{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,14]],"date-time":"2026-11-14T01:10:29Z","timestamp":1794618629699,"version":"4.9.1"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,10,1]],"date-time":"2020-10-01T00:00:00Z","timestamp":1601510400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,1]],"date-time":"2020-10-01T00:00:00Z","timestamp":1601510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["2019_A50"],"award-info":[{"award-number":["2019_A50"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Nasal continuous positive airway pressure (CPAP) applies positive end-expiratory pressure (PEEP) and has been shown to reduce the need for intubation and invasive mechanical ventilation in very low birth weight infants with respiratory distress syndrome. However, CPAP failure rates of 50% are reported in large randomized controlled trials. A possible explanation for these failure rates is the application of insufficient low levels of PEEP during nasal CPAP treatment to maintain adequate functional residual capacity shortly after birth. The optimum PEEP level to treat symptoms of respiratory distress in very low birth weight infants has not been assessed in clinical studies. The aim of the study is to compare two different PEEP levels during nasal CPAP treatment in preterm infants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this randomized multicenter trial, 216 preterm infants born at 26\u2009+\u20090\u201329\u2009+\u20096 gestational weeks will be allocated to receive a higher (6\u20138 cmH\n                      <jats:sub>2<\/jats:sub>\n                      O) or a lower (3\u20135 cmH\n                      <jats:sub>2<\/jats:sub>\n                      O) PEEP during neonatal resuscitation and the first 120\u2009h of life. The PEEP level within each group will be titrated throughout the intervention based on the FiO\n                      <jats:sub>2<\/jats:sub>\n                      (fraction of inspired oxygen concentration) requirements to keep oxygenation within the target range. The primary outcome is defined as the need for intubation and mechanical ventilation for &gt;\u20091\u2009h or being not ventilated but reaching one of the two pre-defined CPAP failure criteria (FiO\n                      <jats:sub>2<\/jats:sub>\n                      &gt;\u20090.5 for &gt;\u20091\u2009h or pCO\n                      <jats:sub>2<\/jats:sub>\n                      \u2265\u200970\u2009mmHg in two consecutive blood gas analyses at least 2\u2009h apart).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Based on available data from the literature, the optimum level of PEEP that most effectively treats respiratory distress syndrome in preterm infants is unknown, since the majority of large clinical trials applied a wide range of PEEP levels (4\u20138 cmH\n                      <jats:sub>2<\/jats:sub>\n                      O). The rationale for our study hypothesis is that the early application of a higher PEEP level will more effectively counteract the collapsing properties of the immature and surfactant-deficient lungs and that the level of inspired oxygen may serve as a surrogate marker to guide PEEP titration. Finding the optimum noninvasive continuous distending pressure during early nasal CPAP is required to improve CPAP efficacy and as a consequence to reduce the exposure to ventilator-induced lung injury and the incidence of chronic lung disease in this vulnerable population of very preterm infants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      drks.de\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.drks.de\/drks_web\/navigate.do?navigationId=trial.HTML&amp;TRIAL_ID=DRKS00019940\">DRKS00019940<\/jats:ext-link>\n                      . Registered on March 13, 2020\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13063-020-04660-0","type":"journal-article","created":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T21:03:09Z","timestamp":1601499789000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Application of two different nasal CPAP levels for the treatment of respiratory distress syndrome in preterm infants\u2014\u201cThe OPTTIMMAL-Trial\u201d\u2014Optimizing PEEP To The IMMAture Lungs: study protocol of a randomized controlled trial"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1213-3922","authenticated-orcid":false,"given":"Markus","family":"Waitz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Engel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Schloesser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Rochwalsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Larsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Zemlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Bohnhorst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Peter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Hoppenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Pabst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus-Peter","family":"Zimmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel R.","family":"Franz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Haertel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Frieauff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Sandk\u00f6tter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Masjosthusmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Deindl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Singer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Heidkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annesuse","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Ehrhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,1]]},"reference":[{"key":"4660_CR1","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1056\/NEJMoa072788","volume":"358","author":"CJ Morley","year":"2008","unstructured":"Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med. 2008;358:700\u20138.","journal-title":"N Engl J Med"},{"key":"4660_CR2","doi-asserted-by":"publisher","first-page":"f5980","DOI":"10.1136\/bmj.f5980","volume":"347","author":"GM Schmolzer","year":"2013","unstructured":"Schmolzer GM, Kumar M, Pichler G, Aziz K, O\u2019Reilly M, Cheung PY. Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ. 2013;347:f5980.","journal-title":"BMJ"},{"key":"4660_CR3","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1542\/peds.2005-0249","volume":"116","author":"RA Ehrenkranz","year":"2005","unstructured":"Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics. 2005;116:1353\u201360.","journal-title":"Pediatrics"},{"key":"4660_CR4","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1159\/000499361","volume":"115","author":"DG Sweet","year":"2019","unstructured":"Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Te Pas A, et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2019 update. Neonatology. 2019;115:432\u201350. https:\/\/doi.org\/10.1159\/000499361.","journal-title":"Neonatology"},{"key":"4660_CR5","doi-asserted-by":"publisher","first-page":"177","DOI":"10.3238\/arztebl.2019.0177","volume":"11","author":"J Behnke","year":"2019","unstructured":"Behnke J, Lemyre B, Czernik C, Zimmer KP, Ehrhardt H, Waitz M. Non-invasive ventilation in neonatology. Dtsch Arztebl Int. 2019;11:177\u201383. https:\/\/doi.org\/10.3238\/arztebl.2019.0177.","journal-title":"Dtsch Arztebl Int"},{"key":"4660_CR6","doi-asserted-by":"publisher","first-page":"1970","DOI":"10.1056\/NEJMoa0911783","volume":"362","author":"NN Finer","year":"2010","unstructured":"Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, Laptook AR, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med. 2010;362:1970\u20139.","journal-title":"N Engl J Med"},{"key":"4660_CR7","doi-asserted-by":"publisher","first-page":"e1069","DOI":"10.1542\/peds.2010-3848","volume":"128","author":"MS Dunn","year":"2011","unstructured":"Dunn MS, Kaempf J, de Klerk A, Reilly M, Howard D, Ferrelli K, et al. Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics. 2011;128:e1069\u201376.","journal-title":"Pediatrics"},{"key":"4660_CR8","doi-asserted-by":"publisher","first-page":"1782","DOI":"10.1007\/s00134-001-1117-1","volume":"27","author":"A Elgellab","year":"2001","unstructured":"Elgellab A, Riou Y, Abbazine A, Truffert P, Matran R, Lequien P, et al. Effects of nasal continuous positive airway pressure (NCPAP) on breathing pattern in spontaneously breathing premature newborn infants. Intensive Care Med. 2001;27:1782\u20137.","journal-title":"Intensive Care Med"},{"key":"4660_CR9","doi-asserted-by":"crossref","unstructured":"Wyllie J, Bruinenberg J, Roehr CC, R\u00fcdiger M , Trevisanuto D, Urlesberger B. European Resuscitation Council Guidelines for Resuscitation 2015: Section 7. Resuscitation and support of transition of babies at birth Resuscitation. 2015; 249\u2013263.","DOI":"10.1016\/j.resuscitation.2015.07.029"},{"key":"4660_CR10","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.jpeds.2017.10.065","volume":"194","author":"NA Bamat","year":"2018","unstructured":"Bamat NA, Guevara JP, Bryan M, Roberts RS, Yoder BA, Lemyre B, et al. Variation in positive end-expiratory pressure levels for mechanically ventilated extremely low birth weight infants. J Pediatr. 2018;194:28\u201333.e5. https:\/\/doi.org\/10.1016\/j.jpeds.2017.10.065 Epub 2017 Dec 22.","journal-title":"J Pediatr"},{"key":"4660_CR11","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.jpeds.2013.08.040","volume":"164","author":"B Buzzella","year":"2014","unstructured":"Buzzella B, Claure N, D'Ugard C, Bancalari E. A randomized controlled trial of two nasal continuous positive airway pressure levels after extubation in preterm infants. J Pediatr. 2014;164:46\u201351. https:\/\/doi.org\/10.1016\/j.jpeds.2013.08.040 Epub 2013 Oct 1.","journal-title":"J Pediatr"},{"key":"4660_CR12","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1164\/rccm.200406-774OC","volume":"171","author":"N Mulrooney","year":"2005","unstructured":"Mulrooney N, Champion Z, Moss TJ, Nitsos I, Ikemagi M, Jobe AH. Surfactant and physiologic responses of preterm lambs to continuous positive airway pressure. Am J Respir Crit Care Med. 2005;171:488\u201393.","journal-title":"Am J Respir Crit Care Med"},{"key":"4660_CR13","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1203\/01.PDR.0000132752.94155.13","volume":"56","author":"ME Probyn","year":"2004","unstructured":"Probyn ME, Hooper SB, Dargaville PA, McCallion N, Crossley K, Harding R, et al. Positive end expiratory pressure during resuscitation of premature lambs rapidly improves blood gases without adversely affecting arterial pressure. Pediatr Res. 2004;56:198\u2013204 Epub 2004 Jun 4.","journal-title":"Pediatr Res"},{"key":"4660_CR14","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1016\/S0140-6736(11)60986-0","volume":"378","author":"W G\u00f6pel","year":"2011","unstructured":"G\u00f6pel W, Kribs A, Ziegler A, Laux R, Hoehn T, Wieg C, et al. Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet. 2011;378:1627\u201334. https:\/\/doi.org\/10.1016\/S0140-6736(11)60986-0 Epub 2011 Sep 29.","journal-title":"Lancet"},{"key":"4660_CR15","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1186\/s13063-016-1498-7","volume":"17","author":"G Vento","year":"2016","unstructured":"Vento G, Pastorino R, Boni L, Cota F, Carnielli V, Cools F, et al. Efficacy of a new technique - INtubate-RECruit-SURfactant-Extubate \u2013 \u201cIN-REC-SUR-E\u201d - in preterm neonates with respiratory distress syndrome: study protocol for a randomized controlled trial. Trials. 2016;17:414. https:\/\/doi.org\/10.1186\/s13063-016-1498-7.","journal-title":"Trials"},{"key":"4660_CR16","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1164\/ajrccm.163.7.2011060","volume":"163","author":"AH Jobe","year":"2001","unstructured":"Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163:1723\u20139.","journal-title":"Am J Respir Crit Care Med"},{"key":"4660_CR17","first-page":"1209","volume":"54","author":"RM Diblasi","year":"2009","unstructured":"Diblasi RM. Nasal continuous positive airway pressure (CPAP) for the respiratory care of the newborn infant. Respir Care. 2009;54:1209\u201335.","journal-title":"Respir Care"},{"key":"4660_CR18","doi-asserted-by":"publisher","first-page":"F361","DOI":"10.1136\/archdischild-2014-306836","volume":"100","author":"GM Schm\u00f6lzer","year":"2015","unstructured":"Schm\u00f6lzer GM, Kumar M, Aziz K, Pichler G, O'Reilly M, Lista G, et al. Sustained inflation versus positive pressure ventilation at birth: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2015;100:F361\u20138. https:\/\/doi.org\/10.1136\/archdischild-2014-306836 Epub 2014 Dec 30.","journal-title":"Arch Dis Child Fetal Neonatal Ed"},{"issue":"321","key":"4660_CR19","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1001\/jama.2019.1660","volume":"26","author":"H Kirpalani","year":"2019","unstructured":"Kirpalani H, Ratcliffe SJ, Keszler M, Davis PG, Foglia EE, Te Pas A, et al. Effect of sustained inflations vs intermittent positive pressure ventilation on bronchopulmonary dysplasia or death among extremely preterm infants: the SAIL randomized clinical trial. JAMA. 2019;26(321):1165\u201375. https:\/\/doi.org\/10.1001\/jama.2019.1660.","journal-title":"JAMA"},{"key":"4660_CR20","doi-asserted-by":"publisher","first-page":"2260","DOI":"10.1152\/jappl.1994.77.5.2260","volume":"77","author":"G Miserocchi","year":"1985","unstructured":"Miserocchi G, Poskurica BH, Del Fabbro M. Pulmonary interstitial pressure in anesthetized paralyzed newborn rabbits. J Appl Physiol. 1985;77:2260\u20138.","journal-title":"J Appl Physiol"},{"issue":"3","key":"4660_CR21","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1136\/adc.2008.153023","volume":"94","author":"DG Sweet","year":"2009","unstructured":"Sweet DG, Halliday HL. The use of surfactants in 2009. Arch Dis Child Educ Pract Ed. 2009;94(3):78\u201383. https:\/\/doi.org\/10.1136\/adc.2008.153023.","journal-title":"Arch Dis Child Educ Pract Ed"},{"key":"4660_CR22","doi-asserted-by":"publisher","first-page":"159","DOI":"10.4187\/respcare.02382","volume":"59","author":"H Sun","year":"2014","unstructured":"Sun H, Cheng R, Kang W, Xiong H, Zhou C, Zhang Y, et al. High-frequency oscillatory ventilation versus synchronized intermittent mandatory ventilation plus pressure support in preterm infants with severe respiratory distress syndrome. Respir Care. 2014;59:159\u201369. https:\/\/doi.org\/10.4187\/respcare.02382 Epub 2013 Jun 13.","journal-title":"Respir Care"},{"issue":"6","key":"4660_CR23","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1164\/rccm.200603-351OC","volume":"174","author":"A De Jaegere","year":"2006","unstructured":"De Jaegere A, van Veenendaal MB, Michiels A, van Kaam AH. Lung recruitment using oxygenation during open lung high-frequency ventilation in preterm infants. Am J Respir Crit Care Med. 2006;174(6):639\u201345 Epub 2006 Jun 8.","journal-title":"Am J Respir Crit Care Med"},{"key":"4660_CR24","doi-asserted-by":"publisher","first-page":"F587","DOI":"10.1136\/archdischild-2018-316240","volume":"104","author":"DG Tingay","year":"2019","unstructured":"Tingay DG, Togo A, Pereira-Fantini PM, Miedema M, McCall KE, Perkins EJ, et al. Aeration strategy at birth influences the physiological response to surfactant in preterm lambs. Arch Dis Child Fetal Neonatal Ed. 2019;104:F587\u201393. https:\/\/doi.org\/10.1136\/archdischild-2018-316240 Epub 2019 Feb 1.","journal-title":"Arch Dis Child Fetal Neonatal Ed"},{"key":"4660_CR25","first-page":"CD005384","volume":"12","author":"B Lemyre","year":"2016","unstructured":"Lemyre B, Laughon M, Bose C, Davis PG. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. Cochrane Database Syst Rev. 2016;12:CD005384.","journal-title":"Cochrane Database Syst Rev"},{"key":"4660_CR26","first-page":"CD003212","volume":"2","author":"B Lemyre","year":"2017","unstructured":"Lemyre B, Davis PG, de Paoli AG, Kirpalani H. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation. Cochrane Database Syst Rev. 2017;2:CD003212.","journal-title":"Cochrane Database Syst Rev"},{"key":"4660_CR27","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/j.clp.2016.07.013","volume":"43","author":"M Waitz","year":"2016","unstructured":"Waitz M, Mense L, Kirpalani H, Lemyre B. Nasal intermittent positive pressure ventilation for preterm neonates: synchronized or not? Clin Perinatol. 2016;43:799\u2013816. https:\/\/doi.org\/10.1016\/j.clp.2016.07.013.","journal-title":"Clin Perinatol"},{"key":"4660_CR28","doi-asserted-by":"publisher","first-page":"e1351","DOI":"10.1542\/peds.2013-1880","volume":"132","author":"HS Fischer","year":"2013","unstructured":"Fischer HS, B\u00fchrer C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta-analysis. Pediatrics. 2013;132:e1351\u201360. https:\/\/doi.org\/10.1542\/peds.2013-1880 Epub 2013 Oct 21.","journal-title":"Pediatrics"},{"key":"4660_CR29","doi-asserted-by":"publisher","unstructured":"Gronbach J, Shahzad T, Radajewski S, Chao CM, Bellusci S, Morty RE, Reicherzer T, Ehrhardt H. The potentials and caveats of mesenchymal stromal cell-based therapies in the preterm infant. Stem Cells Int. 2018:9652897. https:\/\/doi.org\/10.1155\/2018\/9652897.","DOI":"10.1155\/2018\/9652897"}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-020-04660-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13063-020-04660-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-020-04660-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T21:55:32Z","timestamp":1633038932000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-020-04660-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,1]]},"references-count":29,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["4660"],"URL":"https:\/\/doi.org\/10.1186\/s13063-020-04660-0","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,1]]},"assertion":[{"value":"30 April 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 August 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 October 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"822"}}