{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,15]],"date-time":"2026-11-15T10:04:59Z","timestamp":1794737099980,"version":"4.9.1"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,10,5]],"date-time":"2018-10-05T00:00:00Z","timestamp":1538697600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,10,5]],"date-time":"2018-10-05T00:00:00Z","timestamp":1538697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004681","name":"Higher Education Commission, Pakistan","doi-asserted-by":"publisher","award":["4493"],"award-info":[{"award-number":["4493"]}],"id":[{"id":"10.13039\/501100004681","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>Acute Leukaemia (AL) is a neoplasm of WBCs (white blood cells). Being an important class of metabolites, alteration in free fatty acids (FFAs) levels play a key role in cancer development and progression. As they involve in cell signaling, maintain membrane integrity, regulate homeostasis and effect cell and tissue functions. Considering this fact, a comprehensive analysis of FFAs was conducted to monitor their alteration in AL, pre-leukaemic diseases and healthy control. Fifteen FFAs were analyzed in 179 serum samples of myelodysplastic syndrome (MDS), aplastic anemia (APA), acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and healthy control using gas chromatography-multiple reaction monitoring-mass spectrometry (GC-MRM-MS). A multivariate statistical method of random forest (RF) was employed for chemometric analysis. Serum level of two FFAs including C18:0 and C14:0 were found discriminative among all five groups, and between ALL and AML, respectively. Moreover, C14:0 was identified as differentiated FFAs for systematic progression of pre-leukaemic conditions towards AML. C16:0 came as discriminated FFAs between APA and MDS\/AML. Over all it was identified that FFAs profile not only become altered in leukaemia but also in pre-leukaemic diseases.<\/jats:p>","DOI":"10.1038\/s41598-018-33224-1","type":"journal-article","created":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T11:56:19Z","timestamp":1538394979000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Alteration of Serum Free Fatty Acids are Indicators for Progression of Pre-leukaemia Diseases to Leukaemia"],"prefix":"10.1038","volume":"8","author":[{"given":"Ayesha","family":"Khalid","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amna Jabbar","family":"Siddiqui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Hua","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7667-5838","authenticated-orcid":false,"given":"Tahir","family":"Shamsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Ghulam","family":"Musharraf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,10,5]]},"reference":[{"issue":"1_suppl","key":"33224_CR1","doi-asserted-by":"publisher","first-page":"18S","DOI":"10.1177\/0148607115595980","volume":"39","author":"Philip C. Calder","year":"2015","unstructured":"Calder, P. C. Functional roles of fatty acids and their effects on human health. Journal of Parenteral and Enteral Nutrition, 39, 18S\u201332S (2015).","journal-title":"Journal of Parenteral and Enteral Nutrition"},{"key":"33224_CR2","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.1158\/1055-9965.EPI-06-1033","volume":"16","author":"JE Chavarro","year":"2007","unstructured":"Chavarro, J. E. et al. A prospective study of polyunsaturated fatty acid levels in blood and prostate cancer risk. Cancer Epidemiology and Prevention Biomarkers 16, 1364\u20131370 (2007).","journal-title":"Cancer Epidemiology and Prevention Biomarkers"},{"key":"33224_CR3","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/j.jada.2008.12.022","volume":"109","author":"ND Riediger","year":"2009","unstructured":"Riediger, N. D., Othman, R. A., Suh, M. & Moghadasian, M. H. A systemic review of the roles of n-3 fatty acids in health and disease. Journal of the American Dietetic Association 109, 668\u2013679 (2009).","journal-title":"Journal of the American Dietetic Association"},{"key":"33224_CR4","doi-asserted-by":"publisher","unstructured":"Ritchie, S. A. et al. Reduced levels of hydroxylated, polyunsaturated ultra long-chain fatty acids in the serum of colorectal cancer patients: implications for early screening and detection. BMC Medicine 8, https:\/\/doi.org\/10.1186\/1741-7015-8-13 (2010).","DOI":"10.1186\/1741-7015-8-13"},{"key":"33224_CR5","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1097\/00000441-195507000-00018","volume":"230","author":"JP Greenstein","year":"1955","unstructured":"Greenstein, J. P. Biochemistry of cancer. The American Journal of the Medical Sciences 230, 111 (1955).","journal-title":"The American Journal of the Medical Sciences"},{"key":"33224_CR6","doi-asserted-by":"publisher","first-page":"R146","DOI":"10.1152\/ajpregu.1984.247.1.R146","volume":"247","author":"M Ookhtens","year":"1984","unstructured":"Ookhtens, M., Kannan, R., Lyon, I. & Baker, N. Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 247, R146\u2013R153 (1984).","journal-title":"American Journal of Physiology-Regulatory, Integrative and Comparative Physiology"},{"issue":"11","key":"33224_CR7","doi-asserted-by":"publisher","first-page":"2076","DOI":"10.1136\/annrheumdis-2014-205601","volume":"74","author":"Chia-Lung Wu","year":"2014","unstructured":"Wu, C.-L. et al. Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury. Annals of the rheumatic diseases, 74, 2076\u20132083 (2014).","journal-title":"Annals of the Rheumatic Diseases"},{"key":"33224_CR8","doi-asserted-by":"publisher","first-page":"2934","DOI":"10.1002\/ijc.29675","volume":"137","author":"S Roy","year":"2015","unstructured":"Roy, S. et al. Associations of erythrocyte \u03c9\u20103 fatty acids with biomarkers of \u03c9\u20103 fatty acids and inflammation in breast tissue. International journal of cancer 137, 2934\u20132946 (2015).","journal-title":"International journal of cancer"},{"key":"33224_CR9","doi-asserted-by":"publisher","first-page":"2317","DOI":"10.3945\/jn.115.212282","volume":"145","author":"I Reinders","year":"2015","unstructured":"Reinders, I. et al. Higher Plasma Phospholipid n\u20133 PUFAs, but Lower n\u20136 PUFAs, Are Associated with Lower Pulse Wave Velocity among Older Adults. The Journal of Nutrition 145, 2317\u20132324 (2015).","journal-title":"The Journal of nutrition"},{"key":"33224_CR10","doi-asserted-by":"publisher","first-page":"2533","DOI":"10.1007\/s00125-015-3730-5","volume":"58","author":"MA Lankinen","year":"2015","unstructured":"Lankinen, M. A. et al. Plasma fatty acids as predictors of glycaemia and type 2 diabetes. Diabetologia 58, 2533\u20132544 (2015).","journal-title":"Diabetologia"},{"key":"33224_CR11","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-015-0135-x","volume":"14","author":"SR Kim","year":"2015","unstructured":"Kim, S. R., Jeon, S. Y. & Lee, S.-M. The association of cardiovascular risk factors with saturated fatty acids and fatty acid desaturase indices in erythrocyte in middle-aged Korean adults. Lipids in Health and Disease 14, 133 (2015).","journal-title":"Lipids in health and disease"},{"key":"33224_CR12","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1111\/acps.12388","volume":"132","author":"D Solberg","year":"2015","unstructured":"Solberg, D., Bentsen, H., Refsum, H. & Andreassen, O. Association between serum lipids and membrane fatty acids and clinical characteristics in patients with schizophrenia. Acta Psychiatrica Scandinavica 132, 293\u2013300 (2015).","journal-title":"Acta Psychiatrica Scandinavica"},{"key":"33224_CR13","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.jprot.2011.02.034","volume":"74","author":"N Jiang","year":"2011","unstructured":"Jiang, N. et al. Identification of prognostic protein biomarkers in childhood acute lymphoblastic leukemia (ALL). Journal of Proteomics 74, 843\u2013857 (2011).","journal-title":"Journal of proteomics"},{"key":"33224_CR14","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1093\/jnci\/91.12.1051","volume":"91","author":"MS Linet","year":"1999","unstructured":"Linet, M. S., Ries, L. A., Smith, M. A., Tarone, R. E. & Devesa, S. S. Cancer surveillance series: recent trends in childhood cancer incidence and mortality in the United States. Journal of the National Cancer Institute 91, 1051\u20131058 (1999).","journal-title":"Journal of the National Cancer Institute"},{"issue":"1","key":"33224_CR15","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1289\/ehp.9023","volume":"115","author":"Martin Belson","year":"2007","unstructured":"Belson, M., Kingsley, B. & Holmes, A. Risk factors for acute leukemia in children: a review. Environmental Health Perspectives, 138\u2013145 (2007).","journal-title":"Environmental Health Perspectives"},{"key":"33224_CR16","unstructured":"Ferlay, J. et al. GLOBOCAN 2012 v1. 0. Cancer incidence and mortality worldwide: IARC CancerBase, 2014 (2013)."},{"key":"33224_CR17","first-page":"277","volume":"60","author":"A Jemal","year":"2010","unstructured":"Jemal, A., Siegel, R., Xu, J. & Ward, E. Cancer statistics, 2010. CA: A Cancer Journal for Clinicians 60, 277\u2013300 (2010).","journal-title":"CA: a cancer journal for clinicians"},{"issue":"4","key":"33224_CR18","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1002\/hon.2313","volume":"35","author":"Syed Ghulam Musharraf","year":"2016","unstructured":"Musharraf, S. G., Siddiqui, A. J., Shamsi, T. & Naz, A. Serum metabolomics of acute lymphoblastic leukaemia and acute myeloid leukaemia for probing biomarker molecules. Hematological Oncology 35, 769\u2013777 (2017).","journal-title":"Hematological Oncology"},{"key":"33224_CR19","doi-asserted-by":"publisher","first-page":"6590","DOI":"10.1158\/0008-5472.CAN-11-0885","volume":"71","author":"AD Patterson","year":"2011","unstructured":"Patterson, A. D. et al. Aberrant lipid metabolism in hepatocellular carcinoma revealed by plasma metabolomics and lipid profiling. Cancer Research 71, 6590\u20136600 (2011).","journal-title":"Cancer research"},{"key":"33224_CR20","doi-asserted-by":"publisher","first-page":"e82859","DOI":"10.1371\/journal.pone.0082859","volume":"8","author":"S Tiziani","year":"2013","unstructured":"Tiziani, S. et al. Metabolomics of the tumor microenvironment in pediatric acute lymphoblastic leukemia. PloS one 8, e82859 (2013).","journal-title":"PloS one"},{"key":"33224_CR21","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1016\/j.neurobiolaging.2010.09.013","volume":"33","author":"D-C Wang","year":"2012","unstructured":"Wang, D.-C. et al. Serum fatty acid profiles using GC-MS and multivariate statistical analysis: potential biomarkers of Alzheimer\u2019s disease. Neurobiology of Aging 33, 1057\u20131066 (2012).","journal-title":"Neurobiology of aging"},{"key":"33224_CR22","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1039\/b604498k","volume":"131","author":"T Sangster","year":"2006","unstructured":"Sangster, T., Major, H., Plumb, R., Wilson, A. J. & Wilson, I. D. A pragmatic and readily implemented quality control strategy for HPLC-MS and GC-MS-based metabonomic analysis. Analyst 131, 1075\u20131078 (2006).","journal-title":"Analyst"},{"key":"33224_CR23","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.aca.2014.04.008","volume":"827","author":"Z Lin","year":"2014","unstructured":"Lin, Z. et al. Exploring metabolic syndrome serum profiling based on gas chromatography mass spectrometry and random forest models. Analytica Chimica Acta 827, 22\u201327 (2014).","journal-title":"Analytica chimica acta"},{"key":"33224_CR24","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.talanta.2014.12.039","volume":"135","author":"L Dai","year":"2015","unstructured":"Dai, L. et al. Exploring metabolic syndrome serum free fatty acid profiles based on GC\u2013SIM\u2013MS combined with random forests and canonical correlation analysis. Talanta 135, 108\u2013114 (2015).","journal-title":"Talanta"},{"key":"33224_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.talanta.2013.03.039","volume":"110","author":"J-H Huang","year":"2013","unstructured":"Huang, J.-H. et al. Exploring the relationship between 5\u2032 AMP-activated protein kinase and markers related to type 2 diabetes mellitus. Talanta 110, 1\u20137 (2013).","journal-title":"Talanta"},{"key":"33224_CR26","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1021\/ci060164k","volume":"47","author":"DS Palmer","year":"2007","unstructured":"Palmer, D. S., O\u2019Boyle, N. M., Glen, R. C. & Mitchell, J. B. Random forest models to predict aqueous solubility. Journal of Chemical Information and Modeling 47, 150\u2013158 (2007).","journal-title":"Journal of chemical information and modeling"},{"key":"33224_CR27","doi-asserted-by":"publisher","first-page":"1947","DOI":"10.1021\/ci034160g","volume":"43","author":"V Svetnik","year":"2003","unstructured":"Svetnik, V. et al. Random forest: a classification and regression tool for compound classification and QSAR modeling. Journal of Chemical Information and Computer Sciences 43, 1947\u20131958 (2003).","journal-title":"Journal of chemical information and computer sciences"},{"key":"33224_CR28","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1038\/nm.2492","volume":"17","author":"KM Nieman","year":"2011","unstructured":"Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Medicine 17, 1498 (2011).","journal-title":"Nature medicine"},{"key":"33224_CR29","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.bbacli.2017.03.002","volume":"7","author":"T Pabst","year":"2017","unstructured":"Pabst, T. et al. The plasma lipidome in acute myeloid leukemia at diagnosis in relation to clinical disease features. BBA Clinical 7, 105\u2013114 (2017).","journal-title":"BBA clinical"},{"key":"33224_CR30","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/j.tiv.2005.04.003","volume":"19","author":"R Otton","year":"2005","unstructured":"Otton, R. & Curi, R. Toxicity of a mixture of fatty acids on human blood lymphocytes and leukaemia cell lines. Toxicology in vitro 19, 749\u2013755 (2005).","journal-title":"Toxicology in vitro"},{"key":"33224_CR31","doi-asserted-by":"publisher","first-page":"3525","DOI":"10.1158\/1078-0432.CCR-05-2802","volume":"12","author":"PO Iversen","year":"2006","unstructured":"Iversen, P. O. et al. A bioactively modified fatty acid improves survival and impairs metastasis in preclinical models of acute leukemia. Clinical Cancer Research 12, 3525\u20133531 (2006).","journal-title":"Clinical cancer research"},{"key":"33224_CR32","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.2337\/db05-1574","volume":"55","author":"XL Wang","year":"2006","unstructured":"Wang, X. L. et al. Free fatty acids inhibit insulin signaling\u2013stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase. Diabetes 55, 2301\u20132310 (2006).","journal-title":"Diabetes"},{"key":"33224_CR33","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.nut.2005.04.011","volume":"22","author":"L Sauma","year":"2006","unstructured":"Sauma, L. et al. PPAR-\u03b3 response element activity in intact primary human adipocytes: effects of fatty acids. Nutrition 22, 60\u201368 (2006).","journal-title":"Nutrition"},{"issue":"M110","key":"33224_CR34","first-page":"004945","volume":"10","author":"T Chen","year":"2011","unstructured":"Chen, T. et al. Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma. Molecular & Cellular Proteomics 10(M110), 004945 (2011).","journal-title":"Molecular & Cellular Proteomics"},{"key":"33224_CR35","doi-asserted-by":"publisher","first-page":"3590","DOI":"10.1210\/endo.142.8.8293","volume":"142","author":"YM Mu","year":"2001","unstructured":"Mu, Y. M. et al. Saturated FFAs, palmitic acid and stearic acid, induce apoptosis in human granulosa cells. Endocrinology 142, 3590\u20133597 (2001).","journal-title":"Endocrinology"},{"key":"33224_CR36","doi-asserted-by":"publisher","first-page":"e2329","DOI":"10.1371\/journal.pone.0002329","volume":"3","author":"L Zeng","year":"2008","unstructured":"Zeng, L. et al. Saturated fatty acids modulate cell response to DNA damage: implication for their role in tumorigenesis. PLoS One 3, e2329 (2008).","journal-title":"PLoS One"},{"key":"33224_CR37","first-page":"223","volume":"24","author":"A Tsubura","year":"2009","unstructured":"Tsubura, A., Yuri, T., Yoshizawa, K., Uehara, N. & Takada, H. Role of fatty acids in malignancy and visual impairment: epidemiological evidence and experimental studies. Histology and Histopathology 24, 223\u2013234 (2009).","journal-title":"Histology and histopathology"},{"key":"33224_CR38","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1007\/BF00320928","volume":"50","author":"K Apostolov","year":"1985","unstructured":"Apostolov, K., Barker, W., Catovsky, D., Goldman, J. & Matutes, E. Reduction in the stearic to oleic acid ratio in leukaemic cells\u2014a possible chemical marker of malignancy. Blut 50, 349\u2013354 (1985).","journal-title":"Blut"},{"key":"33224_CR39","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1136\/bmj.291.6489.163","volume":"291","author":"C Wood","year":"1985","unstructured":"Wood, C. et al. Increase of oleic acid in erythrocytes associated with malignancies. British Medical Journal (Clin Res Ed) 291, 163\u2013165 (1985).","journal-title":"Br Med J (Clin Res Ed)"},{"key":"33224_CR40","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1038\/bjc.1987.223","volume":"56","author":"N Habib","year":"1987","unstructured":"Habib, N. et al. Stearic acid and carcinogenesis. British Journal of Cancer 56, 455 (1987).","journal-title":"British journal of cancer"},{"key":"33224_CR41","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1182\/blood-2014-12-617498","volume":"126","author":"MR Ricciardi","year":"2015","unstructured":"Ricciardi, M. R. et al. Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias. Blood 126, 1925\u20131929 (2015).","journal-title":"Blood"},{"key":"33224_CR42","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1172\/JCI38942","volume":"120","author":"I Samudio","year":"2010","unstructured":"Samudio, I. et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. The Journal of Clinical Investigation 120, 142\u2013156 (2010).","journal-title":"The Journal of clinical investigation"},{"key":"33224_CR43","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s12154-009-0032-8","volume":"3","author":"MH Wright","year":"2010","unstructured":"Wright, M. H., Heal, W. P., Mann, D. J. & Tate, E. W. Protein myristoylation in health and disease. Journal of Chemical Biology 3, 19\u201335 (2010).","journal-title":"Journal of chemical biology"},{"key":"33224_CR44","doi-asserted-by":"crossref","unstructured":"Gurr, M. I., Harwood, J. L. & Frayn, K. N. Lipid biochemistry (2002).","DOI":"10.1002\/9780470774366"},{"key":"33224_CR45","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.clinbiochem.2011.10.011","volume":"45","author":"W Lv","year":"2012","unstructured":"Lv, W. & Yang, T. Identification of possible biomarkers for breast cancer from free fatty acid profiles determined by GC\u2013MS and multivariate statistical analysis. Clinical Biochemistry 45, 127\u2013133 (2012).","journal-title":"Clinical biochemistry"},{"key":"33224_CR46","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nature20791","volume":"541","author":"G Pascual","year":"2017","unstructured":"Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41 (2017).","journal-title":"Nature"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-33224-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-33224-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-33224-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T10:19:20Z","timestamp":1671617960000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-33224-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,5]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["33224"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-33224-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,5]]},"assertion":[{"value":"2 February 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 September 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 October 2018","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":"14883"}}