{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T08:41:52Z","timestamp":1780648912276,"version":"3.54.1"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T00:00:00Z","timestamp":1633996800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T00:00:00Z","timestamp":1633996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100014584","name":"Universit\u00e4tsmedizin der Johannes Gutenberg-Universit\u00e4t Mainz","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100014584","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Graefes Arch Clin Exp Ophthalmol"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Retinal alterations in inherited metabolic diseases associated with neurodegeneration are poorly studied. The objective was to study retinal thickness, specifically the components of the ganglion cell complex (GCC)\u2014nerve fiber layer (NFL), ganglion cell layer (GCL), and inner plexiform layer (IPL)\u2014using spectral-domain optical coherence tomography (SD-OCT) in two different diseases with potential dopaminergic depletion, phenylketonuria (PKU) and Gaucher disease type 3 (GD3).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Retinal layers in 19 patients with PKU, 15 patients with GD3, and 93 healthy individuals were measured using peripapillary ring scan and macular SD-OCT. Linear mixed models were computed including an adjustment for age, sex, and spherical equivalent. We calculated Spearman\u2019s rank correlations between retinal layer measurements and clinical and\/or laboratory parameters.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Thinning of total retinal thickness was found in the macular inner ring (<jats:italic>p<\/jats:italic>\u2009=\u20090.002), and outer ring (<jats:italic>p<\/jats:italic>\u2009=\u20090.012), sparing the fovea (<jats:italic>p<\/jats:italic>\u2009=\u20090.12) in PKU, while in GD3, all subfields were thinned (fovea <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001, inner ring <jats:italic>p<\/jats:italic>\u2009=\u20090.047, outer ring 0.07). In both conditions, thinning was most evident in the NFL, GCL, and IPL, while OPL (outer plexiform layer) was thickened. Peripapillary retinal nerve fiber layer measurements remained normal. GCL and IPL in PKU correlated with tyrosine serum concentration.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Thinning of the NFL, GCL, and IPL, with thickened OPL, are both found in PKU and in GD3. Low dopamine concentrations in the retina might promote these effects. However, these data do not give evidence that retinal measurements can be used as a biomarker for disease severity in patients with GD3.<\/jats:p>\n                \n              <\/jats:sec>","DOI":"10.1007\/s00417-021-05424-5","type":"journal-article","created":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T22:20:33Z","timestamp":1634077233000},"page":"1153-1160","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Retinal thinning in phenylketonuria and Gaucher disease type 3"],"prefix":"10.1007","volume":"260","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7989-9420","authenticated-orcid":false,"given":"Susanne","family":"Hopf","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander K.","family":"Schuster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia B.","family":"Hennermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Pfeiffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Pitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,12]]},"reference":[{"key":"5424_CR1","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.jcjo.2018.06.024","volume":"54","author":"CA Moreira-Neto","year":"2019","unstructured":"Moreira-Neto CA, Bergeron S, Coblentz J et al (2019) Optimizing optical coherence tomography and histopathology correlation in retinal imaging. Can J Ophthalmol 54:280\u2013287. https:\/\/doi.org\/10.1016\/j.jcjo.2018.06.024","journal-title":"Can J Ophthalmol"},{"key":"5424_CR2","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.exer.2018.08.003","volume":"177","author":"W Xie","year":"2018","unstructured":"Xie W, Zhao M, Tsai S-H et al (2018) Correlation of spectral domain optical coherence tomography with histology and electron microscopy in the porcine retina. Exp Eye Res 177:181\u2013190. https:\/\/doi.org\/10.1016\/j.exer.2018.08.003","journal-title":"Exp Eye Res"},{"key":"5424_CR3","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1055\/a-0715-7961","volume":"235","author":"A Papadopoulou","year":"2018","unstructured":"Papadopoulou A, Oertel FC, Zimmermann H et al (2018) Optical coherence tomography in disorders of the central nervous system. Klin Monbl Augenheilkd 235:1242\u20131258. https:\/\/doi.org\/10.1055\/a-0715-7961","journal-title":"Klin Monbl Augenheilkd"},{"key":"5424_CR4","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.msard.2018.03.007","volume":"22","author":"R Alonso","year":"2018","unstructured":"Alonso R, Gonzalez-Moron D, Garcea O (2018) Optical coherence tomography as a biomarker of neurodegeneration in multiple sclerosis: a review. Mult Scler Relat Disord 22:77\u201382. https:\/\/doi.org\/10.1016\/j.msard.2018.03.007","journal-title":"Mult Scler Relat Disord"},{"key":"5424_CR5","doi-asserted-by":"publisher","first-page":"204062231988220","DOI":"10.1177\/2040622319882205","volume":"10","author":"TE Yap","year":"2019","unstructured":"Yap TE, Balendra SI, Almonte MT, Cordeiro MF (2019) Retinal correlates of neurological disorders. Ther Adv Chronic Dis 10:2040622319882205. https:\/\/doi.org\/10.1177\/2040622319882205","journal-title":"Ther Adv Chronic Dis"},{"key":"5424_CR6","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.parkreldis.2019.04.023","volume":"64","author":"A Chrysou","year":"2019","unstructured":"Chrysou A, Jansonius NM, van Laar T (2019) Retinal layers in Parkinson\u2019s disease: a meta-analysis of spectral-domain optical coherence tomography studies. Parkinsonism Relat Disord 64:40\u201349. https:\/\/doi.org\/10.1016\/j.parkreldis.2019.04.023","journal-title":"Parkinsonism Relat Disord"},{"key":"5424_CR7","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1016\/j.ophtha.2009.05.025","volume":"116","author":"O Tan","year":"2009","unstructured":"Tan O, Chopra V, Lu AT-H et al (2009) Detection of macular ganglion cell loss in glaucoma by Fourier-domain optical coherence tomography. Ophthalmology 116:2305-2314.e2. https:\/\/doi.org\/10.1016\/j.ophtha.2009.05.025","journal-title":"Ophthalmology"},{"key":"5424_CR8","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1002\/ana.25972","volume":"89","author":"J-Y Lee","year":"2021","unstructured":"Lee J-Y, Ahn J, Shin JY, Jeon B (2021) Parafoveal change and dopamine loss in the retina with Parkinson\u2019s disease. Ann Neurol 89:421\u2013422. https:\/\/doi.org\/10.1002\/ana.25972","journal-title":"Ann Neurol"},{"key":"5424_CR9","doi-asserted-by":"publisher","first-page":"197","DOI":"10.3233\/JPD-130306","volume":"4","author":"J-Y Lee","year":"2014","unstructured":"Lee J-Y, Ahn J, Kim TW, Jeon BS (2014) Optical coherence tomography in Parkinson\u2019s disease: is the retina a biomarker? J Parkinsons Dis 4:197\u2013204. https:\/\/doi.org\/10.3233\/JPD-130306","journal-title":"J Parkinsons Dis"},{"key":"5424_CR10","doi-asserted-by":"publisher","first-page":"433","DOI":"10.3980\/j.issn.2222-3959.2011.04.21","volume":"4","author":"T Tian","year":"2011","unstructured":"Tian T, Zhu X-H, Liu Y-H (2011) Potential role of retina as a biomarker for progression of Parkinson\u2019s disease. Int J Ophthalmol 4:433\u2013438. https:\/\/doi.org\/10.3980\/j.issn.2222-3959.2011.04.21","journal-title":"Int J Ophthalmol"},{"key":"5424_CR11","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/j.neubiorev.2007.09.004","volume":"32","author":"R Brandies","year":"2008","unstructured":"Brandies R, Yehuda S (2008) The possible role of retinal dopaminergic system in visual performance. Neurosci Biobehav Rev 32:611\u2013656. https:\/\/doi.org\/10.1016\/j.neubiorev.2007.09.004","journal-title":"Neurosci Biobehav Rev"},{"key":"5424_CR12","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/BF02821713","volume":"19","author":"J Nguyen-Legros","year":"1999","unstructured":"Nguyen-Legros J, Versaux-Botteri C, Vernier P (1999) Dopamine receptor localization in the mammalian retina. Mol Neurobiol 19:181\u2013204. https:\/\/doi.org\/10.1007\/BF02821713","journal-title":"Mol Neurobiol"},{"key":"5424_CR13","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1023\/b:doop.0000019487.88486.0a","volume":"108","author":"P Witkovsky","year":"2004","unstructured":"Witkovsky P (2004) Dopamine and retinal function. Doc Ophthalmol 108:17\u201340. https:\/\/doi.org\/10.1023\/b:doop.0000019487.88486.0a","journal-title":"Doc Ophthalmol"},{"key":"5424_CR14","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1002\/cne.902100108","volume":"210","author":"JM Frederick","year":"1982","unstructured":"Frederick JM, Rayborn ME, Laties AM et al (1982) Dopaminergic neurons in the human retina. J Comp Neurol 210:65\u201379. https:\/\/doi.org\/10.1002\/cne.902100108","journal-title":"J Comp Neurol"},{"key":"5424_CR15","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1002\/cne.10891","volume":"466","author":"SJ Eglen","year":"2003","unstructured":"Eglen SJ, Raven MA, Tamrazian E, Reese BE (2003) Dopaminergic amacrine cells in the inner nuclear layer and ganglion cell layer comprise a single functional retinal mosaic. J Comp Neurol 466:343\u2013355. https:\/\/doi.org\/10.1002\/cne.10891","journal-title":"J Comp Neurol"},{"key":"5424_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2020.100649","volume":"25","author":"C Serfozo","year":"2020","unstructured":"Serfozo C, Barta AG, Horvath E et al (2020) Altered visual functions, macular ganglion cell and papillary retinal nerve fiber layer thickness in early-treated adult PKU patients. Mol Genet Metab Rep 25:100649. https:\/\/doi.org\/10.1016\/j.ymgmr.2020.100649","journal-title":"Mol Genet Metab Rep"},{"key":"5424_CR17","doi-asserted-by":"publisher","first-page":"2211","DOI":"10.1002\/mds.28256","volume":"35","author":"AAG Tantawy","year":"2020","unstructured":"Tantawy AAG, Adly AAM, Hashem NH et al (2020) Ganglion cell complex thinning in young Gaucher patients: relation to prodromal parkinsonian markers. Mov Disord 35:2211\u20132219. https:\/\/doi.org\/10.1002\/mds.28256","journal-title":"Mov Disord"},{"key":"5424_CR18","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1007\/s10545-012-9473-2","volume":"35","author":"T Pascucci","year":"2012","unstructured":"Pascucci T, Giacovazzo G, Andolina D et al (2012) In vivo catecholaminergic metabolism in the medial prefrontal cortex of ENU2 mice: an investigation of the cortical dopamine deficit in phenylketonuria. J Inherit Metab Dis 35:1001\u20131009. https:\/\/doi.org\/10.1007\/s10545-012-9473-2","journal-title":"J Inherit Metab Dis"},{"key":"5424_CR19","doi-asserted-by":"publisher","unstructured":"Weill Y, Zimran A, Zadok D et al (2020) Macular ganglion cell complex and peripapillary retinal nerve fiber layer thinning in patients with type-1 Gaucher disease. Int J Mol Sci 21. https:\/\/doi.org\/10.3390\/ijms21197027","DOI":"10.3390\/ijms21197027"},{"key":"5424_CR20","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/j.ymgme.2013.04.001","volume":"109","author":"A McNeill","year":"2013","unstructured":"McNeill A, Roberti G, Lascaratos G et al (2013) Retinal thinning in Gaucher disease patients and carriers: results of a pilot study. Mol Genet Metab 109:221\u2013223. https:\/\/doi.org\/10.1016\/j.ymgme.2013.04.001","journal-title":"Mol Genet Metab"},{"key":"5424_CR21","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1186\/s13023-020-01407-7","volume":"15","author":"S Hopf","year":"2020","unstructured":"Hopf S, Nowak C, Hennermann JB et al (2020) Saccadic reaction time and ocular findings in phenylketonuria. Orphanet J Rare Dis 15:124. https:\/\/doi.org\/10.1186\/s13023-020-01407-7","journal-title":"Orphanet J Rare Dis"},{"key":"5424_CR22","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1186\/s13023-019-1244-9","volume":"14","author":"S Hopf","year":"2019","unstructured":"Hopf S, Pfeiffer N, Liesenfeld M et al (2019) A comprehensive monocentric ophthalmic study with Gaucher disease type 3 patients: vitreoretinal lesions, retinal atrophy and characterization of abnormal saccades. Orphanet J Rare Dis 14:257. https:\/\/doi.org\/10.1186\/s13023-019-1244-9","journal-title":"Orphanet J Rare Dis"},{"key":"5424_CR23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0204008","volume":"13","author":"S Hopf","year":"2018","unstructured":"Hopf S, Liesenfeld M, Schmidtmann I et al (2018) Age dependent normative data of vertical and horizontal reflexive saccades. PLoS ONE 13:e0204008. https:\/\/doi.org\/10.1371\/journal.pone.0204008","journal-title":"PLoS ONE"},{"key":"5424_CR24","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1186\/s13023-017-0685-2","volume":"12","author":"AMJ van Wegberg","year":"2017","unstructured":"van Wegberg AMJ, MacDonald A, Ahring K et al (2017) The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 12:162. https:\/\/doi.org\/10.1186\/s13023-017-0685-2","journal-title":"Orphanet J Rare Dis"},{"key":"5424_CR25","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1007\/s10545-011-9347-z","volume":"34","author":"EH Davies","year":"2011","unstructured":"Davies EH, Mengel E, Tylki-Szymanska A et al (2011) Four-year follow-up of chronic neuronopathic Gaucher disease in Europeans using a modified severity scoring tool. J Inherit Metab Dis 34:1053\u20131059. https:\/\/doi.org\/10.1007\/s10545-011-9347-z","journal-title":"J Inherit Metab Dis"},{"key":"5424_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2021.100767","volume":"27","author":"C Serfozo","year":"2021","unstructured":"Serfozo C, Barta AG, Horvath E et al (2021) Reduced macular thickness and macular vessel density in early-treated adult patients with PKU. Mol Genet Metab Rep 27:100767. https:\/\/doi.org\/10.1016\/j.ymgmr.2021.100767","journal-title":"Mol Genet Metab Rep"},{"key":"5424_CR27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0194169","volume":"13","author":"M Nieves-Moreno","year":"2018","unstructured":"Nieves-Moreno M, Mart\u00ednez-de-la-Casa JM, Morales-Fern\u00e1ndez L et al (2018) Impacts of age and sex on retinal layer thicknesses measured by spectral domain optical coherence tomography with Spectralis. PLoS ONE 13:e0194169. https:\/\/doi.org\/10.1371\/journal.pone.0194169","journal-title":"PLoS ONE"},{"issue":"Suppl 3","key":"5424_CR28","first-page":"2","volume":"79","author":"J Campistol Plana","year":"2019","unstructured":"Campistol Plana J (2019) Early diagnosis of phenylketonuria. Physiopathology of the neuronal damage and therapeutic options. Medicina (B Aires) 79(Suppl 3):2\u20135","journal-title":"Medicina (B Aires)"},{"key":"5424_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.neuint.2012.10.010","volume":"62","author":"MWJ Cleeter","year":"2013","unstructured":"Cleeter MWJ, Chau K-Y, Gluck C et al (2013) Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage. Neurochem Int 62:1\u20137. https:\/\/doi.org\/10.1016\/j.neuint.2012.10.010","journal-title":"Neurochem Int"},{"key":"5424_CR30","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1093\/brain\/awy147","volume":"141","author":"AD Klein","year":"2018","unstructured":"Klein AD, Mazzulli JR (2018) Is Parkinson\u2019s disease a lysosomal disorder? Brain 141:2255\u20132262. https:\/\/doi.org\/10.1093\/brain\/awy147","journal-title":"Brain"},{"key":"5424_CR31","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1136\/bjophthalmol-2018-312846","volume":"103","author":"AW Winter","year":"2019","unstructured":"Winter AW, Salimi A, Ospina LH, Roos JCP (2019) Ophthalmic manifestations of Gaucher disease: the most common lysosomal storage disorder. Br J Ophthalmol 103:315\u2013326. https:\/\/doi.org\/10.1136\/bjophthalmol-2018-312846","journal-title":"Br J Ophthalmol"},{"key":"5424_CR32","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1001\/archopht.122.9.1395","volume":"122","author":"EM Shrier","year":"2004","unstructured":"Shrier EM, Barr CC, Grabowski GA (2004) Vitreous opacities and retinal vascular abnormalities in Gaucher disease. Arch Ophthalmol 122:1395\u20131398. https:\/\/doi.org\/10.1001\/archopht.122.9.1395","journal-title":"Arch Ophthalmol"},{"key":"5424_CR33","doi-asserted-by":"publisher","unstructured":"Matos A, Gurgel V, Gon\u00e7alves M (2017) Ophthalmologic findings in Gaucher\u2019s disease type III: case report. Revista Brasileira de Oftalmologia 76. https:\/\/doi.org\/10.5935\/0034-7280.20170066","DOI":"10.5935\/0034-7280.20170066"},{"key":"5424_CR34","doi-asserted-by":"publisher","first-page":"710","DOI":"10.3389\/fneur.2017.00710","volume":"8","author":"C La Morgia","year":"2017","unstructured":"La Morgia C, Di Vito L, Carelli V, Carbonelli M (2017) Patterns of retinal ganglion cell damage in neurodegenerative disorders: parvocellular vs magnocellular degeneration in optical coherence tomography studies. Front Neurol 8:710. https:\/\/doi.org\/10.3389\/fneur.2017.00710","journal-title":"Front Neurol"}],"container-title":["Graefe's Archive for Clinical and Experimental Ophthalmology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00417-021-05424-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00417-021-05424-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00417-021-05424-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T02:05:06Z","timestamp":1646964306000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00417-021-05424-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,12]]},"references-count":34,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["5424"],"URL":"https:\/\/doi.org\/10.1007\/s00417-021-05424-5","relation":{},"ISSN":["0721-832X","1435-702X"],"issn-type":[{"value":"0721-832X","type":"print"},{"value":"1435-702X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,12]]},"assertion":[{"value":"3 August 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 September 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 September 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 October 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 February 2022","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The original version of this paper was updated to add the missing compact agreement Open Access funding note.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was approved by the Medical Ethical Committee of the State Chamber of Medicine of Rhineland Palatinate in Mainz, Germany (reference number 837.373.14). The research adhered to the tenets of the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained from all individual participants included in the study, or from legal guardians.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Participants signed informed consent regarding publishing their data.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}