{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T00:50:10Z","timestamp":1793235010325,"version":"4.5.0"},"reference-count":60,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T00:00:00Z","timestamp":1637884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Spinal muscular atrophy (SMA) is a neuromuscular progressive disease, characterized by decreased amounts of survival motor neuron (SMN) protein, due to an autosomal recessive genetic defect. Despite recent research, there is still no cure. Nusinersen, an antisense oligonucleotide acting on the SMN2 gene, is intrathecally administered all life long, while onasemnogene abeparvovec-xioi, a gene therapy, is administered intravenously only once. Both therapies have proven efficacy, with best outcomes obtained when administered presymptomatically. In recent years, disease-modifying therapies such as nusinersen and onasemnogene abeparvovec-xioi have changed the natural history of SMA. Methods: We observed seven SMA type I patients, who received both therapies. We compared their motor function trajectories, ventilation hours and cough assist sessions to a control group of patients who received one therapy, in order to investigate whether combination therapy may be more effective than a single intervention alone. Results: Patients who received both therapies, compared to the monotherapy cohort, had the same motor function trajectory. Moreover, it was observed that the evolution of motor function was better in the 6 months following the first therapy than in the first 6 months after adding the second treatment. Conclusions: Our results suggest that early treatment is more important than combined therapy.<\/jats:p>","DOI":"10.3390\/jcm10235540","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T01:43:22Z","timestamp":1638323002000},"page":"5540","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Combination Therapy with Nusinersen and Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy Type I"],"prefix":"10.3390","volume":"10","author":[{"given":"Andrada","family":"Mirea","sequence":"first","affiliation":[{"name":"Faculty of Midwifery and Nursing, University of Medicine and Pharmacy \u201cCarol Davila\u201d, 37 Dionisie Lupu Street, 020021 Bucharest, Romania"},{"name":"Scientific Research Nucleus, National University Center for Children Neurorehabilitation \u201cDr. Nicolae Robanescu\u201d, 44 Dumitru Minca Street, 041408 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4658-2416","authenticated-orcid":false,"given":"Elena-Silvia","family":"Shelby","sequence":"additional","affiliation":[{"name":"Scientific Research Nucleus, National University Center for Children Neurorehabilitation \u201cDr. Nicolae Robanescu\u201d, 44 Dumitru Minca Street, 041408 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela","family":"Axente","sequence":"additional","affiliation":[{"name":"Faculty of Midwifery and Nursing, University of Medicine and Pharmacy \u201cCarol Davila\u201d, 37 Dionisie Lupu Street, 020021 Bucharest, Romania"},{"name":"Scientific Research Nucleus, National University Center for Children Neurorehabilitation \u201cDr. Nicolae Robanescu\u201d, 44 Dumitru Minca Street, 041408 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela","family":"Badina","sequence":"additional","affiliation":[{"name":"Faculty of Midwifery and Nursing, University of Medicine and Pharmacy \u201cCarol Davila\u201d, 37 Dionisie Lupu Street, 020021 Bucharest, Romania"},{"name":"Scientific Research Nucleus, National University Center for Children Neurorehabilitation \u201cDr. Nicolae Robanescu\u201d, 44 Dumitru Minca Street, 041408 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Padure","sequence":"additional","affiliation":[{"name":"Scientific Research Nucleus, National University Center for Children Neurorehabilitation \u201cDr. Nicolae Robanescu\u201d, 44 Dumitru Minca Street, 041408 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalina","family":"Leanca","sequence":"additional","affiliation":[{"name":"Scientific Research Nucleus, National University Center for Children Neurorehabilitation \u201cDr. Nicolae Robanescu\u201d, 44 Dumitru Minca Street, 041408 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5969-9205","authenticated-orcid":false,"given":"Vlad","family":"Dima","sequence":"additional","affiliation":[{"name":"Clinical Hospital of Obstetrics and Gynecology \u201cFilantropia\u201d, 11 Ion Mihalache Avenue, 011132 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3481-9690","authenticated-orcid":false,"given":"Corina","family":"Sporea","sequence":"additional","affiliation":[{"name":"Faculty of Midwifery and Nursing, University of Medicine and Pharmacy \u201cCarol Davila\u201d, 37 Dionisie Lupu Street, 020021 Bucharest, Romania"},{"name":"Scientific Research Nucleus, National University Center for Children Neurorehabilitation \u201cDr. Nicolae Robanescu\u201d, 44 Dumitru Minca Street, 041408 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,26]]},"reference":[{"key":"ref_1","unstructured":"(2021, May 17). SMN1 Gene Survival of Motor Neuron 1, Telomeric, Available online: https:\/\/medlineplus.gov\/genetics\/gene\/smn1\/#location."},{"key":"ref_2","unstructured":"(2021, May 17). Spinal Muscular Atrophy, Available online: https:\/\/ghr.nlm.nih.gov\/condition\/spinal-muscular-atrophy#statistics."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2751","DOI":"10.1093\/hmg\/11.22.2751","article-title":"Involvement of survival motor neuron (SMN) protein in cell death","volume":"11","author":"Vyas","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8691","DOI":"10.1523\/JNEUROSCI.0417-15.2015","article-title":"Disease mechanisms and therapeutic approaches in spinal muscular atrophy","volume":"35","author":"Tisdale","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2879","DOI":"10.1093\/brain\/awu169","article-title":"Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies","volume":"137","author":"Peeters","year":"2014","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s13023-017-0671-8","article-title":"Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy\u2014A literature review","volume":"12","author":"Verhaart","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1007\/s13311-014-0314-x","article-title":"The genetics of spinal muscular atrophy: Progress and challenges","volume":"12","author":"Farrar","year":"2015","journal-title":"Neurotherapeutics"},{"key":"ref_8","unstructured":"(2018). Appendix 7 Clinical Features, Epidemiology, Natural History, and Management of Spinal Muscular Atrophy. Clinical Review Report: Nusinersen (Spinraza), Biogen Canada Inc.. Indication: Treatment of patients with 5q SMA."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1093\/hmg\/ddi078","article-title":"SMN\u03947, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN","volume":"14","author":"Le","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6307","DOI":"10.1073\/pnas.96.11.6307","article-title":"A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy","volume":"96","author":"Lorson","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/ng854","article-title":"Disruption of an SF2\/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1","volume":"30","author":"Cartegni","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1093\/hmg\/6.8.1205","article-title":"The survival motor neuron protein in spinal muscular atrophy","volume":"6","author":"Coovert","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1097\/00125817-200201000-00004","article-title":"Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2","volume":"4","author":"Mailman","year":"2002","journal-title":"Genet. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3389\/fmolb.2016.00007","article-title":"Copy number variations in the survival motor neuron genes: Implications for spinal muscular atrophy and other neurodegenerative diseases","volume":"3","author":"Butchbach","year":"2016","journal-title":"Front. Mol. Biosci."},{"key":"ref_15","unstructured":"(2021, May 17). Muscular Distrophy Association. Available online: https:\/\/www.mda.org\/disease\/spinal-muscular-atrophy\/types."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2147\/TACG.S239603","article-title":"Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance","volume":"14","author":"Keinath","year":"2021","journal-title":"Appl. Clin. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S1090-3798(99)80012-9","article-title":"Very severe spinal muscular atrophy (SMA type 0): An expanding clinical phenotype","volume":"3","author":"Dubowitz","year":"1999","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e66","DOI":"10.1542\/pir.30.9.e66","article-title":"The Floppy Infant","volume":"30","author":"Peredo","year":"2009","journal-title":"Pediatr. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.pediatrneurol.2019.06.007","article-title":"From Clinical Trials to Clinical Practice: Practical Considerations for Gene Replacement Therapy in SMA Type 1","volume":"100","author":"Mendell","year":"2019","journal-title":"Pediatr. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.nmd.2017.11.004","article-title":"Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics","volume":"28","author":"Finkel","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.nmd.2017.11.005","article-title":"Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care","volume":"28","author":"Mercuri","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_22","unstructured":"(2021, May 17). U.S. Food & Drug Administration, Available online: https:\/\/www.fda.gov."},{"key":"ref_23","unstructured":"(2021, May 17). European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/dmcn.14027","article-title":"Nusinersen treatment of spinal muscular atrophy: Current knowledge and existing gaps","volume":"61","author":"Gidaro","year":"2019","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1056\/NEJMoa2009965","article-title":"Risdiplam in type 1 spinal muscular atrophy","volume":"384","author":"Baranello","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s11940-019-0568-z","article-title":"Current Treatment Options in Neurology\u2014SMA Therapeutics","volume":"21","author":"Waldrop","year":"2019","journal-title":"Curr. Treat. Options Neurol."},{"key":"ref_27","unstructured":"(2021, May 17). Summarry of Product INN Nusinersen. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/spinraza-epar-product-information_en.pdf."},{"key":"ref_28","unstructured":"(2021, May 17). AHFS Approved Spinraza. Available online: https:\/\/www.ahfsdruginformation.com\/spinraza-nusinersen-approved\/."},{"key":"ref_29","unstructured":"(2021, May 17). EMA Nusinersen Approved. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/orphan-designations\/eu312976."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1101\/gad.1941310","article-title":"Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model","volume":"24","author":"Hua","year":"2010","journal-title":"Genes Dev."},{"key":"ref_31","unstructured":"(2021, May 17). Healthcare Information SAFETY-NUSINERSEN. Available online: https:\/\/www.spinraza.com\/en_us\/home\/taking-spinraza\/dosing.html."},{"key":"ref_32","unstructured":"(2021, May 17). Intrathecal Administration with SPINRAZA\u00ae (Nusinersen). Available online: https:\/\/www.spinraza.com\/content\/dam\/commercial\/spinraza\/caregiver\/en_us\/pdf\/SPZ-US-0603-Intrathecal-Discussion-Tool.pdf."},{"key":"ref_33","unstructured":"Figueiredo, M. (2021, May 17). Motor Function Improved after Spinraza. Available online: https:\/\/smanewstoday.com\/2020\/06\/24\/spinraza-improves-motor-function-after-1-year-children-sma-type-1-2-real-life-study-france\/."},{"key":"ref_34","unstructured":"(2021, May 17). SMA NEWS TODAY-SPINRAZA. Available online: https:\/\/smanewstoday.com\/spinraza-nusinersen\/."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1164\/rccm.201906-1175LE","article-title":"Effect of nusinersen on respiratory muscle function in different subtypes of type 1 spinal muscular atrophy","volume":"200","author":"LoMauro","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1007\/s40263-019-00656-w","article-title":"An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials","volume":"33","author":"Darras","year":"2019","journal-title":"CNS Drugs"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"127","DOI":"10.4103\/ijabmr.IJABMR_190_19","article-title":"Onasemnogene abeparvovec for spinal muscular atrophy: The costlier drug ever","volume":"9","author":"Mahajan","year":"2019","journal-title":"Int. J. Appl. Basic Med. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.jhep.2020.11.001","article-title":"Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy","volume":"74","author":"Chand","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.jpeds.2020.11.054","article-title":"Thrombotic Microangiopathy Following Onasemnogene Abeparvovec for Spinal Muscular Atrophy: A Case Series","volume":"231","author":"Chand","year":"2021","journal-title":"J. Pediatr."},{"key":"ref_40","unstructured":"FDA (2021, May 17). Statement on Data Accuracy Issues with Recently Approved Gene Therapy, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/statement-data-accuracy-issues-recently-approved-gene-therapy."},{"key":"ref_41","unstructured":"(2021, May 17). AVEXIS EC APPROVAL-Day 1. Available online: https:\/\/www.novartis.com\/news\/media-releases\/avexis-receives-ec-approval-and-activates-%22day-one%22-access-program-zolgensma-only-gene-therapy-spinal-muscular-atrophy-sma."},{"key":"ref_42","unstructured":"(2021, May 17). Clear for Use AVEXIS. Available online: https:\/\/www.novartis.com\/news\/media-releases\/avexis-receives-ec-approval-and-activates-day-one-access-program-zolgensma-only-gene-therapy-spinal-muscular-atrophy-sma."},{"key":"ref_43","unstructured":"(2021, May 17). MAP AVEXIS. Available online: https:\/\/smanewstoday.com\/2019\/12\/28\/novartis-global-access-program-for-zolgensma\/."},{"key":"ref_44","unstructured":"Company News HQ. Novartis (2021, May 17). Novartis Gene Therapies Recommits to Global Man-Aged Access Program for 2021. Available online: https:\/\/www.companynewshq.com\/company-news\/pharmaceutical-company-news\/novartis-gene-therapies-recommits-to-global-managed-access-program-for-2021\/."},{"key":"ref_45","unstructured":"National Health Insurance House (2021, May 17). PRESS RELEASE\u2013Romania Has Started Treating Patients with Spinal Amyotrophy with the Drug Nusinersen. Available online: http:\/\/www.cnas.ro\/post\/type\/local\/comunicat-romania-a-inceput-tratarea-pacientilor-cu-amiotrofie-spinala-cu-medicamentul-nusinersen.html."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/mus.27034","article-title":"Combination molecular therapies for type 1 spinal muscular atrophy","volume":"62","author":"Harada","year":"2020","journal-title":"Muscle Nerve"},{"key":"ref_47","unstructured":"(2021, May 17). MLPA. Available online: https:\/\/www.sciencedirect.com\/topics\/medicine-and-dentistry\/multiplex-ligation-dependent-probe-amplification."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1177\/0883073807305788","article-title":"Consensus statement for standard of care in spinal muscular atrophy","volume":"22","author":"Wang","year":"2007","journal-title":"J. Child. Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.nmd.2009.11.014","article-title":"The Children\u2019s Hospital of Philadelphia infant test of neuromuscular disorders (CHOP INTEND): Test development and reliability","volume":"20","author":"Glanzman","year":"2010","journal-title":"Neuromuscul. Disord."},{"key":"ref_50","unstructured":"(2021, May 17). CHOP INTEND Score Sheet. Available online: http:\/\/www.musculardystrophyuk.org\/wp-content\/uploads\/2017\/06\/CHOP-INTEND_Score-Sheet.pdf."},{"key":"ref_51","first-page":"e161","article-title":"Spinal muscular atrophy type 1: Are proactive respiratory interventions associated with longer survival?","volume":"13","author":"Lemoine","year":"2012","journal-title":"Pediatr. Crit Care Med. J. Soc. Crit. Care Med. World Fed. Pediatr. Intensive Crit. Care Soc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.chest.2016.11.043","article-title":"POINT: Is Noninvasive Ventilation Always the Most Appropriate Manner of Long-term Ventilation for Infants With Spinal Muscular Atrophy Type 1? Yes, Almost Always","volume":"151","author":"Bach","year":"2017","journal-title":"Chest"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"S245","DOI":"10.1542\/peds.2008-2952K","article-title":"Special considerations in the respiratory management of spinal muscular atrophy","volume":"123","author":"Schroth","year":"2009","journal-title":"Pediatrics"},{"key":"ref_54","first-page":"976","article-title":"The Impact of Lung Volume Recruitment on Pulmonary Function in Progressive Childhood Onset Neuromuscular Disease: A Systematic Review","volume":"102","author":"Carrier","year":"2020","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"S27.009","DOI":"10.1212\/WNL.92.15_supplement.S27.009","article-title":"Association of Phosphorylated Neurofilament Heavy Chain (pNF-H) Levels With Motor Function Achievement in Individuals With Spinal Muscular Atrophy (SMA) Treated With Nusinersen (S27.009)","volume":"92","author":"Sumner","year":"2019","journal-title":"Neurology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1007\/s12325-019-00923-8","article-title":"Survival, motor function, and motor milestones: Comparison of AVXS-101 relative to nusinersen for the treatment of infants with spinal muscular atrophy type 1","volume":"36","author":"Dabbous","year":"2019","journal-title":"Adv. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.nmd.2019.09.007","article-title":"Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study","volume":"29","author":"Bertini","year":"2019","journal-title":"Neuromuscul. Disord."},{"key":"ref_58","unstructured":"(2021, May 17). Zolgensma Presymptomatics, SPRINT. Available online: https:\/\/www.novartis.com\/news\/media-releases\/avexis-presented-robust-data-aan-demonstrating-efficacy-zolgensma-broad-spectrum-spinal-muscular-atrophy-sma-patients."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1126\/science.360.6396.1385","article-title":"Newborn screening urged for fatal neurological disorder","volume":"360","author":"Wadman","year":"2018","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1002\/acn3.23","article-title":"Electrophysiological biomarkers in spinal muscular atrophy: Proof of concept","volume":"1","author":"Arnold","year":"2014","journal-title":"Ann. Clin. Transl. Neurol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/23\/5540\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:36:13Z","timestamp":1760168173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/23\/5540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,26]]},"references-count":60,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["jcm10235540"],"URL":"https:\/\/doi.org\/10.3390\/jcm10235540","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,26]]}}}