{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T11:50:43Z","timestamp":1791546643710,"version":"4.3.4"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100006093","name":"Patient-Centered Outcomes Research Institute","doi-asserted-by":"publisher","award":["PCS-1609-36195"],"award-info":[{"award-number":["PCS-1609-36195"]}],"id":[{"id":"10.13039\/100006093","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Cancer"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Swallowing therapy is commonly provided as a treatment to lessen the risk or severity of dysphagia secondary to radiotherapy (RT) for head and neck cancer (HNC); however, best practice is not yet established. This trial will compare the effectiveness of prophylactic (high and low intensity) versus reactive interventions for swallowing in patients with HNC undergoing RT.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This multi-site, international randomized clinical trial (RCT) will include 952 adult patients receiving radiotherapy for HNC and who are at high risk for post-RT dysphagia. Participants will be randomized to receive one of three interventions for swallowing during RT: RE-ACTIVE, started promptly if\/when dysphagia is identified; PRO-ACTIVE EAT, low intensity prophylactic intervention started before RT commences; or, PRO-ACTIVE EAT+EXERCISE, high intensity prophylactic intervention also started before RT commences. We hypothesize that the PRO-ACTIVE therapies are more effective than late RE-ACTIVE therapy; and, that the more intensive PRO-ACTIVE (EAT + EXERCISE) is superior to the low intensive PRO-ACTIVE (EAT). The primary endpoint of effectiveness is duration of feeding tube dependency one year post radiation therapy, selected as a pragmatic outcome valued equally by diverse stakeholders (e.g., patients, caregivers and clinicians). Secondary outcomes will include objective measures of swallow physiology and function, pneumonia and weight loss, along with various patient-reported swallowing-related outcomes, such as quality of life, symptom burden, and self-efficacy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>Dysphagia is a common and potentially life-threatening chronic toxicity of radiotherapy, and a priority issue for HNC survivors. Yet, the optimal timing and intensity of swallowing therapy provided by a speech-language pathologist is not known. With no clearly preferred strategy, current practice is fraught with substantial variation. The pragmatic PRO-ACTIVE trial aims to specifically address the decisional dilemma of when swallowing therapy should begin (i.e., before or after a swallowing problem develops). The critical impact of this dilemma is heightened by the growing number of young HNC patients in healthcare systems that need to allocate resources most effectively. The results of the PRO-ACTIVE trial will address the global uncertainty regarding best practice for dysphagia management in HNC patients receiving radiotherapy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>The protocol is registered with the US Patient Centered Outcomes Research Institute, and the PRO-ACTIVE trial was prospectively registered at <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>, under the identifier <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03455608\">NCT03455608<\/jats:ext-link>; First posted: Mar 6, 2018; Last verified: Jun 17, 2021.<\/jats:p>\n                <jats:p><jats:bold>Protocol Version:<\/jats:bold> 1.3 (January 27, 2020).<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12885-021-08826-0","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T06:31:33Z","timestamp":1634106693000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["The PRO-ACTIVE trial protocol: a randomized study comparing the effectiveness of PROphylACTic swallow InterVEntion for patients receiving radiotherapy for head and neck cancer"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3298-7714","authenticated-orcid":false,"given":"R.","family":"Martino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. I.","family":"Fitch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. D.","family":"Fuller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Hope","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Krisciunas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. E.","family":"Langmore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Lazarus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. L.","family":"Macdonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"McCulloch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Mills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. A.","family":"Palma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Pytynia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Ringash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Sultanem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Theurer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. E.","family":"Thorpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Hutcheson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"issue":"8","key":"8826_CR1","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1002\/cncr.29207","volume":"121","author":"B Xu","year":"2015","unstructured":"Xu B, Boero IJ, Hwang L, Le QT, Moiseenko V, Sanghvi PR, et al. Aspiration pneumonia after concurrent chemoradiotherapy for head and neck cancer. Cancer. 2015;121(8):1303\u201311. https:\/\/doi.org\/10.1002\/cncr.29207.","journal-title":"Cancer."},{"issue":"1","key":"8826_CR2","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1002\/hed.23275","volume":"36","author":"KU Hunter","year":"2014","unstructured":"Hunter KU, Lee OE, Lyden TH, Haxer MJ, Feng FY, Schipper M, et al. Aspiration pneumonia after chemo-intensity-modulated radiation therapy of oropharyngeal carcinoma and its clinical and dysphagia-related predictors. Head Neck. 2014;36(1):120\u20135. https:\/\/doi.org\/10.1002\/hed.23275.","journal-title":"Head Neck."},{"issue":"11","key":"8826_CR3","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1001\/jamaoto.2013.4715","volume":"139","author":"KA Hutcheson","year":"2013","unstructured":"Hutcheson KA, Bhayani MK, Beadle BM, Gold KA, Shinn EH, Lai SY, et al. Eat and exercise during radiotherapy or chemoradiotherapy for pharyngeal cancers: use it or lose it. JAMA Otolaryngol Head Neck Surg. 2013;139(11):1127\u201334. https:\/\/doi.org\/10.1001\/jamaoto.2013.4715.","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"issue":"2","key":"8826_CR4","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1002\/cncr.29022","volume":"121","author":"J Setton","year":"2015","unstructured":"Setton J, Lee NY, Riaz N, Huang SH, Waldron J, O'Sullivan B, et al. A multi-institution pooled analysis of gastrostomy tube dependence in patients with oropharyngeal cancer treated with definitive intensity-modulated radiotherapy. Cancer. 2015;121(2):294\u2013301. https:\/\/doi.org\/10.1002\/cncr.29022.","journal-title":"Cancer."},{"issue":"3","key":"8826_CR5","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1007\/s00455-015-9600-y","volume":"30","author":"HR Mortensen","year":"2015","unstructured":"Mortensen HR, Jensen K, Aksglaede K, Lambertsen K, Eriksen E, Grau C. Prophylactic swallowing exercises in head and neck cancer radiotherapy. Dysphagia. 2015;30(3):304\u201314. https:\/\/doi.org\/10.1007\/s00455-015-9600-y.","journal-title":"Dysphagia."},{"issue":"4","key":"8826_CR6","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1002\/hed.23913","volume":"38","author":"S Ohba","year":"2016","unstructured":"Ohba S, Yokoyama J, Kojima M, Fujimaki M, Anzai T, Komatsu H, et al. Significant preservation of swallowing function in chemoradiotherapy for advanced head and neck cancer by prophylactic swallowing exercise. Head Neck. 2016;38(4):517\u201321. https:\/\/doi.org\/10.1002\/hed.23913.","journal-title":"Head Neck"},{"issue":"5","key":"8826_CR7","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1007\/s00405-013-2640-8","volume":"271","author":"L van der Molen","year":"2014","unstructured":"van der Molen L, van Rossum MA, Rasch CR, Smeele LE, Hilgers FJ. Two-year results of a prospective preventive swallowing rehabilitation trial in patients treated with chemoradiation for advanced head and neck cancer. Eur Arch Otorhinolaryngol. 2014;271(5):1257\u201370. https:\/\/doi.org\/10.1007\/s00405-013-2640-8.","journal-title":"Eur Arch Otorhinolaryngol"},{"issue":"1","key":"8826_CR8","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1097\/MLG.0b013e31815659b0","volume":"118","author":"WR Carroll","year":"2008","unstructured":"Carroll WR, Locher JL, Canon CL, Bohannon IA, McColloch NL, Magnuson JS. Pretreatment swallowing exercises improve swallow function after chemoradiation. Laryngoscope. 2008;118(1):39\u201343. https:\/\/doi.org\/10.1097\/MLG.0b013e31815659b0.","journal-title":"Laryngoscope."},{"issue":"2","key":"8826_CR9","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1007\/s00455-014-9592-z","volume":"30","author":"SM Shaw","year":"2015","unstructured":"Shaw SM, Flowers H, O'Sullivan B, Hope A, Liu LW, Martino R. The effect of prophylactic percutaneous endoscopic gastrostomy (PEG) tube placement on swallowing and swallow-related outcomes in patients undergoing radiotherapy for head and neck cancer: a systematic review. Dysphagia. 2015;30(2):152\u201375. https:\/\/doi.org\/10.1007\/s00455-014-9592-z.","journal-title":"Dysphagia."},{"issue":"2","key":"8826_CR10","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.radonc.2016.01.019","volume":"118","author":"MD Anderson Head and Neck Cancer Symptom Working Group","year":"2016","unstructured":"MD Anderson Head and Neck Cancer Symptom Working Group. Beyond mean pharyngeal constrictor dose for beam path toxicity in non-target swallowing muscles: dose-volume correlates of chronic radiation-associated dysphagia (RAD) after oropharyngeal intensity modulated radiotherapy. Radiother Oncol. 2016;118(2):304\u201314. https:\/\/doi.org\/10.1016\/j.radonc.2016.01.019.","journal-title":"Radiother Oncol"},{"issue":"3","key":"8826_CR11","doi-asserted-by":"publisher","first-page":"E93","DOI":"10.1016\/j.ijrobp.2010.12.067","volume":"81","author":"A Eisbruch","year":"2011","unstructured":"Eisbruch A, Kim HM, Feng FY, Lyden TH, Haxer MJ, Feng M, et al. Chemo-IMRT of oropharyngeal cancer aiming to reduce dysphagia: swallowing organs late complication probabilities and dosimetric correlates. Int J Radiat Oncol Biol Phys. 2011;81(3):E93\u2013E9. https:\/\/doi.org\/10.1016\/j.ijrobp.2010.12.067.","journal-title":"Int J Radiat Oncol Biol Phys"},{"issue":"23","key":"8826_CR12","doi-asserted-by":"publisher","first-page":"5793","DOI":"10.1002\/cncr.27631","volume":"118","author":"KA Hutcheson","year":"2012","unstructured":"Hutcheson KA, Lewin JS, Barringer DA, Lisec A, Gunn GB, Moore MW, et al. Late dysphagia after radiotherapy-based treatment of head and neck cancer. Cancer. 2012;118(23):5793\u20139. https:\/\/doi.org\/10.1002\/cncr.27631.","journal-title":"Cancer."},{"issue":"10","key":"8826_CR13","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1001\/jamainternmed.2016.4362","volume":"176","author":"EB Rubin","year":"2016","unstructured":"Rubin EB, Buehler AE, Halpern SD. States worse than death among hospitalized patients with serious illnesses. JAMA Intern Med. 2016;176(10):1557\u20139. https:\/\/doi.org\/10.1001\/jamainternmed.2016.4362.","journal-title":"JAMA Intern Med"},{"issue":"1","key":"8826_CR14","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","volume":"71","author":"RL Siegel","year":"2021","unstructured":"Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7\u201333. https:\/\/doi.org\/10.3322\/caac.21654.","journal-title":"CA Cancer J Clin"},{"key":"8826_CR15","volume-title":"Canadian Cancer Statistics 2016. Toronto, ON","author":"Statistics","year":"2016","unstructured":"Statistics. CCSsACoC. Canadian Cancer Statistics 2016. Toronto, ON; 2016."},{"issue":"32","key":"8826_CR16","doi-asserted-by":"publisher","first-page":"4294","DOI":"10.1200\/JCO.2011.36.4596","volume":"29","author":"AK Chaturvedi","year":"2011","unstructured":"Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29(32):4294\u2013301. https:\/\/doi.org\/10.1200\/JCO.2011.36.4596.","journal-title":"J Clin Oncol"},{"issue":"1","key":"8826_CR17","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1056\/NEJMoa0912217","volume":"363","author":"KK Ang","year":"2010","unstructured":"Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24\u201335. https:\/\/doi.org\/10.1056\/NEJMoa0912217.","journal-title":"N Engl J Med"},{"issue":"5","key":"8826_CR18","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1200\/JCO.2004.00.3335","volume":"24","author":"PM Weinberger","year":"2006","unstructured":"Weinberger PM, Yu Z, Haffty BG, Kowalski D, Harigopal M, Brandsma J, et al. Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis. J Clinic Oncol. 2006;24(5):736\u201347. https:\/\/doi.org\/10.1200\/JCO.2004.00.3335.","journal-title":"J Clinic Oncol"},{"issue":"4","key":"8826_CR19","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1007\/s00455-012-9404-2","volume":"27","author":"GP Krisciunas","year":"2012","unstructured":"Krisciunas GP, Sokoloff W, Stepas K, Langmore SE. Survey of usual practice: dysphagia therapy in head and neck cancer patients. Dysphagia. 2012;27(4):538\u201349. https:\/\/doi.org\/10.1007\/s00455-012-9404-2.","journal-title":"Dysphagia."},{"issue":"9","key":"8826_CR20","doi-asserted-by":"publisher","first-page":"2390","DOI":"10.1002\/hed.26250","volume":"42","author":"KA Hutcheson","year":"2020","unstructured":"Hutcheson KA, Gomes A, Rodriguez V, Barringer D, Khan M, Martino R. Eat all through radiation therapy (EAT-RT): structured therapy model to facilitate continued oral intake through head and neck radiotherapy-user acceptance and content validation. Head Neck. 2020;42(9):2390\u20136. https:\/\/doi.org\/10.1002\/hed.26250.","journal-title":"Head Neck."},{"issue":"2","key":"8826_CR21","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.ijrobp.2018.01.097","volume":"101","author":"E Greco","year":"2018","unstructured":"Greco E, Simic T, Ringash J, Tomlinson G, Inamoto Y, Martino R. Dysphagia treatment for patients with head and neck Cancer undergoing radiation therapy: a Meta-analysis review. Int J Radiat Oncol Biol Phys. 2018;101(2):421\u201344. https:\/\/doi.org\/10.1016\/j.ijrobp.2018.01.097.","journal-title":"Int J Radiat Oncol Biol Phys"},{"issue":"4","key":"8826_CR22","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.oraloncology.2011.11.003","volume":"48","author":"JW Roe","year":"2012","unstructured":"Roe JW, Carding PN, Rhys-Evans PH, Newbold KL, Harrington KJ, Nutting CM. Assessment and management of dysphagia in patients with head and neck cancer who receive radiotherapy in the United Kingdom - a web-based survey. Oral Oncol. 2012;48(4):343\u20138. https:\/\/doi.org\/10.1016\/j.oraloncology.2011.11.003.","journal-title":"Oral Oncol"},{"key":"8826_CR23","doi-asserted-by":"publisher","first-page":"CD011112","DOI":"10.1002\/14651858.CD011112.pub2","volume":"8","author":"A Perry","year":"2016","unstructured":"Perry A, Lee SH, Cotton S, Kennedy C. Therapeutic exercises for affecting post-treatment swallowing in people treated for advanced-stage head and neck cancers. Cochrane Database Syst Rev. 2016;8:CD011112. https:\/\/doi.org\/10.1002\/14651858.CD011112.pub2.","journal-title":"Cochrane Database Syst Rev"},{"issue":"2","key":"8826_CR24","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1002\/cncr.30350","volume":"123","author":"BM Beadle","year":"2017","unstructured":"Beadle BM, Liao KP, Giordano SH, Garden AS, Hutcheson KA, Lai SY, et al. Reduced feeding tube duration with intensity-modulated radiation therapy for head and neck cancer: a surveillance, epidemiology, and end results-Medicare analysis. Cancer. 2017;123(2):283\u201393. https:\/\/doi.org\/10.1002\/cncr.30350.","journal-title":"Cancer."},{"issue":"4","key":"8826_CR25","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1007\/s00520-015-3021-1","volume":"24","author":"S McEwen","year":"2016","unstructured":"McEwen S, Rodriguez AM, Martino R, Poon I, Dunphy C, Rios JN, et al. \"I didn't actually know there was such a thing as rehab\": survivor, family, and clinician perceptions of rehabilitation following treatment for head and neck cancer. Support Care Cancer. 2016;24(4):1449\u201353. https:\/\/doi.org\/10.1007\/s00520-015-3021-1.","journal-title":"Support Care Cancer"},{"issue":"4","key":"8826_CR26","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1007\/s00455-014-9527-8","volume":"29","author":"RL Nund","year":"2014","unstructured":"Nund RL, Ward EC, Scarinci NA, Cartmill B, Kuipers P, Porceddu SV. Carers' experiences of dysphagia in people treated for head and neck cancer: a qualitative study. Dysphagia. 2014;29(4):450\u20138. https:\/\/doi.org\/10.1007\/s00455-014-9527-8.","journal-title":"Dysphagia."},{"issue":"may08 1","key":"8826_CR27","doi-asserted-by":"publisher","first-page":"h2147","DOI":"10.1136\/bmj.h2147","volume":"350","author":"K Loudon","year":"2015","unstructured":"Loudon K, Treweek S, Sullivan F, Donnan P, Thorpe KE, Zwarenstein M. The PRECIS-2 tool: designing trials that are fit for purpose. BMJ. 2015;350(may08 1):h2147. https:\/\/doi.org\/10.1136\/bmj.h2147.","journal-title":"BMJ."},{"issue":"5","key":"8826_CR28","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1016\/j.jclinepi.2008.12.011","volume":"62","author":"KE Thorpe","year":"2009","unstructured":"Thorpe KE, Zwarenstein M, Oxman AD, Treweek S, Furberg CD, Altman DG, et al. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. J Clin Epidemiol. 2009;62(5):464\u201375. https:\/\/doi.org\/10.1016\/j.jclinepi.2008.12.011.","journal-title":"J Clin Epidemiol"},{"issue":"4","key":"8826_CR29","doi-asserted-by":"publisher","first-page":"e94879","DOI":"10.1371\/journal.pone.0094879","volume":"9","author":"K Wopken","year":"2014","unstructured":"Wopken K, Bijl HP, van der Schaaf A, Christianen ME, Chouvalova O, Oosting SF, et al. Development and validation of a prediction model for tube feeding dependence after curative (chemo-) radiation in head and neck cancer. PLoS One. 2014;9(4):e94879. https:\/\/doi.org\/10.1371\/journal.pone.0094879.","journal-title":"PLoS One"},{"issue":"1","key":"8826_CR30","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.ijsu.2011.10.001","volume":"10","author":"D Moher","year":"2012","unstructured":"Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. Int J Surg. 2012;10(1):28\u201355. https:\/\/doi.org\/10.1016\/j.ijsu.2011.10.001.","journal-title":"Int J Surg"},{"issue":"8","key":"8826_CR31","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1016\/j.ijsu.2011.09.004","volume":"9","author":"KF Schulz","year":"2011","unstructured":"Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. Int J Surg. 2011;9(8):672\u20137. https:\/\/doi.org\/10.1016\/j.ijsu.2011.09.004.","journal-title":"Int J Surg"},{"issue":"1","key":"8826_CR32","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1002\/cncr.30283","volume":"123","author":"KA Hutcheson","year":"2017","unstructured":"Hutcheson KA, Barrow MP, Barringer DA, Knott JK, Lin HY, Weber RS, et al. Dynamic imaging grade of swallowing toxicity (DIGEST): scale development and validation. Cancer. 2017;123(1):62\u201370. https:\/\/doi.org\/10.1002\/cncr.30283.","journal-title":"Cancer."},{"issue":"10","key":"8826_CR33","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1002\/hed.20602","volume":"29","author":"DI Rosenthal","year":"2007","unstructured":"Rosenthal DI, Mendoza TR, Chambers MS, Asper JA, Gning I, Kies MS, et al. Measuring head and neck cancer symptom burden: the development and validation of the M. D. Anderson symptom inventory, head and neck module. Head Neck. 2007;29(10):923\u201331. https:\/\/doi.org\/10.1002\/hed.20602.","journal-title":"Head Neck."},{"key":"8826_CR34","volume-title":"Understanding heterogeneity of treatment effects in pragmatic trials with an example of a large, simple trial of a drug treatment for osteoporosis (white paper). Center for Medical Technology and Policy","author":"J Segal","year":"2012","unstructured":"Segal J, Weiss C, Varadhan R. Understanding heterogeneity of treatment effects in pragmatic trials with an example of a large, simple trial of a drug treatment for osteoporosis (white paper). Center for Medical Technology and Policy; 2012."},{"issue":"5","key":"8826_CR35","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1177\/0194599811414506","volume":"145","author":"JA Wilson","year":"2011","unstructured":"Wilson JA, Carding PN, Patterson JM. Dysphagia after nonsurgical head and neck cancer treatment: Patients' perspectives. Otolaryng Head Neck. 2011;145(5):767\u201371. https:\/\/doi.org\/10.1177\/0194599811414506.","journal-title":"Otolaryng Head Neck"},{"issue":"1","key":"8826_CR36","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1186\/s12885-015-1598-x","volume":"15","author":"W Owadally","year":"2015","unstructured":"Owadally W, Hurt C, Timmins H, Parsons E, Townsend S, Patterson J, et al. PATHOS: a phase II\/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for human papillomavirus (HPV) positive oropharyngeal cancer. BMC Cancer. 2015;15(1):602. https:\/\/doi.org\/10.1186\/s12885-015-1598-x.","journal-title":"BMC Cancer"},{"issue":"3","key":"8826_CR37","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1023\/a:1026419023481","volume":"6","author":"MA List","year":"1997","unstructured":"List MA, Mumby P, Haraf D, Siston A, Mick R, MacCracken E, et al. Performance and quality of life outcome in patients completing concomitant chemoradiotherapy protocols for head and neck cancer. Qual Life Res. 1997;6(3):274\u201384. https:\/\/doi.org\/10.1023\/a:1026419023481.","journal-title":"Qual Life Res"},{"issue":"6","key":"8826_CR38","doi-asserted-by":"publisher","first-page":"e466","DOI":"10.3747\/co.24.3543","volume":"24","author":"R Martino","year":"2017","unstructured":"Martino R, Ringash J, Durkin L, Greco E, Huang SH, Xu W, et al. Feasibility of assessing patient health benefits and incurred costs resulting from early dysphagia intervention during and immediately after chemoradiotherapy for head-and-neck cancer. Curr Oncol. 2017;24(6):e466\u2013e76. https:\/\/doi.org\/10.3747\/co.24.3543.","journal-title":"Curr Oncol"},{"issue":"7","key":"8826_CR39","first-page":"870","volume":"127","author":"AY Chen","year":"2001","unstructured":"Chen AY, Frankowski R, Bishop-Leone J, Hebert T, Leyk S, Lewin J, et al. The development and validation of a dysphagia-specific quality-of-life questionnaire for patients with head and neck cancer: the M.D. Anderson dysphagia inventory. Arch Otolaryngol Head Neck Surg. 2001;127(7):870\u20136.","journal-title":"Arch Otolaryngol Head Neck Surg"},{"issue":"3","key":"8826_CR40","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1007\/s00455-011-9375-8","volume":"27","author":"S Carlsson","year":"2012","unstructured":"Carlsson S, Ryden A, Rudberg I, Bove M, Bergquist H, Finizia C. Validation of the Swedish M. D. Anderson dysphagia inventory (MDADI) in patients with head and neck cancer and neurologic swallowing disturbances. Dysphagia. 2012;27(3):361\u20139. https:\/\/doi.org\/10.1007\/s00455-011-9375-8.","journal-title":"Dysphagia."},{"issue":"2","key":"8826_CR41","first-page":"97","volume":"129","author":"A Schindler","year":"2008","unstructured":"Schindler A, Borghi E, Tiddia C, Ginocchio D, Felisati G, Ottaviani F. Adaptation and validation of the Italian MD Anderson dysphagia inventory (MDADI). Revue de laryngologie - otologie - rhinologie. 2008;129(2):97\u2013100.","journal-title":"Revue de laryngologie - otologie - rhinologie"},{"issue":"4","key":"8826_CR42","doi-asserted-by":"publisher","first-page":"479","DOI":"10.5535\/arm.2013.37.4.479","volume":"37","author":"CH Kwon","year":"2013","unstructured":"Kwon CH, Kim YH, Park JH, Oh BM, Han TR. Validity and reliability of the korean version of the MD Anderson dysphagia inventory for head and neck cancer patients. Ann Rehabil Med. 2013;37(4):479\u201387. https:\/\/doi.org\/10.5535\/arm.2013.37.4.479.","journal-title":"Ann Rehabil Med"},{"issue":"4","key":"8826_CR43","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1007\/s00405-011-1756-y","volume":"269","author":"RC Dwivedi","year":"2012","unstructured":"Dwivedi RC, Chisholm EJ, Khan AS, Harris NJ, Bhide SA, St Rose S, et al. An exploratory study of the influence of clinico-demographic variables on swallowing and swallowing-related quality of life in a cohort of oral and oropharyngeal cancer patients treated with primary surgery. Eur Arch Otorhinolaryngol. 2012;269(4):1233\u20139. https:\/\/doi.org\/10.1007\/s00405-011-1756-y.","journal-title":"Eur Arch Otorhinolaryngol"},{"issue":"5","key":"8826_CR44","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1002\/lary.25778","volume":"126","author":"KA Hutcheson","year":"2016","unstructured":"Hutcheson KA, Barrow MP, Lisec A, Barringer DA, Gries K, Lewin JS. What is a clinically relevant difference in MDADI scores between groups of head and neck cancer patients? Laryngoscope. 2016;126(5):1108\u201313. https:\/\/doi.org\/10.1002\/lary.25778.","journal-title":"Laryngoscope."},{"issue":"7","key":"8826_CR45","doi-asserted-by":"publisher","first-page":"1634","DOI":"10.1002\/1097-0142(20001001)89:7<1634::AID-CNCR29>3.0.CO;2-V","volume":"89","author":"CS Cleeland","year":"2000","unstructured":"Cleeland CS, Mendoza TR, Wang XS, Chou C, Harle MT, Morrissey M, et al. Assessing symptom distress in cancer patients - the MD Anderson Symptom Inventory. Cancer. 2000;89(7):1634\u201346. https:\/\/doi.org\/10.1002\/1097-0142(20001001)89:7<1634::AID-CNCR29>3.0.CO;2-V.","journal-title":"Cancer"},{"issue":"13","key":"8826_CR46","doi-asserted-by":"publisher","first-page":"1975","DOI":"10.1002\/cncr.28672","volume":"120","author":"DI Rosenthal","year":"2014","unstructured":"Rosenthal DI, Mendoza TR, Fuller CD, Hutcheson KA, Wang XS, Hanna EY, et al. Patterns of symptom burden during radiotherapy or concurrent chemoradiotherapy for head and neck cancer. Cancer. 2014;120(13):1975\u201384. https:\/\/doi.org\/10.1002\/cncr.28672.","journal-title":"Cancer."},{"issue":"1","key":"8826_CR47","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s00455-009-9258-4","volume":"26","author":"R Leonard","year":"2011","unstructured":"Leonard R, Rees CJ, Belafsky P, Allen J. Fluoroscopic surrogate for pharyngeal strength: the pharyngeal constriction ratio (PCR). Dysphagia. 2011;26(1):13\u20137. https:\/\/doi.org\/10.1007\/s00455-009-9258-4.","journal-title":"Dysphagia."},{"issue":"2","key":"8826_CR48","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/BF00417897","volume":"11","author":"JC Rosenbek","year":"1996","unstructured":"Rosenbek JC, Robbins JA, Roecker EB, Coyle JL, Wood JL. A penetration-aspiration scale. Dysphagia. 1996;11(2):93\u20138. https:\/\/doi.org\/10.1007\/BF00417897.","journal-title":"Dysphagia."},{"key":"8826_CR49","unstructured":"Leonard R, Kendall K. Dysphagia assessment and treatment planning : a team approach. Fourth edition. ed. San Diego: Plural Publishing; 2019. xiv, 388 pages p."},{"issue":"11","key":"8826_CR50","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1001\/jamaoto.2019.2725","volume":"145","author":"KA Hutcheson","year":"2019","unstructured":"Hutcheson KA, Warneke CL, Yao C, Zaveri J, Elgohari BE, Goepfert R, et al. Dysphagia After Primary Transoral Robotic Surgery With Neck Dissection vs Nonsurgical Therapy in Patients With Low- to Intermediate-Risk Oropharyngeal Cancer. JAMA Otolaryngol Head Neck Surg. 2019;145(11):1053\u201363.","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"issue":"1","key":"8826_CR51","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1097\/MCG.0000000000000100","volume":"49","author":"Y Lan","year":"2015","unstructured":"Lan Y, Xu G, Dou Z, Lin T, Yu F, Jiang L. The correlation between manometric and videofluoroscopic measurements of the swallowing function in brainstem stroke patients with dysphagia. J Clin Gastroenterol. 2015;49(1):24\u201330. https:\/\/doi.org\/10.1097\/MCG.0000000000000100.","journal-title":"J Clin Gastroenterol"},{"issue":"12","key":"8826_CR52","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1177\/000348940611501207","volume":"115","author":"R Leonard","year":"2006","unstructured":"Leonard R, Belafsky PC, Rees CJ. Relationship between fluoroscopic and manometric measures of pharyngeal constriction: the pharyngeal constriction ratio. Ann Otol Rhinol Laryngol. 2006;115(12):897\u2013901. https:\/\/doi.org\/10.1177\/000348940611501207.","journal-title":"Ann Otol Rhinol Laryngol"},{"issue":"1","key":"8826_CR53","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1002\/lio2.226","volume":"4","author":"R Leonard","year":"2019","unstructured":"Leonard R. Predicting aspiration risk in patients with dysphagia: evidence from fluoroscopy. Laryngoscope Investig Otolaryngol. 2019;4(1):83\u20138. https:\/\/doi.org\/10.1002\/lio2.226.","journal-title":"Laryngoscope Investig Otolaryngol"},{"issue":"3","key":"8826_CR54","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1002\/1097-0142(19900801)66:3<564::AID-CNCR2820660326>3.0.CO;2-D","volume":"66","author":"MA List","year":"1990","unstructured":"List MA, Rittersterr C, Lansky SB. A performance status scale for head and neck-cancer patients. Cancer. 1990;66(3):564\u20139. https:\/\/doi.org\/10.1002\/1097-0142(19900801)66:3<564::AID-CNCR2820660326>3.0.CO;2-D.","journal-title":"Cancer."},{"issue":"11","key":"8826_CR55","doi-asserted-by":"publisher","first-page":"2294","DOI":"10.1002\/(SICI)1097-0142(19960601)77:11<2294::AID-CNCR17>3.0.CO;2-S","volume":"77","author":"MA List","year":"1996","unstructured":"List MA, D'Antonio LL, Cella DF, Siston A, Mumby P, Haraf D, et al. The performance status scale for head and neck Cancer patients and the functional assessment of Cancer therapy-head and neck scale. A study of utility and validity. Cancer. 1996;77(11):2294\u2013301. https:\/\/doi.org\/10.1002\/(SICI)1097-0142(19960601)77:11<2294::AID-CNCR17>3.0.CO;2-S.","journal-title":"Cancer."},{"issue":"5","key":"8826_CR56","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.jclinepi.2008.05.007","volume":"62","author":"R Martino","year":"2009","unstructured":"Martino R, Beaton D, Diamant NE. Using different perspectives to generate items for a new scale measuring medical outcomes of dysphagia (MOD). J Clin Epidemiol. 2009;62(5):518\u201326. https:\/\/doi.org\/10.1016\/j.jclinepi.2008.05.007.","journal-title":"J Clin Epidemiol"},{"key":"8826_CR57","doi-asserted-by":"publisher","unstructured":"Heitzmann CAMT, Jean-Pierre P, Roscoe JA, Kirsh KL, Passik SD. Assessing self-efficacy for coping with cancer: development and psycometric analysis of the brief version of Cancer behavior inventory (CBI-B). Psycho-oncology. 2011;20(3):302\u201312. https:\/\/doi.org\/10.1002\/pon.1735.","DOI":"10.1002\/pon.1735"},{"key":"8826_CR58","doi-asserted-by":"publisher","unstructured":"Merluzzi TVMSM. Assessment of self-efficacy and coping with cancer: development and validation of the Cancer and behaviour inventory. Health Psychol. 1997;16(2):163\u201370. https:\/\/doi.org\/10.1037\/0278-6133.16.2.163.","DOI":"10.1037\/0278-6133.16.2.163"},{"key":"8826_CR59","doi-asserted-by":"publisher","unstructured":"Mertuzzi TVNR, Hedge K, Martinez Sanchez MA, Dunn L. Self-efficacy for coping with cancer: revision of the Cancer behavior inventory (version 2.0). Psycho-oncology. 2001;10(3):206\u201317. https:\/\/doi.org\/10.1002\/pon.511.","DOI":"10.1002\/pon.511"},{"key":"8826_CR60","doi-asserted-by":"crossref","unstructured":"Merluzzi TVPE, Heitzmann Ruhf CA, Liu H, Yang M, Conley CC. Self-efficacy for coping with cancer: revision of the Cancer behavior inventory (version 3.0). Psychological Assessment. 2017.","DOI":"10.1037\/t67018-000"},{"key":"8826_CR61","doi-asserted-by":"crossref","unstructured":"Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727\u201336.","DOI":"10.1007\/s11136-011-9903-x"},{"issue":"1","key":"8826_CR62","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/1472-6831-12-48","volume":"12","author":"DS Saund","year":"2012","unstructured":"Saund DS, Pearson D, Dietrich T. Reliability and validity of self-assessment of mouth opening: a validation study. BMC Oral Health. 2012;12(1):48. https:\/\/doi.org\/10.1186\/1472-6831-12-48.","journal-title":"BMC Oral Health"},{"key":"8826_CR63","unstructured":"(CTEP) CTEP. Common Terminology Criteria for Adverse Events (CTCAE) v5.0 USA: U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES; 2017 [Available from: https:\/\/ctep.cancer.gov\/protocolDevelopment\/electronic_applications\/ctc.htm."},{"issue":"15","key":"8826_CR64","doi-asserted-by":"publisher","first-page":"2387","DOI":"10.1002\/sim.1526","volume":"22","author":"A Dmitrienko","year":"2003","unstructured":"Dmitrienko A, Offen WW, Westfall PH. Gatekeeping strategies for clinical trials that do not require all primary effects to be significant. Stat Med. 2003;22(15):2387\u2013400. https:\/\/doi.org\/10.1002\/sim.1526.","journal-title":"Stat Med"},{"issue":"2","key":"8826_CR65","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1007\/s11121-011-0221-x","volume":"14","author":"R Wang","year":"2013","unstructured":"Wang R, Ware JH. Detecting moderator effects using subgroup analyses. Prev Sci. 2013;14(2):111\u201320. https:\/\/doi.org\/10.1007\/s11121-011-0221-x.","journal-title":"Prev Sci"},{"issue":"1","key":"8826_CR66","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1002\/mpr.329","volume":"20","author":"MJ Azur","year":"2011","unstructured":"Azur MJ, Stuart EA, Frangakis C, Leaf PJ. Multiple imputation by chained equations: what is it and how does it work? Int J Methods Psychiatr Res. 2011;20(1):40\u20139. https:\/\/doi.org\/10.1002\/mpr.329.","journal-title":"Int J Methods Psychiatr Res"},{"issue":"5","key":"8826_CR67","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1586\/14737167.4.5.581","volume":"4","author":"GR Norman","year":"2004","unstructured":"Norman GR, Sloan JA, Wyrwich KW. The truly remarkable universality of half a standard deviation: confirmation through another look. Expert Rev Pharmacoecon Outcomes Res. 2004;4(5):581\u20135. https:\/\/doi.org\/10.1586\/14737167.4.5.581.","journal-title":"Expert Rev Pharmacoecon Outcomes Res"},{"issue":"3","key":"8826_CR68","doi-asserted-by":"publisher","first-page":"117","DOI":"10.3342\/ceo.2013.6.3.117","volume":"6","author":"N Denaro","year":"2013","unstructured":"Denaro N, Merlano MC, Russi EG. Dysphagia in head and neck cancer patients: pretreatment evaluation, predictive factors, and assessment during radio-chemotherapy, recommendations. Clin Exp Otorhinolaryngol. 2013;6(3):117\u201326. https:\/\/doi.org\/10.3342\/ceo.2013.6.3.117.","journal-title":"Clin Exp Otorhinolaryngol"},{"issue":"8","key":"8826_CR69","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1016\/j.oraloncology.2015.04.008","volume":"51","author":"M Naik","year":"2015","unstructured":"Naik M, Ward MC, Bledsoe TJ, Kumar AM, Rybicki LA, Saxton JP, et al. It is not just IMRT: human papillomavirus related oropharynx squamous cell carcinoma is associated with better swallowing outcomes after definitive chemoradiotherapy. Oral Oncol. 2015;51(8):800\u20134. https:\/\/doi.org\/10.1016\/j.oraloncology.2015.04.008.","journal-title":"Oral Oncol"},{"issue":"10","key":"8826_CR70","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1002\/hed.23465","volume":"36","author":"HM Starmer","year":"2014","unstructured":"Starmer HM, Tippett D, Webster K, Quon H, Jones B, Hardy S, et al. Swallowing outcomes in patients with oropharyngeal cancer undergoing organ-preservation treatment. Head Neck. 2014;36(10):1392\u20137. https:\/\/doi.org\/10.1002\/hed.23465.","journal-title":"Head Neck."},{"issue":"2","key":"8826_CR71","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1007\/s00455-016-9757-z","volume":"32","author":"LR Wall","year":"2016","unstructured":"Wall LR, Ward EC, Cartmill B, Hill AJ, Porceddu SV. Adherence to a prophylactic swallowing therapy program during (chemo) radiotherapy: impact of service-delivery model and patient factors. Dysphagia. 2016;32(2):279\u201392. https:\/\/doi.org\/10.1007\/s00455-016-9757-z.","journal-title":"Dysphagia."}],"container-title":["BMC Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12885-021-08826-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12885-021-08826-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12885-021-08826-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T06:42:21Z","timestamp":1634107341000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmccancer.biomedcentral.com\/articles\/10.1186\/s12885-021-08826-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,13]]},"references-count":71,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["8826"],"URL":"https:\/\/doi.org\/10.1186\/s12885-021-08826-0","relation":{},"ISSN":["1471-2407"],"issn-type":[{"value":"1471-2407","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,13]]},"assertion":[{"value":"21 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 October 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 October 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All versions of the study protocol and informed consent forms will be reviewed and approved by the Research Ethics Board (REB\/Institutional Review Board (IRB) of each site before the trial is implemented. The Princess Margaret Cancer Centre (PM), part of the University Health Network (UHN) in Toronto, ON is the prime site and was reviewed by Clinical Trials Ontario, as the review of record (CTO Project ID: 1363). In addition, the remaining ten participating sites also underwent local ethics review. Across all sites, PRO-ACTIVE informed consent forms are harmonized for relevant trial particulars while adhering to local REB\/IRB standards. As part of the informed consent process, the PRO-ACTIVE study team will only approach participants once they have shown interest in the trial to a member from their direct circle of care. The study team will explain the research study to the participant and answer any questions that may arise. A verbal explanation will be provided in terms suited to the participant\u2019s comprehension of the purposes, procedures, and potential risks of the study and of their rights as research participants. Participants will have the opportunity to carefully review the written consent form, ask questions and discuss the study with their family or surrogates prior to agreeing to participate. The participant will sign the informed consent document prior to any procedures being done specifically for the study. Participants will be informed that participation is voluntary and that they may withdraw from the study at any time, without prejudice. A copy of the informed consent document will be given to the participants for their records. The informed consent process will be conducted and documented in the source document (including the date), and the form signed, before the participant undergoes any study-specific procedures. The rights and welfare of the participants will be protected by emphasizing to them that the quality of their medical care will not be adversely affected if they decline to participate in this study.","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 that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1100"}}