{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T12:40:51Z","timestamp":1791549651161,"version":"4.3.4"},"reference-count":53,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T00:00:00Z","timestamp":1683936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Salud Carlos III (ISCIII, Madrid, Spain)","award":["AES, ICI20\/00146"],"award-info":[{"award-number":["AES, ICI20\/00146"]}]},{"name":"FEDER funds","award":["AES, ICI20\/00146"],"award-info":[{"award-number":["AES, ICI20\/00146"]}]},{"name":"Instituto de Investigaci\u00f3n Sanitaria y Biom\u00e9dica de Alicante (ISABIAL)","award":["AES, ICI20\/00146"],"award-info":[{"award-number":["AES, ICI20\/00146"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Analgesic-response variability in chronic noncancer pain (CNCP) has been reported due to several biological and environmental factors. This study was undertaken to explore sex differences linked to OPRM1 and COMT DNA methylation changes and genetic variants in analgesic response. A retrospective study with 250 real-world CNCP outpatients was performed in which data from demographic, clinical, and pharmacological variables were collected. DNA methylation levels (CpG island) were evaluated by pyrosequencing, and their interaction with the OPRM1 (A118G) and COMT (G472A) gene polymorphisms was studied. A priori-planned statistical analyses were conducted to compare responses between females and males. Sex-differential OPRM1 DNA methylation was observed to be linked to lower opioid use disorder (OUD) cases for females (p = 0.006). Patients with lower OPRM1 DNA methylation and the presence of the mutant G-allele reduced opioid dose requirements (p = 0.001), equal for both sexes. Moreover, COMT DNA methylation levels were negatively related to pain relief (p = 0.020), quality of life (p = 0.046), and some adverse events (probability &gt; 90%) such as constipation, insomnia, or nervousness. Females were, significantly, 5 years older with high anxiety levels and a different side-effects distribution than males. The analyses demonstrated significant differences between females and males related to OPRM1 signalling efficiency and OUD, with a genetic\u2013epigenetic interaction in opioid requirements. These findings support the importance of sex as a biological variable to be factored into chronic pain-management studies.<\/jats:p>","DOI":"10.3390\/jcm12103449","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T02:02:11Z","timestamp":1684116131000},"page":"3449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Sex Differences in Opioid Response Linked to OPRM1 and COMT genes DNA Methylation\/Genotypes Changes in Patients with Chronic Pain"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8739-0456","authenticated-orcid":false,"given":"Laura","family":"Agull\u00f3","sequence":"first","affiliation":[{"name":"Pharmacogenetic Unit, Alicante Institute for Health and Biomedical Research (ISABIAL), Dr. Balmis General University Hospital, Pintor Baeza, 12, 03010 Alicante, Spain"},{"name":"Clinical Pharmacology, Toxicology and Chemical Safety Unit, Institute of Bioengineering, Miguel Hern\u00e1ndez University, Avda. de la Universidad s\/n, 03202 Elche, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Muriel","sequence":"additional","affiliation":[{"name":"Pharmacogenetic Unit, Alicante Institute for Health and Biomedical Research (ISABIAL), Dr. Balmis General University Hospital, Pintor Baeza, 12, 03010 Alicante, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9sar","family":"Margarit","sequence":"additional","affiliation":[{"name":"Pain Unit, Department of Health of Alicante, Dr. Balmis General University Hospital, c\/Pintor Baeza, 12, 03010 Alicante, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Escorial","sequence":"additional","affiliation":[{"name":"Pharmacogenetic Unit, Alicante Institute for Health and Biomedical Research (ISABIAL), Dr. Balmis General University Hospital, Pintor Baeza, 12, 03010 Alicante, Spain"},{"name":"Clinical Pharmacology, Toxicology and Chemical Safety Unit, Institute of Bioengineering, Miguel Hern\u00e1ndez University, Avda. de la Universidad s\/n, 03202 Elche, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Garcia","sequence":"additional","affiliation":[{"name":"Epigenomics Core Facility, La Fe Health Research Institute, Ave. Fernando Abril Martorell, 106, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6042-4185","authenticated-orcid":false,"given":"Mar\u00eda Jos\u00e9","family":"Herrero","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Unit, La Fe Health Research Institute, Ave. Fernando Abril Martorell, 106, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0635-4961","authenticated-orcid":false,"given":"David","family":"Herv\u00e1s","sequence":"additional","affiliation":[{"name":"Department of Applied Statistics and Operations Research and Quality, Universitat Polit\u00e8cnica de Val\u00e9ncia, 46022 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Sandoval","sequence":"additional","affiliation":[{"name":"Epigenomics Core Facility, La Fe Health Research Institute, Ave. Fernando Abril Martorell, 106, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2385-3749","authenticated-orcid":false,"given":"Ana M.","family":"Peir\u00f3","sequence":"additional","affiliation":[{"name":"Pharmacogenetic Unit, Alicante Institute for Health and Biomedical Research (ISABIAL), Dr. Balmis General University Hospital, Pintor Baeza, 12, 03010 Alicante, Spain"},{"name":"Clinical Pharmacology, Toxicology and Chemical Safety Unit, Institute of Bioengineering, Miguel Hern\u00e1ndez University, Avda. de la Universidad s\/n, 03202 Elche, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e13751","DOI":"10.1111\/nmo.13751","article-title":"Sex Differences in the Epigenetic Regulation of Chronic Visceral Pain Following Unpredictable Early Life Stress","volume":"32","author":"Louwies","year":"2020","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1265\/jjh.71.200","article-title":"Epigenetic Effect of Environmental Factors on Neurodevelopmenal Disorders","volume":"71","author":"Kubota","year":"2016","journal-title":"Jpn. J. Hyg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1002\/jnr.23841","article-title":"Sex Differences in Pain","volume":"95","author":"Sorge","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.addbeh.2017.03.024","article-title":"Non-Medical Opioid Use in Youth: Gender Differences in Risk Factors and Prevalence","volume":"72","author":"Osborne","year":"2017","journal-title":"Addict. Behav."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"116926","DOI":"10.1016\/j.lfs.2019.116926","article-title":"Sex Differences in Pain and Opioid Mediated Antinociception: Modulatory Role of Gonadal Hormones","volume":"237","author":"Nasser","year":"2019","journal-title":"Life Sci."},{"key":"ref_6","first-page":"184","article-title":"Gender Differences in Pain and Its Relief","volume":"52","author":"Pieretti","year":"2016","journal-title":"Ann. Dell\u2019istituto Super. Di Sanita"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"104447","DOI":"10.1016\/j.phrs.2019.104447","article-title":"Sex Differences in the Response to Opioids for Pain Relief: A Systematic Review and Meta-Analysis","volume":"148","author":"Pisanu","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4751","DOI":"10.1093\/hmg\/dds314","article-title":"Genetic-Epigenetic Interaction Modulates \u03bc-Opioid Receptor Regulation","volume":"21","author":"Oertel","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1007\/s00109-022-02227-x","article-title":"Epigenetic Mechanisms Regulate Sex-Specific Bias in Disease Manifestations","volume":"100","author":"Chlamydas","year":"2022","journal-title":"J. Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.jpain.2008.12.001","article-title":"Sex, Gender, and Pain: A Review of Recent Clinical and Experimental Findings","volume":"10","author":"Fillingim","year":"2009","journal-title":"J. Pain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/B978-0-444-53630-3.00009-9","article-title":"Sex and Gender Differences in Pain and Analgesia","volume":"186","author":"Mogil","year":"2010","journal-title":"Prog. Brain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1093\/hmg\/ddi013","article-title":"Genetic Basis for Individual Variations in Pain Perception and the Development of a Chronic Pain Condition","volume":"14","author":"Diatchenko","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1093\/bja\/aet127","article-title":"Sex Differences in Pain: A Brief Review of Clinical and Experimental Findings","volume":"111","author":"Bartley","year":"2013","journal-title":"Br. J. Anaesth."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.jaac.2010.06.001","article-title":"Epigenetics and the Biological Basis of Gene \u00d7 Environment Interactions","volume":"49","author":"Bagot","year":"2010","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1002\/phar.1986","article-title":"Review of Opioid Pharmacogenetics and Considerations for Pain Management","volume":"37","author":"Hamadeh","year":"2017","journal-title":"Pharmacotherapy"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/npr2.12003","article-title":"A Pharmacogenetics Approach to Pain Management","volume":"38","author":"Yoshida","year":"2018","journal-title":"Neuropsychopharmacol. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/bcpt.13155","article-title":"Pharmacogenetics and Prediction of Adverse Events in Prescription Opioid Use Disorder Patients","volume":"124","author":"Muriel","year":"2019","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.jpain.2013.03.008","article-title":"Influence of Mu-Opioid Receptor Variant on Morphine Use and Self-Rated Pain Following Abdominal Hysterectomy","volume":"14","author":"Sia","year":"2013","journal-title":"J. Pain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/cpt.23","article-title":"Pharmacogenetics of Opioid Response","volume":"97","author":"Somogyi","year":"2015","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1002\/cpt.2149","article-title":"Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy","volume":"110","author":"Crews","year":"2021","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1159\/000435937","article-title":"Genetic and Epigenetic Mechanisms Linking Pain and Psychiatric Disorders","volume":"30","author":"Swiergiel","year":"2015","journal-title":"Pain Psychiatr. Disord."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/j.apmr.2018.09.118","article-title":"When Environment Meets Genetics: A Clinical Review of the Epigenetics of Pain, Psychological Factors, and Physical Activity","volume":"100","author":"Polli","year":"2019","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1111\/aas.13243","article-title":"Health Benefits of an Adverse Events Reporting System for Chronic Pain Patients Using Long-Term Opioids","volume":"63","author":"Planelles","year":"2019","journal-title":"Acta Anaesthesiol. Scand."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1111\/papr.12816","article-title":"Genetic Contribution in Low Back Pain: A Prospective Genetic Association Study","volume":"19","author":"Margarit","year":"2019","journal-title":"Pain Pract."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"91","DOI":"10.26502\/aimr.0061","article-title":"Global Pain State Questionnaire: Reliability, Validity, and Gender Gap","volume":"4","author":"Barrachina","year":"2021","journal-title":"Arch. Intern. Med. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1477-7525-1-29","article-title":"The Hospital Anxiety And Depression Scale","volume":"1","author":"Snaith","year":"2003","journal-title":"Health Qual Life Outcomes."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1533-2500.2008.00204.x","article-title":"Opioids and the Management of Chronic Severe Pain in the Elderly: Consensus Statement of an International Expert Panel with Focus on the Six Clinically Most Often Used World Health Organization Step III Opioids (Buprenorphine, Fentanyl, Hydromorphone, Methadone, Morphine, Oxycodone)","volume":"8","author":"Pergolizzi","year":"2008","journal-title":"Pain Pract."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1038\/npp.2008.108","article-title":"Increased OPRM1 DNA Methylation in Lymphocytes of Methadone-Maintained Former Heroin Addicts","volume":"34","author":"Nielsen","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.3892\/etm.2016.3757","article-title":"Catechol-O-Methyltransferase Promoter Hypomethylation Is Associated with the Risk of Coronary Heart Disease","volume":"12","author":"Zhong","year":"2016","journal-title":"Exp. Ther. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/B978-0-12-380866-0.60002-2","article-title":"Chapter 2\u2014DNA Methylation and Cancer","volume":"70","author":"Kulis","year":"2010","journal-title":"Adv. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.jpain.2017.04.001","article-title":"OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients","volume":"18","author":"Viet","year":"2017","journal-title":"J. Pain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1080\/00952990.2016.1275659","article-title":"Elevated Levels of DNA Methylation at the OPRM1 Promoter Region in Men with Opioid Use Disorder","volume":"44","author":"Ebrahimi","year":"2018","journal-title":"Am. J. Drug Alcohol Abus."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Nielsen, R., Korneliussen, T., Albrechtsen, A., Li, Y., and Wang, J. (2012). SNP Calling, Genotype Calling, and Sample Allele Frequency Estimation from New-Generation Sequencing Data. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037558"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13148-020-00868-8","article-title":"Effect of Short-Term Prescription Opioids on DNA Methylation of the OPRM1 Promoter","volume":"12","author":"Brooks","year":"2020","journal-title":"Clin. Epigenetics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1016\/j.spinee.2021.06.002","article-title":"Exercise Attenuates Low Back Pain and Alters Epigenetic Regulation in Intervertebral Discs in a Mouse Model","volume":"21","author":"Kawarai","year":"2021","journal-title":"Spine J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"112396","DOI":"10.1016\/j.bbr.2019.112396","article-title":"Prenatal Maternal Stress Is Associated with Increased Sensitivity to Neuropathic Pain and Sex-Specific Changes in Supraspinal MRNA Expression of Epigenetic- and Stress-Related Genes in Adulthood","volume":"380","author":"Jang","year":"2020","journal-title":"Behav. Brain Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Stephens, K.E., Zhou, W., Ji, Z., Chen, Z., He, S., Ji, H., Guan, Y., and Taverna, S.D. (2019). Sex Differences in Gene Regulation in the Dorsal Root Ganglion after Nerve Injury. BMC Genom., 20.","DOI":"10.1186\/s12864-019-5512-9"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1002\/da.22167","article-title":"Sex Differences in Dna Methylation May Contribute to Risk of PTSD and Depression: A Review of Existing Evidence","volume":"30","author":"Uddin","year":"2013","journal-title":"Depress Anxiety"},{"key":"ref_39","first-page":"157","article-title":"Dna Methylation at the Mu-1 Opioid Receptor Gene (OPRM1) Promoter Predicts Preoperative, Acute, and Chronic Postsurgical Pain after Spine Fusion","volume":"10","author":"Chidambaran","year":"2017","journal-title":"Pharm. Pers. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1097\/FPC.0b013e3283560c46","article-title":"Catechol-O-Methyltransferase Gene Polymorphism and Chronic Human Pain: A Systematic Review and Meta-Analysis","volume":"22","year":"2012","journal-title":"Pharm. Genom."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.jpsychires.2021.01.008","article-title":"Association between COMT Methylation and Response to Treatment in Children with ADHD","volume":"135","author":"Fageera","year":"2021","journal-title":"J. Psychiatr. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1002\/jnr.23952","article-title":"Dopamine D3 Receptor Knockout Mice Exhibit Abnormal Nociception in a Sex-Different Manner","volume":"95","author":"Liu","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1097\/WNR.0b013e32835d8540","article-title":"Sex-Specific Differences in Pain Response by Dopamine in the Bed Nucleus of the Stria Terminalis in Rats","volume":"24","author":"Hagiwara","year":"2013","journal-title":"Neuroreport"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3389\/fnbeh.2015.00127","article-title":"Both the COMT Val158Met Single-Nucleotide Polymorphism and Sex-Dependent Differences Influence Response Inhibition","volume":"9","author":"Mione","year":"2015","journal-title":"Front. Behav. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"20160","DOI":"10.1073\/pnas.1214397109","article-title":"Effects of Sex and COMT Genotype on Environmentally Modulated Cognitive Control in Mice","volume":"109","author":"Papaleo","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/7854_2010_97","article-title":"Importance of the COMT Gene for Sex Differences in Brain Function and Predisposition to Psychiatric Disorders","volume":"8","author":"Tunbridge","year":"2011","journal-title":"Biol. Basis Sex Differ. Psychopharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1300\/J074v14n03_02","article-title":"Older Women\u2019s Experiences with Chronic Pain: Daily Challenges and Self-Care Practices","volume":"14","author":"Roberto","year":"2002","journal-title":"J. Women Aging"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1080\/10826084.2019.1594904","article-title":"Alcohol Use Disorder and Motives for Prescription Opioid Misuse: A Latent Class Analysis","volume":"54","author":"Votaw","year":"2019","journal-title":"Subst. Use Misuse"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.cpr.2009.05.003","article-title":"Brave Men and Timid Women? A Review of the Gender Differences in Fear and Anxiety","volume":"29","author":"McLean","year":"2009","journal-title":"Clin. Psychol. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1080\/15504263.2021.1904162","article-title":"Sex Differences in Opioid Use Disorder Prevalence and Multimorbidity Nationally in the Veterans Health Administration","volume":"17","author":"Peltier","year":"2021","journal-title":"J. Dual Diagn."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1080\/00952990.2018.1454934","article-title":"Sex Differences in Daily Life Stress and Craving in Opioid-Dependent Patients","volume":"44","author":"Moran","year":"2018","journal-title":"Am. J. Drug Alcohol Abus."},{"key":"ref_52","first-page":"109","article-title":"Gender Bias in Therapeutic Effort: From Research to Health Care","volume":"44","year":"2020","journal-title":"Farm. Hosp."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1097\/j.pain.0000000000000536","article-title":"Health Care Providers\u2019 Judgments in Chronic Pain: The Influence of Gender and Trustworthiness","volume":"157","author":"Prkachin","year":"2016","journal-title":"Pain"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/10\/3449\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:34:28Z","timestamp":1760124868000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/10\/3449"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,13]]},"references-count":53,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["jcm12103449"],"URL":"https:\/\/doi.org\/10.3390\/jcm12103449","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,13]]}}}