{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:28:20Z","timestamp":1792114100855,"version":"4.4.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,1,14]],"date-time":"2019-01-14T00:00:00Z","timestamp":1547424000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,1,14]],"date-time":"2019-01-14T00:00:00Z","timestamp":1547424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F&amp;#x00F6;rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["320030_160327"],"award-info":[{"award-number":["320030_160327"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The rationale of this paper is to investigate right ventricular (RV) hemodynamics in relation to changes in cardiac output, and in particular to study exercise-induced stresses at the RV outflow tract (RVOT), which is a common site of ventricular arrhythmias in the athlete\u2019s heart. We hypothesize that the thin-walled RVOT is exposed to high wall shear stresses (WSS) during physiological states associated with high cardiac output such as exercise, and therefore, may be particularly prone to substrate formation leading to ventricular tachyarrhythmias. 3D Particle Tracking Velocimetry (3D-PTV), an optical imaging method, has been performed in a novel anatomically accurate compliant silicone right heart model derived from a high resolution MRI heart scan of a healthy male proband. RV and RVOT flow patterns at resting conditions were obtained from two healthy athletic male proband\u2019s hearts and two patients with arrhythmogenic right ventricular cardiomyopathy\/dysplasia (ARVC\/D) via phase contrast magnetic resonance imaging (PC-MRI). The healthy case was used as a reference for validating the <jats:italic>in vitro<\/jats:italic> flow patterns of the silicone model, while the diseased cases were used to generalize our findings and investigate possible changes in hemodynamic stresses with RV morphological remodelling. Our results showed that both healthy and diseased geometries consistently displayed an increased WSS in the RVOT relative to the rest of the RV. We found that increases in cardiac output may lead to increases of mean kinetic energy (MKE), laminar viscous dissipation and WSS at the RVOT. Furthermore, higher peak WSS magnitudes were found for the diseased cases. The identified high WSS regions may correlate with the common site of RVOT ventricular tachycardia in athletes and patients with ARVC\/D. Our results imply that exercise, as well as anatomical and functional remodeling might alter RV wall shear stress both in magnitude and spatial distribution, leading to increased hemodynamic stresses in the RVOT.<\/jats:p>","DOI":"10.1038\/s41598-018-36614-7","type":"journal-article","created":{"date-parts":[[2019,1,8]],"date-time":"2019-01-08T18:35:36Z","timestamp":1546972536000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Hemodynamic Changes in the Right Ventricle Induced by Variations of Cardiac Output: A Possible Mechanism for Arrhythmia Occurrence in the Outflow Tract"],"prefix":"10.1038","volume":"9","author":[{"given":"Utku","family":"G\u00fclan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ardan Muammer","family":"Saguner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deniz","family":"Akdis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Gotschy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix C.","family":"Tanner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Kozerke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Manka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Brunckhorst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Holzner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firat","family":"Duru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,1,14]]},"reference":[{"key":"36614_CR1","doi-asserted-by":"publisher","first-page":"1652","DOI":"10.1016\/S0735-1097(96)00393-2","volume":"28","author":"J Niebauer","year":"1996","unstructured":"Niebauer, J. & Cooke, J. P. Cardiovascular effects of exercise: Role of endothelial shear stress. Journal of the American College of Cardiology 28, 1652\u20131660, https:\/\/doi.org\/10.1016\/S0735-1097(96)00393-2 (1996).","journal-title":"Journal of the American College of Cardiology"},{"key":"36614_CR2","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/S0025-6196(11)60548-X","volume":"84","author":"CJ Lavie","year":"2009","unstructured":"Lavie, C. J., Thomas, R. J., Squires, R. W., Allison, T. G. & Milani, R. V. Exercise training and cardiac rehabilitation in primary and secondary prevention of coronary heart disease. Mayo Clinic Proceedings 84, 373\u2013383 (2009).","journal-title":"Mayo Clinic Proceedings"},{"issue":"587","key":"36614_CR3","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.mayocp.2012.04.005","volume":"87","author":"JH O\u2019Keefe","year":"2012","unstructured":"O\u2019Keefe, J. H. et al. Potential adverse cardiovascular effects from excessive endurance exercise. Mayo Clinic Proceedings 87(587), 595, https:\/\/doi.org\/10.1016\/j.mayocp.2012.04.005 (2012).","journal-title":"Mayo Clinic Proceedings"},{"key":"36614_CR4","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1002\/cphy.c100091","volume":"2","author":"R Naeije","year":"2012","unstructured":"Naeije, R. & Chesler, N. Pulmonary circulation at exercise. Comprehensive Physiology 2, 711\u2013741 (2012).","journal-title":"Comprehensive Physiology"},{"key":"36614_CR5","doi-asserted-by":"publisher","unstructured":"Baggish, A. L. et al. The impact of endurance exercise training on left ventricular systolic mechanics. American Journal of Physiology-Heart and Circulatory Physiology 295, H1109\u2013H1116, https:\/\/doi.org\/10.1152\/ajpheart.00395.2008 PMID: 18621855 (2008).","DOI":"10.1152\/ajpheart.00395.2008"},{"key":"36614_CR6","doi-asserted-by":"publisher","unstructured":"Stohr, E. J., Gonz\u00e1lez-Alonso, J., Bezodis, I. N. & Shave, R. Left ventricular energetics: new insight into the plasticity of regional contributions at rest and during exercise. American Journal of Physiology-Heart and Circulatory Physiology 306, H225\u2013H232, https:\/\/doi.org\/10.1152\/ajpheart.00938.2012 PMID: 24213618 (2014).","DOI":"10.1152\/ajpheart.00938.2012"},{"key":"36614_CR7","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1249\/MSS.0000000000000282","volume":"46","author":"G Claessen","year":"2014","unstructured":"Claessen, G. et al. Right ventricular fatigue developing during endurance exercise: An exercise cardiac magnetic resonance study. Medicine & Science in Sports & Exercise 46, 1717\u20131726 (2014).","journal-title":"Medicine & Science in Sports & Exercise"},{"key":"36614_CR8","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1136\/bjsports-2014-093895","volume":"49","author":"AD Elliott","year":"2015","unstructured":"Elliott, A. D. & La Gerche, A. The right ventricle following prolonged endurance exercise: are we overlooking the more important side of the heart? a meta-analysis. British Journal of Sports Medicine 49, 724\u2013729, https:\/\/doi.org\/10.1136\/bjsports-2014-093895 (2015).","journal-title":"British Journal of Sports Medicine"},{"key":"36614_CR9","doi-asserted-by":"crossref","unstructured":"La Gerche, A., Claessen, G. & Van De Bruaene, A. Right Ventricular Structure and Function During Exercise, 83\u201398 (Springer London, London, 2014).","DOI":"10.1007\/978-1-4471-2398-9_7"},{"key":"36614_CR10","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1136\/hrt.2009.189621","volume":"96","author":"A La Gerche","year":"2010","unstructured":"La Gerche, A. et al. Lower than expected desmosomal gene mutation prevalence in endurance athletes with complex ventricular arrhythmias of right ventricular origin. Heart 96, 1268\u20131274, https:\/\/doi.org\/10.1136\/hrt.2009.189621 (2010).","journal-title":"Heart"},{"key":"36614_CR11","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1016\/j.jacc.2013.06.033","volume":"62","author":"CA James","year":"2013","unstructured":"James, C. A. et al. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia\/cardiomyopathy\u2013associated desmosomal mutation carriers. Journal of the American College of Cardiology 62, 1290\u20131297, https:\/\/doi.org\/10.1016\/j.jacc.2013.06.033 (2013).","journal-title":"Journal of the American College of Cardiology"},{"key":"36614_CR12","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1093\/eurheartj\/ehr397","volume":"33","author":"A La Gerche","year":"2012","unstructured":"La Gerche, A. et al. Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes. European Heart Journal 33, 998\u20131006, https:\/\/doi.org\/10.1093\/eurheartj\/ehr397 (2012).","journal-title":"European Heart Journal"},{"key":"36614_CR13","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1016\/S0735-1097(02)02478-6","volume":"40","author":"J Scharhag","year":"2002","unstructured":"Scharhag, J. et al. Athlete\u2019s heart: Right and left ventricular mass and function in male endurance athletes and untrained individuals determined by magnetic resonance imaging. Journal of the American College of Cardiology 40, 1856\u20131863 (2002).","journal-title":"Journal of the American College of Cardiology"},{"key":"36614_CR14","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.jacc.2016.11.041","volume":"69","author":"J Venlet","year":"2017","unstructured":"Venlet, J. et al. Isolated subepicardial right ventricular outflow tract scar in athletes with ventricular tachycardia. Journal of the American College of Cardiology 69, 497\u2013507 (2017).","journal-title":"Journal of the American College of Cardiology"},{"key":"36614_CR15","doi-asserted-by":"publisher","unstructured":"de la Garza, M. S. et al. Severity of structural and functional right ventricular remodeling depends on training load in an experimental model of endurance exercise. American Journal of Physiology-Heart and Circulatory Physiology 313, H459\u2013H468, https:\/\/doi.org\/10.1152\/ajpheart.00763.2016 PMID: 28550178 (2017).","DOI":"10.1152\/ajpheart.00763.2016"},{"key":"36614_CR16","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/nrcardio.2016.173","volume":"14","author":"E Guasch","year":"2017","unstructured":"Guasch, E. & Mont, L. Diagnosis, pathophysiology, and management of exercise-induced arrhythmias. Nat Rev Cardiol 14, 88\u2013101 (2017).","journal-title":"Nat Rev Cardiol"},{"key":"36614_CR17","doi-asserted-by":"publisher","unstructured":"Fredriksson, A. et al. Turbulent kinetic energy in the right ventricle: Potential mr marker for risk stratification of adults with repaired tetralogy of fallot. Journal of Magnetic Resonance Imaging n\/a\u2013n\/a., https:\/\/doi.org\/10.1002\/jmri.25830.","DOI":"10.1002\/jmri.25830"},{"key":"36614_CR18","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.jbiomech.2017.03.006","volume":"56","author":"U G\u00fclan","year":"2017","unstructured":"G\u00fclan, U., Binter, C., Kozerke, S. & Holzner, M. Shear-scaling-based approach for irreversible energy loss estimation in stenotic aortic flow \u2013 an in vitro study. Journal of Biomechanics 56, 89\u201396 (2017).","journal-title":"Journal of Biomechanics"},{"key":"36614_CR19","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1002\/jmri.24633","volume":"41","author":"J Zajac","year":"2015","unstructured":"Zajac, J. et al. Turbulent kinetic energy in normal and myopathic left ventricles. Journal of Magnetic Resonance Imaging 41, 1021\u20131029, https:\/\/doi.org\/10.1002\/jmri.24633 (2015).","journal-title":"Journal of Magnetic Resonance Imaging"},{"key":"36614_CR20","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1002\/jmri.22407","volume":"33","author":"P Dyverfeldt","year":"2011","unstructured":"Dyverfeldt, P. et al. Hemodynamic aspects of mitral regurgitation assessed by generalized phase-contrast mri. Journal of Magnetic Resonance Imaging 33, 582\u2013588, https:\/\/doi.org\/10.1002\/jmri.22407 (2011).","journal-title":"Journal of Magnetic Resonance Imaging"},{"key":"36614_CR21","doi-asserted-by":"publisher","unstructured":"Binter, C. et al. Turbulent kinetic energy assessed by multipoint 4-dimensional flow magnetic resonance imaging provides additional information relative to echocardiography for the determination of aortic stenosis severityclinical perspective. Circulation: Cardiovascular Imaging 10, https:\/\/doi.org\/10.1161\/CIRCIMAGING.116.005486 (2017).","DOI":"10.1161\/CIRCIMAGING.116.005486"},{"key":"36614_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17117-3","volume":"7","author":"U G\u00fclan","year":"2017","unstructured":"G\u00fclan, U. et al. Investigation of atrial vortices using a novel right heart model and possible implications for atrial thrombus formation. Scientific Reports 7, 16772, https:\/\/doi.org\/10.1038\/s41598-017-17117-3 (2017).","journal-title":"Scientific Reports"},{"key":"36614_CR23","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1093\/cvr\/cvt044","volume":"99","author":"V Peiffer","year":"2013","unstructured":"Peiffer, V., Sherwin, S. & Weinberg, P. Does low and oscillatory wall shear stress correlate spatially with early atherosclerosis? a systematic review. Cardiovascular Research 99, 242\u2013250, https:\/\/doi.org\/10.1093\/cvr\/cvt044 (2013).","journal-title":"Cardiovascular Research"},{"key":"36614_CR24","doi-asserted-by":"publisher","first-page":"2120","DOI":"10.1111\/j.1540-8159.1996.tb03287.x","volume":"19","author":"BB Lerman","year":"1996","unstructured":"Lerman, B. B., Stein, K. M. & Markowitz, S. M. Idiopathic right ventricular outflow tract tachycardia: A clinical approach. Pacing and Clinical Electrophysiology 19, 2120\u20132137, https:\/\/doi.org\/10.1111\/j.1540-8159.1996.tb03287.x (1996).","journal-title":"Pacing and Clinical Electrophysiology"},{"key":"36614_CR25","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/S0195-668X(02)00654-1","volume":"24","author":"D O\u2019Donnell","year":"2003","unstructured":"O\u2019Donnell, D., Cox, D., Bourke, J., Mitchell, L. & Furniss, S. Clinical and electrophysiological differences between patients with arrhythmogenic right ventricular dysplasia and right ventricular outflow tract tachycardia. European Heart Journal 24, 801\u2013810, https:\/\/doi.org\/10.1016\/S0195-668X(02)00654-1 (2003).","journal-title":"European Heart Journal"},{"key":"36614_CR26","doi-asserted-by":"publisher","first-page":"2854","DOI":"10.1253\/circj.CJ-14-0474","volume":"78","author":"AM Saguner","year":"2014","unstructured":"Saguner, A. M. et al. Clinical role of atrial arrhythmias in patients with arrhythmogenic right ventricular dysplasia. Circulation Journal 78, 2854\u20132861 (2014).","journal-title":"Circulation Journal"},{"key":"36614_CR27","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/0002-8703(82)90190-9","volume":"104","author":"EV Palileo","year":"1982","unstructured":"Palileo, E. V. et al. Exercise provocable right ventricular outflow tract tachycardia. American Heart Journal 104, 185\u2013193, https:\/\/doi.org\/10.1016\/0002-8703(82)90190-9 (1982).","journal-title":"American Heart Journal"},{"key":"36614_CR28","doi-asserted-by":"publisher","first-page":"H113","DOI":"10.1152\/ajpheart.00544.2015","volume":"310","author":"K Steding-Ehrenborg","year":"2016","unstructured":"Steding-Ehrenborg, K. et al. Determinants of kinetic energy of blood flow in the four-chambered heart in athletes and sedentary controls. American Journal of Physiology - Heart and Circulatory Physiology 310, H113\u2013H122, https:\/\/doi.org\/10.1152\/ajpheart.00544.2015 (2016).","journal-title":"American Journal of Physiology - Heart and Circulatory Physiology"},{"key":"36614_CR29","doi-asserted-by":"publisher","unstructured":"Carlsson, M. et al. Quantification of left and right ventricular kinetic energy using four-dimensional intracardiac magnetic resonance imaging flow measurements. American Journal of Physiology-Heart and Circulatory Physiology 302, H893\u2013H900, https:\/\/doi.org\/10.1152\/ajpheart.00942.2011, PMID: 22180653 (2012).","DOI":"10.1152\/ajpheart.00942.2011"},{"key":"36614_CR30","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.4022\/jafib.1038","volume":"7","author":"A Fuenmayor","year":"2014","unstructured":"Fuenmayor, A. Treatment or cure of right ventricular outflow tract tachycardia. Journal of Atrial Fibrillation 7, 1038, https:\/\/doi.org\/10.4022\/jafib.1038 (2014).","journal-title":"Journal of Atrial Fibrillation"},{"key":"36614_CR31","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.11604\/pamj.2015.20.60.5864","volume":"20","author":"Y Kambire","year":"2015","unstructured":"Kambire, Y., Konate, L. & Millogo, G. R. C. Right ventricular outflow tract tachycardia worsened during pregnancy. The Pan African Medical Journal 20, 1038, https:\/\/doi.org\/10.11604\/pamj.2015.20.60.5864 (2015).","journal-title":"The Pan African Medical Journal"},{"key":"36614_CR32","first-page":"230","volume":"7","author":"AM Saguner","year":"2014","unstructured":"Saguner, A. M. et al. Different prognostic value of functional right ventricular parameters in arrhythmogenic right ventricular cardiomyopathy\/dysplasiaclinical perspective. Circulation: Cardiovascular Imaging 7, 230\u2013239 (2014).","journal-title":"Circulation: Cardiovascular Imaging"},{"key":"36614_CR33","doi-asserted-by":"publisher","unstructured":"Mangual, J., Domenichini, F. & Pedrizzetti, G. Three dimensional numerical assessment of the right ventricular flow using 4d echocardiography boundary data. European Journal of Mechanics - B\/Fluids 35, 25\u201330, https:\/\/doi.org\/10.1016\/j.euromechflu.2012.01.022 Cardiovascular Flows (2012).","DOI":"10.1016\/j.euromechflu.2012.01.022"},{"key":"36614_CR34","doi-asserted-by":"publisher","first-page":"H1064","DOI":"10.1152\/ajpheart.00804.2002","volume":"284","author":"A Pasipoularides","year":"2003","unstructured":"Pasipoularides, A., Shu, M., Shah, A., Womack, M. S. & Glower, D. D. Diastolic right ventricular filling vortex in normal and volume overload states. American Journal of Physiology - Heart and Circulatory Physiology 284, H1064\u2013H1072, https:\/\/doi.org\/10.1152\/ajpheart.00804.2002 (2003).","journal-title":"American Journal of Physiology - Heart and Circulatory Physiology"},{"key":"36614_CR35","doi-asserted-by":"publisher","unstructured":"G\u00fclan, U., Calen, C., Duru, F. & Holzner, M. Blood flow patterns and pressure loss in the ascending aorta: A comparative study on physiological and aneurysmal conditions. Journal of Biomechanics, https:\/\/doi.org\/10.1016\/j.jbiomech.2018.05.033 (2018).","DOI":"10.1016\/j.jbiomech.2018.05.033"},{"key":"36614_CR36","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1007\/s00348-012-1371-8","volume":"53","author":"U Gulan","year":"2012","unstructured":"Gulan, U. et al. Experimental study of aortic flow in the ascending aorta via particle tracking velocimetry. Experiments in Fluids 53, 1469\u20131485 (2012).","journal-title":"Experiments in Fluids"},{"key":"36614_CR37","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1002\/mrm.24370","volume":"69","author":"C Binter","year":"2013","unstructured":"Binter, C., Knobloch, V., Manka, R., Sigfridsson, A. & Kozerke, S. Bayesian multipoint velocity encoding for concurrent flow and turbulence mapping. Magnetic Resonance in Medicine 69, 1337\u20131345, https:\/\/doi.org\/10.1002\/mrm.24370 (2013).","journal-title":"Magnetic Resonance in Medicine"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-36614-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-36614-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-36614-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T04:49:28Z","timestamp":1671252568000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-36614-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,14]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["36614"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-36614-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,14]]},"assertion":[{"value":"23 February 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"100"}}