{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:13:45Z","timestamp":1787004825567,"version":"build-2736575974"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,3,31]],"date-time":"2016-03-31T00:00:00Z","timestamp":1459382400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,3,31]],"date-time":"2016-03-31T00:00:00Z","timestamp":1459382400000},"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":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common cause of hypersensitivity reactions, with pyrazolones the most frequent drugs inducing selective reactions. Immediate selective hypersensitivity to pyrazolones is thought to be mediated by specific-IgE. Sensitivity of<jats:italic>in vitro<\/jats:italic>diagnostic tests is low and this may be due to the incomplete characterization of the structures involved. Here we investigated whether main metabolites of metamizole (dipyrone) in human could be involved in the immune response using the basophil activation test (BAT). We studied subjects with confirmed selective immediate hypersensitivity to metamizole and performed BAT with metamizole and its metabolites: 4-methylamino-antipyrine (MAA), 4-aminoantipyrine (AA), 4-acetylamino-antipyrine (AAA) and 4-formylamino-antipyrine (FAA). BAT results showed an increase of positive results from 37.5% to 62.5% using metamizole plus metabolites as compared with the BAT carried out only with the parent drug, demonstrating that metamizole metabolites have a role in the reaction and can induce specific basophil activation in patients with immediate hypersensitivity to this drug. Our findings indicate that pyrazolone metabolites are useful for improving the<jats:italic>in vitro<\/jats:italic>diagnosis of allergic reactions to metamizole.<\/jats:p>","DOI":"10.1038\/srep23845","type":"journal-article","created":{"date-parts":[[2016,3,31]],"date-time":"2016-03-31T09:29:08Z","timestamp":1459416548000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Pyrazolones metabolites are relevant for identifying selective anaphylaxis to metamizole"],"prefix":"10.1038","volume":"6","author":[{"given":"Adriana","family":"Ariza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Garc\u00eda-Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Salas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda I.","family":"Monta\u00f1ez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristobalina","family":"Mayorga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Blanca-Lopez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inmaculada","family":"Andreu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Perkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Blanca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 A. G.","family":"Ag\u00fandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda J.","family":"Torres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,3,31]]},"reference":[{"key":"BFsrep23845_CR1","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1111\/j.1365-2125.2010.03774.x","volume":"71","author":"BY Thong","year":"2011","unstructured":"Thong, B. Y. & Tan, T. C. Epidemiology and risk factors for drug allergy. Br. J. Clin. Pharmacol. 71, 684\u2013700 (2011).","journal-title":"Br. J. Clin. Pharmacol."},{"key":"BFsrep23845_CR2","first-page":"363","volume":"22","author":"I Do\u00f1a","year":"2012","unstructured":"Do\u00f1a, I. et al. Drug hypersensitivity reactions: response patterns, drug involved and temporal variations in a large series of patients. J. Investig. Allergol. Clin. Immunol. 22, 363\u2013371 (2012).","journal-title":"J. Investig. Allergol. Clin. Immunol."},{"key":"BFsrep23845_CR3","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1136\/bmj.1.5949.67","volume":"1","author":"A Szczeklik","year":"1975","unstructured":"Szczeklik, A., Gryglewski, R. J. & Czerniawska-Mysik, G. Relationship of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks in aspirin-sensitive patients. Br. Med. J. 1, 67\u201369 (1975).","journal-title":"Br. Med. J"},{"key":"BFsrep23845_CR4","unstructured":"Stevenson, D. D. & Simon, R. A. In Middletons\u2019s Allergy. Principles & Practice (ed. Adkinson, N. F. et al.) 1225\u20131234 (Mosby-Elsevier, 1998)."},{"key":"BFsrep23845_CR5","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1111\/all.12260","volume":"68","author":"ML Kowalski","year":"2013","unstructured":"Kowalski, M. L. et al. Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs. Allergy 68, 1219\u20131232 (2013).","journal-title":"Allergy"},{"key":"BFsrep23845_CR6","doi-asserted-by":"publisher","first-page":"3327","DOI":"10.2174\/138161206778194042","volume":"12","author":"C Antunez","year":"2006","unstructured":"Antunez, C. et al. Immediate hypersensitivity reactions to penicillins and other betalactams. Curr. Pharm. Des. 12, 3327\u20133333 (2006).","journal-title":"Curr. Pharm. Des"},{"key":"BFsrep23845_CR7","doi-asserted-by":"publisher","first-page":"971","DOI":"10.2174\/138920009790711841","volume":"10","author":"JA Cornejo-Garcia","year":"2009","unstructured":"Cornejo-Garcia, J. A. et al. Hypersensitivity reactions to non-steroidal anti-inflammatory drugs. Curr. Drug Metab. 10, 971\u2013980 (2009).","journal-title":"Curr. Drug Metab."},{"key":"BFsrep23845_CR8","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1097\/ACI.0b013e32832db943","volume":"9","author":"MG Canto","year":"2009","unstructured":"Canto, M. G., Andreu, I., Fernandez, J. & Blanca, M. Selective immediate hypersensitivity reactions to NSAIDs. Curr. Opin. Allergy Clin. Immunol. 9, 293\u2013297 (2009).","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"BFsrep23845_CR9","first-page":"295","volume":"62","author":"M Blanca","year":"1989","unstructured":"Blanca, M. et al. Angioedema and IgE antibodies to aspirin: a case report. Ann. Allergy 62, 295\u2013298 (1989).","journal-title":"Ann. Allergy"},{"key":"BFsrep23845_CR10","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.jaci.2004.10.045","volume":"115","author":"C Fontaine","year":"2005","unstructured":"Fontaine, C., Bousquet, P. J. & Demoly, P. Anaphylactic shock caused by a selective allergy to celecoxib, with no allergy to rofecoxib or sulfamethoxazole. J. Allergy Clin. Immunol. 115, 633\u2013634 (2005).","journal-title":"J. Allergy Clin. Immunol."},{"key":"BFsrep23845_CR11","doi-asserted-by":"publisher","first-page":"e13707","DOI":"10.1371\/journal.pone.0013707","volume":"5","author":"A Harrer","year":"2010","unstructured":"Harrer, A. et al. Diclofenac hypersensitivity: antibody responses to the parent drug and relevant metabolites. Plos One 5, e13707 (2010).","journal-title":"Plos One"},{"key":"BFsrep23845_CR12","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1067\/mai.2001.113241","volume":"107","author":"E Scala","year":"2001","unstructured":"Scala, E. et al. Selective severe anaphylactic reaction due to ketorolac tromethamine without nonsteroidal anti-inflammatory drug intolerance. J. Allergy Clin. Immunol. 107, 557 (2001).","journal-title":"J. Allergy Clin. Immunol."},{"key":"BFsrep23845_CR13","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1111\/j.1398-9995.1987.tb00390.x","volume":"42","author":"CH Schneider","year":"1987","unstructured":"Schneider, C. H., Kasper, M. F., de Weck, A. L., Rolli, H. & Angst, B. D. Diagnosis of antibody-mediated drug allergy. Pyrazolinone and pyrazolidinedione cross-reactivity relationships. Allergy 42, 597\u2013603 (1987).","journal-title":"Allergy"},{"key":"BFsrep23845_CR14","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1034\/j.1398-9995.2003.00096.x","volume":"58","author":"PM Gamboa","year":"2003","unstructured":"Gamboa, P. M. et al. Use of CD63 expression as a marker of in vitro basophil activation and leukotriene determination in metamizol allergic patients. Allergy 58, 312\u2013317 (2003).","journal-title":"Allergy"},{"key":"BFsrep23845_CR15","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1067\/mai.2003.163","volume":"111","author":"M Himly","year":"2003","unstructured":"Himly, M. et al. IgE-mediated immediate-type hypersensitivity to the pyrazolone drug propyphenazone. J. Allergy Clin. Immunol. 111, 882\u2013888 (2003).","journal-title":"J. Allergy Clin. Immunol."},{"key":"BFsrep23845_CR16","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1111\/j.1398-9995.1981.tb01842.x","volume":"36","author":"G Czerniawska-Mysik","year":"1981","unstructured":"Czerniawska-Mysik, G. & Szczeklik, A. Idiosyncrasy to pyrazolone drugs. Allergy 36, 381\u2013384 (1981).","journal-title":"Allergy"},{"key":"BFsrep23845_CR17","doi-asserted-by":"publisher","first-page":"347","DOI":"10.2500\/108854199778251799","volume":"20","author":"ML Kowalski","year":"1999","unstructured":"Kowalski, M. L., Bienkiewicz, B., Woszczek, G., Iwaszkiewicz, J. & Poniatowska, M. Diagnosis of pyrazolone drug sensitivity: clinical history versus skin testing and in vitro testing. Allergy Asthma Proc. 20, 347\u2013352 (1999).","journal-title":"Allergy Asthma Proc."},{"key":"BFsrep23845_CR18","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1016\/S1081-1206(10)62580-X","volume":"85","author":"BJ de Paramo","year":"2000","unstructured":"de Paramo, B. J. et al. Paracetamol (acetaminophen) hypersensitivity. Ann. Allergy Asthma Immunol. 85, 508\u2013511 (2000).","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"BFsrep23845_CR19","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1007\/BF00549594","volume":"27","author":"M Levy","year":"1984","unstructured":"Levy, M., Flusser, D., Zylber-Katz, E. & Granit, L. Plasma kinetics of dipyrone metabolites in rapid and slow acetylators. Eur. J. Clin. Pharmacol. 27, 453\u2013458 (1984).","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"BFsrep23845_CR20","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1111\/j.1365-2222.2009.03237.x","volume":"39","author":"E Gomez","year":"2009","unstructured":"Gomez, E. et al. Immunoglobulin E-mediated immediate allergic reactions to dipyrone: value of basophil activation test in the identification of patients. Clin. Exp. Allergy 39, 1217\u20131224 (2009).","journal-title":"Clin. Exp. Allergy"},{"key":"BFsrep23845_CR21","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/S0091-6749(99)70386-6","volume":"104","author":"N Abuaf","year":"1999","unstructured":"Abuaf, N. et al. Validation of a flow cytometric assay detecting in vitro basophil activation for the diagnosis of muscle relaxant allergy. J. Allergy Clin. Immunol. 104, 411\u2013418 (1999).","journal-title":"J. Allergy Clin. Immunol."},{"key":"BFsrep23845_CR22","doi-asserted-by":"publisher","first-page":"1768","DOI":"10.1111\/j.1365-2222.2004.02110.x","volume":"34","author":"MJ Torres","year":"2004","unstructured":"Torres, M. J. et al. The diagnostic interpretation of basophil activation test in immediate allergic reactions to betalactams. Clin. Exp. Allergy 34, 1768\u20131775 (2004).","journal-title":"Clin. Exp. Allergy"},{"key":"BFsrep23845_CR23","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1586\/eci.11.14","volume":"7","author":"J Leysen","year":"2011","unstructured":"Leysen, J. et al. The basophil activation test in the diagnosis of immediate drug hypersensitivity. Expert. Rev. Clin. Immunol. 7, 349\u2013355 (2011).","journal-title":"Expert. Rev. Clin. Immunol."},{"key":"BFsrep23845_CR24","doi-asserted-by":"publisher","first-page":"2","DOI":"10.3389\/fphar.2012.00002","volume":"3","author":"JA Agundez","year":"2012","unstructured":"Agundez, J. A. et al. Trends in qualifying biomarkers in drug safety. Consensus of the 2011 meeting of the spanish society of clinical pharmacology. Front. Pharmacol. 3, 2 (2012).","journal-title":"Front. Pharmacol"},{"key":"BFsrep23845_CR25","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1111\/j.1365-2222.2010.03651.x","volume":"41","author":"I Dona","year":"2011","unstructured":"Dona, I. et al. Characteristics of subjects experiencing hypersensitivity to non-steroidal anti-inflammatory drugs: patterns of response. Clin. Exp. Allergy 41, 86\u201395 (2011).","journal-title":"Clin. Exp. Allergy"},{"key":"BFsrep23845_CR26","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1111\/cea.12140","volume":"43","author":"P Ayuso","year":"2013","unstructured":"Ayuso, P. et al. Advanced phenotyping in hypersensitivity drug reactions to NSAIDs. Clin. Exp. Allergy 43, 1097\u20131109 (2013).","journal-title":"Clin. Exp. Allergy"},{"key":"BFsrep23845_CR27","doi-asserted-by":"publisher","first-page":"1448","DOI":"10.1111\/j.1365-2222.2004.02050.x","volume":"34","author":"P Gamboa","year":"2004","unstructured":"Gamboa, P. et al. The flow-cytometric determination of basophil activation induced by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is useful for in vitro diagnosis of the NSAID hypersensitivity syndrome. Clin. Exp. Allergy 34, 1448\u20131457 (2004).","journal-title":"Clin. Exp. Allergy"},{"key":"BFsrep23845_CR28","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1159\/000082586","volume":"136","author":"ML Sanz","year":"2005","unstructured":"Sanz, M. L., Gamboa, P. & de Weck, A. L. A new combined test with flowcytometric basophil activation and determination of sulfidoleukotrienes is useful for in vitro diagnosis of hypersensitivity to aspirin and other nonsteroidal anti-inflammatory drugs. Int. Arch. Allergy Immunol. 136, 58\u201372 (2005).","journal-title":"Int. Arch. Allergy Immunol."},{"key":"BFsrep23845_CR29","first-page":"348","volume":"45","author":"P Vasileva-Aleksandrova","year":"1990","unstructured":"Vasileva-Aleksandrova, P. & Aleksandrov, A. Study of the interaction of noramidopyrine methanesulfonate sodium (Analgin) with tetrazolium salts in alkaline medium. Pharmazie 45, 348\u2013349 (1990).","journal-title":"Pharmazie"},{"key":"BFsrep23845_CR30","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1097\/00007691-199406000-00014","volume":"16","author":"JA Agundez","year":"1994","unstructured":"Agundez, J. A., Martinez, C., Martin, R. & Benitez, J. Determination of aminopyrine, dipyrone and its metabolites in urine by high-performance liquid chromatography. Ther. Drug Monit. 16, 316\u2013322 (1994).","journal-title":"Ther. Drug Monit."},{"key":"BFsrep23845_CR31","doi-asserted-by":"publisher","first-page":"417","DOI":"10.3109\/00498259509061862","volume":"25","author":"JA Agundez","year":"1995","unstructured":"Agundez, J. A., Martinez, C. & Benitez, J. Metabolism of aminopyrine and derivatives in man: in vivo study of monomorphic and polymorphic metabolic pathways. Xenobiotica 25, 417\u2013427 (1995).","journal-title":"Xenobiotica"},{"key":"BFsrep23845_CR32","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/0165-2370(87)80017-7","volume":"10","author":"HM Schiebel","year":"1987","unstructured":"Schiebel, H. M., Gries, O., Schuppel, R. & Schulze, P. Identification of conjugated metabolites of pyrazolones drugs in human urine by pyrolysis-mass spectrometry. J Anal Appl Pyrol 10, 267\u2013281 (1987).","journal-title":"J Anal Appl Pyrol"},{"key":"BFsrep23845_CR33","doi-asserted-by":"publisher","first-page":"8727","DOI":"10.1021\/jm101208x","volume":"53","author":"N Uramaru","year":"2010","unstructured":"Uramaru, N. et al. Design, synthesis and pharmacological activity of nonallergenic pyrazolone-type antipyretic analgesics. J. Med. Chem. 53, 8727\u20138733 (2010).","journal-title":"J. Med. Chem."},{"key":"BFsrep23845_CR34","doi-asserted-by":"publisher","first-page":"216","DOI":"10.2165\/00003088-199528030-00004","volume":"28","author":"M Levy","year":"1995","unstructured":"Levy, M., Zylber-Katz, E. & Rosenkranz, B. Clinical pharmacokinetics of dipyrone and its metabolites. Clin. Pharmacokinet. 28, 216\u2013234 (1995).","journal-title":"Clin. Pharmacokinet."},{"key":"BFsrep23845_CR35","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/BF00547371","volume":"29","author":"E Zylber-Katz","year":"1985","unstructured":"Zylber-Katz, E., Granit, L. & Levy, M. Plasma protein binding of dipyrone metabolites in man. Eur. J. Clin. Pharmacol. 29, 67\u201371 (1985).","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"BFsrep23845_CR36","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1111\/j.1398-9995.2008.01713.x","volume":"64","author":"TD Fernandez","year":"2009","unstructured":"Fernandez, T. D. et al. Negativization rates of IgE radioimmunoassay and basophil activation test in immediate reactions to penicillins. Allergy 64, 242\u2013248 (2009).","journal-title":"Allergy"},{"key":"BFsrep23845_CR37","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1016\/j.jaci.2009.11.032","volume":"125","author":"MJ Torres","year":"2010","unstructured":"Torres, M. J. et al. Clavulanic acid can be the component in amoxicillin-clavulanic acid responsible for immediate hypersensitivity reactions. J. Allergy Clin. Immunol. 125, 502\u2013505 (2010).","journal-title":"J. Allergy Clin. Immunol."},{"key":"BFsrep23845_CR38","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1067\/mai.2003.1511","volume":"112","author":"A Mochizuki","year":"2003","unstructured":"Mochizuki, A., McEuen, A. R., Buckley, M. G. & Walls, A. F. The release of basogranulin in response to IgE-dependent and IgE-independent stimuli: validity of basogranulin measurement as an indicator of basophil activation. J. Allergy Clin. Immunol. 112, 102\u2013108 (2003).","journal-title":"J. Allergy Clin. Immunol."},{"key":"BFsrep23845_CR39","doi-asserted-by":"crossref","unstructured":"Ariza, A. et al. Protein haptenation by amoxicillin: High resolution mass spectrometry analysis and identification of target proteins in serum. J. Proteomics (2012).","DOI":"10.1016\/j.jprot.2012.09.030"},{"key":"BFsrep23845_CR40","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1046\/j.0105-4538.2001.00001.x-i8","volume":"57","author":"K Brockow","year":"2002","unstructured":"Brockow, K. et al. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy 57, 45\u201351 (2002).","journal-title":"Allergy"},{"key":"BFsrep23845_CR41","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.bcp.2014.09.005","volume":"92","author":"C Martinez","year":"2014","unstructured":"Martinez, C. et al. Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole. Biochem. Pharmacol. 92, 457\u2013466 (2014).","journal-title":"Biochem. Pharmacol."},{"key":"BFsrep23845_CR42","doi-asserted-by":"publisher","first-page":"2199","DOI":"10.1182\/blood.V96.6.2199","volume":"96","author":"K Miura","year":"2000","unstructured":"Miura, K. & MacGlashan, D. W. Phosphatidylinositol-3 kinase regulates p21ras activation during IgE-mediated stimulation of human basophils. Blood 96, 2199\u20132205 (2000).","journal-title":"Blood"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep23845","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep23845.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep23845.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,15]],"date-time":"2024-06-15T11:25:47Z","timestamp":1718450747000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep23845"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,31]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,7,26]]}},"alternative-id":["BFsrep23845"],"URL":"https:\/\/doi.org\/10.1038\/srep23845","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,31]]},"assertion":[{"value":"5 January 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 March 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 March 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"23845"}}