{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:48:52Z","timestamp":1791895732967,"version":"4.3.4"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T00:00:00Z","timestamp":1676592000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T00:00:00Z","timestamp":1676592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["No. NARS3270Q"],"award-info":[{"award-number":["No. NARS3270Q"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Anesthesiol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>During general anesthesia, the surgical pleth index (SPI) monitors nociception. The evidence of SPI in the elderly remains scarce. We aimed to investigate whether there is a difference in perioperative outcomes following intraoperative opioid administration according to the surgical pleth index (SPI) value versus hemodynamic parameters (heart rate or blood pressure) in elderly patients.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Patients aged 65\u201390\u00a0years who underwent laparoscopic colorectal cancer surgery under sevoflurane\/remifentanil anesthesia were randomized to receive remifentanil guided by SPI (SPI group) or conventional clinical judgment based on hemodynamic parameters (conventional group). The primary endpoint was intraoperative remifentanil consumption. Secondary endpoints were intraoperative hemodynamic instability, pain score, fentanyl consumption and delirium in the post-anesthesia care unit (PACU), and perioperative changes in interleukin-6 and natural killer (NK) cell activity.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Seventy-five patients (38, SPI; 37, conventional) were included in the study. The SPI group consumed significantly more remifentanil intraoperatively than the conventional group (mean\u2009\u00b1\u2009SD, 0.13\u2009\u00b1\u20090.05 vs. 0.06\u2009\u00b1\u20090.04\u00a0\u03bcg\/kg\/min, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001). Intraoperative hypertension and tachycardia were more common in the conventional group than in the SPI group. Pain score in the PACU (<jats:italic>P<\/jats:italic>\u2009=\u20090.013) and the incidence of delirium in the PACU were significantly lower in the SPI group than the conventional group (5.2% vs. 24.3%, <jats:italic>P<\/jats:italic>\u2009=\u20090.02). There was no significant difference in NK cell activity and interleukin-6 level.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>In the elderly patients, SPI-guided analgesia provided appropriate analgesia with sufficient intraoperative remifentanil consumption, lower incidence of hypertension\/ tachycardia events, and a lower incidence of delirium in the PACU than the conventional analgesia. However, SPI-guided analgesia may not prevent perioperative immune system deterioration.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>The randomized controlled trial was retrospectively registered in the UMIN Clinical Trials Registry (trial number: UMIN000048351; date of registration: 12\/07\/2022).<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12871-023-02011-5","type":"journal-article","created":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T06:03:24Z","timestamp":1676613804000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Effect of surgical pleth index-guided remifentanil administration on perioperative outcomes in elderly patients: a prospective randomized controlled trial"],"prefix":"10.1186","volume":"23","author":[{"given":"Young Ju","family":"Won","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seok Kyeong","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung Gun","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Sung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do Yeop","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Hak","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,2,17]]},"reference":[{"issue":"Suppl 5","key":"2011_CR1","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1016\/S0020-1383(07)70005-0","volume":"37","author":"PV Giannoudis","year":"2006","unstructured":"Giannoudis PV, Dinopoulos H, Chalidis B, Hall GM. Surgical stress response. Injury. 2006;37(Suppl 5):S3-9.","journal-title":"Injury"},{"key":"2011_CR2","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1016\/j.suc.2017.06.006","volume":"97","author":"SE Brooks","year":"2017","unstructured":"Brooks SE, Peetz AB. Evidence-based care of geriatric trauma patients. Surg Clin North Am. 2017;97:1157\u201374.","journal-title":"Surg Clin North Am"},{"key":"2011_CR3","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.arr.2015.10.003","volume":"24","author":"J Hazeldine","year":"2015","unstructured":"Hazeldine J, Lord JM, Hampson P. Immunesenescence and inflammaging: a contributory factor in the poor outcome of the geriatric trauma patient. Ageing Res Rev. 2015;24:349\u201357.","journal-title":"Ageing Res Rev"},{"key":"2011_CR4","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1615\/CritRevOncog.2013010597","volume":"18","author":"T Fulop","year":"2013","unstructured":"Fulop T, Larbi A, Witkowski JM, Kotb R, Hirokawa K, Pawelec G. Immunosenescence and cancer. Crit Rev Oncog. 2013;18:489\u2013513.","journal-title":"Crit Rev Oncog"},{"key":"2011_CR5","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.bja.2020.09.051","volume":"126","author":"S Funcke","year":"2021","unstructured":"Funcke S, Pinnschmidt HO, Brinkmann C, Wesseler S, Beyer B, Fischer M, et al. Nociception level-guided opioid administration in radical retropubic prostatectomy: a randomised controlled trial. Br J Anaesth. 2021;126:516\u201324.","journal-title":"Br J Anaesth"},{"key":"2011_CR6","doi-asserted-by":"publisher","first-page":"112","DOI":"10.4097\/kja.22002","volume":"75","author":"P Martinez-Vazquez","year":"2022","unstructured":"Martinez-Vazquez P, Jensen EW. Different perspectives for monitoring nociception during general anesthesia. Korean J Anesthesiol. 2022;75:112\u201323.","journal-title":"Korean J Anesthesiol"},{"key":"2011_CR7","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1093\/bja\/aeq291","volume":"106","author":"V Bonhomme","year":"2011","unstructured":"Bonhomme V, Uutela K, Hans G, Maquoi I, Born JD, Brichant JF, et al. Comparison of the surgical Pleth Index\u2122 with haemodynamic variables to assess nociception-anti-nociception balance during general anaesthesia. Br J Anaesth. 2011;106:101\u201311.","journal-title":"Br J Anaesth"},{"key":"2011_CR8","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1093\/bja\/aem004","volume":"98","author":"M Huiku","year":"2007","unstructured":"Huiku M, Uutela K, van Gils M, Korhonen I, Kym\u00e4l\u00e4inen M, Meril\u00e4inen P, et al. Assessment of surgical stress during general anaesthesia. Br J Anaesth. 2007;98:447\u201355.","journal-title":"Br J Anaesth"},{"key":"2011_CR9","doi-asserted-by":"publisher","first-page":"4386","DOI":"10.1177\/0300060518796749","volume":"46","author":"YJ Won","year":"2018","unstructured":"Won YJ, Lim BG, Kim YS, Lee M, Kim H. Usefulness of surgical pleth index-guided analgesia during general anesthesia: a systematic review and meta-analysis of randomized controlled trials. J Int Med Res. 2018;46:4386\u201398.","journal-title":"J Int Med Res"},{"key":"2011_CR10","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1097\/00000542-199701000-00005","volume":"86","author":"CF Minto","year":"1997","unstructured":"Minto CF, Schnider TW, Shafer SL. Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. Anesthesiology. 1997;86:24\u201333.","journal-title":"Anesthesiology"},{"key":"2011_CR11","doi-asserted-by":"publisher","first-page":"e4743","DOI":"10.1097\/MD.0000000000004743","volume":"95","author":"YJ Won","year":"2016","unstructured":"Won YJ, Lim BG, Lee SH, Park S, Kim H, Lee IO, et al. Comparison of relative oxycodone consumption in surgical pleth index-guided analgesia versus conventional analgesia during sevoflurane anesthesia: A randomized controlled trial. Medicine (Baltimore). 2016;95:e4743.","journal-title":"Medicine (Baltimore)"},{"key":"2011_CR12","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1016\/j.bbrc.2014.02.040","volume":"445","author":"SB Lee","year":"2014","unstructured":"Lee SB, Cha J, Kim IK, Yoon JC, Lee HJ, Park SW, et al. A high-throughput assay of NK cell activity in whole blood and its clinical application. Biochem Biophys Res Commun. 2014;445:584\u201390.","journal-title":"Biochem Biophys Res Commun"},{"key":"2011_CR13","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1093\/bja\/aes426","volume":"110","author":"I Bergmann","year":"2013","unstructured":"Bergmann I, G\u00f6hner A, Crozier TA, Hesjedal B, Wiese CH, Popov AF, et al. Surgical pleth index-guided remifentanil administration reduces remifentanil and propofol consumption and shortens recovery times in outpatient anaesthesia. Br J Anaesth. 2013;110:622\u20138.","journal-title":"Br J Anaesth"},{"key":"2011_CR14","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1097\/ALN.0b013e3181d3d641","volume":"112","author":"X Chen","year":"2010","unstructured":"Chen X, Thee C, Gruenewald M, Wnent J, Illies C, Hoecker J, et al. Comparison of surgical stress index-guided analgesia with standard clinical practice during routine general anesthesia: a pilot study. Anesthesiology. 2010;112:1175\u201383.","journal-title":"Anesthesiology"},{"key":"2011_CR15","first-page":"480","volume":"81","author":"M Gruenewald","year":"2015","unstructured":"Gruenewald M, Herz J, Schoenherr T, Thee C, Steinfath M, Bein B. Measurement of the nociceptive balance by Analgesia Nociception Index and Surgical Pleth Index during sevoflurane-remifentanil anesthesia. Minerva Anestesiol. 2015;81:480\u20139.","journal-title":"Minerva Anestesiol"},{"key":"2011_CR16","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1093\/bja\/85.5.763","volume":"85","author":"HJ Priebe","year":"2000","unstructured":"Priebe HJ. The aged cardiovascular risk patient. BJA: Br J Anaesth. 2000;85:763\u201378.","journal-title":"BJA: Br J Anaesth"},{"key":"2011_CR17","doi-asserted-by":"publisher","first-page":"R3","DOI":"10.1152\/ajpregu.00031.2007","volume":"293","author":"KD Monahan","year":"2007","unstructured":"Monahan KD. Effect of aging on baroreflex function in humans. Am J Physiol Regul Integr Comp Physiol. 2007;293:R3-r12.","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2011_CR18","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1097\/00000539-200205000-00014","volume":"94","author":"SR Arain","year":"2002","unstructured":"Arain SR, Williams DJ, Robinson BJ, Uhrich TD, Ebert TJ. Vascular responsiveness to brachial artery infusions of phenylephrine during isoflurane and desflurane anesthesia. Anesth Analg. 2002;94:1137\u201340 (table of contents).","journal-title":"Anesth Analg"},{"key":"2011_CR19","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1093\/bja\/aet485","volume":"112","author":"M Gruenewald","year":"2014","unstructured":"Gruenewald M, Willms S, Broch O, Kott M, Steinfath M, Bein B. Sufentanil administration guided by surgical pleth index vs standard practice during sevoflurane anaesthesia: a randomized controlled pilot study. Br J Anaesth. 2014;112:898\u2013905.","journal-title":"Br J Anaesth"},{"key":"2011_CR20","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.1097\/ALN.0000000000000650","volume":"122","author":"JH Park","year":"2015","unstructured":"Park JH, Lim BG, Kim H, Lee IO, Kong MH, Kim NS. Comparison of Surgical Pleth Index-guided Analgesia with Conventional Analgesia Practices in Children: A Randomized Controlled Trial. Anesthesiology. 2015;122:1280\u20137.","journal-title":"Anesthesiology"},{"key":"2011_CR21","doi-asserted-by":"publisher","first-page":"2275","DOI":"10.1113\/JP270597","volume":"594","author":"DH Thijssen","year":"2016","unstructured":"Thijssen DH, Carter SE, Green DJ. Arterial structure and function in vascular ageing: are you as old as your arteries? J Physiol. 2016;594:2275\u201384.","journal-title":"J Physiol"},{"key":"2011_CR22","doi-asserted-by":"publisher","first-page":"266","DOI":"10.2478\/v10048-012-0036-3","volume":"12","author":"Q Yousef","year":"2012","unstructured":"Yousef Q, Reaz M, Ali MAM. The analysis of PPG morphology: investigating the effects of aging on arterial compliance. Meas Sci Rev. 2012;12:266.","journal-title":"Meas Sci Rev"},{"key":"2011_CR23","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1088\/0967-3334\/24\/2\/306","volume":"24","author":"J Allen","year":"2003","unstructured":"Allen J, Murray A. Age-related changes in the characteristics of the photoplethysmographic pulse shape at various body sites. Physiol Meas. 2003;24:297.","journal-title":"Physiol Meas"},{"key":"2011_CR24","doi-asserted-by":"publisher","first-page":"H493","DOI":"10.1152\/ajpheart.00392.2021","volume":"322","author":"PH Charlton","year":"2022","unstructured":"Charlton PH, Paliakait\u0117 B, Pilt K, Bachler M, Zanelli S, Kulin D, et al. Assessing hemodynamics from the photoplethysmogram to gain insights into vascular age: a review from VascAgeNet. Am J Physiol Heart Circ Physiol. 2022;322:H493-h522.","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2011_CR25","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1093\/bja\/aex300","volume":"119","author":"T Ledowski","year":"2017","unstructured":"Ledowski T, Sommerfield D, Slevin L, Conrad J, von Ungern-Sternberg BS. Surgical pleth index: prediction of postoperative pain in children? Br J Anaesth. 2017;119:979\u201383.","journal-title":"Br J Anaesth"},{"key":"2011_CR26","doi-asserted-by":"publisher","first-page":"380","DOI":"10.17085\/apm.2019.14.4.380","volume":"14","author":"BG Lim","year":"2019","unstructured":"Lim BG. Nociception monitoring tools using autonomic tone changes for intraoperative analgesic guidance in pediatric patients. Anesth Pain Med (Seoul). 2019;14:380\u201392.","journal-title":"Anesth Pain Med (Seoul)"},{"key":"2011_CR27","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1213\/00000539-199804001-00037","volume":"86","author":"EP Lynch","year":"1998","unstructured":"Lynch EP, Lazor MA, Gellis JE, Orav J, Goldman L, Marcantonio ER. The impact of postoperative pain on the development of postoperative delirium. Anesth Analg. 1998;86:781\u20135.","journal-title":"Anesth Analg"},{"key":"2011_CR28","doi-asserted-by":"publisher","first-page":"S9","DOI":"10.1097\/EJA.0000000000001382","volume":"38","author":"J Hu","year":"2021","unstructured":"Hu J, Zhu M, Gao Z, Zhao S, Feng X, Chen J, et al. Dexmedetomidine for prevention of postoperative delirium in older adults undergoing oesophagectomy with total intravenous anaesthesia: a double-blind, randomised clinical trial. Eur J Anaesthesiol. 2021;38:S9\u201317.","journal-title":"Eur J Anaesthesiol"},{"key":"2011_CR29","doi-asserted-by":"publisher","first-page":"358","DOI":"10.23736\/S0375-9393.18.12954-3","volume":"85","author":"N Jain","year":"2019","unstructured":"Jain N, Gera A, Sharma B, Sood J, Chugh P. Comparison of Surgical Pleth Index-guided analgesia using fentanyl versus conventional analgesia technique in laparoscopic cholecystectomy. Minerva Anestesiol. 2019;85:358\u201365.","journal-title":"Minerva Anestesiol"},{"key":"2011_CR30","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1213\/ANE.0000000000004958","volume":"131","author":"JH Kim","year":"2020","unstructured":"Kim JH, Jwa EK, Choung Y, Yeon HJ, Kim SY, Kim E. Comparison of pupillometry with surgical pleth index monitoring on perioperative opioid consumption and nociception during propofol-remifentanil anesthesia: a prospective randomized controlled trial. Anesth Analg. 2020;131:1589\u201398.","journal-title":"Anesth Analg"},{"key":"2011_CR31","doi-asserted-by":"publisher","first-page":"859","DOI":"10.2147\/JIR.S275986","volume":"13","author":"B Lisowska","year":"2020","unstructured":"Lisowska B, Jakubiak J, Siewruk K, Sady M, Kosson D. Which idea is better with regard to immune response? Opioid anesthesia or opioid free anesthesia. J Inflamm Res. 2020;13:859\u201369.","journal-title":"J Inflamm Res"},{"key":"2011_CR32","first-page":"11427","volume":"13","author":"X Cong","year":"2021","unstructured":"Cong X, Huang Z, Zhang L, Sun M, Chang E, Zhang W, et al. Effect of different anaesthesia methods on perioperative cellular immune function and long-term outcome in patients undergoing radical resection of esophageal cancer: a prospective cohort study. Am J Transl Res. 2021;13:11427\u201338.","journal-title":"Am J Transl Res"},{"key":"2011_CR33","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1097\/00000542-199304000-00013","volume":"78","author":"SN Markovic","year":"1993","unstructured":"Markovic SN, Knight PR, Murasko DM. Inhibition of interferon stimulation of natural killer cell activity in mice anesthetized with halothane or isoflurane. Anesthesiology. 1993;78:700\u20136.","journal-title":"Anesthesiology"},{"key":"2011_CR34","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1159\/000078444","volume":"11","author":"Y Shavit","year":"2004","unstructured":"Shavit Y, Ben-Eliyahu S, Zeidel A, Beilin B. Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. Dose and timing study. Neuroimmunomodulation. 2004;11:255\u201360.","journal-title":"Neuroimmunomodulation"},{"key":"2011_CR35","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.toxlet.2016.12.007","volume":"266","author":"K Tazawa","year":"2017","unstructured":"Tazawa K, Koutsogiannaki S, Chamberlain M, Yuki K. The effect of different anesthetics on tumor cytotoxicity by natural killer cells. Toxicol Lett. 2017;266:23\u201331.","journal-title":"Toxicol Lett"},{"key":"2011_CR36","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1093\/bja\/aeg273","volume":"91","author":"AJ Cronin","year":"2003","unstructured":"Cronin AJ, Aucutt-Walter NM, Budinetz T, Bonafide CP, DiVittore NA, Gordin V, et al. Low-dose remifentanil infusion does not impair natural killer cell function in healthy volunteers. Br J Anaesth. 2003;91:805\u20139.","journal-title":"Br J Anaesth"},{"key":"2011_CR37","doi-asserted-by":"publisher","first-page":"e6154","DOI":"10.1097\/MD.0000000000006154","volume":"96","author":"YJ Won","year":"2017","unstructured":"Won YJ, Lim BG, Yeo GE, Lee MK, Lee DK, Kim H, et al. The effect of nicardipine on the surgical pleth index during thyroidectomy under general anesthesia: a prospective double-blind randomized controlled trial. Medicine (Baltimore). 2017;96:e6154.","journal-title":"Medicine (Baltimore)"}],"container-title":["BMC Anesthesiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12871-023-02011-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12871-023-02011-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12871-023-02011-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T06:04:00Z","timestamp":1676613840000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcanesthesiol.biomedcentral.com\/articles\/10.1186\/s12871-023-02011-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,17]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["2011"],"URL":"https:\/\/doi.org\/10.1186\/s12871-023-02011-5","relation":{},"ISSN":["1471-2253"],"issn-type":[{"value":"1471-2253","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,17]]},"assertion":[{"value":"25 August 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 February 2023","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 study was approved by the Ethics Committee of the Korea University Guro Hospital Institutional Review Board (approval number: 2019GR0178) on May 22, 2019, and written informed consent was obtained from all subjects and their legal guardian(s) prior to data collection or study intervention. All procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"57"}}