{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:38:46Z","timestamp":1790779126968,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T00:00:00Z","timestamp":1677456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"BOF research fellowship","award":["BOF 01N04315"],"award-info":[{"award-number":["BOF 01N04315"]}]},{"name":"BOF research fellowship","award":["BOF08\/01M01108"],"award-info":[{"award-number":["BOF08\/01M01108"]}]},{"name":"BOF research fellowship","award":["GOA019-21"],"award-info":[{"award-number":["GOA019-21"]}]},{"name":"Research Foundation Flanders","award":["BOF 01N04315"],"award-info":[{"award-number":["BOF 01N04315"]}]},{"name":"Research Foundation Flanders","award":["BOF08\/01M01108"],"award-info":[{"award-number":["BOF08\/01M01108"]}]},{"name":"Research Foundation Flanders","award":["GOA019-21"],"award-info":[{"award-number":["GOA019-21"]}]},{"name":"Methusalem grant","award":["BOF 01N04315"],"award-info":[{"award-number":["BOF 01N04315"]}]},{"name":"Methusalem grant","award":["BOF08\/01M01108"],"award-info":[{"award-number":["BOF08\/01M01108"]}]},{"name":"Methusalem grant","award":["GOA019-21"],"award-info":[{"award-number":["GOA019-21"]}]},{"name":"GOA grant","award":["BOF 01N04315"],"award-info":[{"award-number":["BOF 01N04315"]}]},{"name":"GOA grant","award":["BOF08\/01M01108"],"award-info":[{"award-number":["BOF08\/01M01108"]}]},{"name":"GOA grant","award":["GOA019-21"],"award-info":[{"award-number":["GOA019-21"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Pseudoxanthoma elasticum (PXE) is a rare ectopic calcification disorder affecting soft connective tissues that is caused by biallelic ABCC6 mutations. While the underlying pathomechanisms are incompletely understood, reduced circulatory levels of inorganic pyrophosphate (PPi)\u2014a potent mineralization inhibitor\u2014have been reported in PXE patients and were suggested to be useful as a disease biomarker. In this study, we explored the relation between PPi, the ABCC6 genotype and the PXE phenotype. For this, we optimized and validated a PPi measurement protocol with internal calibration that can be used in a clinical setting. An analysis of 78 PXE patients, 69 heterozygous carriers and 14 control samples revealed significant differences in the measured PPi levels between all three cohorts, although there was overlap between all groups. PXE patients had a \u00b150% reduction in PPi levels compared to controls. Similarly, we found a \u00b128% reduction in carriers. PPi levels were found to correlate with age in PXE patients and carriers, independent of the ABCC6 genotype. No correlations were found between PPi levels and the Phenodex scores. Our results suggest that other factors besides PPi are at play in ectopic mineralization, which limits the use of PPi as a predictive biomarker for severity and disease progression.<\/jats:p>","DOI":"10.3390\/jcm12051893","type":"journal-article","created":{"date-parts":[[2023,3,6]],"date-time":"2023-03-06T03:02:32Z","timestamp":1678071752000},"page":"1893","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Inorganic Pyrophosphate Plasma Levels Are Decreased in Pseudoxanthoma Elasticum Patients and Heterozygous Carriers but Do Not Correlate with the Genotype or Phenotype"],"prefix":"10.3390","volume":"12","author":[{"given":"Matthias","family":"Van Gils","sequence":"first","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium"},{"name":"Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium"},{"name":"Ghent Ectopic Mineralization Research Group, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Depauw","sequence":"additional","affiliation":[{"name":"Ghent Ectopic Mineralization Research Group, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Coucke","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium"},{"name":"Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium"},{"name":"Ghent Ectopic Mineralization Research Group, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shari","family":"Aerts","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium"},{"name":"Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium"},{"name":"Ghent Ectopic Mineralization Research Group, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shana","family":"Verschuere","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium"},{"name":"Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium"},{"name":"Ghent Ectopic Mineralization Research Group, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0464-0190","authenticated-orcid":false,"given":"Lukas","family":"Nollet","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium"},{"name":"Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium"},{"name":"Ghent Ectopic Mineralization Research Group, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4491-0332","authenticated-orcid":false,"given":"Olivier M.","family":"Vanakker","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium"},{"name":"Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium"},{"name":"Ghent Ectopic Mineralization Research Group, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15872","DOI":"10.1074\/jbc.M701116200","article-title":"Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phosphatase activity","volume":"282","author":"Addison","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1161\/CIRCRESAHA.111.247965","article-title":"Genetics in arterial calcification: Pieces of a puzzle and cogs in a wheel","volume":"109","author":"Rutsch","year":"2011","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Orriss, I.R. (2020). Extracellular pyrophosphate: The body\u2019s \u201cwater softener\u201d. Bone, 134.","DOI":"10.1016\/j.bone.2020.115243"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/76109","article-title":"Mutations in ABCC6 cause pseudoxanthoma elasticum","volume":"25","author":"Bergen","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/76102","article-title":"Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum","volume":"25","author":"Urban","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ajhg.2011.11.020","article-title":"Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6","volume":"90","author":"Nitschke","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.1161\/ATVBAHA.113.301901","article-title":"Characterization of cardiovascular involvement in pseudoxanthoma elasticum families","volume":"33","author":"Campens","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1111\/bpa.12620","article-title":"Pathogenic variants in the ABCC6 gene are associated with an increased risk for ischemic stroke","volume":"28","author":"Cardoen","year":"2018","journal-title":"Brain Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1136\/jmedgenet-2020-107565","article-title":"Clinical and subclinical findings in heterozygous ABCC6 carriers: Results from a Belgian cohort and clinical practice guidelines","volume":"59","author":"Nollet","year":"2021","journal-title":"J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1161\/01.CIR.0000028420.27813.C0","article-title":"Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease","volume":"106","author":"Trip","year":"2002","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Vanakker, O.M., Leroy, B.P., Coucke, P., Bercovitch, L.G., Uitto, J., Viljoen, D., Terry, S.F., Van Acker, P., Matthys, D., and Loeys, B. (2008). Novel clinico-molecular insights in pseudoxanthoma elasticum provide an efficient molecular screening method and a comprehensive diagnostic flowchart. Hum. Mutat., 29.","DOI":"10.1002\/humu.9514"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20206","DOI":"10.1073\/pnas.1319582110","article-title":"ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release","volume":"110","author":"Jansen","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1016\/j.jid.2018.02.023","article-title":"Alteration of extracellular nucleotide metabolism in pseudoxanthoma elasticum","volume":"138","author":"Kauffenstein","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Szeri, F., Lundkvist, S., Donnelly, S., Engelke, U.F.H., Rhee, K., Williams, C.J., Sundberg, J.P., Wevers, R.A., Tomlinson, R.E., and Jansen, R.S. (2020). The membrane protein ANKH is crucial for bone mechanical performance by mediating cellular export of citrate and ATP. PLoS Genet., 16.","DOI":"10.1371\/journal.pgen.1008884"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-T\u00e9var, A.M., Garc\u00eda-Fern\u00e1ndez, M., Murcia-Casas, B., Rioja-Villodres, J., Carrillo, J.L., Camacho, M., Van Gils, M., S\u00e1nchez-Chaparro, M.A., Vanakker, O., and Valdivielso, P. (2019). Plasma inorganic pyrophosphate and alkaline phosphatase in patients with pseudoxanthoma elasticum. Ann. Transl. Med., 7.","DOI":"10.21037\/atm.2019.12.73"},{"key":"ref_16","first-page":"1227","article-title":"Mutant Enpp1asj mice as a model for generalized arterial calcification of infancy","volume":"6","author":"Li","year":"2013","journal-title":"Dis. Model. Mech."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1002\/humu.23057","article-title":"Effects of different variants in the ENPP1 gene on the functional properties of ectonucleotide pyrophosphatase\/phosphodiesterase family member 1","volume":"37","author":"Stella","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jdermsci.2013.12.008","article-title":"Fibroblasts from patients affected by Pseudoxanthoma elasticum exhibit an altered PPi metabolism and are more responsive to pro-calcifying stimuli","volume":"74","author":"Boraldi","year":"2014","journal-title":"J. Dermatol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lefth\u00e9riotis, G., Navasiolava, N., Clotaire, L., Duranton, C., Le Saux, O., Bendahhou, S., Laurain, A., Rubera, I., and Martin, L. (2022). Relationships between Plasma Pyrophosphate, Vascular Calcification and Clinical Severity in Patients Affected by Pseudoxanthoma Elasticum. J. Clin. Med., 11.","DOI":"10.3390\/jcm11092588"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.cellsig.2018.12.009","article-title":"Cellular signaling in pseudoxanthoma elasticum: An update","volume":"55","author":"Nollet","year":"2019","journal-title":"Cell. Signal."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"B\u00e4ck, M., Ar\u00e1nyi, T., Cancela, M.L., Carracedo, M., Concei\u00e7\u00e3o, N., Leftheriotis, G., Macrae, V., Martin, L., Nitschke, Y., and Pasch, A. (2018). Endogenous calcification inhibitors in the prevention of vascular calcification: A consensus statement from the COST Action EuroSoftCalcNet. Front. Cardiovasc. Med., 5.","DOI":"10.3389\/fcvm.2018.00196"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Nollet, L., Van Gils, M., Verschuere, S., and Vanakker, O.M. (2019). The role of vitamin K and its related compounds in Mendelian and acquired ectopic mineralization disorders. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092142"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.ajpath.2017.02.009","article-title":"Pyrophosphate supplementation prevents chronic and acute calcification in ABCC6-deficient mice","volume":"187","author":"Pomozi","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1016\/j.jid.2018.10.040","article-title":"Dietary pyrophosphate modulates calcification in a mouse model of pseudoxanthoma elasticum: Implication for treatment of patients","volume":"139","author":"Pomozi","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1038\/jid.2014.421","article-title":"Efficiency of exome sequencing for the molecular diagnosis of pseudoxanthoma elasticum","volume":"135","author":"Hosen","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/gim.2017.37","article-title":"Sherloc: A comprehensive refinement of the ACMG-AMP variant classification criteria","volume":"19","author":"Nykamp","year":"2017","journal-title":"Genet. Med."},{"key":"ref_27","first-page":"205","article-title":"Reassessment of causality of ABCC6 missense variants associated with pseudoxanthoma elasticum based on Sherloc","volume":"29","author":"Verschuere","year":"2020","journal-title":"Genet. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1136\/jmg.2007.051094","article-title":"Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum","volume":"44","author":"Pfendner","year":"2007","journal-title":"J. Med. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1161\/ATVBAHA.114.304017","article-title":"ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report","volume":"34","author":"Jansen","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00216-022-04430-8","article-title":"A new enzymatic assay to quantify inorganic pyrophosphate in plasma","volume":"415","author":"Lundkvist","year":"2023","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"R206","DOI":"10.1093\/hmg\/ddr386","article-title":"Multi-ethnic studies in complex traits","volume":"20","author":"Fu","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e4337","DOI":"10.1210\/clinem\/dgaa612","article-title":"Race, Ancestry, and Vitamin D Metabolism: The Multi-Ethnic Study of Atherosclerosis","volume":"105","author":"Hsu","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1038\/s41366-021-00795-5","article-title":"Polygenic risk for obesity and its interaction with lifestyle and sociodemographic factors in European children and adolescents","volume":"45","author":"Wright","year":"2021","journal-title":"Int. J. Obes."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1375\/twin.10.5.749","article-title":"Heritability of body mass index: A comparison between the Netherlands and Spain","volume":"10","author":"Willemsen","year":"2007","journal-title":"Twin Res. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.jped.2017.01.002","article-title":"Association between dietary pattern and cardiometabolic risk in children and adolescents: A systematic review","volume":"93","author":"Rocha","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sofi, F., Cesari, F., Abbate, R., Gensini, G.F., and Casina, A. (2008). Adherence to Mediterranean diet and health status: Meta-analysis. BMJ, 337.","DOI":"10.1136\/bmj.a1344"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1016\/j.jid.2017.06.006","article-title":"Plasma PPi deficiency is the major, but not the exclusive, cause of ectopic mineralization in an Abcc6\u2212\/\u2212 mouse model of PXE","volume":"137","author":"Zhao","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.atherosclerosis.2021.03.012","article-title":"Genotype-phenotype correlation in pseudoxanthoma elasticum","volume":"324","author":"Bartstra","year":"2021","journal-title":"Atherosclerosis"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.18632\/aging.101821","article-title":"Accelerated peripheral vascular aging in pseudoxanthoma elasticum\u2014Proof of concept for arterial calcification-induced cardiovascular disease","volume":"11","author":"Bartstra","year":"2019","journal-title":"Aging"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s13670-013-0063-4","article-title":"Cardiovascular Calcifications in Old Age: Mechanisms and Clinical Implications","volume":"2","author":"Giallauria","year":"2013","journal-title":"Curr. Transl. Geriatr. Exp. Gerontol. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1038\/jid.2012.460","article-title":"Matrix gla protein and alkaline phosphatase are differentially modulated in human dermal fibroblasts from PXE patients and controls","volume":"133","author":"Boraldi","year":"2013","journal-title":"J. Investig. Dermatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1016\/j.jid.2022.01.022","article-title":"Inhibition of the DNA damage response attenuates ectopic calcification in pseudoxanthoma elasticum","volume":"142","author":"Huang","year":"2022","journal-title":"J. Investig. Dermatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1038\/jid.2009.423","article-title":"Overexpression of fetuin-a counteracts ectopic mineralization in a mouse model of pseudoxanthoma elatcium (Abcc6(\u2212\/\u2212))","volume":"130","author":"Jiang","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1111\/j.1600-0625.2012.01553.x","article-title":"Restricting dietary magnesium accelerates ectopic connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6 (\u2212\/\u2212))","volume":"21","author":"Jiang","year":"2012","journal-title":"Exp. Dermatol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Nollet, L., Van Gils, M., Fischer, S., Campens, L., Karthik, S., Pasch, A., De Zaeytijd, J., Leroy, B.P., Devos, D., and De Backer, T. (2022). Serum calcification propensity T50 associates with disease severity in patents with pseudoxanthoma elasticum. J. Clin. Med., 11.","DOI":"10.3390\/jcm11133727"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1016\/j.jid.2021.10.019","article-title":"Minocycline attentuates excessive DNA damage response and reduces ectopic calcification in pseudoxanthoma elasticum","volume":"142","author":"Nollet","year":"2022","journal-title":"J. Investig. Dermatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1139\/bcb-2019-0045","article-title":"The impact of epigenetics on cardiovascular disease","volume":"98","author":"Prasher","year":"2020","journal-title":"Biochem. Cell Biol."},{"key":"ref_48","first-page":"247","article-title":"Role of pyrophosphate in vascular calcification in chronic kidney disease","volume":"38","author":"Azpiazu","year":"2018","journal-title":"Nephrologia"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/5\/1893\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:44:10Z","timestamp":1760121850000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/5\/1893"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,27]]},"references-count":48,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["jcm12051893"],"URL":"https:\/\/doi.org\/10.3390\/jcm12051893","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,27]]}}}