{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:28:52Z","timestamp":1785414532868,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100032613","name":"Blair Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100032613","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/03kkzdv75","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: While trefoil factor 3 (TFF3) has been linked to cardiovascular disease, its role in peripheral artery disease (PAD) remains largely unexplored. In this prospective study, we assessed three pre-selected circulating biomarkers and found that TFF3 demonstrated the strongest association with the presence of PAD. Building on this finding, we integrated plasma TFF3 concentrations with clinical characteristics to construct predictive models aimed at identifying individuals with PAD and estimating their risk of major adverse limb events (MALE) over a two-year follow-up period. Methods: A total of 476 individuals were prospectively recruited, including 312 patients with PAD and 164 controls without PAD. At study entry, circulating concentrations of TFF3, oncostatin M (OSM), and brain-derived neurotrophic factor (BDNF) were quantified, and all participants were subsequently monitored for a two-year period. The primary endpoint was the occurrence of MALE within two years, comprising acute limb ischemia, major amputation, or lower extremity revascularization by either open surgical or endovascular approaches. PAD diagnosis served as the secondary outcome and was established by an ankle\u2013brachial index (ABI) \u2264 0.9 or toe\u2013brachial index (TBI) \u2264 0.67 in the presence of reduced or absent pedal pulses. For predictive model development, the cohort was randomly divided into training (70%) and testing (30%) sets. A random forest algorithm incorporating clinical variables and plasma TFF3 levels was developed and optimized using 10-fold cross-validation. Model discrimination was quantified using the area under the receiver operating characteristic curve (AUROC). For prognostic evaluation, patients were classified into low- and high-risk groups based on the optimal ROC-derived probability threshold of 0.60, and MALE-free survival between groups was assessed using Cox proportional hazards regression. Results: Among the three candidate biomarkers evaluated, only TFF3 demonstrated a significant association with PAD. Patients with PAD exhibited higher circulating TFF3 concentrations than those without PAD (7.27 \u00b1 3.36 vs. 5.89 \u00b1 2.67 pg\/mL; p &lt; 0.001), whereas OSM and BDNF showed no significant differences between groups. Over the two-year follow-up period, MALE occurred in 28 patients (9%). Predictive models combining plasma TFF3 measurements with clinical variables achieved strong performance for both PAD detection and 2-year MALE risk estimation, yielding AUROCs of 0.79 and 0.85, respectively. Furthermore, patients classified as high risk by the model experienced a significantly increased hazard of MALE during follow-up (HR 1.12, 95% CI 1.10\u20131.19; p = 0.003). Variable importance analysis revealed that TFF3 was the most influential predictor of MALE, followed by age and smoking history. Conclusions: Combining plasma TFF3 levels with readily available clinical characteristics enabled the development of a predictive model with good discriminatory ability for both PAD diagnosis and estimation of 2-year MALE risk. Such an approach may enhance risk stratification by identifying patients at elevated risk earlier in their disease course, thereby informing decisions related to vascular testing, referral for specialist evaluation, and implementation of targeted treatment strategies.<\/jats:p>","DOI":"10.3390\/biom16060892","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:49:42Z","timestamp":1781743782000},"page":"892","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Trefoil Factor 3 as a Biomarker for Peripheral Artery Disease"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7191-1034","authenticated-orcid":false,"given":"Ben","family":"Li","sequence":"first","affiliation":[{"name":"Division of Vascular Surgery, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada"},{"name":"Department of Surgery, University of Toronto, Toronto, ON M5S 1A1, Canada"},{"name":"Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A1, Canada"},{"name":"Temerty Centre for Artificial Intelligence Research and Education in Medicine (T-CAIREM), University of Toronto, Toronto, ON M5S 1A1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5252-3370","authenticated-orcid":false,"given":"Hamzah","family":"Khan","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada"},{"name":"Department of Surgery, University of Toronto, Toronto, ON M5S 1A1, Canada"},{"name":"Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah","family":"Shaikh","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelrahman","family":"Zamzam","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravel","family":"Raphael","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4697-5260","authenticated-orcid":false,"given":"Muzammil H.","family":"Syed","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rawand","family":"Abdin","sequence":"additional","affiliation":[{"name":"Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Qadura","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada"},{"name":"Department of Surgery, University of Toronto, Toronto, ON M5S 1A1, Canada"},{"name":"Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A1, Canada"},{"name":"Heart, Vascular & Thoracic Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi 112412, United Arab Emirates"},{"name":"Li Ka Shing Knowledge Institute, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref_1","unstructured":"Zemaitis, M.R., Boll, J.M., and Dreyer, M.A. (2021). Peripheral Arterial Disease. StatPearls, StatPearls Publishing."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"678","DOI":"10.4065\/mcp.2010.0133","article-title":"Peripheral Artery Disease: Current Insight Into the Disease and Its Diagnosis and Management","volume":"85","author":"Olin","year":"2010","journal-title":"Mayo Clin. Proc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.tcm.2020.06.005","article-title":"Premature Atherosclerotic Peripheral Artery Disease: An Underrecognized and Undertreated Disorder with a Rising Global Prevalence","volume":"31","author":"Mehta","year":"2021","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1177\/00033197241230973","article-title":"Serum Trefoil Factor-3 Predicts Survival in Peripheral Artery Disease","volume":"76","author":"Pesau","year":"2025","journal-title":"Angiology"},{"key":"ref_5","first-page":"100829","article-title":"Oncostatin M Is a Novel Biomarker for Coronary Artery Disease\u2014A Possibility as a Screening Tool of Silent Myocardial Ischemia for Diabetes Mellitus","volume":"35","author":"Ikeda","year":"2021","journal-title":"Int. J. Cardiol. Heart Vasc."},{"key":"ref_6","first-page":"684","article-title":"Brain Derived Neurotrophic Factor (BDNF) in Cardiometabolic Physiology and Diseases","volume":"12","author":"Kabul","year":"2012","journal-title":"Anatol. J. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1016\/j.jvs.2018.07.027","article-title":"Medical and Lifestyle Management of Peripheral Arterial Disease","volume":"68","author":"Parvar","year":"2018","journal-title":"J. Vasc. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cornejo Del R\u00edo, V., Mostaza, J., Lahoz, C., S\u00e1nchez-Arroyo, V., Sab\u00edn, C., L\u00f3pez, S., Patr\u00f3n, P., Fern\u00e1ndez-Garc\u00eda, P., Fern\u00e1ndez-Puntero, B., and Vicent, D. (2017). Prevalence of Peripheral Artery Disease (PAD) and Factors Associated: An Epidemiological Analysis from the Population-Based Screening PRE-Diabetes and Type 2 DIAbetes (SPREDIA-2) Study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186220"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1177\/1358863X12445102","article-title":"An Evidence-Based Score to Detect Prevalent Peripheral Artery Disease (PAD)","volume":"17","author":"Duval","year":"2012","journal-title":"Vasc. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.atherosclerosis.2021.07.003","article-title":"Clinical Factors Associated with Peripheral Artery Disease in Patients with Documented Coronary Artery Disease: A Post Hoc Analysis of the COMPASS Trial","volume":"331","author":"Gouda","year":"2021","journal-title":"Atherosclerosis"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"World Medical Association (2013). World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA, 310, 2191\u20132194.","DOI":"10.1001\/jama.2013.281053"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e078378","DOI":"10.1136\/bmj-2023-078378","article-title":"TRIPOD+AI Statement: Updated Guidance for Reporting Clinical Prediction Models That Use Regression or Machine Learning Methods","volume":"385","author":"Collins","year":"2024","journal-title":"BMJ"},{"key":"ref_13","unstructured":"Gul, F., and Janzer, S.F. (2021). Peripheral Vascular Disease. StatPearls, StatPearls Publishing."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1016\/j.jacc.2025.11.016","article-title":"2026 ACC\/AHA\/AACVPR\/ABC\/ACPM\/ADA\/AGS\/APhA\/ASPC\/NLA\/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"87","author":"Blumenthal","year":"2026","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s11906-026-01372-9","article-title":"Updates in the 2025 AHA\/ACC Hypertension Guideline","volume":"28","author":"Brown","year":"2026","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_16","unstructured":"(2023, May 06). Luminex Assays, Multiplex Immunoassays. Available online: https:\/\/www.bio-techne.com\/."},{"key":"ref_17","unstructured":"(2021, December 18). MAGPIX\u00ae System | xMAP Instrument | Luminex Corporation. Available online: https:\/\/www.luminexcorp.com\/magpix-system\/."},{"key":"ref_18","unstructured":"(2021, December 18). Luminex Assays\u2014CA. Available online: www.thermofisher.com\/ca\/en\/home\/life-science\/antibodies\/immunoassays\/procartaplex-assays-luminex.html."},{"key":"ref_19","unstructured":"(xPONENT\u00ae Software for xMAP\u00ae Instruments, 2019). xPONENT\u00ae Software for xMAP\u00ae Instruments, version 4.3."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"31","DOI":"10.17849\/insm-47-01-31-39.1","article-title":"Random Forest","volume":"47","author":"Rigatti","year":"2017","journal-title":"J. Insur. Med."},{"key":"ref_21","first-page":"130","article-title":"Decision Tree Methods: Applications for Classification and Prediction","volume":"27","author":"Song","year":"2015","journal-title":"Shanghai Arch. Psychiatry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.jss.2021.02.045","article-title":"Machine Learning and Surgical Outcomes Prediction: A Systematic Review","volume":"264","author":"Elfanagely","year":"2021","journal-title":"J. Surg. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.1007\/s00268-022-06728-1","article-title":"Machine Learning Algorithms for Predicting Surgical Outcomes after Colorectal Surgery: A Systematic Review","volume":"46","author":"Tuynman","year":"2022","journal-title":"World J. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.wneu.2017.09.149","article-title":"Machine Learning and Neurosurgical Outcome Prediction: A Systematic Review","volume":"109","author":"Senders","year":"2018","journal-title":"World Neurosurg."},{"key":"ref_25","first-page":"627","article-title":"Receiver Operating Characteristic (ROC) Curve Analysis for Medical Diagnostic Test Evaluation","volume":"4","year":"2013","journal-title":"Casp. J. Intern. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"569","DOI":"10.6339\/21-JDS1023","article-title":"Variable Importance Scores","volume":"19","author":"Loh","year":"2021","journal-title":"J. Data Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1002\/bimj.200710415","article-title":"Youden Index and Optimal Cut-Point Estimated from Observations Affected by a Lower Limit of Detection","volume":"50","author":"Ruopp","year":"2008","journal-title":"Biom. J."},{"key":"ref_28","unstructured":"(2021, December 18). SPSS Software, Available online: https:\/\/www.ibm.com\/analytics\/spss-statistics-software."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e004741","DOI":"10.1161\/CIRCOUTCOMES.118.004741","article-title":"Predicting Future Cardiovascular Events in Patients With Peripheral Artery Disease Using Electronic Health Record Data","volume":"12","author":"Ross","year":"2019","journal-title":"Circ. Cardiovasc. Qual. Outcomes"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1021\/acsptsci.0c00023","article-title":"Structure, Function, and Therapeutic Potential of the Trefoil Factor Family in the Gastrointestinal Tract","volume":"3","author":"Brierley","year":"2020","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lau, W.-H., Pandey, V., Kong, X., Wang, X.-N., Wu, Z., Zhu, T., and Lobie, P.E. (2015). Trefoil Factor-3 (TFF3) Stimulates De Novo Angiogenesis in Mammary Carcinoma Both Directly and Indirectly via IL-8\/CXCR2. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141947"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41419-022-04504-6","article-title":"Pathological and Therapeutic Roles of Bioactive Peptide Trefoil Factor 3 in Diverse Diseases: Recent Progress and Perspective","volume":"13","author":"Yang","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1002\/ehf2.14167","article-title":"Biomarker Profiles in Heart Failure with Preserved vs. Reduced Ejection Fraction: Results from the DIAST-CHF Study","volume":"10","author":"Eidizadeh","year":"2023","journal-title":"ESC Heart Fail."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1111\/j.1553-2712.2011.01185.x","article-title":"Logistic Regression: A Brief Primer","volume":"18","author":"Stoltzfus","year":"2011","journal-title":"Acad. Emerg. Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kia, B., Mendes, A., Parnami, A., George, R., Mobley, K., and Ditto, W.L. (2020). Nonlinear Dynamics Based Machine Learning: Utilizing Dynamics-Based Flexibility of Nonlinear Circuits to Implement Different Functions. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0228534"},{"key":"ref_36","first-page":"e88163","article-title":"Nonlinear Systems in Healthcare towards Intelligent Disease Prediction","volume":"1","author":"Chatterjee","year":"2019","journal-title":"Nonlinear Syst.-Theor. Asp. Recent Appl."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1007\/s12551-021-00849-y","article-title":"Human Disease Biomarker Panels through Systems Biology","volume":"13","author":"Smith","year":"2021","journal-title":"Biophys. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Couronn\u00e9, R., Probst, P., and Boulesteix, A.-L. (2018). Random Forest versus Logistic Regression: A Large-Scale Benchmark Experiment. BMC Bioinform., 19.","DOI":"10.1186\/s12859-018-2264-5"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/med4.48","article-title":"Lack of Causal Association between Cheese Intake and Risk of Peripheral Vascular Diseases: A Two-Sample Mendelian Randomization Study","volume":"2","author":"Wen","year":"2024","journal-title":"Med. Adv."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1111\/andr.12731","article-title":"Is Androgen Deprivation Therapy for Prostate Cancer Associated with Cardiovascular Disease? A Meta-Analysis and Systematic Review","volume":"8","author":"Liang","year":"2020","journal-title":"Andrology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1161\/CIRCRESAHA.121.318224","article-title":"Leveraging Machine Learning and Artificial Intelligence to Improve Peripheral Artery Disease Detection, Treatment, and Outcomes","volume":"128","author":"Flores","year":"2021","journal-title":"Circ. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1136\/jms.9.3.133","article-title":"Baseline Tests or Screening: What Tests Do Family Physicians Order Routinely on Their Healthy Patients?","volume":"9","author":"Nakar","year":"2002","journal-title":"J. Med. Screen."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/S0895-7967(02)70029-X","article-title":"Accreditation and Credentialing in the Vascular Laboratory","volume":"15","author":"Akbari","year":"2002","journal-title":"Semin. Vasc. Surg."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1136\/bmj.326.7389.584","article-title":"Management of Peripheral Arterial Disease in Primary Care","volume":"326","author":"Burns","year":"2003","journal-title":"BMJ"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1111\/j.1445-2197.2007.04058.x","article-title":"Vascular Surgery Consults: A Significant Workload","volume":"77","author":"Koh","year":"2007","journal-title":"ANZ J. Surg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e313","DOI":"10.1161\/ATVBAHA.120.313609","article-title":"Recent Advances in Vascular Imaging","volume":"40","author":"Nishimiya","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1056\/NEJMoa1709118","article-title":"Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease","volume":"377","author":"Eikelboom","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1056\/NEJMoa2207899","article-title":"Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia","volume":"387","author":"Farber","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1007\/s00270-020-02604-4","article-title":"Successful Revascularization Has a Significant Impact on Limb Salvage Rate and Wound Healing for Patients with Diabetic Foot Ulcers: Single-Centre Retrospective Analysis with a Multidisciplinary Approach","volume":"43","author":"Caetano","year":"2020","journal-title":"Cardiovasc. Interv. Radiol."},{"key":"ref_50","first-page":"727","article-title":"Health Care Resources and Costs for Treating Peripheral Artery Disease in a Managed Care Population: Results from Analysis of Administrative Claims Data","volume":"11","author":"Margolis","year":"2005","journal-title":"J. Manag. Care Pharm."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/6\/892\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:45:54Z","timestamp":1781844354000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/6\/892"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["biom16060892"],"URL":"https:\/\/doi.org\/10.3390\/biom16060892","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]}}}