{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T02:08:49Z","timestamp":1768270129143,"version":"3.49.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,3,5]],"date-time":"2020-03-05T00:00:00Z","timestamp":1583366400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,3,5]],"date-time":"2020-03-05T00:00:00Z","timestamp":1583366400000},"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>Lipopolysaccharide (LPS) induces fever through cytokines like receptor-activator of nuclear factor \u03baB ligand (RANKL), triggering mediators like prostaglandins (PG), endothelin-1 (ET-1), corticotrophin-releasing factor (CRF), substance P (SP) and endogenous opioids. LPS-induced fever is reduced in females compared with males except in ovariectomized (OVX) females which show increased fever mediated by PG. The present study aimed to identify the mediators involved in fever in intact and OVX female rats. Fever was induced with LPS (50 \u03bcg\/kg) intraperitoneally or CRF (2.5\u2009\u03bcg), ET-1 (1\u2009pg), morphine (10 \u03bcg) and SP (500\u2009ng) intracerebroventricularly in sham-operated and OVX rats. The role of RANKL was evaluated with osteoprotegerin (OPG, 1 \u03bcg, intracerebroventricularly). Expression of RANK, CRF<jats:sub>I\/II<\/jats:sub>, ET<jats:sub>B<\/jats:sub>, \u03bc-opioid (MOR) and NK<jats:sub>1<\/jats:sub> receptors was evaluated by confocal microscopy. Besides LPS, only morphine induced fever in OVX rats while all mediators induced fever in sham-operated animals. OPG abolished LPS-induced fever in OVX but not sham-operated animals. Overall, fever involves similar central mediators in cycling females and males but only morphine induced fever in OVX females. Importantly, RANK\/RANKL participates in LPS-induced fever in OVX females, as in males but not in cycling females.<\/jats:p>","DOI":"10.1038\/s41598-020-61210-z","type":"journal-article","created":{"date-parts":[[2020,3,5]],"date-time":"2020-03-05T11:06:26Z","timestamp":1583406386000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Immune-mediated febrile response in female rats: Role of central hypothalamic mediators"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1189-8130","authenticated-orcid":false,"given":"Haissa Oliveira","family":"Brito","sequence":"first","affiliation":[]},{"given":"D\u00e9bora","family":"Radulski","sequence":"additional","affiliation":[]},{"given":"Daniel Bj\u00f6rk","family":"Wilhelms","sequence":"additional","affiliation":[]},{"given":"Andrea","family":"Stojakovic","sequence":"additional","affiliation":[]},{"given":"Luciane Maria Oliveira","family":"Brito","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2151-2449","authenticated-orcid":false,"given":"Rui Miguel","family":"Gil da Costa","sequence":"additional","affiliation":[]},{"given":"Edvaldo","family":"Trindade","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6501-9077","authenticated-orcid":false,"given":"David","family":"Engblom","sequence":"additional","affiliation":[]},{"given":"Celia Regina Cavichiolo","family":"Franco","sequence":"additional","affiliation":[]},{"given":"Aleksander Roberto","family":"Zampronio","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2020,3,5]]},"reference":[{"key":"61210_CR1","first-page":"009","volume":"4","author":"S Dalal","year":"2006","unstructured":"Dalal, S. & Zhukovsky, D. S. Pathophysiology and management of fever. J. Support. Oncol. 4, 009\u2013016 (2006).","journal-title":"J. Support. Oncol."},{"key":"61210_CR2","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1093\/clinids\/10.1.168","volume":"10","author":"CA Dinarello","year":"1988","unstructured":"Dinarello, C. A., Cannon, J. G. & Wolff, S. M. New concepts on the pathogenesis of fever. Rev. Infect. Dis. 10, 168\u2013189 (1988).","journal-title":"Rev. Infect. Dis."},{"key":"61210_CR3","doi-asserted-by":"publisher","first-page":"R37","DOI":"10.1152\/ajpregu.00668.2006","volume":"292","author":"AA Romanowsky","year":"2007","unstructured":"Romanowsky, A. A. Thermoregulation: some concepts have changed. Functional architecture of the thermoregulatory system. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R37\u201346 (2007).","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"61210_CR4","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1093\/humupd\/dmi008","volume":"11","author":"A Bouman","year":"2005","unstructured":"Bouman, A., Heineman, M. J. & Faas, M. M. Sex hormones and the immune response in humans. Hum. Reprod. Update. 11, 411\u201323 (2005).","journal-title":"Hum. Reprod. Update."},{"key":"61210_CR5","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.cyto.2013.10.004","volume":"65","author":"T Iwasa","year":"2014","unstructured":"Iwasa, T. et al. Changes in central and peripheral inflammatory responses to lipopolysaccharide in ovareictomized female rats. Cytokine. 65, 65\u201373 (2014).","journal-title":"Cytokine."},{"key":"61210_CR6","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.jneuroim.2014.09.017","volume":"277","author":"T Iwasa","year":"2014","unstructured":"Iwasa, T. et al. Effects of ovariectomy on the inflammatory responses of female rats to the central injection of lipopolysaccharide. J. Neuroimmunol. 277, 50\u201356 (2014).","journal-title":"J. Neuroimmunol."},{"key":"61210_CR7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jneuroim.2016.01.016","volume":"15","author":"HO Brito","year":"2016","unstructured":"Brito, H. O. et al. Evidence of substance P autocrine circuitry that involves TNF-\u03b1, IL-6, and PGE2 in endogenous pyrogen-induced fever. J. Neuroimmunol. 15, 1\u20137 (2016).","journal-title":"J. Neuroimmunol."},{"key":"61210_CR8","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/nature08596","volume":"462","author":"R Hanada","year":"2009","unstructured":"Hanada, R. et al. Central control of fever and female body temperature by RANKL\/RANK. Nature. 462, 505\u2013509 (2009).","journal-title":"Nature."},{"key":"61210_CR9","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1152\/physrev.1991.71.1.93","volume":"71","author":"MJ Kluger","year":"1991","unstructured":"Kluger, M. J. Fever: role of pyrogens and cryogens. Physiol. Rev. 71, 83\u2013127 (1991).","journal-title":"Physiol. Rev."},{"key":"61210_CR10","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.brainres.2008.07.069","volume":"1233","author":"DM Soares","year":"2008","unstructured":"Soares, D. M., Machado, R. R., Yamashiro, L. H., Melo, M. C. & Souza, G. E. Cytokine-induced neutrophil chemoattractant (CINC)-1 induces fever by a prostaglandin-dependent mechanism in rats. Brain Res. 1233, 79\u201388 (2008).","journal-title":"Brain Res."},{"key":"61210_CR11","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1155\/S0962935194000517","volume":"3","author":"AR Zampronio","year":"1994","unstructured":"Zampronio, A. R. et al. A pre-formed Pyrogenic Factor Released by Lipopolysaccharide Stimulated Macrophages. Mediators Inflamm. 3, 365\u2013373 (1994).","journal-title":"Mediators Inflamm."},{"key":"61210_CR12","first-page":"1670","volume":"266","author":"AR Zampronio","year":"1994","unstructured":"Zampronio, A. R., Souza, G. E., Silva, C. A., Cunha, F. Q. & Ferreira, S. H. Interleukin-8 induces fever by a prostaglandin-independent mechanism. Am. J. Physiol. 266, 1670\u20131674 (1994).","journal-title":"Am. J. Physiol."},{"key":"61210_CR13","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1097\/00001756-199808030-00017","volume":"9","author":"E Tavares","year":"1998","unstructured":"Tavares, E. & Minano, F. J. Macrophage inflammatory protein-1beta induces dexamethasone-unresponsive fever in rats. Neuroreport. 9, 19\u201322 (1998).","journal-title":"Neuroreport."},{"key":"61210_CR14","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1080\/23328940.2015.1102802","volume":"2","author":"AR Zampronio","year":"2015","unstructured":"Zampronio, A. R., Soares, D. M. & Souza, G. E. Central mediators involved in the febrile response: effects of antipyretic drugs. Temperature (Austin) 2, 506\u2013521 (2015).","journal-title":"Temperature (Austin)"},{"key":"61210_CR15","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1007\/s00109-011-0749-z","volume":"89","author":"R Hanada","year":"2011","unstructured":"Hanada, R., Hanada, T., Sigl, V., Schramek, D. & Penninger, J. M. RANKL\/RANK-beyond bones. J. Mol. Med. (Berl.) 89, 647\u2013656 (2011).","journal-title":"J. Mol. Med. (Berl.)"},{"key":"61210_CR16","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1002\/1096-9861(20001204)428:1<20::AID-CNE3>3.0.CO;2-X","volume":"428","author":"T Oka","year":"2000","unstructured":"Oka, T. et al. Relationship of EP(1\u20134) prostaglandin receptors with rat hypothalamic cell groups involved in lipopolysaccharide fever responses. J. Comp. Neurol. 428, 20\u201332 (2000).","journal-title":"J. Comp. Neurol."},{"key":"61210_CR17","doi-asserted-by":"publisher","first-page":"R800","DOI":"10.1152\/ajpregu.00258.2002","volume":"283","author":"A Mouihate","year":"2002","unstructured":"Mouihate, A. et al. Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283, R800\u2013R805 (2002).","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"61210_CR18","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1152\/ajpcell.1993.265.3.C834","volume":"265","author":"T Nakamori","year":"1993","unstructured":"Nakamori, T. et al. Effect of a central CRF antagonist on cardiovascular and thermoregulatory responses induced by stress or IL-1 b. Am. J. Physiol. 265, 834\u2013839 (1993).","journal-title":"Am. J. Physiol."},{"key":"61210_CR19","first-page":"589","volume":"11","author":"AR Zampronio","year":"2000","unstructured":"Zampronio, A. R. et al. Interleukin (IL)-6 release and fever induced by a pre-formed pyrogenic factor (PFPF) derived from LPS-stimulated macrophages. Eur. Cytokine Netw. 11, 589\u2013596 (2000).","journal-title":"Eur. Cytokine Netw."},{"key":"61210_CR20","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1038\/sj.bjp.0702075","volume":"125","author":"AS Fabricio","year":"1998","unstructured":"Fabricio, A. S., Silva, C. A., Rae, G. A., D\u2019orleans-Juste, P. & Souza, G. E. Essential role for endothelin ET(B) receptors in fever induced by LPS (E. coli) in rats. Br. J. Pharmacol. 125, 542\u2013548 (1998).","journal-title":"Br. J. Pharmacol."},{"key":"61210_CR21","first-page":"R671","volume":"288","author":"ASC Fabricio","year":"2005","unstructured":"Fabricio, A. S. C., Veiga, F. H., Cristofoletti, R., Navarra, P. & Souza, G. E. The effects of selective and nonselective cyclooxygenase inhibitors on endothelin-1-induced fever in rats. Am. J. Physiol. 288, R671\u2013R677 (2005).","journal-title":"Am. J. Physiol."},{"key":"61210_CR22","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.brainres.2005.10.037","volume":"1066","author":"ASC Fabr\u00edcio","year":"2005","unstructured":"Fabr\u00edcio, A. S. C., Rae, G. A., D\u2019orleans-Juste, P. & Souza, G. E. P. Endothelin-1 as a central mediator of LPS-induced fever in rats. Brain Res. 1066, 92\u2013100 (2005).","journal-title":"Brain Res."},{"key":"61210_CR23","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1038\/sj.bjp.0703114","volume":"129","author":"JG Filep","year":"2000","unstructured":"Filep, J. G. Role of endogenous endothelin in the regulation of plasma volume and albumin escape during endotoxin shock in conscious rats. Br. J. Pharmacol. 129, 975\u2013983 (2000).","journal-title":"Br. J. Pharmacol."},{"key":"61210_CR24","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1111\/j.1476-5381.2010.01150.x","volume":"162","author":"DC Malvar","year":"2011","unstructured":"Malvar, D. C. et al. The antipyretic effect of dipyrone is unrelated to inhibition of PGE(2) synthesis in the hypothalamus. Br. J. Pharmacol. 162, 1401\u20131409 (2011).","journal-title":"Br. J. Pharmacol."},{"key":"61210_CR25","doi-asserted-by":"publisher","first-page":"R164","DOI":"10.1152\/ajpregu.00337.2005","volume":"290","author":"AS Fabr\u00edcio","year":"2006","unstructured":"Fabr\u00edcio, A. S., Rae, G. A., Zampronio, A. R., D\u2019Orl\u00e9ans-Juste, P. & Souza, G. E. Central endothelin receptors mediate IL-1-dependent fever induced by preformed pyrogenic factor and corticotropin-releasing factor in the rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290, R164\u2013R171 (2006).","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"61210_CR26","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.lfs.2016.01.010","volume":"159","author":"EY Gohar","year":"2016","unstructured":"Gohar, E. Y., Yusuf, C. & Pollock, D. M. Ovarian hormones endothelin A and B receptor expression. Life Sci. 159, 148\u2013152 (2016).","journal-title":"Life Sci."},{"key":"61210_CR27","doi-asserted-by":"publisher","first-page":"2665","DOI":"10.1016\/S0024-3205(03)00605-2","volume":"73","author":"Z Tan","year":"2003","unstructured":"Tan, Z., Wang, T. H., Yang, D., Fu, X. D. & Pan, J. Y. Mechanisms of 17beta-estradiol on the production of ET-1 in ovariectomized rats. Life Sci. 73, 2665\u20132674 (2003).","journal-title":"Life Sci."},{"key":"61210_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-00213-9","volume":"7","author":"M Subramanian","year":"2017","unstructured":"Subramanian, M. et al. Chronic exposure to low doses of estradiol-17\u03b2 increases blood pressure in young female rats: a possible role for central endothelin-1. Sci. Rep. 7, 139 (2017).","journal-title":"Sci. Rep."},{"key":"61210_CR29","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1111\/j.1749-6632.1998.tb08336.x","volume":"856","author":"CM Handler","year":"1998","unstructured":"Handler, C. M., Price, R. W., Geller, E. B. & Adler, M. W. Effect of mu-selective opioid antagonists on MIP-1 b and IL-1 b-induced fever. Ann. N. Y. Acad. Sci. 856, 270\u2013273 (1998).","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"61210_CR30","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/0361-9230(91)90230-H","volume":"26","author":"CM Blatteis","year":"1991","unstructured":"Blatteis, C. M., Xin, L. & Quan, N. Neuromodulation of fever: apparent involvement of opioids. Brain. Res. Bull. 26, 219\u2013223 (1991).","journal-title":"Brain. Res. Bull."},{"key":"61210_CR31","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/S0014-2999(00)00424-6","volume":"401","author":"K Benamar","year":"2000","unstructured":"Benamar, K., Xin, L., Geller, E. B. & Adler, M. W. Blockade of lipopolysaccharide-induced fever by a mu-opioid receptor-selective antagonist in rats. Eur. J. Pharmacol. 401, 161\u2013165 (2000).","journal-title":"Eur. J. Pharmacol."},{"key":"61210_CR32","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1152\/ajpregu.00465.2007","volume":"294","author":"D Fraga","year":"2008","unstructured":"Fraga, D., Machado, R. R., Fernandes, L. C., Souza, G. E. & Zampronio, A. R. Endogenous opioids: role in prostaglandin-dependent and -independent fever. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, 411\u2013420 (2008).","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"61210_CR33","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1111\/j.1749-6632.1997.tb51713.x","volume":"813","author":"Z Szelenyi","year":"1997","unstructured":"Szelenyi, Z., Szekely, M. & Balasko, M. Role of substance P (SP) in the mediation of endotoxin (LPS) fever in rats. Ann. N. Y. Acad. Sci. 813, 316\u2013323 (1997).","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"61210_CR34","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/0304-3940(94)90793-5","volume":"182","author":"H Too","year":"1994","unstructured":"Too, H., Marriott, D. R. & Wilkin, G. P. Preprotachykinin-A and substance P receptor (NK1) gene expression in rat astrocytes in vitro. Neurosci. Lett. 182, 185\u2013187 (1994).","journal-title":"Neurosci. Lett."},{"key":"61210_CR35","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/0006-8993(95)01014-M","volume":"698","author":"DP Behan","year":"1995","unstructured":"Behan, D. P., Maciejewski, D., Chalmers, D. & De Souza, E. B. Corticotropin releasing factor binding protein (CRF-BP) is expressed in neuronal and astrocytic cells. Brain Res. 698, 259\u201364 (1995).","journal-title":"Brain Res."},{"key":"61210_CR36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1742-2094-10-51","volume":"10","author":"Y Koyama","year":"2013","unstructured":"Koyama, Y. et al. Different actions of endothelin-1 on chemokine production in rat cultured astrocytes: reduction of CX3CL1\/fractalkine and an increase in CCL2\/MCP-1 and CXCL1\/CINC-1. J. Neuroinflammation. 10, 1\u201311 (2013).","journal-title":"J. Neuroinflammation."},{"key":"61210_CR37","doi-asserted-by":"publisher","first-page":"2269","DOI":"10.1016\/j.peptides.2010.09.007","volume":"31","author":"T Filipovich-Rimon","year":"2010","unstructured":"Filipovich-Rimon, T. & Fleisher-Berkovich, S. Glial response to lipopolysaccharide: possible role of endothelins. Peptides. 31, 2269\u20132275 (2010).","journal-title":"Peptides."},{"key":"61210_CR38","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1016\/j.neuroscience.2008.04.027","volume":"155","author":"E Hansson","year":"2008","unstructured":"Hansson, E., Westerlund, A., Bjorklund, U. & Olsson, T. \u00b5-Opioid agonists inhibit the enhanced intracellular Ca2+ responses in inflammatory activated astrocytes co-cultured with brain endothelial cells. Neuroscience. 155, 1237\u20131249 (2008).","journal-title":"Neuroscience."},{"key":"61210_CR39","doi-asserted-by":"publisher","first-page":"2476","DOI":"10.1038\/sj.npp.1301007","volume":"31","author":"M Narita","year":"2006","unstructured":"Narita, M. et al. Direct evidence of astrocytic modulation in the development of rewarding effects induced by drugs of abuse. Neuropsychopharmacol. 31, 2476\u20132488 (2006).","journal-title":"Neuropsychopharmacol."},{"key":"61210_CR40","doi-asserted-by":"publisher","unstructured":"Brito H.O. et al. Female sex hormones influence the febrile response induced by lipopolysaccharide, cytokines and prostaglandins but not by interleukin-1\u03b2 in rats. J. Neuroendocrinol. 28, https:\/\/doi.org\/10.1111\/jne.12414.","DOI":"10.1111\/jne.12414"},{"key":"61210_CR41","unstructured":"Paxinos, G. & Watson, C. The rat brain in steriotaxic coordinates (Academic Press, 2005)."},{"key":"61210_CR42","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1016\/0031-9384(90)90025-Y","volume":"47","author":"CJ Gordon","year":"1990","unstructured":"Gordon, C. J. Thermal biology of the laboratory rat. Physiol. Behav. 47, 963\u2013991 (1990).","journal-title":"Physiol. Behav."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-61210-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-61210-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-61210-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T08:05:31Z","timestamp":1670313931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-61210-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,5]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["61210"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-61210-z","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,5]]},"assertion":[{"value":"16 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 March 2020","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":"4073"}}