{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T03:35:50Z","timestamp":1782790550748,"version":"3.54.5"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T00:00:00Z","timestamp":1478476800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T00:00:00Z","timestamp":1478476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Microsyst Nanoeng"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The higher risk of vaso-occlusion events and sudden death for sickle-cell trait (SCT) athletes has been speculatively ascribed to SCT red blood cell (RBC) stiffening during strenuous exercise. However, the microenvironmental changes that could induce the stiffening of SCT RBCs are unknown. To address this question, we measured the mechanical properties of and changes in SCT RBCs under deoxygenated and acidic environments, which are two typical conditions present in the circulation of athletes undertaking strenuous exercise. The results reveal that SCT RBCs are inherently stiffer than RBCs from non-SCT healthy subjects, and a lower pH further stiffens the SCT cells. Furthermore, at both normal and low pH levels, deoxygenation was found to not be the cause of the stiffness of SCT RBCs. This study confirms that the stiffening of SCT RBCs occurs at a low pH and implies that SCT RBC stiffening could be responsible for vaso-occlusion in SCT athletes during strenuous exercise.<\/jats:p>","DOI":"10.1038\/micronano.2016.61","type":"journal-article","created":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T05:10:07Z","timestamp":1478495407000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Stiffening of sickle cell trait red blood cells under simulated strenuous exercise conditions"],"prefix":"10.1038","volume":"2","author":[{"given":"Zhensong","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Shehata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaorong","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,11,7]]},"reference":[{"key":"BFmicronano201661_CR1","doi-asserted-by":"publisher","first-page":"1594","DOI":"10.1161\/CIRCULATIONAHA.110.004622","volume":"123","author":"KG Harmon","year":"2011","unstructured":"Harmon KG, Asif IM, Klossner D et al. Incidence of sudden cardiac death in national collegiate athletic association athletes. Circulation 2011; 123: 1594\u20131600.","journal-title":"Circulation"},{"key":"BFmicronano201661_CR2","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1161\/CIRCULATIONAHA.108.804617","volume":"119","author":"BJ Maron","year":"2009","unstructured":"Maron BJ, Doerer JJ, Haas TS et al. Sudden deaths in young competitive athletes analysis of 1866 deaths in the United States, 1980\u20132006. Circulation 2009; 119: 1085\u20131092.","journal-title":"Circulation"},{"key":"BFmicronano201661_CR3","first-page":"1738","volume":"329","author":"DM Hyslop","year":"1923","unstructured":"Hyslop DM . Sudden death in young athletes. The New England Journal of Medicine 1923; 329: 1738.","journal-title":"The New England Journal of Medicine"},{"key":"BFmicronano201661_CR4","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1136\/bjsports-2011-090896","volume":"46","author":"KG Harmon","year":"2012","unstructured":"Harmon KG, Drezner Ja, Klossner D et al. Sickle cell trait associated with a RR of death of 37 times in national collegiate athletic association football athletes: A database with 2 million athlete-years as the denominator. British Journal of Sports Medicine 2012; 46: 325\u2013330.","journal-title":"British Journal of Sports Medicine"},{"key":"BFmicronano201661_CR5","doi-asserted-by":"publisher","first-page":"931","DOI":"10.2165\/00007256-200838110-00004","volume":"38","author":"P Connes","year":"2008","unstructured":"Connes P, Reid H, Hardy-Dessources MD et al. Physiological responses of sickle cell trait carriers during exercise. Sports Medicine 2008; 38: 931\u2013946.","journal-title":"Sports Medicine"},{"key":"BFmicronano201661_CR6","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/j.amjmed.2008.12.020","volume":"122","author":"G Tsaras","year":"2009","unstructured":"Tsaras G, Owusu-Ansah A, Boateng FO et al. Complications associated with sickle cell trait: A brief narrative review. The American Journal of Medicine 2009; 122: 507\u2013512.","journal-title":"The American Journal of Medicine"},{"key":"BFmicronano201661_CR7","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1182\/asheducation-2013.1.632","volume":"2013","author":"Aa Thompson","year":"2013","unstructured":"Thompson Aa . Sickle cell trait testing and athletic participation: A solution in search of a problem? ASH Hematology, The Education Program 2013; 2013: 632\u2013637.","journal-title":"ASH Hematology, The Education Program"},{"key":"BFmicronano201661_CR8","first-page":"825","volume":"160","author":"A Ashley-Koch","year":"2000","unstructured":"Ashley-Koch A, Yang Q, Olney RS . Sickle hemoglobin (Hb S) allele and sickle cell disease: A HuGe review. American Journal of Epidemiology 2000; 160: 825\u2013841.","journal-title":"American Journal of Epidemiology"},{"key":"BFmicronano201661_CR9","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1182\/blood-2012-08-449397","volume":"121","author":"HF Bunn","year":"2013","unstructured":"Bunn HF . The triumph of good over evil: Protection by the sickle gene against malaria. Blood 2013; 121: 20\u201325.","journal-title":"Blood"},{"key":"BFmicronano201661_CR10","first-page":"300","volume":"99","author":"BL Mitchell","year":"2007","unstructured":"Mitchell BL . Sickle cell trait and sudden death--bringing it home. Journal of the National Medical Association 2007; 99: 300\u2013305.","journal-title":"Journal of the National Medical Association"},{"key":"BFmicronano201661_CR11","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1111\/j.1475-6773.2011.01357.x","volume":"47","author":"BethA Tarini","year":"2012","unstructured":"Tarini Beth A, Brooks Margaret Alison, Bundy David G . A policy impact analysis of the mandatory NCAA sickle cell trait screening program. Health Services Research 2012; 47: 446\u2013461.","journal-title":"Health Services Research"},{"key":"BFmicronano201661_CR12","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3233\/CH-131687","volume":"55","author":"Tripette Julien","year":"2013","unstructured":"Julien Tripette, Dessources Hardy, Dominique Marie et al. Exercise-related complications in sickle cell trait. Clinical Hemorheology and Microcirculation 2013; 55: 29\u201337.","journal-title":"Clinical Hemorheology and Microcirculation"},{"key":"BFmicronano201661_CR13","doi-asserted-by":"publisher","first-page":"20496","DOI":"10.1073\/pnas.0707122105","volume":"104","author":"JM Higgins","year":"2007","unstructured":"Higgins JM, Eddington DT, Bhatia SN et al. Sickle cell vasoocclusion and rescue in a microfluidic device. Proceedings of the National Academy of Sciences of the United States of America 2007; 104: 20496\u201320500.","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFmicronano201661_CR14","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1146\/annurev-bioeng-070909-105339","volume":"12","author":"GildaA Barabino","year":"2010","unstructured":"Barabino Gilda A, Platt Manu O, Kaul Dhananjay K . Sickle cell biomechanics. Annual Review of Biomedical Engineering 2010; 12: 345\u2013367.","journal-title":"Annual Review of Biomedical Engineering"},{"key":"BFmicronano201661_CR15","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1152\/jappl.1972.32.1.59","volume":"32","author":"JB Osnes","year":"1972","unstructured":"Osnes JB, Hermansen L . Acid-base balance after maximal exercise of short duration. Journal of Applied Physiology 1972; 32: 59\u201363.","journal-title":"Journal of Applied Physiology"},{"key":"BFmicronano201661_CR16","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1152\/jappl.1972.32.3.304","volume":"32","author":"L Hermansen","year":"1972","unstructured":"Hermansen L, Osnes JB . Blood and muscle pH after maximal exercise in man. Journal of Applied Physiology 1972; 32: 304\u2013308.","journal-title":"Journal of Applied Physiology"},{"key":"BFmicronano201661_CR17","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/S0927-7765(99)00164-2","volume":"19","author":"KD Tachev","year":"2000","unstructured":"Tachev KD, Angarska JK, Danov KD et al. Erythrocyte attachment to substrates\u202f: Determination of membrane tension and adhesion energy. Colloids and Surfaces B: Biointerfaces 2000; 19: 61\u201380.","journal-title":"Colloids and Surfaces B: Biointerfaces"},{"key":"BFmicronano201661_CR18","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1002\/(SICI)1099-0488(20000201)38:3<415::AID-POLB8>3.0.CO;2-Z","volume":"38","author":"TC Merkel","year":"2000","unstructured":"Merkel TC, Bondar VI, Nagai K et al. Gas sorption, diffusion, and permeation in poly (dimethylsiloxane). Journal of Polymer Sciences B: Polymer Physics 2000; 38: 415\u2013434.","journal-title":"Journal of Polymer Sciences B: Polymer Physics"},{"key":"BFmicronano201661_CR19","doi-asserted-by":"publisher","first-page":"3138","DOI":"10.1039\/C5LC00543D","volume":"15","author":"Yi Zheng","year":"2015","unstructured":"Zheng Yi, Cachia Mark A, Ge Ji et al. Mechanical differences of sickle cell trait (SCT) and normal red blood cells. Lab on a Chip 2015; 15: 3138\u20133146.","journal-title":"Lab on a Chip"},{"key":"BFmicronano201661_CR20","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1007\/s11517-008-0330-2","volume":"46","author":"RobertS Reneman","year":"2008","unstructured":"Reneman Robert S, Hoeks AP . Wall shear stress as measured in vivo: Consequences for the design of the arterial system. Medical & Biological Engineering & Computing 2008; 46: 499\u2013507.","journal-title":"Medical & Biological Engineering & Computing"},{"key":"BFmicronano201661_CR21","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1016\/S0006-3495(73)86036-9","volume":"13","author":"EA Evans","year":"1973","unstructured":"Evans EA . New membrane concept applied to the analysis of fluid shear- and micropipette-deformed red blood cells. Biophysical Journal 1973; 13: 941\u2013954.","journal-title":"Biophysical Journal"},{"key":"BFmicronano201661_CR22","doi-asserted-by":"publisher","first-page":"11240","DOI":"10.1039\/c2sm26513c","volume":"8","author":"Susanne Braunm\u00fcller","year":"2012","unstructured":"Braunm\u00fcller Susanne, Schmid Lothar, Sackmannc Erich et al. Hydrodynamic deformation reveals two coupled modes\/time scales of red blood cell relaxation. Soft Matter 2012; 8: 11240\u201311248.","journal-title":"Soft Matter"},{"key":"BFmicronano201661_CR23","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/S0006-3495(76)85713-X","volume":"16","author":"EA Evans","year":"1976","unstructured":"Evans EA, Waugh R, Melnik L . Elastic area compressibility modulus of red cell membrane. Biophysical Journal 1976; 16: 585\u2013595.","journal-title":"Biophysical Journal"},{"key":"BFmicronano201661_CR24","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.mbs.2006.09.026","volume":"209","author":"Xiao Liu","year":"2007","unstructured":"Liu Xiao, Tang Zhi-yu, Zeng Zhu et al. The measurement of shear modulus and membrane surface viscosity of RBC membrane with Ektacytometry: A new technique. Mathematical Biosciences 2007; 209: 190\u2013204.","journal-title":"Mathematical Biosciences"},{"key":"BFmicronano201661_CR25","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.jbiomech.2010.11.008","volume":"44","author":"JamieL Maciaszek","year":"2011","unstructured":"Maciaszek Jamie L, Lykotrafitis George . Sickle cell trait human erythrocytes are significantly stiffer than normal. Journal of Biomechanics 2011; 44: 657\u2013661.","journal-title":"Journal of Biomechanics"},{"key":"BFmicronano201661_CR26","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1081\/PRG-120005387","volume":"21","author":"B Schauf","year":"2002","unstructured":"Schauf B, Lang U, Stute P et al. Reduced red blood cell deformability, an indicator for high fetal or maternal risk, is found in preeclampsia and IUGR. Hypertension in Pregnancy 2002; 21: 147\u2013160.","journal-title":"Hypertension in Pregnancy"},{"key":"BFmicronano201661_CR27","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1055\/s-2003-44551","volume":"29","author":"OK Baskurt","year":"2003","unstructured":"Baskurt OK, Meiselman HJ . Blood rheology and hemodynamics. Seminars in Thrombosis and Hemostasis 2003; 29: 435\u2013450.","journal-title":"Seminars in Thrombosis and Hemostasis"},{"key":"BFmicronano201661_CR28","doi-asserted-by":"publisher","first-page":"1634","DOI":"10.1152\/jappl.1988.65.4.1634","volume":"65","author":"TS Hakim","year":"1988","unstructured":"Hakim TS . Erythrocyte deformability and segmental pulmonary vascular resistance: Osmolarity and heat treatment. Journal of Applied Physiology 1988; 65: 1634\u20131641.","journal-title":"Journal of Applied Physiology"},{"key":"BFmicronano201661_CR29","first-page":"H375","volume":"298","author":"Lucile Vincent","year":"2010","unstructured":"Vincent Lucile, F\u00e9asson L\u00e9onard, Oyono-Engu\u00e9ll\u00e9 Samuel et al. Remodeling of skeletal muscle microvasculature in sickle cell trait and alpha-thalassemia. American Journal of Physiology: Heart and Circulatory Physiology 2010; 298: H375\u2013H384.","journal-title":"American Journal of Physiology: Heart and Circulatory Physiology"},{"key":"BFmicronano201661_CR30","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1007\/s004240000061","volume":"440","author":"D Kuzman","year":"2000","unstructured":"Kuzman D, \u017dnidar\u010di\u010d T, Gros M et al. Effect of pH on red blood cell deformability. Pfl\u00fcgers Archiv 2000; 440: 193\u2013194.","journal-title":"Pfl\u00fcgers Archiv"},{"key":"BFmicronano201661_CR31","doi-asserted-by":"publisher","first-page":"e71219","DOI":"10.1371\/journal.pone.0071219","volume":"8","author":"MichaelJ Simmonds","year":"2013","unstructured":"Simmonds Michael J, Connes Philippe, Sabapathy Surendran . Exercise-induced blood lactate increase does not change red blood cell deformability in cyclists. PLoS One 2013; 8: e71219.","journal-title":"PLoS One"},{"key":"BFmicronano201661_CR32","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3233\/CH-2011-1507","volume":"51","author":"Nemeth Norbert","year":"2012","unstructured":"Norbert Nemeth, Iren Miko, Andrea Furka et al. Concerning the importance of changes in hemorheological parameters caused by acid-base and blood gas alterations in experimental surgical models. Clinical Hemorheology and Microcirculation 2012; 51: 43\u201350.","journal-title":"Clinical Hemorheology and Microcirculation"},{"key":"BFmicronano201661_CR33","doi-asserted-by":"crossref","first-page":"179","DOI":"10.3233\/CH-2008-1078","volume":"39","author":"Connes Philippe","year":"2008","unstructured":"Philippe Connes, Olivier Hue, Julien Tripette et al. Blood rheology abnormalities and vascular cell adhesion mechanisms in sickle cell trait carriers during exercise. Clinical Hemorheology and Microcirculation 2008; 39: 179\u2013184.","journal-title":"Clinical Hemorheology and Microcirculation"},{"key":"BFmicronano201661_CR34","doi-asserted-by":"publisher","first-page":"021012","DOI":"10.1115\/1.4032187","volume":"138","author":"DavidA Schreier","year":"2016","unstructured":"Schreier David A, Forouzan Omid, Hacker Timothy A et al. Increased red blood cell stiffness increases pulmonary vascular resistance and pulmonary arterial pressure. Journal of Biomechanical Engineering 2016; 138: 021012.","journal-title":"Journal of Biomechanical Engineering"},{"key":"BFmicronano201661_CR35","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1111\/ejh.12293","volume":"93","author":"Jessica Campos","year":"2014","unstructured":"Campos Jessica, Lobo Clarisse, Queiroz Ana Maria Mach et al. Treatment of the acute sickle cell vaso-occlusive crisis in the Emergency Department: A Brazilian method of switching from intravenous to oral morphine. European Journal of Haematology 2014; 93: 34\u201340.","journal-title":"European Journal of Haematology"},{"key":"BFmicronano201661_CR36","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.jsb.2005.02.001","volume":"150","author":"Fei Liu","year":"2005","unstructured":"Liu Fei, Mizukami Hiroshi, Sarnaik Sharada et al. Calcium-dependent human erythrocyte cytoskeleton stability analysis through atomic force microscopy. Journal of Structural Biology 2005; 150: 200\u2013210.","journal-title":"Journal of Structural Biology"},{"key":"BFmicronano201661_CR37","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/0304-4157(86)90009-2","volume":"864","author":"PS Low","year":"1986","unstructured":"Low PS . Structure and function of the cytoplasmic domain of band 3: Center of erythrocyte membrane-peripheral protein interactions. Biochimica et Biophysica Acta\u2013Reviews on Biomembranes 1986; 864: 145\u2013167.","journal-title":"Biochimica et Biophysica Acta\u2013Reviews on Biomembranes"},{"key":"BFmicronano201661_CR38","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1152\/japplphysiol.00771.2005","volume":"100","author":"Sara Fagn\u00e9t\u00e9","year":"2006","unstructured":"Fagn\u00e9t\u00e9 Sara, Philippe Connes, Olivier Hue et al. Faster lactate transport across red blood cell membrane in sickle cell trait carriers. Journal of Applied Physiology 2006; 100: 427\u2013432.","journal-title":"Journal of Applied Physiology"},{"key":"BFmicronano201661_CR39","first-page":"617","volume":"1","author":"MiriamL Wahl","year":"2002","unstructured":"Wahl Miriam L, Owen Judith A, Burd Randy et al. Regulation of intracellular pH in human melanoma: Potential therapeutic implications. Molecular Cancer Therapeutics 2002; 1: 617\u2013628.","journal-title":"Molecular Cancer Therapeutics"},{"key":"BFmicronano201661_CR40","doi-asserted-by":"publisher","first-page":"385","DOI":"10.2170\/jjphysiol.S653","volume":"55","author":"Philippe Connes","year":"2005","unstructured":"Connes Philippe, Sara Fagn\u00e9t\u00e9, Hardy-Dessources Marie-Dominique et al. Does higher red blood cell (RBC) lactate transporter activity explain impaired RBC deformability in sickle cell trait? The Japanese Journal of Physiology 2005; 55: 385\u2013387.","journal-title":"The Japanese Journal of Physiology"},{"key":"BFmicronano201661_CR41","doi-asserted-by":"publisher","first-page":"R502","DOI":"10.1152\/ajpregu.00114.2004","volume":"287","author":"RobertA Robergs","year":"2004","unstructured":"Robergs Robert A, Ghiasvand Farzenah, Parker Daryl . Biochemistry of exercise-induced metabolic acidosis. American Journal of Physology\u2013Regulatory, Integrative and Comparative Physiology 2004; 287: R502\u2013R516.","journal-title":"American Journal of Physology\u2013Regulatory, Integrative and Comparative Physiology"},{"key":"BFmicronano201661_CR42","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1016\/j.bpj.2012.01.050","volume":"102","author":"JamieL Maciaszek","year":"2012","unstructured":"Maciaszek Jamie L, Andemariam Biree, Huber Greg et al. Epinephrine modulates BCAM\/Lu and ICAM-4 expression on the sickle cell trait red blood cell membrane. Biophysical Journal 2012; 102: 1137\u20131143.","journal-title":"Biophysical Journal"},{"key":"BFmicronano201661_CR43","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/2110-5820-3-2","volume":"3","author":"C\u00e9cile Aubron","year":"2013","unstructured":"Aubron C\u00e9cile, Nichol Alistair, Cooper D Jamie et al. Age of red blood cells and transfusion in critically ill patients. Annals of Intensive Care 2013; 3: 2.","journal-title":"Annals of Intensive Care"},{"key":"BFmicronano201661_CR44","first-page":"3","volume":"25","author":"A Nitin John","year":"2010","unstructured":"Nitin John A . Review of clinical profile in sickle cell traits. Oman Medical Journal 2010; 25: 3\u20138.","journal-title":"Oman Medical Journal"}],"container-title":["Microsystems &amp; Nanoengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/micronano201661.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/micronano201661","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/micronano201661.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T08:33:35Z","timestamp":1672821215000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/micronano201661"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,7]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,19]]}},"alternative-id":["BFmicronano201661"],"URL":"https:\/\/doi.org\/10.1038\/micronano.2016.61","relation":{},"ISSN":["2055-7434"],"issn-type":[{"value":"2055-7434","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,7]]},"assertion":[{"value":"15 May 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 July 2016","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 July 2016","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 November 2016","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16061"}}