{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:53:10Z","timestamp":1785430390304,"version":"3.56.0"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T00:00:00Z","timestamp":1619136000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T00:00:00Z","timestamp":1619136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["STA 1331\/3-1"],"award-info":[{"award-number":["STA 1331\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DO 721\/9-1"],"award-info":[{"award-number":["DO 721\/9-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Imaging Biol"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Glioblastomas (GB) and solitary brain metastases (BM) are the most common brain tumors in adults. GB and BM may appear similar in conventional magnetic resonance imaging (cMRI). Their management strategies, however, are quite different with significant consequences on clinical outcome. The aim of this study was to evaluate the usefulness of a previously presented physiological MRI approach scoping to obtain quantitative information about microvascular architecture and perfusion, neovascularization activity, and oxygen metabolism to differentiate GB from BM.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Procedures<\/jats:title>\n                <jats:p>Thirty-three consecutive patients with newly diagnosed, untreated, and histopathologically confirmed GB or BM were preoperatively examined with our physiological MRI approach as part of the cMRI protocol.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Physiological MRI biomarker maps revealed several significant differences in the pathophysiology of GB and BM: Central necrosis was more hypoxic in GB than in BM (30 %; <jats:italic>P<\/jats:italic> = 0.036), which was associated with higher neovascularization activity (65 %; <jats:italic>P<\/jats:italic> = 0.043) and metabolic rate of oxygen (48 %; <jats:italic>P<\/jats:italic> = 0.004) in the adjacent contrast-enhancing viable tumor parts of GB. In peritumoral edema, GB infiltration caused neovascularization activity (93 %; <jats:italic>P<\/jats:italic> = 0.018) and higher microvascular perfusion (30 %; <jats:italic>P<\/jats:italic> = 0.022) associated with higher tissue oxygen tension (33 %; <jats:italic>P<\/jats:italic> = 0.020) and lower oxygen extraction from vasculature (32 %; <jats:italic>P<\/jats:italic> = 0.040).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our physiological MRI approach, which requires only 7 min of extra data acquisition time, might be helpful to noninvasively distinguish GB and BM based on pathophysiological differences. However, further studies including more patients are required.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s11307-021-01604-1","type":"journal-article","created":{"date-parts":[[2021,4,24]],"date-time":"2021-04-24T16:13:13Z","timestamp":1619280793000},"page":"787-795","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Physiological MRI Biomarkers in the Differentiation Between Glioblastomas and Solitary Brain Metastases"],"prefix":"10.1007","volume":"23","author":[{"given":"Elisabeth","family":"Heynold","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Zimmermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirjhar","family":"Hore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Buchfelder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnd","family":"Doerfler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Stadlbauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4002-3197","authenticated-orcid":false,"given":"Natalia","family":"Kremenevski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,23]]},"reference":[{"issue":"Suppl 5","key":"1604_CR1","doi-asserted-by":"publisher","first-page":"v1","DOI":"10.1093\/neuonc\/noz150","volume":"21","author":"QT Ostrom","year":"2019","unstructured":"Ostrom QT, Cioffi G, Gittleman H et al (2019) J.S. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016. Neuro Oncol 21(Suppl 5):v1\u2013v100","journal-title":"Neuro Oncol"},{"key":"1604_CR2","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/s11940-001-0027-4","volume":"3","author":"D Schiff","year":"2001","unstructured":"Schiff D (2001) Single Brain Metastasis. Curr Treat Options Neurol 3:89\u201399","journal-title":"Curr Treat Options Neurol"},{"key":"1604_CR3","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1023\/A:1006413001375","volume":"50","author":"MT Giordana","year":"2000","unstructured":"Giordana MT, Cordera S, Boghi A (2000) Cerebral metastases as first symptom of cancer: a clinico-pathologic study. J Neurooncol 50:265\u2013273","journal-title":"J Neurooncol"},{"key":"1604_CR4","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1007\/s12094-016-1497-x","volume":"18","author":"PD Delgado-L\u00f3pez","year":"2016","unstructured":"Delgado-L\u00f3pez PD, Corrales-Garc\u00eda EM (2016) Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol 18:1062\u20131071","journal-title":"Clin Transl Oncol"},{"key":"1604_CR5","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.radonc.2011.08.041","volume":"102","author":"S Scoccianti","year":"2012","unstructured":"Scoccianti S, Ricardi U (2012) Treatment of brain metastases: review of phase III randomized controlled trials. Radiother Oncol 102:168\u2013179","journal-title":"Radiother Oncol"},{"key":"1604_CR6","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1001\/jama.2013.280319","volume":"10","author":"A Omuro","year":"2013","unstructured":"Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. JAMA 10:1842\u20131850","journal-title":"JAMA"},{"key":"1604_CR7","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1093\/neuonc\/now241","volume":"19","author":"R Soffietti","year":"2017","unstructured":"Soffietti R, Abacioglu U, Baumert B, Combs SE, Kinhult S, Kros JM, Marosi C, Metellus P, Radbruch A, Villa Freixa SS, Brada M, Carapella CM, Preusser M, le Rhun E, Rud\u00e0 R, Tonn JC, Weber DC, Weller M (2017) Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro Oncol 19:162\u2013174","journal-title":"Neuro Oncol"},{"key":"1604_CR8","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1007\/s00062-011-0073-6","volume":"21","author":"J Faehndrich","year":"2011","unstructured":"Faehndrich J, Weidauer S, Pilatus U, Oszvald A, Zanella FE, Hattingen E (2011) Neuroradiological viewpoint on the diagnostics of space-occupying brain lesions. Clin Neuroradiol 21:123\u2013139","journal-title":"Clin Neuroradiol"},{"key":"1604_CR9","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1177\/0271678X16655549","volume":"37","author":"A Stadlbauer","year":"2017","unstructured":"Stadlbauer A, Zimmermann M, Heinz G, Oberndorfer S, Doerfler A, Buchfelder M, R\u00f6ssler K (2017) Magnetic resonance imaging biomarkers for clinical routine assessment of microvascular architecture in glioma. J Cereb Blood Flow Metab 37:632\u2013643","journal-title":"J Cereb Blood Flow Metab"},{"key":"1604_CR10","doi-asserted-by":"publisher","first-page":"8508","DOI":"10.1038\/s41598-017-09048-w","volume":"7","author":"A Stadlbauer","year":"2017","unstructured":"Stadlbauer A, Zimmermann M, Oberndorfer S, Doerfler A, Buchfelder M, Heinz G, Roessler K (2017) Vascular hysteresis loops and vascular architecture mapping in patients with glioblastoma treated with antiangiogenic therapy. Sci Rep 7:8508","journal-title":"Sci Rep"},{"key":"1604_CR11","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1038\/nrn2175","volume":"8","author":"RK Jain","year":"2007","unstructured":"Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT (2007) Angiogenesis in brain tumours. Nat Rev Neurosci 8:610\u2013622","journal-title":"Nat Rev Neurosci"},{"key":"1604_CR12","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1002\/mrm.21052","volume":"56","author":"JH Jensen","year":"2006","unstructured":"Jensen JH, Lu H, Inglese M (2006) Microvessel density estimation in the human brain by means of dynamic contrast-enhanced echo-planar imaging. Magn Reson Med 56:1145\u20131150","journal-title":"Magn Reson Med"},{"key":"1604_CR13","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1148\/radiol.2016161422","volume":"283","author":"A Stadlbauer","year":"2017","unstructured":"Stadlbauer A, Zimmermann M, Kitzw\u00f6gerer M, Oberndorfer S, R\u00f6ssler K, D\u00f6rfler A, Buchfelder M, Heinz G (2017) mr imaging-derived oxygen metabolism and neovascularization characterization for grading and IDH gene mutation detection of gliomas. Radiology 283:799\u2013809","journal-title":"Radiology"},{"key":"1604_CR14","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1093\/neuonc\/noy066","volume":"20","author":"A Stadlbauer","year":"2018","unstructured":"Stadlbauer A, Zimmermann M, Doerfler A, Oberndorfer S, Buchfelder M, Coras R, Kitzw\u00f6gerer M, Roessler K (2018) Intratumoral heterogeneity of oxygen metabolism and neovascularization uncovers 2 survival-relevant subgroups of IDH1 wild-type glioblastoma. Neuro Oncol 20:1536\u20131546","journal-title":"Neuro Oncol"},{"key":"1604_CR15","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1177\/0271678X17694905","volume":"38","author":"A Stadlbauer","year":"2018","unstructured":"Stadlbauer A, Mouridsen K, Doerfler A, Bo Hansen M, Oberndorfer S, Zimmermann M, Buchfelder M, Heinz G, Roessler K (2018) Recurrence of glioblastoma is associated with elevated microvascular transit time heterogeneity and increased hypoxia. J Cereb Blood Flow Metab 38:422\u2013432","journal-title":"J Cereb Blood Flow Metab"},{"key":"1604_CR16","doi-asserted-by":"publisher","DOI":"10.3171\/2019.9.FOCUS19613","volume":"47","author":"A Stadlbauer","year":"2019","unstructured":"Stadlbauer A, Ey\u00fcpoglu I, Buchfelder M, D\u00f6rfler A, Zimmermann M, Heinz G, Oberndorfer S (2019) Vascular architecture mapping for early detection of glioblastoma recurrence. Neurosurg. Focus 47:E14","journal-title":"Neurosurg. Focus"},{"key":"1604_CR17","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.3174\/ajnr.A0993","volume":"29","author":"GB Caseiras","year":"2008","unstructured":"Caseiras GB, Thornton JS, Yousry T, Benton C, Rees J, Waldman AD, J\u00e4ger HR (2008) Inclusion or exclusion of intratumoral vessels in relative cerebral blood volume characterization in low-grade gliomas: does it make a difference? AJNR Am J Neuroradiol 29:1140\u20131141","journal-title":"AJNR Am J Neuroradiol"},{"key":"1604_CR18","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1016\/j.neuroimage.2004.01.016","volume":"22","author":"J C\u00edzek","year":"2004","unstructured":"C\u00edzek J, Herholz K, Vollmar S et al (2004) Fast and robust registration of PET and MR images of human brain. Neuroimage 22:434\u2013442","journal-title":"Neuroimage"},{"key":"1604_CR19","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1007\/s00234-015-1524-6","volume":"57","author":"AH Bauer","year":"2015","unstructured":"Bauer AH, Erly W, Moser FG, Maya M, Nael K (2015) Differentiation of solitary brain metastasis from glioblastoma multiforme: a predictive multiparametric approach using combined MR diffusion and perfusion. Neuroradiology 57:697\u2013703","journal-title":"Neuroradiology"},{"key":"1604_CR20","doi-asserted-by":"publisher","first-page":"3819","DOI":"10.1007\/s00330-018-5335-0","volume":"28","author":"CH Suh","year":"2018","unstructured":"Suh CH, Kim HS, Jung SC, Choi CG, Kim SJ (2018) Perfusion MRI as a diagnostic biomarker for differentiating glioma from brain metastasis: a systematic review and meta-analysis. Eur Radiol 28:3819\u20133831","journal-title":"Eur Radiol"},{"key":"1604_CR21","doi-asserted-by":"publisher","first-page":"4133","DOI":"10.1007\/s00330-018-5832-1","volume":"29","author":"K Kamimura","year":"2019","unstructured":"Kamimura K, Nakajo M, Yoneyama T, Fukukura Y, Hirano H, Goto Y, Sasaki M, Akamine Y, Keupp J, Yoshiura T (2019) Histogram analysis of amide proton transfer-weighted imaging: comparison of glioblastoma and solitary brain metastasis in enhancing tumors and peritumoral regions. Eur Radiol 29:4133\u20134140","journal-title":"Eur Radiol"},{"key":"1604_CR22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0115018","volume":"9","author":"E Scribner","year":"2014","unstructured":"Scribner E, Saut O, Province P, Bag A, Colin T, Fathallah-Shaykh HM (2014) Effects of anti-angiogenesis on glioblastoma growth and migration: model to clinical predictions. PLoS One 9:e115018","journal-title":"PLoS One"},{"key":"1604_CR23","doi-asserted-by":"publisher","first-page":"796","DOI":"10.3389\/fonc.2020.00796","volume":"10","author":"W Lin","year":"2020","unstructured":"Lin W, Wu S, Chen X, Ye Y, Weng Y, Pan Y, Chen Z, Chen L, Qiu X, Qiu S (2020) Characterization of hypoxia signature to evaluate the tumor immune microenvironment and predict prognosis in glioma groups. Front Oncol 10:796","journal-title":"Front Oncol"},{"key":"1604_CR24","doi-asserted-by":"publisher","first-page":"414","DOI":"10.6004\/jnccn.2011.0038","volume":"9","author":"DA Reardon","year":"2011","unstructured":"Reardon DA, Turner S, Peters KB, Desjardins A, Gururangan S, Sampson JH, McLendon RE, Herndon JE II, Jones LW, Kirkpatrick JP, Friedman AH, Vredenburgh JJ, Bigner DD, Friedman HS (2011) A review of VEGF\/VEGFR-targeted therapeutics for recurrent glioblastoma. J Natl Compr Canc Netw 9:414\u2013427","journal-title":"J Natl Compr Canc Netw"},{"key":"1604_CR25","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1215\/15228517-2009-005","volume":"11","author":"A Pirzkall","year":"2009","unstructured":"Pirzkall A, McGue C, Saraswathy S, Cha S, Liu R, Vandenberg S, Lamborn KR, Berger MS, Chang SM, Nelson SJ (2009) Tumor regrowth between surgery and initiation of adjuvant therapy in patients with newly diagnosed glioblastoma. Neuro Oncol 11:842\u2013852","journal-title":"Neuro Oncol"},{"key":"1604_CR26","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.jocn.2018.06.018","volume":"55","author":"JM Treiber","year":"2018","unstructured":"Treiber JM, Steed TC, Brandel MG, Patel KS, Dale AM, Carter BS, Chen CC (2018) Molecular physiology of contrast enhancement in glioblastomas: an analysis of the cancer imaging archive (TCIA). J Clin Neurosci 55:86\u201392","journal-title":"J Clin Neurosci"},{"key":"1604_CR27","doi-asserted-by":"publisher","first-page":"12550","DOI":"10.1073\/pnas.1405839111","volume":"111","author":"BJ Gill","year":"2014","unstructured":"Gill BJ, Pisapia DJ, Malone HR, Goldstein H, Lei L, Sonabend A, Yun J, Samanamud J, Sims JS, Banu M, Dovas A, Teich AF, Sheth SA, McKhann GM, Sisti MB, Bruce JN, Sims PA, Canoll P (2014) MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma. Proc Natl Acad Sci U S A 111:12550\u201312555","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1604_CR28","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1093\/neuonc\/nor133","volume":"13","author":"D Kuhnt","year":"2011","unstructured":"Kuhnt D, Becker A, Ganslandt O, Bauer M, Buchfelder M, Nimsky C (2011) Correlation of the extent of tumor volume resection and patient survival in surgery of glioblastoma multiforme with high-field intraoperative MRI guidance. Neuro Oncol 13:1339\u20131348","journal-title":"Neuro Oncol"},{"key":"1604_CR29","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.3171\/2014.7.JNS132449","volume":"121","author":"MM Grabowski","year":"2014","unstructured":"Grabowski MM, Recinos PF, Nowacki AS, Schroeder JL, Angelov L, Barnett GH, Vogelbaum MA (2014) Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma. J. Neurosurg 121:1115\u20131123","journal-title":"J. Neurosurg"},{"key":"1604_CR30","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1148\/radiol.2020191711","volume":"295","author":"D Paech","year":"2020","unstructured":"Paech D, Nagel AM, Schultheiss MN, Umathum R, Regnery S, Scherer M, Wick A, Platt T, Wick W, Bendszus M, Unterberg A, Schlemmer HP, Ladd ME, Niesporek SC (2020) Quantitative dynamic oxygen 17 MRI at 7.0 T for the cerebral oxygen metabolism in glioma. Radiology 295:181\u2013189","journal-title":"Radiology"},{"key":"1604_CR31","doi-asserted-by":"crossref","unstructured":"Preibisch C, Shi K, Kluge A, Lukas M, Wiestler B, G\u00f6ttler J, Gempt J, Ringel F, al Jaberi M, Schlegel J, Meyer B, Zimmer C, Pyka T, F\u00f6rster S (2017) Characterizing hypoxia in human glioma: a simultaneous multimodal MRI and PET study. NMR Biomed 30(11)","DOI":"10.1002\/nbm.3775"},{"key":"1604_CR32","first-page":"693","volume":"24","author":"S Bulnes","year":"2009","unstructured":"Bulnes S, Bilbao J, Lafuente JV (2009) Microvascular adaptive changes in experimental endogenous brain gliomas. Histol Histopathol 24:693\u2013706","journal-title":"Histol Histopathol"},{"key":"1604_CR33","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1007\/978-1-61779-191-8_28","volume":"763","author":"J Lee","year":"2011","unstructured":"Lee J, Baird A, Eliceiri BP (2011) In vivo measurement of glioma-induced vascular permeability. Methods Mol Biol 763:417\u2013422","journal-title":"Methods Mol Biol"},{"key":"1604_CR34","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1161\/01.STR.12.2.211","volume":"12","author":"KA Hossman","year":"1981","unstructured":"Hossman KA, Bl\u00f6ink M (1981) Blood flow and regulation of blood flow in experimental peritumoral edema. Stroke 12:211\u2013217","journal-title":"Stroke"}],"container-title":["Molecular Imaging and Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11307-021-01604-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11307-021-01604-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11307-021-01604-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T15:31:58Z","timestamp":1630510318000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11307-021-01604-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,23]]},"references-count":34,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,10]]}},"alternative-id":["1604"],"URL":"https:\/\/doi.org\/10.1007\/s11307-021-01604-1","relation":{},"ISSN":["1536-1632","1860-2002"],"issn-type":[{"value":"1536-1632","type":"print"},{"value":"1860-2002","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,23]]},"assertion":[{"value":"25 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 March 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 April 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 April 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee of Lower Austria (ethic code: GS1-EK-4\/339-2015) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed Consent"}},{"value":"The authors declare that they have no conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}