{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:22:09Z","timestamp":1792624929074,"version":"4.5.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,10,22]],"date-time":"2015-10-22T00:00:00Z","timestamp":1445472000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,10,22]],"date-time":"2015-10-22T00:00:00Z","timestamp":1445472000000},"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><jats:italic>Staphylococcus aureus<\/jats:italic> (<jats:italic>S. aureus<\/jats:italic>) is an opportunistic bacterial pathogen responsible for a diverse spectrum of human diseases, resulting in considerable yearly mortality rates. Due to its rapid acquisition of antibiotic resistance, it becomes increasingly difficult to cure <jats:italic>S. aureus<\/jats:italic> infections with conventional antibiotics. Immunotherapy represents a promising alternative strategy to prevent and\/or treat the infection. In the present study, passive immunization with polyclonal antibodies targeting three possible <jats:italic>S. aureus<\/jats:italic> antigens, Hla, SEB and MntC (termed \u201cSAvac-pcAb\u201d) after challenge with lethal dose of <jats:italic>S. aureus<\/jats:italic> resulted in reduced bacterial loads, inflammatory cell infiltration and decreased pathology and was able to provide nearly complete protection in a murine sepsis model. <jats:italic>In vitro<\/jats:italic> studies confirmed the direct interaction of SAvac-pcAb with <jats:italic>S. aureus<\/jats:italic> bacteria. Additional studies validated that SAvac-pcAb contained both opsonic and neutralizing antibodies that contributed to its protective efficacy. The former mediated opsonophagocytosis in a neutrophil-dependent manner, while the later inhibited the biological functions of Hla and SEB, two major virulence factors secreted by <jats:italic>S. aureus.<\/jats:italic> Critically, we demonstrated that SAvac-pcAb was cross-reactive with different clinical strains of <jats:italic>S. aureus.<\/jats:italic> These results confirmed the efficacy for treatment of <jats:italic>S. aureus<\/jats:italic> infection by passive immunization as an important therapeutic option.<\/jats:p>","DOI":"10.1038\/srep15553","type":"journal-article","created":{"date-parts":[[2015,10,22]],"date-time":"2015-10-22T09:21:24Z","timestamp":1445505684000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Protective Efficacy and Mechanism of Passive Immunization with Polyclonal Antibodies in a Sepsis Model of Staphylococcus aureus Infection"],"prefix":"10.1038","volume":"5","author":[{"given":"Jinyong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyan","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changzhi","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yandong","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yudong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanming","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,10,22]]},"reference":[{"key":"BFsrep15553_CR1","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/nrmicro3161","volume":"12","author":"TJ Foster","year":"2014","unstructured":"Foster, T. J., Geoghegan, J. A., Ganesh, V. K. & Hook, M. Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat Rev Microbiol 12, 49\u201362, (2014).","journal-title":"Nat Rev Microbiol"},{"key":"BFsrep15553_CR2","doi-asserted-by":"publisher","first-page":"e1003134","DOI":"10.1371\/journal.ppat.1003134","volume":"9","author":"R Kouyos","year":"2013","unstructured":"Kouyos, R., Klein, E. & Grenfell, B. Hospital-community interactions foster coexistence between methicillin-resistant strains of Staphylococcus aureus. PLoS pathogens 9, e1003134 (2013).","journal-title":"PLoS pathogens"},{"key":"BFsrep15553_CR3","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1056\/NEJMp0804651","volume":"360","author":"CA Arias","year":"2009","unstructured":"Arias, C. A. & Murray, B. E. Antibiotic-resistant bugs in the 21st century\u2014a clinical super-challenge. N Engl J Med 360, 439\u2013443 (2009).","journal-title":"N Engl J Med"},{"key":"BFsrep15553_CR4","doi-asserted-by":"publisher","first-page":"S71","DOI":"10.1016\/j.ijantimicag.2008.06.009","volume":"32","author":"AC Schaffer","year":"2008","unstructured":"Schaffer, A. C. & Lee, J. C. Vaccination and passive immunisation against Staphylococcus aureus. Int J Antimicrob Agents 32 Suppl 1, S71\u201378 (2008).","journal-title":"Int J Antimicrob Agents"},{"key":"BFsrep15553_CR5","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1097\/01.inf.0000199887.18267.9a","volume":"25","author":"HR Shinefield","year":"2006","unstructured":"Shinefield, H. R. & Black, S. Prospects for active and passive immunization against Staphylococcus aureus. Pediatr Infect Dis J 25, 167\u2013168 (2006).","journal-title":"Pediatr Infect Dis J"},{"key":"BFsrep15553_CR6","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/nrmicro3308","volume":"12","author":"W Salgado-Pabon","year":"2014","unstructured":"Salgado-Pabon, W. & Schlievert, P. M. Models matter: the search for an effective Staphylococcus aureus vaccine. Nat Rev Microbiol 12, 585\u2013591 (2014).","journal-title":"Nat Rev Microbiol"},{"key":"BFsrep15553_CR7","doi-asserted-by":"publisher","first-page":"6752","DOI":"10.1128\/IAI.73.10.6752-6762.2005","volume":"73","author":"T Maira-Litran","year":"2005","unstructured":"Maira-Litran, T., Kropec, A., Goldmann, D. A. & Pier, G. B. Comparative opsonic and protective activities of Staphylococcus aureus conjugate vaccines containing native or deacetylated Staphylococcal Poly-N-acetyl-beta-(1-6)-glucosamine. Infect Immun 73, 6752\u20136762 (2005).","journal-title":"Infect Immun"},{"key":"BFsrep15553_CR8","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1086\/656043","volume":"202","author":"AD Kennedy","year":"2010","unstructured":"Kennedy, A. D. et al. Targeting of alpha-hemolysin by active or passive immunization decreases severity of USA300 skin infection in a mouse model. J Infect Dis 202, 1050\u20131058 (2010).","journal-title":"J Infect Dis"},{"key":"BFsrep15553_CR9","doi-asserted-by":"publisher","first-page":"2215","DOI":"10.1128\/IAI.74.4.2215-2223.2006","volume":"74","author":"NA Kuklin","year":"2006","unstructured":"Kuklin, N. A. et al. A novel Staphylococcus aureus vaccine: iron surface determinant B induces rapid antibody responses in rhesus macaques and specific increased survival in a murine S. aureus sepsis model. Infect Immun 74, 2215\u20132223 (2006).","journal-title":"Infect Immun"},{"key":"BFsrep15553_CR10","doi-asserted-by":"publisher","first-page":"e81212","DOI":"10.1371\/journal.pone.0081212","volume":"8","author":"QF Zuo","year":"2013","unstructured":"Zuo, Q. F. et al. Evaluation of the protective immunity of a novel subunit fusion vaccine in a murine model of systemic MRSA infection. PLoS One 8, e81212, (2013).","journal-title":"PLoS One"},{"key":"BFsrep15553_CR11","doi-asserted-by":"publisher","first-page":"e90445","DOI":"10.1371\/journal.pone.0090445","volume":"9","author":"Z Zhao","year":"2014","unstructured":"Zhao, Z. et al. Fine-mapping of immunodominant linear B-cell epitopes of the Staphylococcus aureus SEB antigen using short overlapping peptides. PLoS One 9, e90445 (2014).","journal-title":"PLoS One"},{"key":"BFsrep15553_CR12","doi-asserted-by":"publisher","first-page":"041001","DOI":"10.1088\/1752-7155\/8\/4\/041001","volume":"8","author":"HD Bean","year":"2014","unstructured":"Bean, H. D., Zhu, J., Sengle, J. C. & Hill, J. E. Identifying methicillin-resistant Staphylococcus aureus (MRSA) lung infections in mice via breath analysis using secondary electrospray ionization-mass spectrometry (SESI-MS). J Breath Res 8, 041001 (2014).","journal-title":"J Breath Res"},{"key":"BFsrep15553_CR13","first-page":"21","volume":"8","author":"H Birch","year":"2011","unstructured":"Birch, H. Antibodies could lead to MRSA vaccine. Chem World 8, 21\u201321 (2011).","journal-title":"Chem World"},{"key":"BFsrep15553_CR14","doi-asserted-by":"publisher","first-page":"e56846","DOI":"10.1371\/journal.pone.0056846","volume":"8","author":"I Pastar","year":"2013","unstructured":"Pastar, I. et al. Interactions of methicillin resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in polymicrobial wound infection. PLoS One 8, e56846 (2013).","journal-title":"PLoS One"},{"key":"BFsrep15553_CR15","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.1093\/infdis\/jis272","volume":"205","author":"AS Anderson","year":"2012","unstructured":"Anderson, A. S. et al. Staphylococcus aureus manganese transport protein C is a highly conserved cell surface protein that elicits protective immunity against S. aureus and Staphylococcus epidermidis. J Infect Dis 205, 1688\u20131696 (2012).","journal-title":"J Infect Dis"},{"key":"BFsrep15553_CR16","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1099\/00222615-36-4-223","volume":"36","author":"MB Taylor","year":"1992","unstructured":"Taylor, M. B., Phillips, M. & Easmon, C. S. Opsonophagocytosis of Pneumocystis carinii. J Med Microbiol 36, 223\u2013228 (1992).","journal-title":"J Med Microbiol"},{"key":"BFsrep15553_CR17","doi-asserted-by":"publisher","first-page":"e54661","DOI":"10.1371\/journal.pone.0054661","volume":"8","author":"B Thay","year":"2013","unstructured":"Thay, B., Wai, S. N. & Oscarsson, J. Staphylococcus aureus alpha-toxin-dependent induction of host cell death by membrane-derived vesicles. PLoS One 8, e54661 (2013).","journal-title":"PLoS One"},{"key":"BFsrep15553_CR18","doi-asserted-by":"publisher","first-page":"25203","DOI":"10.1074\/jbc.M112.364075","volume":"287","author":"H Karauzum","year":"2012","unstructured":"Karauzum, H. et al. Synthetic human monoclonal antibodies toward staphylococcal enterotoxin B (SEB) protective against toxic shock syndrome. J Biol Chem 287, 25203\u20132521 (2012).","journal-title":"J Biol Chem"},{"key":"BFsrep15553_CR19","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1128\/CVI.00078-10","volume":"17","author":"TK Inskeep","year":"2010","unstructured":"Inskeep, T. K. et al. Oral vaccine formulations stimulate mucosal and systemic antibody responses against staphylococcal enterotoxin B in a piglet model. Clin Vaccine Immunol 17, 1163\u20131169 (2010).","journal-title":"Clin Vaccine Immunol"},{"key":"BFsrep15553_CR20","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/1742-4690-11-8","volume":"11","author":"AM Sholukh","year":"2014","unstructured":"Sholukh, A. M. et al. Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV: outcome depends on IgG dose. Retrovirology 11, 8 (2014).","journal-title":"Retrovirology"},{"key":"BFsrep15553_CR21","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1016\/j.anaerobe.2014.07.006","volume":"30","author":"A Mizrahi","year":"2014","unstructured":"Mizrahi, A., Collignon, A. & Pechine, S. Passive and active immunization strategies against Clostridium difficile infections: State of the art. Anaerobe 30, 210\u2013219 (2014).","journal-title":"Anaerobe"},{"key":"BFsrep15553_CR22","doi-asserted-by":"publisher","first-page":"e1004192","DOI":"10.1371\/journal.ppat.1004192","volume":"10","author":"Y Itoh","year":"2014","unstructured":"Itoh, Y. et al. Protective efficacy of passive immunization with monoclonal antibodies in animal models of H5N1 highly pathogenic avian influenza virus infection. PLoS Pathog 10, e1004192 (2014).","journal-title":"PLoS Pathog"},{"key":"BFsrep15553_CR23","first-page":"187","volume":"8","author":"JJ Varrone","year":"2011","unstructured":"Varrone, J. J., Li, D., Daiss, J. L. & Schwarz, E. M. Anti-Glucosaminidase Monoclonal Antibodies as a Passive Immunization for Methicillin-Resistant Staphylococcus aureus (MRSA) Orthopaedic Infections. Bonekey Osteovision 8, 187\u2013194 (2011).","journal-title":"Bonekey Osteovision"},{"key":"BFsrep15553_CR24","doi-asserted-by":"publisher","first-page":"e1636","DOI":"10.1371\/journal.pntd.0001636","volume":"6","author":"PC Li","year":"2012","unstructured":"Li, P. C. et al. Development of a humanized antibody with high therapeutic potential against dengue virus type 2. PLoS Negl Trop Dis 6, e1636 (2012).","journal-title":"PLoS Negl Trop Dis"},{"key":"BFsrep15553_CR25","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1007\/s10482-008-9252-0","volume":"94","author":"NJ Pokorny","year":"2008","unstructured":"Pokorny, N. J., Boulter-Bitzer, J. I., Hall, J. C., Trevors, J. T. & Lee, H. Inhibition of Cryptosporidium parvum infection of a mammalian cell culture by recombinant scFv antibodies. Antonie Van Leeuwenhoek 94, 353\u2013364 (2008).","journal-title":"Antonie Van Leeuwenhoek"},{"key":"BFsrep15553_CR26","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1006\/mpat.1996.0048","volume":"21","author":"IS Aaberge","year":"1996","unstructured":"Aaberge, I. S., Hvalbye, B. & Lovik, M. Enhancement of Streptococcus pneumoniae serotype 6B infection in mice after passive immunization with human serum. Microb Pathog 21, 125\u2013137 (1996).","journal-title":"Microb Pathog"},{"key":"BFsrep15553_CR27","doi-asserted-by":"publisher","first-page":"261","DOI":"10.4149\/av_2011_03_261","volume":"55","author":"J Kiraly","year":"2011","unstructured":"Kiraly, J., Vareckova, E., Mucha, V. & Kostolansky, F. Evaluation of anti-influenza efficiency of polyclonal IgG antibodies specific to the ectodomain of M2 protein of influenza A virus by passive immunization of mice. Acta Virol 55, 261\u2013265 (2011).","journal-title":"Acta Virol"},{"key":"BFsrep15553_CR28","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1128\/IAI.01088-07","volume":"76","author":"TO Yarovinsky","year":"2008","unstructured":"Yarovinsky, T. O., Monick, M. M., Husmann, M. & Hunninghake, G. W. Interferons increase cell resistance to Staphylococcal alpha-toxin. Infect Immun 76, 571\u2013577 (2008).","journal-title":"Infect Immun"},{"key":"BFsrep15553_CR29","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1038\/nm1207-1405","volume":"13","author":"J Bubeck Wardenburg","year":"2007","unstructured":"Bubeck Wardenburg, J., Bae, T., Otto, M., Deleo, F. R. & Schneewind, O. Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia. Nat Med 13, 1405\u20131406 (2007).","journal-title":"Nat Med"},{"key":"BFsrep15553_CR30","doi-asserted-by":"publisher","first-page":"3085","DOI":"10.2169\/internalmedicine.51.7295","volume":"51","author":"T Kashiwada","year":"2012","unstructured":"Kashiwada, T. et al. Staphylococcal enterotoxin B toxic shock syndrome induced by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). Intern Med 51, 3085\u20133088 (2012).","journal-title":"Intern Med"},{"key":"BFsrep15553_CR31","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1093\/infdis\/jiu198","volume":"210","author":"AK Varshney","year":"2014","unstructured":"Varshney, A. K. et al. Humanized staphylococcal enterotoxin B (SEB)-specific monoclonal antibodies protect from SEB intoxication and Staphylococcus aureus infections alone or as adjunctive therapy with vancomycin. J Infect Dis 210, 973\u2013981 (2014).","journal-title":"J Infect Dis"},{"key":"BFsrep15553_CR32","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1046\/j.1365-2958.2002.02944.x","volume":"44","author":"MJ Horsburgh","year":"2002","unstructured":"Horsburgh, M. J. et al. MntR modulates expression of the PerR regulon and superoxide resistance in Staphylococcus aureus through control of manganese uptake. Mol Microbiol 44, 1269\u20131286 (2002).","journal-title":"Mol Microbiol"},{"key":"BFsrep15553_CR33","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.1093\/infdis\/jis272","volume":"205","author":"AS Anderson","year":"2012","unstructured":"Anderson, A. S. et al. Staphylococcus aureus manganese transport protein C is a highly conserved cell surface protein that elicits protective immunity against S. aureus and Staphylococcus epidermidis. J Infect Dis 205, 1688\u20131696 (2012).","journal-title":"J Infect Dis"},{"key":"BFsrep15553_CR34","doi-asserted-by":"publisher","first-page":"573","DOI":"10.18388\/abp.2014_1879","volume":"61","author":"B Kalenik","year":"2014","unstructured":"Kalenik, B., Sawicka, R., Gora-Sochacka, A. & Sirko, A. Influenza prevention and treatment by passive immunization. Acta Biochim Pol 61, 573\u2013587 (2014).","journal-title":"Acta Biochim Pol"},{"key":"BFsrep15553_CR35","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1038\/nm.2296","volume":"17","author":"Y Zhang","year":"2011","unstructured":"Zhang, Y. et al. Kinase suppressor of Ras-1 protects against pulmonary Pseudomonas aeruginosa infections. Nat Med 17, 341\u2013346 (2011).","journal-title":"Nat Med"},{"key":"BFsrep15553_CR36","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1128\/CVI.00046-07","volume":"14","author":"Y Li","year":"2007","unstructured":"Li, Y. et al. Immunization with recombinant Sao protein confers protection against Streptococcus suis infection. Clin Vaccine Immunol 14, 937\u2013943 (2007).","journal-title":"Clin Vaccine Immunol"},{"key":"BFsrep15553_CR37","doi-asserted-by":"publisher","first-page":"3429","DOI":"10.1016\/j.jmb.2013.06.033","volume":"425","author":"A Gribenko","year":"2013","unstructured":"Gribenko, A. et al. Three-dimensional structure and biophysical characterization of Staphylococcus aureus cell surface antigen-manganese transporter MntC. J Mol Biol 425, 3429\u20133445 (2013).","journal-title":"J Mol Biol"},{"key":"BFsrep15553_CR38","doi-asserted-by":"publisher","first-page":"1957","DOI":"10.1007\/s11033-010-0317-6","volume":"38","author":"Z Jinyong","year":"2011","unstructured":"Jinyong, Z. et al. Fusion expression and immunogenicity of Bordetella pertussis PTS1-FHA protein: implications for the vaccine development. Mol Biol Rep 38, 1957\u20131963 (2011).","journal-title":"Mol Biol Rep"},{"key":"BFsrep15553_CR39","first-page":"5","volume":"32","author":"JM Walker","year":"1994","unstructured":"Walker, J. M. The bicinchoninic acid (BCA) assay for protein quantitation. Methods Mol Biol 32, 5\u20138, (1994).","journal-title":"Methods Mol Biol"},{"key":"BFsrep15553_CR40","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1128\/CVI.00086-12","volume":"19","author":"RL Burton","year":"2012","unstructured":"Burton, R. L. & Nahm, M. H. Development of a fourfold multiplexed opsonophagocytosis assay for pneumococcal antibodies against additional serotypes and discovery of serological subtypes in Streptococcus pneumoniae serotype 20. Clin Vaccine Immunol 19, 835\u2013841 (2012).","journal-title":"Clin Vaccine Immunol"},{"key":"BFsrep15553_CR41","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1128\/CVI.00667-13","volume":"21","author":"F Yang","year":"2014","unstructured":"Yang, F. et al. Specific humoral immune response induced by propionibacterium acnes can prevent Actinobacillus pleuropneumoniae infection in mice. Clin Vaccine Immunol 21, 407\u2013416 (2014).","journal-title":"Clin Vaccine Immunol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep15553.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep15553","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep15553.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T14:45:26Z","timestamp":1672929926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep15553"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,22]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,7]]}},"alternative-id":["BFsrep15553"],"URL":"https:\/\/doi.org\/10.1038\/srep15553","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,10,22]]},"assertion":[{"value":"19 June 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 September 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 October 2015","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":"15553"}}