{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T14:23:21Z","timestamp":1784816601486,"version":"3.55.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,8,15]],"date-time":"2021-08-15T00:00:00Z","timestamp":1628985600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,8,15]],"date-time":"2021-08-15T00:00:00Z","timestamp":1628985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"University Hospital Marburg"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Oral Maxillofac Surg"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Analysis of the influence of geranyl-geraniol (GG) addition on four bisphosphonate derivatives regarding their influence on cell viability and migration ability of bone metabolism and endothelial cells in vitro.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Clodronate, pamidronate, ibandronate, and zoledronate were observed with and without GG addition, for their effect on human osteoblasts (HOB), normal human dermal fibroblasts (NHDF), human endothelial progenitor cells (EPC), and endothelial cells of the human umbilical cord (HUVEC) using migration-, MTT-, and colony-forming cell assays.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Data pointed to a depressing effect of all bisphosphonates on the migration ability of NHDF, EPC, and HOB. MTT assay demonstrated a decreased cell viability of HUVEC of all bisphosphonates in a 50\u00a0\u03bcM concentration and of NHDF when treated with 50\u00a0\u03bcM of clodronate, ibandronate, or zoledronate. Tested drugs showed a depressing effect on colony-forming potential of EPC even in a 5\u00a0\u03bcM concentration. GG addition demonstrated an attenuate impact on bisphosphonate effect on all primary cell cultures, respectively.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>In vitro comparison showed that the addition of GG weakens the effect of all bisphosphonates examined. It supports investigations that suggest GG to be able to prevent bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) in vivo. Future clinical trials may discover the local therapeutic use of GG for the prevention of BP-ONJ.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10006-021-00982-8","type":"journal-article","created":{"date-parts":[[2021,8,15]],"date-time":"2021-08-15T04:13:35Z","timestamp":1629000815000},"page":"321-332","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Geranyl-geraniol addition affects potency of bisphosphonates\u2014a comparison in vitro promising a therapeutic approach for bisphosphonate-associated osteonecrosis of the jaw and oral wound healing"],"prefix":"10.1007","volume":"26","author":[{"given":"Marius","family":"Otto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Lux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tilo","family":"Schlittenbauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Halling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3296-7630","authenticated-orcid":false,"given":"Thomas","family":"Ziebart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,15]]},"reference":[{"key":"982_CR1","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.14219\/jada.archive.2006.0355","volume":"137","author":"American Dental Association Council on Scientific Affairs","year":"2006","unstructured":"American Dental Association Council on Scientific Affairs (2006) Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. J Am Dent Assoc 137:1144\u20131150. https:\/\/doi.org\/10.14219\/jada.archive.2006.0355","journal-title":"J Am Dent Assoc"},{"key":"982_CR2","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.4065\/83.9.1032","volume":"83","author":"MT Drake","year":"2008","unstructured":"Drake MT, Clarke BL, Khosla S (2008) Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 83:1032\u20131045. https:\/\/doi.org\/10.4065\/83.9.1032","journal-title":"Mayo Clin Proc"},{"key":"982_CR3","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1016\/S1470-2045(06)70726-4","volume":"7","author":"CA Migliorati","year":"2006","unstructured":"Migliorati CA, Siegel MA, Elting LS (2006) Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol 7:508\u2013514. https:\/\/doi.org\/10.1016\/S1470-2045(06)70726-4","journal-title":"Lancet Oncol"},{"key":"982_CR4","doi-asserted-by":"publisher","first-page":"210","DOI":"10.4103\/0973-029X.98893","volume":"16","author":"B Varun","year":"2012","unstructured":"Varun B, Sivakumar T, Nair BJ, Joseph AP (2012) Bisphosphonate induced osteonecrosis of jaw in breast cancer patients: a systematic review. J Oral Maxillofac Pathol 16:210\u2013214. https:\/\/doi.org\/10.4103\/0973-029X.98893","journal-title":"J Oral Maxillofac Pathol"},{"key":"982_CR5","volume-title":"Oral and intravenous bisphosphonate-induced osteonecrosis of the jaws: history, etiology, prevention, and treatment, 2nd","author":"RE Marx","year":"2011","unstructured":"Marx RE (2011) Oral and intravenous bisphosphonate-induced osteonecrosis of the jaws: history, etiology, prevention, and treatment, 2nd, ed. Quintessence books. Quintessence Pub. Co., Inc Chicago","edition":"ed"},{"key":"982_CR6","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1016\/s0278-2391(03)00720-1","volume":"61","author":"RE Marx","year":"2003","unstructured":"Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115\u20131117. https:\/\/doi.org\/10.1016\/s0278-2391(03)00720-1","journal-title":"J Oral Maxillofac Surg"},{"key":"982_CR7","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/j.jcms.2014.01.010","volume":"42","author":"AM Pabst","year":"2014","unstructured":"Pabst AM, Ackermann M, Wagner W, Haberth\u00fcr D, Ziebart T, Konerding MA (2014) Imaging angiogenesis: perspectives and opportunities in tumour research-a method display. J Craniomaxillofac Surg 42:915\u2013923. https:\/\/doi.org\/10.1016\/j.jcms.2014.01.010","journal-title":"J Craniomaxillofac Surg"},{"key":"982_CR8","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1177\/0022034511407918","volume":"90","author":"EL Scheller","year":"2011","unstructured":"Scheller EL, Baldwin CM, Kuo S, D\u2019Silva NJ, Feinberg SE, Krebsbach PH, Edwards PC (2011) Bisphosphonates inhibit expression of p63 by oral keratinocytes. J Dent Res 90:894\u2013899. https:\/\/doi.org\/10.1177\/0022034511407918","journal-title":"J Dent Res"},{"key":"982_CR9","doi-asserted-by":"publisher","DOI":"10.3892\/or.19.5.1109","author":"D Ribatti","year":"2008","unstructured":"Ribatti D, Maruotti N, Nico B, Longo V, Mangieri D, Vacca A, Cantatore F (2008) Clodronate inhibits angiogenesis in vitro and in vivo. Oncol Rep. https:\/\/doi.org\/10.3892\/or.19.5.1109","journal-title":"Oncol Rep"},{"key":"982_CR10","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1007\/s10067-006-0455-3","volume":"26","author":"D Ribatti","year":"2007","unstructured":"Ribatti D, Nico B, Mangieri D, Maruotti N, Longo V, Vacca A, Cantatore FP (2007) Neridronate inhibits angiogenesis in vitro and in vivo. Clin Rheumatol 26:1094\u20131098. https:\/\/doi.org\/10.1007\/s10067-006-0455-3","journal-title":"Clin Rheumatol"},{"key":"982_CR11","first-page":"2893","volume":"9","author":"D Santini","year":"2003","unstructured":"Santini D, Vincenzi B, Dicuonzo G, Avvisati G, Massacesi C, Battistoni F, Gavasci M, Rocci L, Tirindelli MC, Altomare V, Tocchini M, Bonsignori M, Tonini G (2003) Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 9:2893\u20132897","journal-title":"Clin Cancer Res"},{"key":"982_CR12","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.cden.2007.09.002","volume":"52","author":"SL Ruggiero","year":"2008","unstructured":"Ruggiero SL, Woo S-B (2008) Biophosphonate-related osteonecrosis of the jaws. Dent Clin North Am 52:111\u2013128. https:\/\/doi.org\/10.1016\/j.cden.2007.09.002","journal-title":"Dent Clin North Am"},{"key":"982_CR13","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.oraloncology.2010.12.003","volume":"47","author":"T Ziebart","year":"2011","unstructured":"Ziebart T, Koch F, Klein MO, Guth J, Adler J, Pabst A, Al-Nawas B, Walter C (2011) Geranylgeraniol\u2013a new potential therapeutic approach to bisphosphonate associated osteonecrosis of the jaw. Oral Oncol 47:195\u2013201. https:\/\/doi.org\/10.1016\/j.oraloncology.2010.12.003","journal-title":"Oral Oncol"},{"key":"982_CR14","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/S0925-4773(00)00522-0","volume":"100","author":"D Ribatti","year":"2001","unstructured":"Ribatti D, Vacca A, Nico B, Roncali L, Dammacco F (2001) Postnatal vasculogenesis. Mech Dev 100:157\u2013163","journal-title":"Mech Dev"},{"key":"982_CR15","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1161\/hh1301.093953","volume":"89","author":"M Vasa","year":"2001","unstructured":"Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S (2001) Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89:E1-7","journal-title":"Circ Res"},{"key":"982_CR16","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1084\/jem.115.3.453","volume":"115","author":"S Boyden","year":"1962","unstructured":"Boyden S (1962) The chemotactic effect of mixtures of antibody and antigen on polymorphonuclear leucocytes. J Exp Med 115:453\u2013466. https:\/\/doi.org\/10.1084\/jem.115.3.453","journal-title":"J Exp Med"},{"key":"982_CR17","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1385\/1-59259-860-9:015","volume":"294","author":"H-C Chen","year":"2005","unstructured":"Chen H-C (2005) Boyden chamber assay. Methods Mol Biol 294:15\u201322. https:\/\/doi.org\/10.1385\/1-59259-860-9:015","journal-title":"Methods Mol Biol"},{"key":"982_CR18","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","volume":"65","author":"T Mosmann","year":"1983","unstructured":"Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55\u201363. https:\/\/doi.org\/10.1016\/0022-1759(83)90303-4","journal-title":"J Immunol Methods"},{"key":"982_CR19","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/j.coms.2015.06.001","volume":"27","author":"T Aghaloo","year":"2015","unstructured":"Aghaloo T, Hazboun R, Tetradis S (2015) Pathophysiology of osteonecrosis of the jaws. Oral Maxillofac Surg Clin North Am 27:489\u2013496. https:\/\/doi.org\/10.1016\/j.coms.2015.06.001","journal-title":"Oral Maxillofac Surg Clin North Am"},{"key":"982_CR20","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1007\/s00784-010-0507-6","volume":"16","author":"AM Pabst","year":"2012","unstructured":"Pabst AM, Ziebart T, Koch FP, Taylor KY, Al-Nawas B, Walter C (2012) The influence of bisphosphonates on viability, migration, and apoptosis of human oral keratinocytes\u2014in vitro study. Clin Oral Invest 16:87\u201393. https:\/\/doi.org\/10.1007\/s00784-010-0507-6","journal-title":"Clin Oral Invest"},{"key":"982_CR21","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/0026-0495(89)90260-6","volume":"38","author":"MA Khokher","year":"1989","unstructured":"Khokher MA, Dandona P (1989) Diphosphonates inhibit human osteoblast secretion and proliferation. Metabolism 38:184\u2013187. https:\/\/doi.org\/10.1016\/0026-0495(89)90260-6","journal-title":"Metabolism"},{"key":"982_CR22","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1007\/s00223-008-9104-y","volume":"82","author":"AI Idris","year":"2008","unstructured":"Idris AI, Rojas J, Greig IR, van\u2019t Hof RJ, Ralston SH (2008) Aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro. Calcif Tissue Int 82:191\u2013201. https:\/\/doi.org\/10.1007\/s00223-008-9104-y","journal-title":"Calcif Tissue Int"},{"key":"982_CR23","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1016\/j.bone.2006.05.006","volume":"39","author":"K Iwata","year":"2006","unstructured":"Iwata K, Li J, Follet H, Phipps RJ, Burr DB (2006) Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia. Bone 39:1053\u20131058. https:\/\/doi.org\/10.1016\/j.bone.2006.05.006","journal-title":"Bone"},{"key":"982_CR24","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1002\/jcb.21983","volume":"106","author":"IR Orriss","year":"2009","unstructured":"Orriss IR, Key ML, Colston KW, Arnett TR (2009) Inhibition of osteoblast function in vitro by aminobisphosphonates. J Cell Biochem 106:109\u2013118. https:\/\/doi.org\/10.1002\/jcb.21983","journal-title":"J Cell Biochem"},{"key":"982_CR25","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1177\/0960327115569808","volume":"34","author":"S Soydan","year":"2015","unstructured":"Soydan S, Araz K, Senel F, Yurtcu E, Helvacioglu F, Dagdeviren A, Tekindal M, Sahin F (2015) Effects of alendronate and pamidronate on apoptosis and cell proliferation in cultured primary human gingival fibroblasts. Hum Exp Toxicol 34:1073\u20131082. https:\/\/doi.org\/10.1177\/0960327115569808","journal-title":"Hum Exp Toxicol"},{"key":"982_CR26","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1590\/0103-6440201302229","volume":"24","author":"FG Basso","year":"2013","unstructured":"Basso FG, Pansani TN, de Oliveira CF, Turrioni APS, Soares DG, Hebling J, de Costa CAS (2013) Cytotoxic effects of zoledronic acid on human epithelial cells and gingival fibroblasts. Braz Dent J 24:551\u2013558. https:\/\/doi.org\/10.1590\/0103-6440201302229","journal-title":"Braz Dent J"},{"key":"982_CR27","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1124\/jpet.102.035295","volume":"302","author":"J Wood","year":"2002","unstructured":"Wood J, Bonjean K, Ruetz S, Bellahc\u00e8ne A, Devy L, Foidart JM, Castronovo V, Green JR (2002) Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 302:1055\u20131061. https:\/\/doi.org\/10.1124\/jpet.102.035295","journal-title":"J Pharmacol Exp Ther"},{"key":"982_CR28","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1002\/hon.819","volume":"25","author":"A Allegra","year":"2007","unstructured":"Allegra A, Oteri G, Nastro E, Alonci A, Bellomo G, Del Fabro V, Quartarone E, Alati C, De Ponte F, Cicci\u00f9 D, Musolino C (2007) Patients with bisphosphonates-associated osteonecrosis of the jaw have reduced circulating endothelial cells. Hematol Oncol 25:164\u2013169. https:\/\/doi.org\/10.1002\/hon.819","journal-title":"Hematol Oncol"},{"key":"982_CR29","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/s00784-009-0365-2","volume":"15","author":"T Ziebart","year":"2011","unstructured":"Ziebart T, Pabst A, Klein MO, K\u00e4mmerer P, Gauss L, Br\u00fcllmann D, Al-Nawas B, Walter C (2011) Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro. Clin Oral Investig 15:105\u2013111. https:\/\/doi.org\/10.1007\/s00784-009-0365-2","journal-title":"Clin Oral Investig"},{"key":"982_CR30","first-page":"6538","volume":"62","author":"P Fournier","year":"2002","unstructured":"Fournier P, Boissier S, Filleur S, Guglielmi J, Cabon F, Colombel M, Cl\u00e9zardin P (2002) Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 62:6538\u20136544","journal-title":"Cancer Res"},{"key":"982_CR31","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1016\/j.joms.2005.07.010","volume":"63","author":"RE Marx","year":"2005","unstructured":"Marx RE, Sawatari Y, Fortin M, Broumand V (2005) Bisphosphonate-induced exposed bone (osteonecrosis\/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63:1567\u20131575. https:\/\/doi.org\/10.1016\/j.joms.2005.07.010","journal-title":"J Oral Maxillofac Surg"},{"key":"982_CR32","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1006\/bbrc.1997.7145","volume":"237","author":"DC Crick","year":"1997","unstructured":"Crick DC, Andres DA, Waechter CJ (1997) Novel salvage pathway utilizing farnesol and geranylgeraniol for protein isoprenylation. Biochem Biophys Res Commun 237:483\u2013487. https:\/\/doi.org\/10.1006\/bbrc.1997.7145","journal-title":"Biochem Biophys Res Commun"},{"key":"982_CR33","doi-asserted-by":"publisher","first-page":"2564","DOI":"10.1016\/j.joms.2011.03.005","volume":"69","author":"M Cozin","year":"2011","unstructured":"Cozin M, Pinker BM, Solemani K, Zuniga JM, Dadaian SC, Cremers S, Landesberg R, Raghavan S (2011) Novel therapy to reverse the cellular effects of bisphosphonates on primary human oral fibroblasts. J Oral Maxillofac Surg 69:2564\u20132578. https:\/\/doi.org\/10.1016\/j.joms.2011.03.005","journal-title":"J Oral Maxillofac Surg"},{"key":"982_CR34","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1111\/jop.12181","volume":"43","author":"S Zafar","year":"2014","unstructured":"Zafar S, Coates DE, Cullinan MP, Drummond BK, Milne T, Seymour GJ (2014) Zoledronic acid and geranylgeraniol regulate cellular behaviour and angiogenic gene expression in human gingival fibroblasts. J Oral Pathol Med 43:711\u2013721. https:\/\/doi.org\/10.1111\/jop.12181","journal-title":"J Oral Pathol Med"},{"key":"982_CR35","doi-asserted-by":"publisher","first-page":"2023","DOI":"10.1007\/s00784-015-1706-y","volume":"20","author":"S Zafar","year":"2016","unstructured":"Zafar S, Coates DE, Cullinan MP, Drummond BK, Milne T, Seymour GJ (2016) Effects of zoledronic acid and geranylgeraniol on the cellular behaviour and gene expression of primary human alveolar osteoblasts. Clin Oral Invest 20:2023\u20132035. https:\/\/doi.org\/10.1007\/s00784-015-1706-y","journal-title":"Clin Oral Invest"}],"container-title":["Oral and Maxillofacial Surgery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10006-021-00982-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10006-021-00982-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10006-021-00982-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T04:09:43Z","timestamp":1654142983000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10006-021-00982-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,15]]},"references-count":35,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["982"],"URL":"https:\/\/doi.org\/10.1007\/s10006-021-00982-8","relation":{},"ISSN":["1865-1569"],"issn-type":[{"value":"1865-1569","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,15]]},"assertion":[{"value":"14 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethics approval was not required for this in vitro study. Informed consent was obtained from all individual participants included in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}