. Clin. Med. 8. https:\/\/doi.org\/10.3390\/jcm8050713 (2019).","DOI":"10.3390\/jcm8050713"},{"key":"97649_CR28","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1111\/pan.13088","volume":"27","author":"M G\u00f6rges","year":"2017","unstructured":"G\u00f6rges, M., Zhou, G., Brant, R. & Ansermino, J. M. Sequential allocation trial design in anesthesia: an introduction to methods, modeling, and clinical applications. Paediatr Anaesth. 27, 240\u2013247. https:\/\/doi.org\/10.1111\/pan.13088 (2017).","journal-title":"Paediatr Anaesth."},{"key":"97649_CR29","doi-asserted-by":"publisher","first-page":"7645","DOI":"10.1038\/s41598-024-58294-2","volume":"14","author":"D Chen","year":"2024","unstructured":"Chen, D., Liao, M., Wu, X., Zhao, T. & Sun, H. Comparison of efficacy and safety of equivalent doses of remimazolam versus Propofol for gastroscopy anesthesia in elderly patients. Sci. Rep. 14, 7645. https:\/\/doi.org\/10.1038\/s41598-024-58294-2 (2024).","journal-title":"Sci. Rep."},{"key":"97649_CR30","doi-asserted-by":"publisher","unstructured":"Lu, M., Liu, J., Wu, X. & Zhang, Z. Ciprofol: A novel alternative to Propofol in clinical intravenous anesthesia? Biomed. Res. Int. 2023 (7443226). https:\/\/doi.org\/10.1155\/2023\/7443226 (2023).","DOI":"10.1155\/2023\/7443226"},{"key":"97649_CR31","doi-asserted-by":"publisher","unstructured":"International, B. R. Retracted: the clinical application of remimazolam benzenesulfonate combined with esketamine intravenous anesthesia in endoscopic retrograde cholangiopancreatography. Biomed. Res. Int. 2024,  9758358 (2024). https:\/\/doi.org\/10.1155\/2024\/9758358","DOI":"10.1155\/2024\/9758358"},{"key":"97649_CR32","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1097\/01.anes.0000267514.42592.2a","volume":"107","author":"NL Pace","year":"2007","unstructured":"Pace, N. L. & Stylianou, M. P. Advances in and limitations of up-and-down methodology: a pr\u00e9cis of clinical use, study design, and dose Estimation in anesthesia research. Anesthesiology 107, 144\u2013152 (2007).","journal-title":"Anesthesiology"},{"key":"97649_CR33","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1111\/bcp.15072","volume":"88","author":"H Yang","year":"2022","unstructured":"Yang, H. et al. The median effective concentration of Propofol with different doses of Esketamine during Gastrointestinal endoscopy in elderly patients: a randomized controlled trial. Br. J. Clin. Pharmacol. 88, 1279\u20131287. https:\/\/doi.org\/10.1111\/bcp.15072 (2022).","journal-title":"Br. J. Clin. Pharmacol."},{"key":"97649_CR34","doi-asserted-by":"publisher","first-page":"1364546","DOI":"10.3389\/fphar.2024.1364546","volume":"15","author":"J Deng","year":"2024","unstructured":"Deng, J., Yu, Y., Tang, Z., Lei, H. & Tan, C. Efficacy and safety of low-dose Esketamine for painless Gastrointestinal endoscopy in adults: a systematic evaluation and meta-analysis. Front. Pharmacol. 15, 1364546. https:\/\/doi.org\/10.3389\/fphar.2024.1364546 (2024).","journal-title":"Front. Pharmacol."},{"key":"97649_CR35","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1016\/j.bja.2023.08.019","volume":"131","author":"Y Gao","year":"2023","unstructured":"Gao, Y. et al. Pharmacokinetics of remimazolam after intravenous infusion in anaesthetised children. Br. J. Anaesth. 131, 914\u2013920. https:\/\/doi.org\/10.1016\/j.bja.2023.08.019 (2023).","journal-title":"Br. J. Anaesth."},{"key":"97649_CR36","doi-asserted-by":"publisher","first-page":"2875","DOI":"10.2147\/DDDT.S425860","volume":"17","author":"W Li","year":"2023","unstructured":"Li, W. et al. The efficacy and safety of remimazolam besylate combined with Esketamine for outpatient colonoscopy: a prospective, randomized, controlled clinical trial. Drug. Des. Devel. Ther. 17, 2875\u20132887. https:\/\/doi.org\/10.2147\/DDDT.S425860 (2023).","journal-title":"Drug. Des. Devel. Ther."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-97649-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-97649-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-97649-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T05:19:52Z","timestamp":1744607992000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-97649-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,14]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["97649"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-97649-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,14]]},"assertion":[{"value":"7 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12770"}}