{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T11:34:06Z","timestamp":1791891246323,"version":"4.3.4"},"reference-count":54,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T00:00:00Z","timestamp":1645747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Responding to the need for the verification of some experimental animal studies showing the involvement of oxidative stress in germ cell damage in the heat-induced testis, we investigated the possibility of a direct relationship between seminal oxidative stress markers (total antioxidant capacity, catalase activity, superoxide dismutase activity, and malondialdehyde concentration) and ejaculated sperm chromatin\/DNA integrity (DNA fragmentation and chromatin condensation abnormalities) in distinct groups of men exposed and not exposed to prolonged scrotal hyperthermia. A statistical increase in the proportion of sperm with DNA fragmentation was observed in all the studied subgroups compared to the fertile men. In turn, the groups subjected to heat stress as professional drivers or infertile men with varicocele presented greater disturbances in the oxidative stress scavenging system than men not exposed to genital heat stress. Based on the comparative analysis of the studied parameters, we can conclude that alterations in the seminal oxidative stress scavenging system are directly engaged in the pathogenesis of ejaculated sperm DNA damage regardless of the intensity of the impact of thermal insult. To the best of our knowledge, this study, for the first time, revealed the co-existence of oxidative stress and sperm DNA damage in the semen of professional drivers.<\/jats:p>","DOI":"10.3390\/ijerph19052713","type":"journal-article","created":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T10:00:40Z","timestamp":1645783240000},"page":"2713","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["The Role of Seminal Oxidative Stress Scavenging System in the Pathogenesis of Sperm DNA Damage in Men Exposed and Not Exposed to Genital Heat Stress"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1212-4230","authenticated-orcid":false,"given":"Monika","family":"Fraczek","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Lewandowska","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0211-0743","authenticated-orcid":false,"given":"Marta","family":"Budzinska","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9619-8220","authenticated-orcid":false,"given":"Marzena","family":"Kamieniczna","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8338-9570","authenticated-orcid":false,"given":"Lukasz","family":"Wojnar","sequence":"additional","affiliation":[{"name":"Clinic of Urology and Oncological Urology, Poznan University of Medical Sciences, 61-285 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1655-5065","authenticated-orcid":false,"given":"Kamil","family":"Gill","sequence":"additional","affiliation":[{"name":"Department of Histology and Developmental Biology, Pomeranian Medical University in Szczecin, 71-210 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5914-2121","authenticated-orcid":false,"given":"Malgorzata","family":"Piasecka","sequence":"additional","affiliation":[{"name":"Department of Histology and Developmental Biology, Pomeranian Medical University in Szczecin, 71-210 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Kups","sequence":"additional","affiliation":[{"name":"Department and Clinic Urology and Oncological Urology, Regional Specialist Hospital in Szczecin, 71-455 Szczecin, Poland"},{"name":"The Fertility Partnership Vitrolive in Szczecin, 70-483 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9808-8896","authenticated-orcid":false,"given":"Anna","family":"Havrylyuk","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology and Allergology, Danylo Halytskyy Lviv National Medical University, 79008 Lviv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3127-2028","authenticated-orcid":false,"given":"Valentina","family":"Chopyak","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology and Allergology, Danylo Halytskyy Lviv National Medical University, 79008 Lviv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jozef","family":"Nakonechnyy","sequence":"additional","affiliation":[{"name":"Department of Urology, Danylo Halytskyy Lviv National Medical University, 79010 Lviv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrij","family":"Nakonechnyy","sequence":"additional","affiliation":[{"name":"Department of Paediatric Surgery, Danylo Halytskyy Lviv National Medical University, 79059 Lviv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3275-3245","authenticated-orcid":false,"given":"Maciej","family":"Kurpisz","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/j.1365-2605.1995.tb00408.x","article-title":"Testicular heating and its possible contributions to male infertility: A review","volume":"18","author":"Mieusset","year":"1995","journal-title":"Int. J. Androl."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.rbmo.2014.09.018","article-title":"Causes, effects and molecular mechanisms of testicular heat stress","volume":"30","author":"Durairajanayagam","year":"2015","journal-title":"Reprod. Biomed. Online"},{"key":"ref_3","first-page":"48","article-title":"Hyperthermia and sperm quality\u2014A risk factor for male infertility or contraceptive target","volume":"5","author":"Fraczek","year":"2018","journal-title":"Adv. Androl. Online"},{"key":"ref_4","unstructured":"Agarawal, A., Aitken, R.J., and Alvarez, J.G. (2012). Heat and oxidative stress in the germ line. Studies on Men\u2019s Health and Fertility. Oxidative Stress in Applied Basic Research and Clinical Practice, Humana Press."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1530\/rep.1.00531","article-title":"Impact of a mild scrotal heat stress on DNA integrity in murine spermatozoa","volume":"129","author":"Banks","year":"2005","journal-title":"Reproduction"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1080\/10715760500130517","article-title":"Accelerated impairment of spermatogenic cells in SOD1-knockout mice under heat stress","volume":"39","author":"Ishii","year":"2005","journal-title":"Free Radic. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e12656","DOI":"10.1111\/and.12656","article-title":"Capsaicin attenuates spermatogenic cell death induced by scrotal hyperthermia through its antioxidative and anti-apoptotic activities","volume":"49","author":"Park","year":"2017","journal-title":"Andrologia"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zhang, M., Jiang, M., Bi, Y., Zhu, H., Zhou, Z., and Sha, J. (2012). Autophagy and apoptosis act as partners to induce germ cell death after heat stress in mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041412"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1095\/biolreprod.108.071779","article-title":"A single, mild, transient scrotal heat stress causes hypoxia and oxidative stress in mouse testes, which induces germ cell death","volume":"80","author":"Paul","year":"2009","journal-title":"Biol. Reprod."},{"key":"ref_10","first-page":"523","article-title":"The redox system in human semen and peroxidative damage of spermatozoa","volume":"59","author":"Fraczek","year":"2005","journal-title":"Postepy Hig. Med. Dosw. Online"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.mce.2005.12.026","article-title":"Oxidative stress, sperm survival and fertility control","volume":"250","author":"Aitken","year":"2006","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1093\/biolre\/iox104","article-title":"Reactive oxygen species and protein modifications in spermatozoa","volume":"97","year":"2017","journal-title":"Biol. Reprod."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1387\/ijdb.130146ja","article-title":"Causes and consequences of apoptosis in spermatozoa; contributions to infertility and impacts on development","volume":"57","author":"Aitken","year":"2013","journal-title":"Int. J. Dev. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1042\/BJ20110114","article-title":"Phosphoinositide 3-kinase signalling pathway involvement in a truncated apoptotic cascade associated with motility loss and oxidative DNA damage in human spermatozoa","volume":"436","author":"Koppers","year":"2011","journal-title":"Biochem. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1111\/j.1439-0272.2009.00981.x","article-title":"Effects of varicocele upon the expression of apoptosis related proteins","volume":"42","author":"Chang","year":"2010","journal-title":"Andrologia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s00404-015-3822-y","article-title":"DNA damage in spermatozoa from infertile men with varicocele evaluated by sperm chromatin dispersion and DBD-FISH","volume":"293","year":"2016","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8","DOI":"10.4081\/aiua.2013.1.8","article-title":"The study of spermatic DNA fragmentation and sperm motility in infertile subjects","volume":"85","author":"Peluso","year":"2013","journal-title":"Arch. Ital. Urol. Androl."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.fertnstert.2007.12.058","article-title":"Apoptosis-related phenotype of ejaculated spermatozoa in patients with varicocele","volume":"91","author":"Wu","year":"2009","journal-title":"Fertil. Steril."},{"key":"ref_19","first-page":"279","article-title":"Extent of sperm DNA damage in spermatozoa from men examined for infertility. Relationship with oxidative stress","volume":"135","author":"Smith","year":"2007","journal-title":"Rev. Med. Chile"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"450","DOI":"10.2164\/jandrol.05124","article-title":"Impact of body mass index values on sperm quantity and quality","volume":"27","author":"Kort","year":"2006","journal-title":"J. Androl."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1111\/andr.12228","article-title":"Transient scrotal hyperthermia affects human sperm DNA integrity, sperm apoptosis, and sperm protein expression","volume":"4","author":"Rao","year":"2016","journal-title":"Andrology"},{"key":"ref_22","first-page":"15","article-title":"The impact of sedentary work on sperm nuclear DNA integrity","volume":"57","author":"Gill","year":"2019","journal-title":"Folia Histochem. Cytobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.2164\/jandrol.112.016535","article-title":"Reactive oxygen species and sperm function in sickness and in health","volume":"33","author":"Aitken","year":"2012","journal-title":"J. Androl."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"109","DOI":"10.2119\/molmed.2014.00158","article-title":"Investigation on the origin of sperm DNA fragmentation: Role of apoptosis, immaturity and oxidative stress","volume":"21","author":"Muratori","year":"2015","journal-title":"Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Fraczek, M., Wojnar, L., Kamieniczna, M., Piasecka, M., Gill, K., Kups, M., Chopyak, V., Havrylyuk, A., Nakonechnyy, J., and Nakonechnyy, A. (2020). Seminal plasma analysis of oxidative stress in different genitourinary topographical regions involved in reproductive tract disorders associated with genital heat stress. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176427"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/s10815-016-0677-5","article-title":"Diagnostic application of total antioxidant capacity in seminal plasma to assess oxidative stress in male factor infertility","volume":"33","author":"Roychoudhury","year":"2016","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/0003-2697(88)90554-4","article-title":"A spectrophotometric method for determination of catalase activity in small tissue samples","volume":"174","author":"Johansson","year":"1988","journal-title":"Anal. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s12011-010-8868-x","article-title":"Zinc and iron concentration and SOD activity in human semen and seminal plasma","volume":"143","author":"Lakota","year":"2011","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.fertnstert.2014.06.002","article-title":"Fertilizing potential of ejaculated human spermatozoa during in vitro semen bacterial infection","volume":"102","author":"Fraczek","year":"2014","journal-title":"Fertil. Steril."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1023\/A:1009844109023","article-title":"Sperm chromatin structure assay is useful for fertility assessment","volume":"22","author":"Evenson","year":"2000","journal-title":"Methods Cell Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5399","DOI":"10.18632\/aging.102120","article-title":"Age-related changes in human sperm DNA integrity","volume":"11","author":"Gill","year":"2019","journal-title":"Aging"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1007\/s13577-018-0203-4","article-title":"The effect of human sperm chromatin maturity on ICSI outcomes","volume":"31","author":"Gill","year":"2018","journal-title":"Hum. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/978-3-030-21664-1_8","article-title":"Interventions to Prevent Sperm DNA Damage Effects on Reproduction","volume":"1166","author":"Esteves","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Amorini, A.M., Listorti, I., Bilotta, G., Pallisco, R., Saab, M.W., Mangione, R., Manca, B., Lazzarino, G., Tavazzi, B., and Lazzarino, G. (2021). Antioxidant-based therapies in male infertility: Do we have sufficient evidence supporting their effectiveness?. Antioxidants, 10.","DOI":"10.3390\/antiox10020220"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"233","DOI":"10.5534\/wjmh.200196","article-title":"Utility of antioxidants in the treatment of male infertility: Clinical guidelines based on a systematic review and analysis of evidence","volume":"39","author":"Agarwal","year":"2021","journal-title":"World J. Men\u2019s Health"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e12773","DOI":"10.1111\/and.12773","article-title":"Ascorbic acid reduces redox potential in human spermatozoa subjected to heat-induced oxidative stress","volume":"49","author":"Ahmad","year":"2017","journal-title":"Andrologia"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/mrd.23146","article-title":"Vitamin C mitigates heat damage by reducing oxidative stress, inducing HSP expression in TM4 Sertoli cells","volume":"86","author":"Sun","year":"2019","journal-title":"Mol. Reprod. Dev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"186","DOI":"10.4103\/1008-682X.170441","article-title":"Novel insights into the pathophysiology of varicocele and its association with reactive oxygen species and sperm DNA fragmentation","volume":"18","author":"Cho","year":"2016","journal-title":"Asian J. Androl."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"935","DOI":"10.21037\/tau.2016.10.03","article-title":"Clinical utility of sperm DNA fragmentation testing: Practice recommendations based on clinical scenarios","volume":"5","author":"Agarwal","year":"2016","journal-title":"Transl. Androl. Urol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"S594","DOI":"10.21037\/tau.2017.06.03","article-title":"Is the sperm DNA status the best predictor of both natural and assisted conception?","volume":"6","author":"Fraczek","year":"2017","journal-title":"Transl. Androl. Urol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/978-3-030-21664-1_5","article-title":"Sperm DNA Fragmentation: Mechanisms of Origin","volume":"1166","author":"Muratori","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_42","first-page":"2","article-title":"Human sperm DNA fragmentation and its correlation with conventional semen parameters","volume":"15","author":"Evgeni","year":"2014","journal-title":"J. Reprod. Infertil."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Gill, K., Kups, M., Harasny, P., Machalowski, T., Grabowska, M., Lukaszuk, M., Matuszewski, M., Duchnik, E., Fraczek, M., and Kurpisz, M. (2021). The negative impact of varicocele on basic semen parameters, sperm nuclear DNA dispersion and oxidation-reduction potential in semen. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph18115977"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1007\/s10815-015-0451-0","article-title":"Scrotal heat stress causes sperm chromatin damage and cysteinyl aspartate-spicific proteinases 3 changes in fertile men","volume":"32","author":"Zhang","year":"2015","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e13177","DOI":"10.1111\/and.13177","article-title":"Comparison of main molecular markers involved in autophagy and apoptosis pathways between spermatozoa of infertile men with varicocele and fertile individuals","volume":"51","author":"Tavalaee","year":"2019","journal-title":"Andrologia"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1007\/s43032-020-00311-6","article-title":"Increased sperm DNA fragmentation in infertile men with varicocele: Relationship with apoptosis, seminal oxidative stress, and spermatic parameters","volume":"28","author":"Ammar","year":"2021","journal-title":"Reprod. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Baldi, E., and Muratori, M. (2019). Oxidative damage to sperm DNA: Attack and defense. Genetic Damage in Human Spermatozoa, Advances in Experimental Medicine and Biology, Springer Nature Switzerland.","DOI":"10.1007\/978-3-030-21664-1"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1146\/annurev.bi.55.070186.005443","article-title":"The heat-shock response","volume":"55","author":"Lindquist","year":"1986","journal-title":"Annu. Rev. Biochem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4302754","DOI":"10.1155\/2016\/4302754","article-title":"Seminal miRNA relationship with apoptotic markers and oxidative stress in infertile men with varicocele","volume":"2016","author":"Mostafa","year":"2016","journal-title":"Biomed. Res. Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"111672","DOI":"10.18632\/oncotarget.22900","article-title":"Next-generation sequencing-based microRNA profiling of mice testis subjected to transient heat stress","volume":"8","author":"Rao","year":"2017","journal-title":"Oncotarget"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1111\/andr.12445","article-title":"Effect of varicocelectomy and\/or mast cells stabilizer on sperm DNA fragmentation in infertile patients with varicocele","volume":"6","author":"Zaazaa","year":"2018","journal-title":"Andrology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.fertnstert.2021.04.003","article-title":"Effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation rates in infertile men with clinical varicocele: A systematic review and meta-analysis","volume":"116","author":"Roque","year":"2021","journal-title":"Fertil. Steril."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1590\/s1677-5538.ibju.2019.0827","article-title":"Oxidative origin of sperm DNA fragmentation in the adult varicocele","volume":"47","author":"Jeremias","year":"2021","journal-title":"Int. Braz. J. Urol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1093\/biolre\/ioy009","article-title":"Heat exposure induces oxidative stress and DNA damage in the male germ line","volume":"98","author":"Houston","year":"2018","journal-title":"Biol. Reprod."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/19\/5\/2713\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:27:45Z","timestamp":1760135265000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/19\/5\/2713"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,25]]},"references-count":54,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijerph19052713"],"URL":"https:\/\/doi.org\/10.3390\/ijerph19052713","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,25]]}}}