{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:47:40Z","timestamp":1792460860451,"version":"4.5.0"},"reference-count":53,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"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>Objectives: To investigate the diagnostic and prognostic utility of systemic inflammatory biomarkers\u2014including C-reactive protein (CRP), systemic immune-inflammation index (SII), and Fibrinogen\u2014in patients with obstructive sleep apnea syndrome (OSAS), and to develop a machine learning-based stratification model for disease severity and treatment response. Study Design: Prospective observational cohort study. Setting: Single tertiary referral sleep and otolaryngology center. Methods: Adult OSAS patients (n = 195) diagnosed via polysomnography were treated with either CPAP or surgery and reassessed after ~4 months (16\u201320 weeks). Hematologic biomarkers were measured pre- and post-treatment. OSAS severity was staged using a composite polysomnography (PSG)-based index. Statistical analyses included mixed linear modeling, ROC analysis, unsupervised clustering, and machine learning (Random Forest) to evaluate biomarker utility. Results: CRP demonstrated the highest diagnostic accuracy for severe OSAS (AUC = 0.91, sensitivity = 88.2%, specificity = 85.7%). Fibrinogen showed the strongest correlation with disease severity (\u03c1 = 0.81) and the largest post-treatment reduction (Cohen\u2019s d = 1.41). SII also correlated with PSG stage and declined significantly after treatment. Machine learning confirmed CRP, SII, and Fibrinogen as top predictors of severity. Clustering analysis revealed three distinct inflammatory phenotypes of OSAS with differential biomarker responsiveness. Conclusions: CRP, SII, and fibrinogen may support risk stratification and follow-up in OSAS but require prospective validation before clinical use. These findings should be viewed as exploratory and hypothesis-generating. Larger multicenter studies with external validation are needed before these biomarkers or the machine-learning model are applied in routine practice.<\/jats:p>","DOI":"10.3390\/jcm14238437","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T11:19:51Z","timestamp":1764328791000},"page":"8437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Hematological Biomarkers of the Obstructive Sleep Apnea Syndrome: A Machine Learning-Based Diagnostic and Prognostic Model"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9398-4261","authenticated-orcid":false,"given":"Aynur","family":"Aliyeva","sequence":"first","affiliation":[{"name":"Neuroscience Doctoral Program, Yeditepe University, 34755 Istanbul, Turkey"},{"name":"Department of Surgery, Denver Health Medical Center, Denver, CO 80204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1420-3541","authenticated-orcid":false,"given":"Ramil","family":"Hashimli","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, Karabakh University, Khankendi AZ2600, Azerbaijan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2674-6535","authenticated-orcid":false,"given":"Bayram","family":"Y\u0131lmaz","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Dokuz Eylul University, 35340 Izmir, Turkey"},{"name":"Department of Physiology, Faculty of Medicine, Yeditepe University, 34755 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lan, C.-C., Lee, C., Jao, L.-Y., Wu, Y.-K., Huang, K.-L., Su, W.-L., Huang, Y.-C., Wu, C.-W., and Yang, M.-C. (2025). Interrelationship Between Obstructive Sleep Apnea Syndrome and Small Airway Disease: A Comprehensive Review. Biomedicines, 13.","DOI":"10.3390\/biomedicines13040905"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/s41392-023-01496-3","article-title":"Pathophysiological mechanisms and therapeutic approaches in obstructive sleep apnea syndrome","volume":"8","author":"Lv","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s00408-021-00426-w","article-title":"Evaluation and Management of Adults with Obstructive Sleep Apnea Syndrome","volume":"199","author":"Lee","year":"2021","journal-title":"Lung"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"261","DOI":"10.5664\/jcsm.27191","article-title":"Obstructive sleep apnea and cardiovascular disease: Role of the metabolic syndrome and its components","volume":"4","author":"Zizi","year":"2008","journal-title":"J. Clin. Sleep Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Mitra, A.K., Bhuiyan, A.R., and Jones, E.A. (2021). Association and Risk Factors for Obstructive Sleep Apnea and Cardiovascular Diseases: A Systematic Review. Diseases, 9.","DOI":"10.3390\/diseases9040088"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Stec-Martyna, E., Wojtczak, K., Nowak, D., and Stawski, R. (2025). Battle of the Biomarkers of Systemic Inflammation. Biology, 14.","DOI":"10.3390\/biology14040438"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4637","DOI":"10.1007\/s00405-025-09414-9","article-title":"Evaluation of autoimmune and inflammatory markers in bilateral sudden hearing loss","volume":"282","author":"Aliyeva","year":"2025","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"386","DOI":"10.20515\/otd.1612452","article-title":"Evaluating Inflammatory Markers in Sudden Sensorineural Hearing Loss: The Neutrophil-To-Lymphocyte Ratio, The Systemic Immune Inflammation Index, and The Pan Immune Inflammation Value as Prognostic Tools","volume":"47","author":"Aliyeva","year":"2025","journal-title":"Osman. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.5664\/jcsm.10600","article-title":"Inflammation biomarkers in OSA, chronic obstructive pulmonary disease, and chronic obstructive pulmonary disease\/OSA overlap syndrome","volume":"19","author":"Gu","year":"2023","journal-title":"J. Clin. Sleep Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lavalle, S., Masiello, E., Iannella, G., Magliulo, G., Pace, A., Lechien, J.R., Calvo-Henriquez, C., Cocuzza, S., Parisi, F.M., and Favier, V. (2024). Unraveling the Complexities of Oxidative Stress and Inflammation Biomarkers in Obstructive Sleep Apnea Syndrome: A Comprehensive Review. Life, 14.","DOI":"10.3390\/life14040425"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1007\/s11325-021-02557-z","article-title":"Peripheral blood oxidative stress markers for obstructive sleep apnea\u2014A meta-analysis","volume":"26","author":"Hu","year":"2022","journal-title":"Sleep Breath."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.4065\/79.8.1036","article-title":"Obstructive sleep apnea and cardiovascular disease","volume":"79","author":"Parish","year":"2004","journal-title":"Mayo Clin. Proc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"608438","DOI":"10.1155\/2015\/608438","article-title":"Obstructive Sleep Apnea, Oxidative Stress, and Cardiovascular Disease: Evidence from Human Studies","volume":"2015","author":"Eisele","year":"2015","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pintilie, A.L., Zabara Antal, A., Ciuntu, B.M., Toma, D., Tiron, R., Stirbu, R., Zabara, M.L., and Dabija, R.C. (2025). A Possible Missing Link Between Obstructive Sleep Apnea Syndrome (OSA) Associated with Tobacco Use and Inflammation Biomarkers. Healthcare, 13.","DOI":"10.3390\/healthcare13101177"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"20","DOI":"10.5935\/1984-0063.20200117","article-title":"Pro-inflammatory markers in patients with obstructive sleep apnea and the effect of continuous positive airway pressure therapy","volume":"15","author":"Wali","year":"2022","journal-title":"Sleep Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.5664\/jcsm.3070","article-title":"Serum inflammatory markers in obstructive sleep apnea: A meta-analysis","volume":"9","author":"Nadeem","year":"2013","journal-title":"J. Clin. Sleep Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1186\/s13018-023-04157-x","article-title":"Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) to predict postoperative pneumonia in elderly hip fracture patients","volume":"18","author":"Yao","year":"2023","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"195","DOI":"10.2147\/JIR.S500474","article-title":"Systemic Immune-Inflammation Index (SII) and Neutrophil-to-Lymphocyte Ratio (NLR): A Strong Predictor of Disease Severity in Large-Artery Atherosclerosis (LAA) Stroke Patients","volume":"18","author":"Liu","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Modica, R., Minotta, R., Liccardi, A., Cannavale, G., Benevento, E., and Colao, A. (2023). Evaluation of Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR) and Systemic Immune\u2013Inflammation Index (SII) as Potential Biomarkers in Patients with Sporadic Medullary Thyroid Cancer (MTC). J. Pers. Med., 13.","DOI":"10.3390\/jpm13060953"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Chen, K., Wang, L., Ning, H., Pan, H., and Zhang, W. (2025). Neutrophil-to-lymphocyte ratio; platelet-to-lymphocyte ratio; systemic immune-inflammatory Index: Inflammatory indicators of cognitive impairment in schizophrenia patients. Front. Psychiatry, 16.","DOI":"10.3389\/fpsyt.2025.1552451"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5637","DOI":"10.2147\/JIR.S512018","article-title":"The Association of Systemic Immune Inflammation Index (SII) and Platelet-to-Lymphocyte Ratio (PLR) on Coagulopathy and Prognosis in Patients with Traumatic Brain Injury","volume":"18","author":"Chen","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zota, I.M., Adam, C.A., Marcu, D.T.M., St\u0103tescu, C., Sasc\u0103u, R., Anghel, L., Boi\u0219teanu, D., Roca, M., Cozma, C.L.D., and Ma\u0219taleru, A. (2022). CPAP Influence on Readily Available Inflammatory Markers in OSA\u2014A Pilot Study. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012431"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"552","DOI":"10.3109\/09537104.2011.578182","article-title":"The Effects of Continuous Positive Airway Pressure Therapy on Mean Platelet Volume in Patients with Obstructive Sleep Apnea","volume":"22","author":"Varol","year":"2011","journal-title":"Platelets"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1080\/00015385.2017.1315257","article-title":"Left Ventricular Torsion in Patients with Obstructive Sleep Apnoea before and after Continuous Positive Airway Pressure Therapy: Assessment by Two-Dimensional Speckle Tracking Echocardiography","volume":"72","author":"Vural","year":"2017","journal-title":"Acta Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"206","DOI":"10.5578\/tt.29170","article-title":"Platelet Indices in Obstructive Sleep Apnea: The Role of Mean Platelet Volume, Platelet Distribution Widht and Plateletcrit","volume":"64","year":"2016","journal-title":"Tuberk. Toraks"},{"key":"ref_26","first-page":"182","article-title":"Response of Blood Parameters to CPAP Treatment in Patients with Obstructive Sleep Apnea","volume":"56","author":"Kara","year":"2018","journal-title":"Noro Psikiyatr. Arsivi"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e22199","DOI":"10.1002\/jcla.22199","article-title":"Importance of Laboratory Parameters in Patients with Obstructive Sleep Apnea and Their Relationship with Cardiovascular Diseases","volume":"32","author":"Eyuboglu","year":"2018","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1080\/13685538.2019.1652813","article-title":"Is There a Relationship between Hematological Parameters and Duration of Respiratory Events in Severe OSA","volume":"23","author":"Durmaz","year":"2020","journal-title":"Aging Male"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/S0140-6736(07)61602-X","article-title":"The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies","volume":"370","author":"Altman","year":"2007","journal-title":"Lancet"},{"key":"ref_30","first-page":"23","article-title":"Investigation of Clinical, Physiological, and Polysomnographic Parameters in Patients with Obstructive Sleep Apnea Syndrome","volume":"33","author":"Aliyeva","year":"2025","journal-title":"J. Ear Nose Throat Head Neck Surg."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"US Preventive Services Task Force, Mangione, C.M., Barry, M.J., Nicholson, W.K., Cabana, M., Chelmow, D., Rucker Coker, T., Davidson, K.W., Davis, E.M., and Donahue, K.E. (2022). Screening for Obstructive Sleep Apnea in Adults: US Preventive Services Task Force Recommendation Statement. JAMA, 328, 1945\u20131950.","DOI":"10.1001\/jama.2022.20304"},{"key":"ref_32","unstructured":"Gerstenslager, B., and Slowik, J.M. (2025). Sleep Study. StatPearls, StatPearls Publishing."},{"key":"ref_33","unstructured":"Stutz, E.W., and Rondeau, B. (2025). Mallampati Score. StatPearls, StatPearls Publishing."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"103912","DOI":"10.1016\/j.amsu.2022.103912","article-title":"Comparison of modified mallampati classification with Cormack and Lehane grading in predicting difficult laryngoscopy among elective surgical patients who took general anesthesia in Werabie comprehensive specialized hospital-Cross sectional study. Ethiopia, 2021","volume":"79","author":"Yemam","year":"2022","journal-title":"Ann. Med. Surg."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Martinovic, D., Tokic, D., Puizina-Mladinic, E., Kadic, S., Lesin, A., Lupi-Ferandin, S., Kumric, M., and Bozic, J. (2023). Oromaxillofacial Surgery: Both a Treatment and a Possible Cause of Obstructive Sleep Apnea-A Narrative Review. Life, 13.","DOI":"10.3390\/life13010142"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Rugambwa, T.K., Abdihamid, O., Zhang, X., Peng, Y., Cai, C., Shen, H., Zeng, S., and Qiu, W. (2023). Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as potential predictive markers of treatment response in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1181248"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3758068","DOI":"10.1155\/2018\/3758068","article-title":"Neutrophil-to-Lymphocyte Ratio, Monocyte-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Mean Platelet Volume-to-Platelet Count Ratio as Biomarkers in Critically Ill and Injured Patients: Which Ratio to Choose to Predict Outcome and Nature of Bacteremia?","volume":"2018","author":"Djordjevic","year":"2018","journal-title":"Mediat. Inflamm."},{"key":"ref_38","unstructured":"Slowik, J.M., Sankari, A., and Collen, J.F. (2025). Obstructive Sleep Apnea. StatPearls, StatPearls Publishing."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1007\/s11739-022-02983-1","article-title":"Treatment options in obstructive sleep apnea","volume":"17","author":"Gambino","year":"2022","journal-title":"Intern. Emerg. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"157","DOI":"10.5664\/jcsm.27133","article-title":"Clinical guidelines for the manual titration of positive airway pressure in patients with obstructive sleep apnea","volume":"4","author":"Kushida","year":"2008","journal-title":"J. Clin. Sleep Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1001\/jamaoto.2019.0006","article-title":"Indications for and Outcomes of Expansion Sphincter Pharyngoplasty to Treat Lateral Pharyngeal Collapse in Patients with Obstructive Sleep Apnea","volume":"145","author":"Hong","year":"2019","journal-title":"JAMA Otolaryngol. Head Neck Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"108214","DOI":"10.1016\/j.jstrokecerebrovasdis.2024.108214","article-title":"Screening prediction models using artificial intelligence for moderate-to-severe obstructive sleep apnea in patients with acute ischemic stroke","volume":"34","author":"Lin","year":"2025","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5007","DOI":"10.1007\/s00405-024-08729-3","article-title":"Is there a relationship between the severity of obstructive sleep apnea syndrome and the systemic immune inflammation index?","volume":"281","year":"2024","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4573756","DOI":"10.1155\/2017\/4573756","article-title":"Evaluation of Inflammatory Markers in a Large Sample of Obstructive Sleep Apnea Patients without Comorbidities","volume":"2017","author":"Bouloukaki","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Maniaci, A., Iannella, G., Cocuzza, S., Vicini, C., Magliulo, G., Ferlito, S., Cammaroto, G., Meccariello, G., De Vito, A., and Nicolai, A. (2021). Oxidative Stress and Inflammation Biomarker Expression in Obstructive Sleep Apnea Patients. J. Clin. Med., 10.","DOI":"10.3390\/jcm10020277"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Zhou, E.H., Zhou, T.J., Wang, X.T., Zhang, J.-Y., Guan, J., Yin, S.-K., Huang, W.-J., Yi, H.-L., and Zou, J.-Y. (2025). Identifying and validating immunological biomarkers in obstructive sleep apnea through bioinformatics analysis. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-93915-4"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Meliante, P.G., Zoccali, F., Cascone, F., Di Stefano, V., Greco, A., de Vincentiis, M., Petrella, C., Fiore, M., Minni, A., and Barbato, C. (2023). Molecular Pathology, Oxidative Stress, and Biomarkers in Obstructive Sleep Apnea. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065478"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"159","DOI":"10.21053\/ceo.2022.01368","article-title":"Associations Between Systemic Inflammatory Markers Based on Blood Cells and Polysomnographic Factors in Obstructive Sleep Apnea","volume":"16","author":"Kim","year":"2023","journal-title":"Clin. Exp. Otorhinolaryngol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Pinilla, L., Ben\u00edtez, I.D., Santamaria-Martos, F., Targa, A., Moncus\u00ed-Moix, A., Dalmases, M., M\u00ednguez, O., Aguil\u00e0, M., Jov\u00e9, M., and Sol, J. (2022). Plasma profiling reveals a blood-based metabolic fingerprint of obstructive sleep apnea. Biomed. Pharmacother., 145.","DOI":"10.1016\/j.biopha.2021.112425"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Wang, Y., Chen, Y., Lin, W., Huang, M., Xu, Y., and Chen, G. (2023). Inflammatory markers in children with obstructive sleep apnea syndrome. Front. Pediatr., 11.","DOI":"10.3389\/fped.2023.1134678"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Al-Tashi, Q., Saad, M.B., Muneer, A., Qureshi, R., Mirjalili, S., Sheshadri, A., Le, X., Vokes, N.I., Zhang, J., and Wu, J. (2023). Machine Learning Models for the Identification of Prognostic and Predictive Cancer Biomarkers: A Systematic Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24097781"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"413","DOI":"10.2147\/NSS.S453794","article-title":"A Machine Learning Prediction Model of Adult Obstructive Sleep Apnea Based on Systematically Evaluated Common Clinical Biochemical Indicators","volume":"16","author":"Huang","year":"2024","journal-title":"Nat. Sci. Sleep"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1038\/s42256-023-00635-3","article-title":"Deep learning supported discovery of biomarkers for clinical prognosis of liver cancer","volume":"5","author":"Liang","year":"2023","journal-title":"Nat. Mach. Intell."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/23\/8437\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T11:54:21Z","timestamp":1764330861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/23\/8437"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":53,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["jcm14238437"],"URL":"https:\/\/doi.org\/10.3390\/jcm14238437","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,28]]}}}