{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:57:49Z","timestamp":1788872269968,"version":"build-2803163510"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T00:00:00Z","timestamp":1733875200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T00:00:00Z","timestamp":1733875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003252","name":"Lund University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003252","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Headache Pain"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The purpose of this study was to examine whether there are sex differences in vasomotor responses and receptor localization of hormones and neuropeptides with relevance to migraine (vasopressin, oxytocin, estrogen, progesterone, testosterone, amylin, adrenomedullin and calcitonin gene-related peptide (CGRP)) in human intracranial arteries.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human cortical cerebral and middle meningeal arteries were used in this study. The tissues were removed in conjunction with neurosurgery and donated with consent. Vasomotor responses of arteries, after exposure to hormones or neuropeptides, were recorded using a wire myograph. Immunohistochemistry was performed to examine the expression and localization of their receptors within human intracranial arteries.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Vasopressin showed the strongest contractile responses, followed by oxytocin and progesterone. CGRP displayed the strongest vasodilatory response when compared to adrenomedullin, amylin, testosterone and estrogen. No significant differences were observed in vasomotor responses between male and female arteries. The vasomotor effects were supported by the presence of corresponding receptors in the vascular smooth muscle cells. Estrogen receptors (ER\u03b1 and ER\u03b2), progesterone receptor (PR), vasopressin 1a receptor (V1aR), and the oxytocin receptor (OTR) were expressed in the walls of both cerebral arteries overlying the cerebral cortex and intracranial arteries of the dura mater. ER\u03b1, V1aR, and PR were found to be localized in both smooth muscle cells and endothelium, whereas OTR was exclusively located within the smooth muscle cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Hypothalamic, sex hormones and the pancreas hormone (amylin) receptors are expressed in the human intracranial artery walls. The vasomotor responses revealed no sex differences, however contractile responses to vasopressin was higher and more potent in MMA compared to CCA when pooling data from both sexes. Overall, the hormones estrogen, progesterone and oxytocin, which drop in circulating levels at onset of menstruation, only showed modest vasomotor responses as compared to CGRP. This suggests that their role in inducing menstrual migraine attacks is not directly related to vasomotor responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s10194-024-01933-w","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T05:55:27Z","timestamp":1733896527000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Male-female comparison of vasomotor effects of circulating hormones in human intracranial arteries"],"prefix":"10.1186","volume":"25","author":[{"given":"Jacob C. A.","family":"Edvinsson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Grubor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Maddahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Edvinsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,11]]},"reference":[{"key":"1933_CR1","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.brainres.2018.12.030","volume":"1710","author":"LS Robison","year":"2019","unstructured":"Robison LS, Gannon OJ, Salinero AE, Zuloaga KL (2019) Contributions of sex to cerebrovascular function and pathology. Brain Res 1710:43\u201360","journal-title":"Brain Res"},{"key":"1933_CR2","doi-asserted-by":"crossref","unstructured":"Chauhan A, Moser H, McCullough LD (2017) Sex-Specific Factors in Stroke. Neuroprotective Therapy for Stroke and Ischemic Disease.733\u2009\u2013\u200950","DOI":"10.1007\/978-3-319-45345-3_32"},{"issue":"4","key":"1933_CR3","doi-asserted-by":"publisher","first-page":"e62698","DOI":"10.1371\/journal.pone.0062698","volume":"8","author":"H Ahnstedt","year":"2013","unstructured":"Ahnstedt H, Cao L, Krause DN, Warfvinge K, Saveland H, Nilsson OG et al (2013) Male-female differences in upregulation of vasoconstrictor responses in human cerebral arteries. PLoS ONE 8(4):e62698","journal-title":"PLoS ONE"},{"issue":"1","key":"1933_CR4","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/S1474-4422(16)30293-9","volume":"16","author":"KG Vetvik","year":"2017","unstructured":"Vetvik KG, MacGregor EA (2017) Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol 16(1):76\u201387","journal-title":"Lancet Neurol"},{"issue":"10","key":"1933_CR5","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1038\/s41582-021-00544-2","volume":"17","author":"DN Krause","year":"2021","unstructured":"Krause DN, Warfvinge K, Haanes KA, Edvinsson L (2021) Hormonal influences in migraine - interactions of oestrogen, oxytocin and CGRP. Nat Rev Neurol 17(10):621\u2013633","journal-title":"Nat Rev Neurol"},{"key":"1933_CR6","doi-asserted-by":"crossref","unstructured":"Ashina H, Christensen RH, Hay DL, Pradhan AA, Hoffmann J, Reglodi D et al (2024) Pituitary adenylate cyclase-activating polypeptide signalling as a therapeutic target in migraine. Nat Reviews Neurol. 1\u201311","DOI":"10.1038\/s41582-024-01011-4"},{"key":"1933_CR7","doi-asserted-by":"publisher","first-page":"105946","DOI":"10.1016\/j.nbd.2022.105946","volume":"176","author":"S Guo","year":"2023","unstructured":"Guo S, Jansen-Olesen I, Olesen J, Christensen SL (2023) Role of PACAP in migraine: an alternative to CGRP? Neurobiol Dis 176:105946","journal-title":"Neurobiol Dis"},{"issue":"7","key":"1933_CR8","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1111\/bph.12129","volume":"170","author":"C Walker","year":"2013","unstructured":"Walker C, Hay D (2013) CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors? Br J Pharmacol 170(7):1293\u20131307","journal-title":"Br J Pharmacol"},{"issue":"4","key":"1933_CR9","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1002\/ana.25697","volume":"87","author":"LH Schulte","year":"2020","unstructured":"Schulte LH, Mehnert J, May A (2020) Longitudinal neuroimaging over 30 days: temporal characteristics of migraine. Ann Neurol 87(4):646\u2013651","journal-title":"Ann Neurol"},{"issue":"8","key":"1933_CR10","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1111\/head.12150","volume":"53","author":"DC Buse","year":"2013","unstructured":"Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM et al (2013) Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe H eadache: results of the A merican migraine prevalence and prevention (AMPP) study. Headache: J Head Face Pain 53(8):1278\u20131299","journal-title":"Headache: J Head Face Pain"},{"issue":"1","key":"1933_CR11","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s10194-023-01664-4","volume":"24","author":"B Raffaelli","year":"2023","unstructured":"Raffaelli B, Do TP, Chaudhry BA, Ashina M, Amin FM, Ashina H (2023) Menstrual migraine is caused by estrogen withdrawal: revisiting the evidence. J Headache Pain 24(1):131","journal-title":"J Headache Pain"},{"key":"1933_CR12","unstructured":"Edvinsson L, Krause DN (2002) Cerebral blood flow and metabolism. Lippincott Williams & Wilkins"},{"issue":"1","key":"1933_CR13","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1161\/01.RES.41.1.19","volume":"41","author":"MJ Mulvany","year":"1977","unstructured":"Mulvany MJ, Halpern W (1977) Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res 41(1):19\u201326","journal-title":"Circ Res"},{"issue":"24","key":"1933_CR14","doi-asserted-by":"publisher","first-page":"4681","DOI":"10.1111\/bph.14832","volume":"176","author":"E Rubio-Beltr\u00e1n","year":"2019","unstructured":"Rubio-Beltr\u00e1n E, Labastida\u2010Ram\u00edrez A, Haanes KA, van den Bogaerdt A, Bogers AJ, Zanelli E et al (2019) Characterization of binding, functional activity, and contractile responses of the selective 5\u2010HT1F receptor agonist lasmiditan. Br J Pharmacol 176(24):4681\u20134695","journal-title":"Br J Pharmacol"},{"issue":"1","key":"1933_CR15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s10194-022-01524-7","volume":"23","author":"A Maddahi","year":"2022","unstructured":"Maddahi A, Edvinsson L, Warfvinge K (2022) Expression of vasopressin and its receptors in migraine-related regions in CNS and the trigeminal system: influence of sex. J Headache Pain 23(1):1\u201320","journal-title":"J Headache Pain"},{"issue":"6","key":"1933_CR16","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1038\/jcbfm.1987.126","volume":"7","author":"L Edvinsson","year":"1987","unstructured":"Edvinsson L, Ekman R, Jansen I, McCulloch J, Uddman R (1987) Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. J Cereb Blood Flow Metabolism 7(6):720\u2013728","journal-title":"J Cereb Blood Flow Metabolism"},{"issue":"1","key":"1933_CR17","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s10194-020-01197-0","volume":"21","author":"K Warfvinge","year":"2020","unstructured":"Warfvinge K, Krause DN, Maddahi A, Edvinsson JCA, Edvinsson L, Haanes KA (2020) Estrogen receptors alpha, beta and GPER in the CNS and trigeminal system - molecular and functional aspects. J Headache Pain 21(1):131","journal-title":"J Headache Pain"},{"issue":"10","key":"1933_CR18","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1177\/0333102410362122","volume":"30","author":"L Edvinsson","year":"2010","unstructured":"Edvinsson L, Chan KY, Eftekhari S, Nilsson E, de Vries R, Saveland H et al (2010) Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries. Cephalalgia 30(10):1233\u20131240","journal-title":"Cephalalgia"},{"issue":"3","key":"1933_CR19","first-page":"749","volume":"228","author":"S Lluch","year":"1984","unstructured":"Lluch S, Conde MV, Dieguez G, Lopez de Pablo AL, Gonzalez MC, Estrada C et al (1984) Evidence for the direct effect of vasopressin on human and goat cerebral arteries. J Pharmacol Exp Ther 228(3):749\u2013755","journal-title":"J Pharmacol Exp Ther"},{"issue":"1\u20132","key":"1933_CR20","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/0014-2999(94)90302-6","volume":"261","author":"C Mart\u00ednez","year":"1994","unstructured":"Mart\u00ednez C, Vila J, Aldasoro M, Medina P, Chuan P, Lluch S (1994) The human deferential artery: endothelium-mediated contraction in response to adrenergic stimulation. Eur J Pharmacol 261(1\u20132):73\u201378","journal-title":"Eur J Pharmacol"},{"key":"1933_CR21","doi-asserted-by":"publisher","first-page":"109597","DOI":"10.1016\/j.mehy.2020.109597","volume":"138","author":"B Buemann","year":"2020","unstructured":"Buemann B, Uvnas-Moberg K (2020) Oxytocin may have a therapeutical potential against cardiovascular disease. Possible pharmaceutical and behavioral approaches. Med Hypotheses 138:109597","journal-title":"Med Hypotheses"},{"key":"1933_CR22","doi-asserted-by":"publisher","first-page":"929741","DOI":"10.3389\/fpsyg.2022.929741","volume":"13","author":"K Uvnas Moberg","year":"2022","unstructured":"Uvnas Moberg K, Julius H, Handlin L, Petersson M (2022) Editorial: sensory stimulation and oxytocin: their roles in Social Interaction and Health Promotion. Front Psychol 13:929741","journal-title":"Front Psychol"},{"issue":"12","key":"1933_CR23","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1177\/0333102420929027","volume":"40","author":"K Warfvinge","year":"2020","unstructured":"Warfvinge K, Krause DN, Maddahi A, Grell AS, Edvinsson JC, Haanes KA et al (2020) Oxytocin as a regulatory neuropeptide in the trigeminovascular system: localization, expression and function of oxytocin and oxytocin receptors. Cephalalgia 40(12):1283\u20131295","journal-title":"Cephalalgia"},{"issue":"1","key":"1933_CR24","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1186\/s10194-023-01687-x","volume":"24","author":"A Maddahi","year":"2023","unstructured":"Maddahi A, Warfvinge K, Holm A, Edvinsson JC, Reducha PV, Kazantzi S et al (2023) Progesterone distribution in the trigeminal system and its role to modulate sensory neurotransmission: influence of sex. J Headache Pain 24(1):154","journal-title":"J Headache Pain"},{"issue":"12","key":"1933_CR25","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1038\/nrneurol.2017.137","volume":"13","author":"M Ashina","year":"2017","unstructured":"Ashina M, Hansen JM, \u00e1 Dunga BO, Olesen J (2017) Human models of migraine\u2014short-term pain for long-term gain. Nat Reviews Neurol 13(12):713\u2013724","journal-title":"Nat Reviews Neurol"},{"issue":"4","key":"1933_CR26","doi-asserted-by":"publisher","first-page":"151","DOI":"10.5214\/ans.0972.7531.190403","volume":"19","author":"M Aggarwal","year":"2012","unstructured":"Aggarwal M, Puri V, Puri S (2012) Effects of estrogen on the serotonergic system and calcitonin gene-related peptide in trigeminal ganglia of rats. Ann Neurosci 19(4):151\u2013157","journal-title":"Ann Neurosci"},{"issue":"1","key":"1933_CR27","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s10194-020-1079-8","volume":"21","author":"K Warfvinge","year":"2020","unstructured":"Warfvinge K, Krause D, Edvinsson L (2020) The distribution of oxytocin and the oxytocin receptor in rat brain: relation to regions active in migraine. J Headache Pain 21(1):10","journal-title":"J Headache Pain"},{"key":"1933_CR28","doi-asserted-by":"publisher","first-page":"727380","DOI":"10.3389\/fragi.2021.727380","volume":"2","author":"M Davezac","year":"2021","unstructured":"Davezac M, Buscato M, Zahreddine R, Lacolley P, Henrion D, Lenfant F et al (2021) Estrogen Receptor and vascular aging. Front Aging 2:727380","journal-title":"Front Aging"},{"key":"1933_CR29","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.maturitas.2020.12.012","volume":"145","author":"S de Vries Lentsch","year":"2021","unstructured":"de Vries Lentsch S, Rubio-Beltran E, MaassenVanDenBrink A (2021) Changing levels of sex hormones and calcitonin gene-related peptide (CGRP) during a woman\u2019s life: implications for the efficacy and safety of novel antimigraine medications. Maturitas 145:73\u201377","journal-title":"Maturitas"},{"issue":"9","key":"1933_CR30","doi-asserted-by":"publisher","first-page":"3513","DOI":"10.1210\/jc.2009-0278","volume":"94","author":"KM Gavin","year":"2009","unstructured":"Gavin KM, Seals DR, Silver AE, Moreau KL (2009) Vascular endothelial estrogen receptor alpha is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women. J Clin Endocrinol Metab 94(9):3513\u20133520","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"1933_CR31","doi-asserted-by":"publisher","first-page":"283","DOI":"10.2174\/157340209789587717","volume":"5","author":"GR do Nascimento","year":"2009","unstructured":"do Nascimento GR, Barros YV, Wells AK, Khalil RA (2009) Research into specific modulators of vascular sex hormone receptors in the management of Postmenopausal Cardiovascular Disease. Curr Hypertens Rev 5(4):283\u2013306","journal-title":"Curr Hypertens Rev"},{"issue":"4","key":"1933_CR32","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1158\/1055-9965.EPI-21-1157","volume":"31","author":"EX Holder","year":"2022","unstructured":"Holder EX, Houghton SC, Sanchez SS, Eliassen AH, Qian J, Bertone-Johnson ER et al (2022) Estrogenic activity and risk of invasive breast Cancer among Postmenopausal women in the nurses\u2019 Health Study. Cancer Epidemiol Biomarkers Prev 31(4):831\u2013838","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"5","key":"1933_CR33","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.npep.2012.07.001","volume":"46","author":"A Gossen","year":"2012","unstructured":"Gossen A, Hahn A, Westphal L, Prinz S, Schultz RT, Grunder G et al (2012) Oxytocin plasma concentrations after single intranasal oxytocin administration - a study in healthy men. Neuropeptides 46(5):211\u2013215","journal-title":"Neuropeptides"},{"issue":"Suppl 2","key":"1933_CR34","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1159\/000446198","volume":"68","author":"I Guelinckx","year":"2016","unstructured":"Guelinckx I, Vecchio M, Perrier ET, Lemetais G (2016) Fluid intake and vasopressin: connecting the dots. Ann Nutr Metab 68(Suppl 2):6\u201311","journal-title":"Ann Nutr Metab"},{"issue":"7","key":"1933_CR35","doi-asserted-by":"publisher","first-page":"333102424125408","DOI":"10.1177\/03331024241254088","volume":"44","author":"T de Vries","year":"2024","unstructured":"de Vries T, Boucherie DM, Chan KY, Rubio-Beltr\u00e1n E, Labastida-Ram\u00edrez A, Labruijere S et al (2024) Sex differences in CGRP-induced vasodilation of human middle meningeal arteries but not human coronary arteries: implications for migraine. Cephalalgia 44(7):3331024241254088","journal-title":"Cephalalgia"},{"issue":"10","key":"1933_CR36","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1177\/0333102410362122","volume":"30","author":"L Edvinsson","year":"2010","unstructured":"Edvinsson L, Chan KY, Eftekhari S, Nilsson E, de Vries R, S\u00e4veland H et al (2010) Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries. Cephalalgia 30(10):1233\u20131240","journal-title":"Cephalalgia"},{"issue":"1","key":"1933_CR37","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/bph.14075","volume":"175","author":"DL Hay","year":"2018","unstructured":"Hay DL, Garelja ML, Poyner DR, Walker CS (2018) Update on the pharmacology of calcitonin\/CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol 175(1):3\u201317","journal-title":"Br J Pharmacol"},{"issue":"6","key":"1933_CR38","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1177\/0333102420974362","volume":"41","author":"DS van Casteren","year":"2021","unstructured":"van Casteren DS, Verhagen IE, Onderwater GL, MaassenVanDenBrink A, Terwindt GM (2021) Sex differences in prevalence of migraine trigger factors: a cross-sectional study. Cephalalgia 41(6):643\u2013648","journal-title":"Cephalalgia"}],"container-title":["The Journal of Headache and Pain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10194-024-01933-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s10194-024-01933-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10194-024-01933-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T08:06:02Z","timestamp":1733904362000},"score":1,"resource":{"primary":{"URL":"https:\/\/thejournalofheadacheandpain.biomedcentral.com\/articles\/10.1186\/s10194-024-01933-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,11]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["1933"],"URL":"https:\/\/doi.org\/10.1186\/s10194-024-01933-w","relation":{},"ISSN":["1129-2377"],"issn-type":[{"value":"1129-2377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,11]]},"assertion":[{"value":"6 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 December 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Human samples were acquired, with oral and written consent, from patients undergoing neurosurgery at the University Hospital of Lund. The Human Ethics board approved the study design.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors have read and consented to the manuscript for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"216"}}