{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:58:33Z","timestamp":1791259113408,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T00:00:00Z","timestamp":1687132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Advances in spine surgery enable technically safe interventions in older patients with disabling spine disease, yet postoperative delirium (POD) poses a serious risk for postoperative recovery. This study investigates biomarkers of pro-neuroinflammatory states that may help objectively define the pre-operative risk for POD. This study enrolled patients aged \u226560 scheduled for elective spine surgery under general anesthesia. Biomarkers for a pro-neuroinflammatory state included S100 calcium-binding protein \u03b2 (S100\u03b2), brain-derived neurotrophic factor (BDNF), Gasdermin D, and the soluble ectodomain of the triggering receptor expressed on myeloid cells 2 (sTREM2). Postoperative changes of Interleukin-6 (IL-6), Interleukin-1\u03b2 (IL-1\u03b2), and C-reactive protein (CRP) were assessed as markers of systemic inflammation preoperatively, intraoperatively, and early postoperatively (up to 48 h). Patients with POD (n = 19, 75.7 \u00b1 5.8 years) had higher pre-operative levels of sTREM2 (128.2 \u00b1 69.4 pg\/mL vs. 97.2 \u00b1 52.0 pg\/mL, p = 0.049) and Gasdermin D (2.9 \u00b1 1.6 pg\/mL vs. 2.1 \u00b1 1.4 pg\/mL, p = 0.29) than those without POD (n = 25, 75.6 \u00b1 5.1 years). STREM2 was additionally a predictor for POD (OR = 1.01\/(pg\/mL) [1.00\u20131.03], p = 0.05), moderated by IL-6 (Wald-\u03c72 = 4.06, p = 0.04). Patients with POD additionally showed a significant increase in IL-6, IL-1\u03b2, and S100\u03b2 levels on the first postoperative day. This study identified higher levels of sTREM2 and Gasdermin D as potential markers of a pro-neuroinflammatory state that predisposes to the development of POD. Future studies should confirm these results in a larger cohort and determine their potential as an objective biomarker to inform delirium prevention strategies.<\/jats:p>","DOI":"10.3390\/ijms241210335","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T01:37:38Z","timestamp":1687225058000},"page":"10335","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Serum Biomarkers of a Pro-Neuroinflammatory State May Define the Pre-Operative Risk for Postoperative Delirium in Spine Surgery"],"prefix":"10.3390","volume":"24","author":[{"given":"Johanna","family":"Ruhnau","sequence":"first","affiliation":[{"name":"Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Strack","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Sperlich","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1264-5336","authenticated-orcid":false,"given":"Anna","family":"Pohl","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9333-8925","authenticated-orcid":false,"given":"Jasmin","family":"Dilz","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Saar","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick","family":"Veser","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Behr","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Rehberg","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Evangelisches Klinikum Bethel, 33617 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6173-5436","authenticated-orcid":false,"given":"Taras","family":"Usichenko","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Hahnenkamp","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7866-9781","authenticated-orcid":false,"given":"Johannes","family":"Ehler","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, University Hospital Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Fl\u00f6el","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany"},{"name":"Center for Neurodegenerative Diseases Rostock\/Greifswald, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry W. S.","family":"Schroeder","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan-Uwe","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8159-2658","authenticated-orcid":false,"given":"Robert","family":"Fleischmann","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2984-0831","authenticated-orcid":false,"given":"Antje","family":"Vogelgesang","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,19]]},"reference":[{"key":"ref_1","unstructured":"European Commission (2021). The 2021 Ageing Report: Economic and Budgetary Projections for the EU Member States (2019\u20132070), European Commission."},{"key":"ref_2","unstructured":"GBD 2019 Diseases and Injuries Collaborators (2020). Global burden of 369 diseases and injuries in 204 countries and territories, 1990\u20132019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet, 396, 1204\u20131222."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1001\/jamasurg.2020.7260","article-title":"One-Year Medicare Costs Associated With Delirium in Older Patients Undergoing Major Elective Surgery","volume":"156","author":"Gou","year":"2021","journal-title":"JAMA Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1111\/j.1365-2044.2008.05523.x","article-title":"Delirium is associated with early postoperative cognitive dysfunction","volume":"63","author":"Rudolph","year":"2008","journal-title":"Anaesthesia"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"M\u00fcller, J., Nowak, S., Weidemeier, M., Vogelgesang, A., Ruhnau, J., von Sarnowski, B., Saar, A., Veser, Y., Behr, F., and Gross, S. Duration of Surgery and Intraoperative Blood Pressure Management are Modifiable Risk Factors for Postoperative Neurocognitive Disorders Following Spine Surgery: Results of the Prospective CONFESS Study. Spine, 2023 online ahead of print.","DOI":"10.1097\/BRS.0000000000004722"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.bja.2019.07.004","article-title":"State of the clinical science of perioperative brain health: Report from the American Society of Anesthesiologists Brain Health Initiative Summit 2018","volume":"123","author":"Schenning","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1111\/jgs.12684","article-title":"A tale of two methods: Chart and interview methods for identifying delirium","volume":"62","author":"Saczynski","year":"2014","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3389\/fnagi.2015.00112","article-title":"Biomarkers of postoperative delirium and cognitive dysfunction","volume":"7","author":"Androsova","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e163472","DOI":"10.1172\/JCI163472","article-title":"Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients","volume":"133","author":"Watne","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/S0140-6736(09)61158-2","article-title":"Systemic infection and delirium: When cytokines and acetylcholine collide","volume":"375","author":"Eikelenboom","year":"2010","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/glia.22350","article-title":"Microglia and neurodegeneration: The role of systemic inflammation","volume":"61","author":"Cunningham","year":"2013","journal-title":"Glia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1186\/s12974-018-1331-1","article-title":"CSF sTREM2 in delirium-relation to Alzheimer\u2019s disease CSF biomarkers A\u03b242, t-tau and p-tau","volume":"15","author":"Henjum","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"466","DOI":"10.15252\/emmm.201506123","article-title":"sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer\u2019s disease and associate with neuronal injury markers","volume":"8","author":"Kleinberger","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105630","DOI":"10.1016\/j.nbd.2022.105630","article-title":"Soluble TREM2: Innocent bystander or active player in neurological diseases?","volume":"165","author":"Filipello","year":"2022","journal-title":"Neurobiol. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"van Munster, B.C., Korse, C.M., de Rooij, S.E., Bonfrer, J.M., Zwinderman, A.H., and Korevaar, J.C. (2009). Markers of cerebral damage during delirium in elderly patients with hip fracture. BMC Neurol., 9.","DOI":"10.1186\/1471-2377-9-21"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1007\/s00011-018-1187-y","article-title":"S100B promotes microglia M1 polarization and migration to aggravate cerebral ischemia","volume":"67","author":"Zhou","year":"2018","journal-title":"Inflamm. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1093\/bja\/aex103","article-title":"Association of intraoperative changes in brain-derived neurotrophic factor and postoperative delirium in older adults","volume":"119","author":"Wyrobek","year":"2017","journal-title":"Br. J. Anaesth."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1038\/cr.2015.139","article-title":"Gasdermin D is an executor of pyroptosis and required for interleukin-1\u03b2 secretion","volume":"25","author":"He","year":"2015","journal-title":"Cell Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"eaav1447","DOI":"10.1126\/sciimmunol.aav1447","article-title":"Gasdermin D activity in inflammation and host defense","volume":"4","author":"Lieberman","year":"2019","journal-title":"Sci. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1007\/s10753-018-0894-4","article-title":"NLRP3\/Caspase-1 Pathway-Induced Pyroptosis Mediated Cognitive Deficits in a Mouse Model of Sepsis-Associated Encephalopathy","volume":"42","author":"Fu","year":"2019","journal-title":"Inflammation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e15488","DOI":"10.2196\/15488","article-title":"Evaluating Mechanisms of Postoperative Delirium and Cognitive Dysfunction Following Elective Spine Surgery in Elderly Patients (CONFESS): Protocol for a Prospective Observational Trial","volume":"9","author":"Muller","year":"2020","journal-title":"JMIR Res. Protoc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1136386","DOI":"10.1155\/2022\/1136386","article-title":"Correlation Analysis of Inflammatory Markers CRP and IL-6 and Postoperative Delirium (POD) in Elderly Patients: A Meta-Analysis of Observational Studies","volume":"2022","author":"Huang","year":"2022","journal-title":"J. Environ. Public Health"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1186\/s12974-021-02304-x","article-title":"Interleukin-6 mediates delirium-like phenotypes in a murine model of urinary tract infection","volume":"18","author":"Rashid","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1165\/rcmb.2021-0072OC","article-title":"IL-6 Inhibition Reduces Neuronal Injury in a Murine Model of Ventilator-induced Lung Injury","volume":"65","author":"Sparrow","year":"2021","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.bja.2017.11.096","article-title":"Interleukin-6 is both necessary and sufficient to produce perioperative neurocognitive disorder in mice","volume":"120","author":"Hu","year":"2018","journal-title":"Br. J. Anaesth."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1093\/gerona\/63.2.184","article-title":"Chemokines Are Associated With Delirium After Cardiac Surgery","volume":"63","author":"Rudolph","year":"2008","journal-title":"J. Gerontol. Ser. A"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/S0140-6736(13)60688-1","article-title":"Delirium in elderly people","volume":"383","author":"Inouye","year":"2014","journal-title":"Lancet"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3621","DOI":"10.3760\/cma.j.issn.0366-6999.20130211","article-title":"High serum interleukin-6 level is associated with increased risk of delirium in elderly patients after noncardiac surgery: A prospective cohort study","volume":"126","author":"Liu","year":"2013","journal-title":"Chin. Med. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3389\/fendo.2014.00173","article-title":"Pre-Operative, High-IL-6 Blood Level is a Risk Factor of Post-Operative Delirium Onset in Old Patients","volume":"5","author":"Capri","year":"2014","journal-title":"Front. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1002\/gps.2015","article-title":"Pre-operative inflammatory markers and the risk of postoperative delirium in elderly patients","volume":"23","author":"Lemstra","year":"2008","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1093\/oxfordjournals.bja.a013410","article-title":"Do blood concentrations of neurone specific enolase and S-100 beta protein reflect cognitive dysfunction after abdominal surgery?ISPOCD Group","volume":"84","author":"Rasmussen","year":"2000","journal-title":"Br. J. Anaesth."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liu, X., Yu, Y., and Zhu, S. (2018). Inflammatory markers in postoperative delirium (POD) and cognitive dysfunction (POCD): A meta-analysis of observational studies. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0209284"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"855","DOI":"10.2147\/IJGM.S51004","article-title":"S100 calcium binding protein B as a biomarker of delirium duration in the intensive care unit\u2014An exploratory analysis","volume":"6","author":"Khan","year":"2013","journal-title":"Int. J. Gen. Med."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Oris, C., Kahouadji, S., Durif, J., Bouvier, D., and Sapin, V. (2023). S100B, Actor and Biomarker of Mild Traumatic Brain Injury. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076602"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1159\/000443040","article-title":"Astrocyte-Derived CCL2 is Associated with M1 Activation and Recruitment of Cultured Microglial Cells","volume":"38","author":"He","year":"2016","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"824888","DOI":"10.3389\/fnins.2022.824888","article-title":"Microglia and Astrocyte Function and Communication: What Do We Know in Humans?","volume":"16","author":"Garland","year":"2022","journal-title":"Front. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/jnc.13607","article-title":"Neuroinflammation: The devil is in the details","volume":"139","author":"DiSabato","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1093\/cercor\/bhz240","article-title":"CSF sTREM2 and Tau Work Together in Predicting Increased Temporal Lobe Atrophy in Older Adults","volume":"30","author":"Halaas","year":"2019","journal-title":"Cereb. Cortex"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Wang, K., Cao, X., Li, Z., Liu, S., Zhou, Y., Guo, L., and Li, P. (2022). Anesthesia and surgery-induced elevation of CSF sTREM2 is associated with early cognitive dysfunction after thoracoabdominal aortic dissection surgery. BMC Anesthesiol., 22.","DOI":"10.1186\/s12871-022-01955-4"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s12974-021-02150-x","article-title":"Orthopedic surgery-induced cognitive dysfunction is mediated by CX3CL1\/R1 signaling","volume":"18","author":"Cho","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/ni.3102","article-title":"Innate immunity in Alzheimer\u2019s disease","volume":"16","author":"Heneka","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_42","unstructured":"American College of Surgeons (2022, January 07). COVID-19: Guidance for Triage of Non-Emergent Surgical Procedures: Elective Surgery Acuity Scale (ESAS). Available online: https:\/\/www.facs.org\/covid-19\/clinical-guidance\/triage."},{"key":"ref_43","first-page":"19","article-title":"Evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. Revision 2015 (DAS-Guideline 2015)\u2014Short version","volume":"13","author":"Baron","year":"2015","journal-title":"Ger. Med. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1097\/ALN.0000000000002194","article-title":"Neurocognitive Function after Cardiac Surgery: From Phenotypes to Mechanisms","volume":"129","author":"Berger","year":"2018","journal-title":"Anesthesiology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1177\/1740774512438980","article-title":"National Institute of Neurological Disorders and Stroke Common Data Element Project\u2014Approach and methods","volume":"9","author":"Grinnon","year":"2012","journal-title":"Clin. Trials"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1097\/JGP.0b013e318209dd08","article-title":"The Assessment of Changes in Cognitive Functioning: Age-, Education-, and Gender-Specific Reliable Change Indices for Older Adults Tested on the CERAD-NP Battery: Results of the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe)","volume":"20","author":"Stein","year":"2012","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1097\/JGP.0b013e3181cab764","article-title":"Total scores of the CERAD neuropsychological assessment battery: Validation for mild cognitive impairment and dementia patients with diverse etiologies","volume":"18","author":"Seo","year":"2010","journal-title":"Am. J. Geriatr. Psychiatry"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/10335\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:56:26Z","timestamp":1760126186000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/10335"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,19]]},"references-count":47,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms241210335"],"URL":"https:\/\/doi.org\/10.3390\/ijms241210335","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,19]]}}}