{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T22:42:18Z","timestamp":1776897738079,"version":"3.51.2"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["COV20\/00110"],"award-info":[{"award-number":["COV20\/00110"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CP20\/00041"],"award-info":[{"award-number":["CP20\/00041"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["FI20\/00278"],"award-info":[{"award-number":["FI20\/00278"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CD18\/00123"],"award-info":[{"award-number":["CD18\/00123"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008666","name":"Fundaci\u00f3 la Marat\u00f3 de TV3","doi-asserted-by":"publisher","award":["202108-30"],"award-info":[{"award-number":["202108-30"]}],"id":[{"id":"10.13039\/100008666","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008666","name":"Fundaci\u00f3 la Marat\u00f3 de TV3","doi-asserted-by":"publisher","award":["202108-31"],"award-info":[{"award-number":["202108-31"]}],"id":[{"id":"10.13039\/100008666","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014064","name":"Universidad de Salamanca","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100014064","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["GeroScience"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Age is a well-known risk factor to develop severe viral respiratory infections, including severe COVID-19. This study aimed to identify the biological alterations linked to severe disease in elderly patients with COVID-19. For this purpose, we employed a derivation cohort with 450 SARS-CoV-2 infected and unvaccinated patients admitted to hospital wards and a validation cohort with 244 SARS-CoV-2 infected and unvaccinated patients admitted to hospital Intensive Care\u00a0Unit (ICU). Twenty-one biomarkers were measured in plasma samples from patients upon admission, including SARS-CoV-2 RNA, IgG antibodies, and protein biomarkers. Patient cohorts were divided into two groups based on age: adult (\u2264\u200970\u00a0years old) and elderly (&gt;\u200970\u00a0years old) patients. In the derivation cohort, 90-day mortality rate observed in the adult group was 6.0% whereas in the elderly group it rises to 31.6%, same trend was noticed regarding the validation cohort, with 11.2% versus 40.3% 90-day mortality rates for adult and elderly groups, respectively. The machine-learning framework XGBoost-SHAP, fed with the plasma biomarkers information, was used to profile an age-related host response to SARS-CoV-2 infection. Based on SHAP plot, elderly patients had a strong thrombo-inflammatory response profile (significantly elevated plasma levels of: lipocalin-2, endothelin-1, D-dimer) combined with deficient adaptive and cytotoxic antiviral responses. Model performance evaluated with the validation cohort confirmed the robustness and generalizability of the model developed (AUC\u2009=\u20090.710). In conclusion, the machine learning approach we built allowed us to identify the presence of a deranged host response in elderly patients with COVID-19 linked to poor viral control and increased mortality.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s11357-026-02212-z","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T22:13:56Z","timestamp":1776896036000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Key factors of the deranged antiviral response in elderly patients with COVID-19: a machine-learning analysis"],"prefix":"10.1007","author":[{"given":"Tamara","family":"Postigo-Casado","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicia","family":"Ortega","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"\u00c1lvaro-Meca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"V\u00e9lez-Serrano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia","family":"Garc\u00eda-Mateo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana P.","family":"Tedim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raquel","family":"Almansa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose Mar\u00eda","family":"Eiros","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"de Gonzalo-Calvo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Moncus\u00ed-Moix","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Gort-Paniello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manel","family":"Perez-Pons","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Molinero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Dominguez-Gil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"de la Fuente","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Gonz\u00e1lez-Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tania","family":"Luis-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F\u00e1tima","family":"Rodr\u00edguez-Jara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noelia","family":"Jorge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerard","family":"Torres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver Norberto","family":"Guti\u00e9rrez-P\u00e9rez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Jos\u00e9","family":"Villegas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Campo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Ayll\u00f3n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1s Ruiz","family":"Albi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julio","family":"de Frutos Arribas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ainhoa Arroyo","family":"Domingo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Abadia-Otero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia G\u00f3mez","family":"Barquero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wysali","family":"Trapiello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis Javier Garc\u00eda","family":"Frade","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"Inglada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F\u00e9lix","family":"del Campo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ferr\u00e1n","family":"Barb\u00e9","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoni","family":"Torres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ra\u00fal","family":"L\u00f3pez-Izquierdo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jes\u00fas F.","family":"Bermejo-Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"CIBERES-U. C. I.-COVID group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis Jorge","family":"Valdivia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"L\u00f3pez Messa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Vidal-Cort\u00e9s","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nieves","family":"Carbonell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Bustamante-Munguira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda del Carmen","family":"De la Torre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caridad","family":"Mart\u00edn L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milagros","family":"Gonz\u00e1lez Rivera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth Noem\u00ed","family":"Jorge Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"\u00dabeda Iglesias","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Gallego Curto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Socias","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jes\u00fas","family":"Caballero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1ngel","family":"Estella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V\u00edctor","family":"Sagredo Meneses","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Cruz","family":"Mart\u00edn Delgado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amalia","family":"Mart\u00ednez de la G\u00e1ndara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilio","family":"Maseda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"Mart\u00ednez Varela","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Campos-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felipe","family":"P\u00e9rez-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"Tamayo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Loza V\u00e1zquez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salvador","family":"Resino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isidoro","family":"Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Motos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laia","family":"Fern\u00e1ndez-Barat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adri\u00e1n","family":"Ceccato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"2212_CR1","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1016\/S1473-3099(18)30310-4","volume":"18","author":"GBD 2016 Lower Respiratory Infections Collaborators","year":"2018","unstructured":"GBD 2016 Lower Respiratory Infections Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis. 2018;18:1191\u2013210. https:\/\/doi.org\/10.1016\/S1473-3099(18)30310-4.","journal-title":"Lancet Infect Dis"},{"key":"2212_CR2","doi-asserted-by":"publisher","DOI":"10.1177\/1753466621995050","volume":"15","author":"A Watson","year":"2021","unstructured":"Watson A, Wilkinson TMA. Respiratory viral infections in the elderly. Ther Adv Respir Dis. 2021;15:1753466621995050. https:\/\/doi.org\/10.1177\/1753466621995050.","journal-title":"Ther Adv Respir Dis"},{"key":"2212_CR3","unstructured":"World Health Organization. COVID-19 deaths | WHO COVID-19 dashboard. WHO Coronavirus COVID-19 Dashboard n.d. https:\/\/data.who.int\/dashboards\/covid19\/cases (accessed December 19, 2024)."},{"key":"2212_CR4","unstructured":"Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study - PubMed n.d. https:\/\/pubmed.ncbi.nlm.nih.gov\/32444460\/ (accessed December 19, 2024)."},{"key":"2212_CR5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0281052","volume":"18","author":"A Giacomelli","year":"2023","unstructured":"Giacomelli A, Righini E, Micheli V, Pinoli P, Bernasconi A, Rizzo A, et al. SARS-CoV-2 viremia and COVID-19 mortality: a prospective observational study. PLoS One. 2023;18:e0281052. https:\/\/doi.org\/10.1371\/journal.pone.0281052.","journal-title":"PLoS One"},{"key":"2212_CR6","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1038\/s41586-020-2521-4","volume":"584","author":"EJ Williamson","year":"2020","unstructured":"Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584:430\u20136. https:\/\/doi.org\/10.1038\/s41586-020-2521-4.","journal-title":"Nature"},{"key":"2212_CR7","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.2337\/dc20-0598","volume":"43","author":"Q Shi","year":"2020","unstructured":"Shi Q, Zhang X, Jiang F, Zhang X, Hu N, Bimu C, et al. Clinical characteristics and risk factors for mortality of COVID-19 patients with diabetes in Wuhan, China: a two-center, retrospective study. Diabetes Care. 2020;43:1382\u201391. https:\/\/doi.org\/10.2337\/dc20-0598.","journal-title":"Diabetes Care"},{"key":"2212_CR8","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-00934-x","volume":"13","author":"B Wang","year":"2020","unstructured":"Wang B, Van Oekelen O, Mouhieddine TH, Del Valle DM, Richter J, Cho HJ, et al. A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward. J Hematol Oncol. 2020;13:94. https:\/\/doi.org\/10.1186\/s13045-020-00934-x.","journal-title":"J Hematol Oncol"},{"key":"2212_CR9","doi-asserted-by":"publisher","first-page":"84","DOI":"10.31128\/AJGP-07-20-5546","volume":"50","author":"NL Pratt","year":"2021","unstructured":"Pratt NL, Kalisch Ellett LM, Andrade AQ, Le Blanc VT, Barratt J, Roughead EE. Prevalence of multiple risk factors for poor outcomes associated with COVID-19 among an elderly Australian population. Aust J Gen Pract. 2021;50:84\u20139. https:\/\/doi.org\/10.31128\/AJGP-07-20-5546.","journal-title":"Aust J Gen Pract"},{"key":"2212_CR10","unstructured":"Division UP. World population ageing, 2017\u202f: highlights. UN, 2017."},{"key":"2212_CR11","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.14336\/AD.2023.0329","volume":"14","author":"A H\u00e4der","year":"2023","unstructured":"H\u00e4der A, K\u00f6se-Vogel N, Schulz L, Mlynska L, Hornung F, Hagel S, et al. Respiratory infections in the aging lung: Implications for diagnosis, therapy, and prevention. Aging Dis. 2023;14:1091\u2013104. https:\/\/doi.org\/10.14336\/AD.2023.0329.","journal-title":"Aging Dis"},{"key":"2212_CR12","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2019.100935","volume":"54","author":"O Pansarasa","year":"2019","unstructured":"Pansarasa O, Pistono C, Davin A, Bordoni M, Mimmi MC, Guaita A, et al. Altered immune system in frailty: genetics and diet may influence inflammation. Ageing Res Rev. 2019;54:100935. https:\/\/doi.org\/10.1016\/j.arr.2019.100935.","journal-title":"Ageing Res Rev"},{"key":"2212_CR13","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.mad.2006.11.016","volume":"128","author":"C Franceschi","year":"2007","unstructured":"Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007;128:92\u2013105. https:\/\/doi.org\/10.1016\/j.mad.2006.11.016.","journal-title":"Mech Ageing Dev"},{"key":"2212_CR14","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/s1473-3099(02)00437-1","volume":"2","author":"G Gavazzi","year":"2002","unstructured":"Gavazzi G, Krause K-H. Ageing and infection. Lancet Infect Dis. 2002;2:659\u201366. https:\/\/doi.org\/10.1016\/s1473-3099(02)00437-1.","journal-title":"Lancet Infect Dis"},{"key":"2212_CR15","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/692546","volume":"2015","author":"MA Murray","year":"2015","unstructured":"Murray MA, Chotirmall SH. The impact of immunosenescence on pulmonary disease. Mediators Inflamm. 2015;2015:692546. https:\/\/doi.org\/10.1155\/2015\/692546.","journal-title":"Mediators Inflamm"},{"key":"2212_CR16","doi-asserted-by":"publisher","first-page":"e444","DOI":"10.1016\/S2468-2667(20)30146-8","volume":"5","author":"J Hewitt","year":"2020","unstructured":"Hewitt J, Carter B, Vilches-Moraga A, Quinn TJ, Braude P, Verduri A, et al. The effect of frailty on survival in patients with COVID-19 (COPE): a multicentre, European, observational cohort study. Lancet Public Health. 2020;5:e444\u201351. https:\/\/doi.org\/10.1016\/S2468-2667(20)30146-8.","journal-title":"Lancet Public Health"},{"key":"2212_CR17","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-020-03398-0","volume":"24","author":"JF Bermejo-Martin","year":"2020","unstructured":"Bermejo-Martin JF, Gonz\u00e1lez-Rivera M, Almansa R, Micheloud D, Tedim AP, Dom\u00ednguez-Gil M, et al. Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19. Crit Care. 2020;24:691. https:\/\/doi.org\/10.1186\/s13054-020-03398-0.","journal-title":"Crit Care"},{"key":"2212_CR18","doi-asserted-by":"publisher","first-page":"e431","DOI":"10.1016\/S2666-5247(23)00041-1","volume":"4","author":"JF Bermejo-Martin","year":"2023","unstructured":"Bermejo-Martin JF, Garc\u00eda-Mateo N, Motos A, Resino S, Tamayo L, Ryan Murua P, et al. Effect of viral storm in patients admitted to intensive care units with severe COVID-19 in Spain: a multicentre, prospective, cohort study. Lancet Microbe. 2023;4:e431\u201341. https:\/\/doi.org\/10.1016\/S2666-5247(23)00041-1.","journal-title":"Lancet Microbe"},{"key":"2212_CR19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0114468","volume":"9","author":"R Froud","year":"2014","unstructured":"Froud R, Abel G. Using ROC curves to choose minimally important change thresholds when sensitivity and specificity are valued equally: the forgotten lesson of pythagoras. Theoretical considerations and an example application of change in health status. PLoS ONE. 2014;9:e114468. https:\/\/doi.org\/10.1371\/journal.pone.0114468.","journal-title":"PLoS ONE"},{"key":"2212_CR20","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1097\/SLA.0000000000002406","volume":"269","author":"R Almansa","year":"2019","unstructured":"Almansa R, Ortega A, \u00c1vila-Alonso A, Heredia-Rodr\u00edguez M, Mart\u00edn S, Benavides D, et al. Quantification of immune dysregulation by next-generation polymerase chain reaction to improve sepsis diagnosis in surgical patients. Ann Surg. 2019;269:545\u201353. https:\/\/doi.org\/10.1097\/SLA.0000000000002406.","journal-title":"Ann Surg"},{"key":"2212_CR21","doi-asserted-by":"publisher","unstructured":"Chen T, Guestrin C. XGBoost: A Scalable Tree Boosting System. Proc. 22nd ACM SIGKDD Int. Conf. Knowl. Discov. Data Min., New York, NY, USA: Association for Computing Machinery; 2016, p. 785\u201394. https:\/\/doi.org\/10.1145\/2939672.2939785.","DOI":"10.1145\/2939672.2939785"},{"key":"2212_CR22","doi-asserted-by":"publisher","unstructured":"Winter E. Chapter 53 The shapley value. In: Handb. Game Theory Econ. Appl., vol. 3. Elsevier; 2002. p. 2025\u201354. https:\/\/doi.org\/10.1016\/S1574-0005(02)03016-3.","DOI":"10.1016\/S1574-0005(02)03016-3"},{"key":"2212_CR23","doi-asserted-by":"publisher","unstructured":"Lundberg SM, Erion GG, Lee SI. Consistent Individualized Feature Attribution for Tree Ensembles 2019. https:\/\/doi.org\/10.48550\/arXiv.1802.03888.","DOI":"10.48550\/arXiv.1802.03888"},{"key":"2212_CR24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmpb.2021.106584","volume":"214","author":"Y Nohara","year":"2022","unstructured":"Nohara Y, Matsumoto K, Soejima H, Nakashima N. Explanation of machine learning models using shapley additive explanation and application for real data in hospital. Comput Methods Programs Biomed. 2022;214:106584. https:\/\/doi.org\/10.1016\/j.cmpb.2021.106584.","journal-title":"Comput Methods Programs Biomed"},{"key":"2212_CR25","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1016\/j.ijforecast.2023.11.002","volume":"40","author":"B Lantz","year":"2024","unstructured":"Lantz B. Machine learning with R: expert techniques for predictive modelling, 3rd edition. Packt Publishing Ltd, Birmingham, United Kingdom. 2024;40:458\u20133. https:\/\/doi.org\/10.1016\/j.ijforecast.2023.11.002.","journal-title":"Packt Publishing Ltd, Birmingham, United Kingdom"},{"key":"2212_CR26","unstructured":"Hands-on Machine Learning with Scikit-Learn, Keras, and TensorFlow Concepts, Tools, and Techniques to Build Intelligent Systems 3rd Edition Direct Textbook (n.d.) https:\/\/www.directtextbook.com\/isbn\/9781098125974-hands-on-machine-learning-with-scikit-learn-keras-and-tensorflow-concepts-tools-and-techniques-to-build-intelligent-systems (accessed November 3, 2025)."},{"key":"2212_CR27","doi-asserted-by":"publisher","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","volume":"51","author":"D Szklarczyk","year":"2023","unstructured":"Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51:D638-46. https:\/\/doi.org\/10.1093\/nar\/gkac1000.","journal-title":"Nucleic Acids Res"},{"key":"2212_CR28","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101414","volume":"70","author":"DW Dekens","year":"2021","unstructured":"Dekens DW, Eisel ULM, Gouweleeuw L, Schoemaker RG, De Deyn PP, Naud\u00e9 PJW. Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases. Ageing Res Rev. 2021;70:101414. https:\/\/doi.org\/10.1016\/j.arr.2021.101414.","journal-title":"Ageing Res Rev"},{"key":"2212_CR29","first-page":"612","volume":"152","author":"E De la Chesnaye","year":"2016","unstructured":"De la Chesnaye E, Manuel-Apolinar L, Oviedo-de Anda N, Revilla-Monsalve MC, Islas-Andrade S. [Gender differences in lipocalin 2 plasmatic levels are correlated with age and the triglyceride\/high-density lipoprotein ratio in healthy individuals]. Gac Med Mex. 2016;152:612\u20137.","journal-title":"Gac Med Mex"},{"key":"2212_CR30","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.3324\/haematol.2023.283966","volume":"109","author":"M Franchini","year":"2024","unstructured":"Franchini M, Focosi D, Pezzo MP, Mannucci PM. How we manage a high D-dimer. Haematologica. 2024;109:1035\u201345. https:\/\/doi.org\/10.3324\/haematol.2023.283966.","journal-title":"Haematologica"},{"key":"2212_CR31","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.thromres.2013.09.033","volume":"132","author":"C Haase","year":"2013","unstructured":"Haase C, Joergensen M, Ellervik C, Joergensen MK, Bathum L. Age- and sex-dependent reference intervals for D-dimer: evidence for a marked increase by age. Thromb Res. 2013;132:676\u201380. https:\/\/doi.org\/10.1016\/j.thromres.2013.09.033.","journal-title":"Thromb Res"},{"key":"2212_CR32","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.critrevonc.2006.06.004","volume":"60","author":"M Franchini","year":"2006","unstructured":"Franchini M. Hemostasis and aging. Crit Rev Oncol Hematol. 2006;60:144\u201351. https:\/\/doi.org\/10.1016\/j.critrevonc.2006.06.004.","journal-title":"Crit Rev Oncol Hematol"},{"key":"2212_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-57409-z","volume":"14","author":"J Engstr\u00f6m","year":"2024","unstructured":"Engstr\u00f6m J, Koozi H, Didriksson I, Larsson A, Friberg H, Frigyesi A, et al. Plasma neutrophil gelatinase-associated lipocalin independently predicts dialysis need and mortality in critical COVID-19. Sci Rep. 2024;14:6695. https:\/\/doi.org\/10.1038\/s41598-024-57409-z.","journal-title":"Sci Rep"},{"key":"2212_CR34","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1182\/bloodadvances.2020003568","volume":"5","author":"ML Meizlish","year":"2021","unstructured":"Meizlish ML, Pine AB, Bishai JD, Goshua G, Nadelmann ER, Simonov M, et al. A neutrophil activation signature predicts critical illness and mortality in COVID-19. Blood Adv. 2021;5:1164\u201377. https:\/\/doi.org\/10.1182\/bloodadvances.2020003568.","journal-title":"Blood Adv"},{"key":"2212_CR35","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1177\/15353702221091990","volume":"247","author":"A Gupta","year":"2022","unstructured":"Gupta A, Al-Tamimi AO, Halwani R, Alsaidi H, Kannan M, Ahmad F. Lipocalin-2, S100A8\/A9, and cystatin C: potential predictive biomarkers of cardiovascular complications in COVID-19. Exp Biol Med Maywood NJ. 2022;247:1205\u201313. https:\/\/doi.org\/10.1177\/15353702221091990.","journal-title":"Exp Biol Med Maywood NJ"},{"key":"2212_CR36","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.854172","volume":"13","author":"Z Huang","year":"2022","unstructured":"Huang Z, Li H, Liu S, Jia J, Zheng Y, Cao B. Identification of neutrophil-related factor LCN2 for predicting severity of patients with influenza A virus and SARS-CoV-2 infection. Front Microbiol. 2022;13:854172. https:\/\/doi.org\/10.3389\/fmicb.2022.854172.","journal-title":"Front Microbiol"},{"key":"2212_CR37","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1111\/jth.14768","volume":"18","author":"N Tang","year":"2020","unstructured":"Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost JTH. 2020;18:844\u20137. https:\/\/doi.org\/10.1111\/jth.14768.","journal-title":"J Thromb Haemost JTH"},{"key":"2212_CR38","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1515\/cclm-2020-0188","volume":"58","author":"H Han","year":"2020","unstructured":"Han H, Yang L, Liu R, Liu F, Wu K-L, Li J, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med. 2020;58:1116\u201320. https:\/\/doi.org\/10.1515\/cclm-2020-0188.","journal-title":"Clin Chem Lab Med"},{"key":"2212_CR39","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1002\/1097-0142(19940101)73:1<191::AID-CNCR2820730133>3.0.CO;2-X","volume":"73","author":"M Ishibashi","year":"1994","unstructured":"Ishibashi M, Ito N, Fujita M, Furue H, Yamaji T. Endothelin-1 as an aggravating factor of disseminated intravascular coagulation associated with malignant neoplasms. Cancer. 1994;73:191\u20135.","journal-title":"Cancer"},{"key":"2212_CR40","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1038\/s41401-022-00998-0","volume":"44","author":"S-W Xu","year":"2023","unstructured":"Xu S-W, Ilyas I, Weng J-P. Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies. Acta Pharmacol Sin. 2023;44:695\u2013709. https:\/\/doi.org\/10.1038\/s41401-022-00998-0.","journal-title":"Acta Pharmacol Sin"},{"key":"2212_CR41","doi-asserted-by":"publisher","DOI":"10.1177\/1076029619852163","volume":"25","author":"A Walborn","year":"2019","unstructured":"Walborn A, Rondina M, Mosier M, Fareed J, Hoppensteadt D. Endothelial dysfunction is associated with mortality and severity of coagulopathy in patients with sepsis and disseminated intravascular coagulation. Clin Appl Thromb Hemost. 2019;25:1076029619852163. https:\/\/doi.org\/10.1177\/1076029619852163.","journal-title":"Clin Appl Thromb Hemost"},{"key":"2212_CR42","first-page":"111","volume":"44","author":"S Battistelli","year":"1996","unstructured":"Battistelli S, Gori S, Borgogni T, Manasse G. [Variation in the plasma endothelin levels in relation to age]. Minerva Cardioangiol. 1996;44:111\u20134.","journal-title":"Minerva Cardioangiol"},{"issue":"1","key":"2212_CR43","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1152\/japplphysiol.01016.2002","volume":"95","author":"S Maeda","year":"2003","unstructured":"Maeda S, Tanabe T, Miyauchi T, Otsuki T, Sugawara J, Iemitsu M, et al. Aerobic exercise training reduces plasma endothelin-1 concentration in older women. J Appl Physiol. 2003;95(1):336\u201341. https:\/\/doi.org\/10.1152\/japplphysiol.01016.2002.","journal-title":"J Appl Physiol"},{"key":"2212_CR44","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1152\/japplphysiol.00357.2007","volume":"103","author":"DHJ Thijssen","year":"2007","unstructured":"Thijssen DHJ, Rongen GA, van Dijk A, Smits P, Hopman MTE. Enhanced endothelin-1-mediated leg vascular tone in healthy older subjects. J Appl Physiol. 2007;103:852\u20137. https:\/\/doi.org\/10.1152\/japplphysiol.00357.2007.","journal-title":"J Appl Physiol"},{"key":"2212_CR45","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.yjmcc.2022.03.007","volume":"167","author":"GR Abraham","year":"2022","unstructured":"Abraham GR, Kuc RE, Althage M, Greasley PJ, Ambery P, Maguire JJ, et al. Endothelin-1 is increased in the plasma of patients hospitalised with Covid-19. J Mol Cell Cardiol. 2022;167:92\u20136. https:\/\/doi.org\/10.1016\/j.yjmcc.2022.03.007.","journal-title":"J Mol Cell Cardiol"},{"key":"2212_CR46","doi-asserted-by":"publisher","DOI":"10.3390\/jpm13111558","volume":"13","author":"L Turgunova","year":"2023","unstructured":"Turgunova L, Mekhantseva I, Laryushina Y, Alina A, Bacheva I, Zhumadilova Z, et al. The association of endothelin-1 with early and long-term mortality in COVID-19. J Pers Med. 2023;13:1558. https:\/\/doi.org\/10.3390\/jpm13111558.","journal-title":"J Pers Med"},{"key":"2212_CR47","first-page":"449","volume":"2","author":"JS Tilstra","year":"2011","unstructured":"Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD. NF-\u03bab in aging and disease. Aging Dis. 2011;2:449\u201365.","journal-title":"Aging Dis"},{"key":"2212_CR48","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1007\/s10096-020-04138-6","volume":"40","author":"S Beyerstedt","year":"2021","unstructured":"Beyerstedt S, Casaro EB, Rangel \u00c9B. COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2021;40:905\u201319. https:\/\/doi.org\/10.1007\/s10096-020-04138-6.","journal-title":"Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol"},{"key":"2212_CR49","doi-asserted-by":"publisher","first-page":"H1084","DOI":"10.1152\/ajpheart.00217.2020","volume":"318","author":"AM South","year":"2020","unstructured":"South AM, Diz DI, Chappell MC. COVID-19, ACE2, and the cardiovascular consequences. Am J Physiol Heart Circ Physiol. 2020;318:H1084-90. https:\/\/doi.org\/10.1152\/ajpheart.00217.2020.","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2212_CR50","doi-asserted-by":"publisher","DOI":"10.1038\/sigtrans.2017.23","volume":"2","author":"T Liu","year":"2017","unstructured":"Liu T, Zhang L, Joo D, Sun S-C. NF-\u03baB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023. https:\/\/doi.org\/10.1038\/sigtrans.2017.23.","journal-title":"Signal Transduct Target Ther"},{"key":"2212_CR51","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.smim.2014.05.004","volume":"26","author":"MS Hayden","year":"2014","unstructured":"Hayden MS, Ghosh S. Regulation of NF-\u03baB by TNF family cytokines. Semin Immunol. 2014;26:253\u201366. https:\/\/doi.org\/10.1016\/j.smim.2014.05.004.","journal-title":"Semin Immunol"},{"key":"2212_CR52","doi-asserted-by":"publisher","DOI":"10.1038\/sdata.2018.289","volume":"5","author":"E Van Quickelberghe","year":"2018","unstructured":"Van Quickelberghe E, De Sutter D, van Loo G, Eyckerman S, Gevaert K. A protein-protein interaction map of the TNF-induced NF-\u03baB signal transduction pathway. Sci Data. 2018;5:180289. https:\/\/doi.org\/10.1038\/sdata.2018.289.","journal-title":"Sci Data"},{"key":"2212_CR53","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.112002","volume":"142","author":"SA Jaberi","year":"2021","unstructured":"Jaberi SA, Cohen A, D\u2019Souza C, Abdulrazzaq YM, Ojha S, Bastaki S, et al. Lipocalin-2: structure, function, distribution and role in metabolic disorders. Biomed Pharmacother. 2021;142:112002. https:\/\/doi.org\/10.1016\/j.biopha.2021.112002.","journal-title":"Biomed Pharmacother"},{"key":"2212_CR54","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1016\/j.cell.2015.01.004","volume":"160","author":"E Bonavita","year":"2015","unstructured":"Bonavita E, Gentile S, Rubino M, Maina V, Papait R, Kunderfranco P, et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell. 2015;160:700\u201314. https:\/\/doi.org\/10.1016\/j.cell.2015.01.004.","journal-title":"Cell"},{"key":"2212_CR55","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00316","volume":"4","author":"DB Palmer","year":"2013","unstructured":"Palmer DB. The effect of age on thymic function. Front Immunol. 2013;4:316. https:\/\/doi.org\/10.3389\/fimmu.2013.00316.","journal-title":"Front Immunol"},{"key":"2212_CR56","doi-asserted-by":"publisher","first-page":"26263","DOI":"10.18632\/aging.202422","volume":"12","author":"L Omarjee","year":"2020","unstructured":"Omarjee L, Perrot F, Meilhac O, Mahe G, Bousquet G, Janin A. Immunometabolism at the cornerstone of inflammaging, immunosenescence, and autoimmunity in COVID-19. Aging. 2020;12:26263\u201378. https:\/\/doi.org\/10.18632\/aging.202422.","journal-title":"Aging"},{"key":"2212_CR57","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1007\/s11357-020-00186-0","volume":"42","author":"J Nikolich-Zugich","year":"2020","unstructured":"Nikolich-Zugich J, Knox KS, Rios CT, Natt B, Bhattacharya D, Fain MJ. SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes. Geroscience. 2020;42:505\u201314. https:\/\/doi.org\/10.1007\/s11357-020-00186-0.","journal-title":"Geroscience"},{"key":"2212_CR58","doi-asserted-by":"publisher","first-page":"D248","DOI":"10.2741\/linton","volume":"6","author":"P Linton","year":"2001","unstructured":"Linton P, Thoman ML. T cell senescence. Front Biosci J Virtual Libr. 2001;6:D248-261. https:\/\/doi.org\/10.2741\/linton.","journal-title":"Front Biosci J Virtual Libr"},{"key":"2212_CR59","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1038\/ni.2588","volume":"14","author":"JJ Goronzy","year":"2013","unstructured":"Goronzy JJ, Weyand CM. Understanding immunosenescence to improve responses to vaccines. Nat Immunol. 2013;14:428\u201336. https:\/\/doi.org\/10.1038\/ni.2588.","journal-title":"Nat Immunol"},{"key":"2212_CR60","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.coviro.2020.09.007","volume":"46","author":"J Nikolich-\u017dugich","year":"2021","unstructured":"Nikolich-\u017dugich J, Bradshaw CM, Uhrlaub JL, Watanabe M. Immunity to acute virus infections with advanced age. Curr Opin Virol. 2021;46:45\u201358. https:\/\/doi.org\/10.1016\/j.coviro.2020.09.007.","journal-title":"Curr Opin Virol"},{"key":"2212_CR61","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.580237","volume":"11","author":"M Li","year":"2020","unstructured":"Li M, Guo W, Dong Y, Wang X, Dai D, Liu X, et al. Elevated exhaustion levels of NK and CD8+ T cells as indicators for progression and prognosis of COVID-19 disease. Front Immunol. 2020;11:580237. https:\/\/doi.org\/10.3389\/fimmu.2020.580237.","journal-title":"Front Immunol"},{"key":"2212_CR62","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1172\/JCI137244","volume":"130","author":"G Chen","year":"2020","unstructured":"Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620\u20139. https:\/\/doi.org\/10.1172\/JCI137244.","journal-title":"J Clin Invest"},{"key":"2212_CR63","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/s41423-020-0402-2","volume":"17","author":"M Zheng","year":"2020","unstructured":"Zheng M, Gao Y, Wang G, Song G, Liu S, Sun D, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol. 2020;17:533\u20135. https:\/\/doi.org\/10.1038\/s41423-020-0402-2.","journal-title":"Cell Mol Immunol"},{"key":"2212_CR64","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ni.2035","volume":"12","author":"EJ Wherry","year":"2011","unstructured":"Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492\u20139. https:\/\/doi.org\/10.1038\/ni.2035.","journal-title":"Nat Immunol"},{"key":"2212_CR65","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/nri2959","volume":"11","author":"AN Akbar","year":"2011","unstructured":"Akbar AN, Henson SM. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol. 2011;11:289\u201395. https:\/\/doi.org\/10.1038\/nri2959.","journal-title":"Nat Rev Immunol"},{"key":"2212_CR66","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/6104054","volume":"2017","author":"JM Rojas","year":"2017","unstructured":"Rojas JM, Avia M, Mart\u00edn V, Sevilla N. IL-10: a multifunctional cytokine in viral infections. J Immunol Res. 2017;2017:6104054. https:\/\/doi.org\/10.1155\/2017\/6104054.","journal-title":"J Immunol Res"},{"key":"2212_CR67","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1146\/annurev-immunol-041015-055318","volume":"37","author":"LM McLane","year":"2019","unstructured":"McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 2019;37:457\u201395. https:\/\/doi.org\/10.1146\/annurev-immunol-041015-055318.","journal-title":"Annu Rev Immunol"},{"key":"2212_CR68","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.clim.2012.02.005","volume":"143","author":"SR Hofmann","year":"2012","unstructured":"Hofmann SR, R\u00f6sen-Wolff A, Tsokos GC, Hedrich CM. Biological properties and regulation of IL-10 related cytokines and their contribution to autoimmune disease and tissue injury. Clin Immunol. 2012;143:116\u201327. https:\/\/doi.org\/10.1016\/j.clim.2012.02.005.","journal-title":"Clin Immunol"},{"key":"2212_CR69","doi-asserted-by":"publisher","first-page":"155507","DOI":"10.1016\/j.cyto.2021.155507","volume":"143","author":"RL Luporini","year":"2021","unstructured":"Luporini RL, Rodolpho JMdeA, Kubota LT, Martin ACBM, Cominetti MR, Anibal FdeF, et al. IL-6 and IL-10 are associated with disease severity and higher comorbidity in adults with COVID-19. Cytokine. 2021;143:155507. https:\/\/doi.org\/10.1016\/j.cyto.2021.155507.","journal-title":"Cytokine"},{"key":"2212_CR70","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1161067","volume":"14","author":"V Carlini","year":"2023","unstructured":"Carlini V, Noonan DM, Abdalalem E, Goletti D, Sansone C, Calabrone L, et al. The multifaceted nature of IL-10: regulation, role in immunological homeostasis and its relevance to cancer, COVID-19 and post-COVID conditions. Front Immunol. 2023;14:1161067. https:\/\/doi.org\/10.3389\/fimmu.2023.1161067.","journal-title":"Front Immunol"},{"key":"2212_CR71","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.852749","volume":"9","author":"AF Alshammary","year":"2022","unstructured":"Alshammary AF, Alsughayyir JM, Alharbi KK, Al-Sulaiman AM, Alshammary HF, Alshammary HF. T-cell subsets and interleukin-10 levels are predictors of severity and mortality in COVID-19: a systematic review and meta-analysis. Front Med. 2022;9:852749. https:\/\/doi.org\/10.3389\/fmed.2022.852749.","journal-title":"Front Med"},{"key":"2212_CR72","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/9764002","volume":"2022","author":"DR Beserra","year":"2022","unstructured":"Beserra DR, Alberca RW, Branco ACCC, de Mendon\u00e7a Oliveira L, de Souza Andra MM, Gozzi-Silva SC, et al. Upregulation of PD-1 expression and high sPD-L1 levels associated with COVID-19 severity. J Immunol Res. 2022;2022:9764002. https:\/\/doi.org\/10.1155\/2022\/9764002.","journal-title":"J Immunol Res"},{"key":"2212_CR73","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111957","volume":"142","author":"A Awadasseid","year":"2021","unstructured":"Awadasseid A, Yin Q, Wu Y, Zhang W. Potential protective role of the anti-PD-1 blockade against SARS-CoV-2 infection. Biomed Pharmacother. 2021;142:111957. https:\/\/doi.org\/10.1016\/j.biopha.2021.111957.","journal-title":"Biomed Pharmacother"}],"container-title":["GeroScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-026-02212-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11357-026-02212-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-026-02212-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T22:13:59Z","timestamp":1776896039000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11357-026-02212-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,22]]},"references-count":73,"alternative-id":["2212"],"URL":"https:\/\/doi.org\/10.1007\/s11357-026-02212-z","relation":{},"ISSN":["2509-2723"],"issn-type":[{"value":"2509-2723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,22]]},"assertion":[{"value":"14 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}