{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T08:14:29Z","timestamp":1788250469032,"version":"build-2803163510"},"reference-count":124,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":39,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100013928","name":"Millennium Institute on Immunology and Immunotherapy","doi-asserted-by":"crossref","award":["ICN 2021_045"],"award-info":[{"award-number":["ICN 2021_045"]}],"id":[{"id":"10.13039\/501100013928","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100013928","name":"Millennium Institute on Immunology and Immunotherapy","doi-asserted-by":"crossref","award":["ICN 2021_045"],"award-info":[{"award-number":["ICN 2021_045"]}],"id":[{"id":"10.13039\/501100013928","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100013928","name":"Millennium Institute on Immunology and Immunotherapy","doi-asserted-by":"crossref","award":["ICN 2021_045"],"award-info":[{"award-number":["ICN 2021_045"]}],"id":[{"id":"10.13039\/501100013928","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["1240971"],"award-info":[{"award-number":["1240971"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["1231905"],"award-info":[{"award-number":["1231905"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["1231851"],"award-info":[{"award-number":["1231851"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009465","name":"Corporaci\u00f3n de Fomento de la Producci\u00f3n","doi-asserted-by":"crossref","award":["23CTEC-250091-P2"],"award-info":[{"award-number":["23CTEC-250091-P2"]}],"id":[{"id":"10.13039\/100009465","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Clin Immunol"],"DOI":"10.1007\/s10875-026-02054-6","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T03:26:29Z","timestamp":1784863589000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune Dysregulation in Down Syndrome: Implications for Infectious Susceptibility and Vaccine Response"],"prefix":"10.1007","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4338-2784","authenticated-orcid":false,"given":"Sof\u00eda","family":"Solari-Hern\u00e1ndez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1004-451X","authenticated-orcid":false,"given":"Enrique","family":"Gonz\u00e1lez-Madrid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7709-6870","authenticated-orcid":false,"given":"Pablo A.","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7551-8088","authenticated-orcid":false,"given":"Susan M.","family":"Bueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7622-5263","authenticated-orcid":false,"given":"Alexis M.","family":"Kalergis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"2054_CR1","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41572-019-0143-7","volume":"6","author":"SE Antonarakis","year":"2020","unstructured":"Antonarakis SE, Skotko BG, Rafii MS, Strydom A, Pape SE, Bianchi DW, et al. Down syndrome. Nat Rev Dis Prim. 2020;6:9. https:\/\/doi.org\/10.1038\/s41572-019-0143-7.","journal-title":"Nat Rev Dis Prim"},{"key":"2054_CR2","doi-asserted-by":"publisher","first-page":"2344","DOI":"10.1056\/nejmra1706537","volume":"382","author":"MJ Bull","year":"2020","unstructured":"Bull MJ, Down Syndrome. N Engl J Med. 2020;382:2344\u201352. https:\/\/doi.org\/10.1056\/nejmra1706537.","journal-title":"N Engl J Med"},{"key":"2054_CR3","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1002\/ajmg.a.32932","volume":"149A","author":"S Ghosh","year":"2009","unstructured":"Ghosh S, Feingold E, Dey SK. Etiology of Down syndrome: Evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations. Am J M\u00e9d Genet Part A. 2009;149A:1415\u201320. https:\/\/doi.org\/10.1002\/ajmg.a.32932.","journal-title":"Am J M\u00e9d Genet Part A"},{"key":"2054_CR4","doi-asserted-by":"publisher","first-page":"908482","DOI":"10.3389\/fgene.2022.908482","volume":"13","author":"L Chen","year":"2022","unstructured":"Chen L, Wang L, Wang Y, Hu H, Zhan Y, Zeng Z, et al. Global, Regional, and National Burden and Trends of Down Syndrome From 1990 to 2019. Front Genet. 2022;13:908482. https:\/\/doi.org\/10.3389\/fgene.2022.908482.","journal-title":"Front Genet"},{"key":"2054_CR5","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1002\/ajmg.a.37001","volume":"167","author":"G de Graaf","year":"2015","unstructured":"de Graaf G, Buckley F, Skotko BG. Estimates of the live births, natural losses, and elective terminations with Down syndrome in the United States. Am J M\u00e9d Genet Part A. 2015;167:756\u201367. https:\/\/doi.org\/10.1002\/ajmg.a.37001.","journal-title":"Am J M\u00e9d Genet Part A"},{"key":"2054_CR6","doi-asserted-by":"publisher","first-page":"105","DOI":"10.4067\/s0370-41062011000200004","volume":"82","author":"OLC H JN","year":"2011","unstructured":"H JN OLC. Estudio epidemiolgico global del sndrome de Down. Rev Chil pediatra. 2011;82:105\u201312. https:\/\/doi.org\/10.4067\/s0370-41062011000200004.","journal-title":"Rev Chil pediatra"},{"key":"2054_CR7","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1038\/s41431-020-00748-y","volume":"29","author":"G de Graaf","year":"2021","unstructured":"de Graaf G, Buckley F, Skotko BG. Estimation of the number of people with Down syndrome in Europe. Eur J Hum Genet. 2021;29:402\u201310. https:\/\/doi.org\/10.1038\/s41431-020-00748-y.","journal-title":"Eur J Hum Genet"},{"key":"2054_CR8","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.1016\/j.neuron.2022.04.001","volume":"110","author":"AC Martini","year":"2022","unstructured":"Martini AC, Gross TJ, Head E, Mapstone M. Beyond amyloid: Immune, cerebrovascular, and metabolic contributions to Alzheimer disease in people with Down syndrome. Neuron. 2022;110:2063\u201379. https:\/\/doi.org\/10.1016\/j.neuron.2022.04.001.","journal-title":"Neuron"},{"key":"2054_CR9","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.3390\/children11101251","volume":"11","author":"A Szczawi\u0144ska-Pop\u0142onyk","year":"2024","unstructured":"Szczawi\u0144ska-Pop\u0142onyk A, Pop\u0142onyk N, Awdi K. Down Syndrome in Children: A Primary Immunodeficiency with Immune Dysregulation. Children. 2024;11:1251. https:\/\/doi.org\/10.3390\/children11101251.","journal-title":"Children"},{"key":"2054_CR10","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1002\/eji.201445049","volume":"45","author":"R Carsetti","year":"2015","unstructured":"Carsetti R, Valentini D, Marcellini V, Scarsella M, Marasco E, Giustini F, et al. Reduced numbers of switched memory B cells with high terminal differentiation potential in Down syndrome. Eur J Immunol. 2015;45:903\u201314. https:\/\/doi.org\/10.1002\/eji.201445049.","journal-title":"Eur J Immunol"},{"key":"2054_CR11","doi-asserted-by":"publisher","first-page":"5187","DOI":"10.2147\/jir.s280953","volume":"14","author":"H Chung","year":"2021","unstructured":"Chung H, Green PHR, Wang TC, Kong X-F. Interferon-Driven Immune Dysregulation in Down Syndrome: A Review of the Evidence. J Inflamm Res. 2021;14:5187\u2013200. https:\/\/doi.org\/10.2147\/jir.s280953.","journal-title":"J Inflamm Res"},{"key":"2054_CR12","doi-asserted-by":"publisher","first-page":"2074","DOI":"10.1016\/j.immuni.2022.09.007","volume":"55","author":"L Malle","year":"2022","unstructured":"Malle L, Martin-Fernandez M, Buta S, Richardson A, Bush D, Bogunovic D. Excessive negative regulation of type I interferon disrupts viral control in individuals with Down syndrome. Immunity. 2022;55:2074\u201384. https:\/\/doi.org\/10.1016\/j.immuni.2022.09.007. .e5.","journal-title":"Immunity"},{"key":"2054_CR13","doi-asserted-by":"publisher","first-page":"14818","DOI":"10.1038\/s41598-017-13858-3","volume":"7","author":"KD Sullivan","year":"2017","unstructured":"Sullivan KD, Evans D, Pandey A, Hraha TH, Smith KP, Markham N, et al. Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation. Sci Rep. 2017;7:14818. https:\/\/doi.org\/10.1038\/s41598-017-13858-3.","journal-title":"Sci Rep"},{"key":"2054_CR14","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1111\/j.1365-2249.2011.04335.x","volume":"164","author":"G Ram","year":"2011","unstructured":"Ram G, Chinen J. Infections and immunodeficiency in Down syndrome. Clin Exp Immunol. 2011;164:9\u201316. https:\/\/doi.org\/10.1111\/j.1365-2249.2011.04335.x.","journal-title":"Clin Exp Immunol"},{"key":"2054_CR15","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1007\/s10875-020-00803-9","volume":"40","author":"X-F Kong","year":"2020","unstructured":"Kong X-F, Worley L, Rinchai D, Bondet V, Jithesh PV, Goulet M, et al. Three Copies of Four Interferon Receptor Genes Underlie a Mild Type I Interferonopathy in Down Syndrome. J Clin Immunol. 2020;40:807\u201319. https:\/\/doi.org\/10.1007\/s10875-020-00803-9.","journal-title":"J Clin Immunol"},{"key":"2054_CR16","doi-asserted-by":"publisher","first-page":"73","DOI":"10.3389\/fped.2020.00073","volume":"8","author":"D Huggard","year":"2020","unstructured":"Huggard D, Doherty DG, Molloy EJ. Immune Dysregulation in Children With Down Syndrome. Front Pediatr. 2020;8:73. https:\/\/doi.org\/10.3389\/fped.2020.00073.","journal-title":"Front Pediatr"},{"key":"2054_CR17","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1111\/j.1365-2249.2009.03890.x","volume":"156","author":"MAA Kusters","year":"2009","unstructured":"Kusters MAA, Verstegen RHJ, Gemen EFA, Vries ED. Intrinsic defect of the immune system in children with Down syndrome: a review. Clin Exp Immunol. 2009;156:189\u201393. https:\/\/doi.org\/10.1111\/j.1365-2249.2009.03890.x.","journal-title":"Clin Exp Immunol"},{"key":"2054_CR18","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/j.micinf.2010.05.007","volume":"12","author":"BLP Bloemers","year":"2010","unstructured":"Bloemers BLP, Broers CJM, Bont L, Weijerman ME, Gemke RJBJ, van Furth AM. Increased risk of respiratory tract infections in children with Down syndrome: the consequence of an altered immune system. Microbes Infect. 2010;12:799\u2013808. https:\/\/doi.org\/10.1016\/j.micinf.2010.05.007.","journal-title":"Microbes Infect"},{"key":"2054_CR19","doi-asserted-by":"publisher","first-page":"e16220","DOI":"10.7554\/elife.16220","volume":"5","author":"KD Sullivan","year":"2016","unstructured":"Sullivan KD, Lewis HC, Hill AA, Pandey A, Jackson LP, Cabral JM, et al. Trisomy 21 consistently activates the interferon response. eLife. 2016;5:e16220. https:\/\/doi.org\/10.7554\/elife.16220.","journal-title":"eLife"},{"key":"2054_CR20","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.coi.2021.06.006","volume":"72","author":"L Malle","year":"2021","unstructured":"Malle L, Bogunovic D. Down syndrome and type I interferon: not so simple. Curr Opin Immunol. 2021;72:196\u2013205. https:\/\/doi.org\/10.1016\/j.coi.2021.06.006.","journal-title":"Curr Opin Immunol"},{"key":"2054_CR21","doi-asserted-by":"publisher","first-page":"eade7028","DOI":"10.1126\/scitranslmed.ade7028","volume":"15","author":"AD Largent","year":"2023","unstructured":"Largent AD, Lambert K, Chiang K, Shumlak N, Liggitt D, Oukka M, et al. Dysregulated IFN-\u03b3 signals promote autoimmunity in STAT1 gain-of-function syndrome. Sci Transl Med. 2023;15:eade7028\u20137028. https:\/\/doi.org\/10.1126\/scitranslmed.ade7028.","journal-title":"Sci Transl Med"},{"key":"2054_CR22","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1007\/s10875-020-00847-x","volume":"40","author":"S Okada","year":"2020","unstructured":"Okada S, Asano T, Moriya K, Boisson-Dupuis S, Kobayashi M, Casanova J-L, et al. Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy. J Clin Immunol. 2020;40:1065\u201381. https:\/\/doi.org\/10.1007\/s10875-020-00847-x.","journal-title":"J Clin Immunol"},{"key":"2054_CR23","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1189\/jlb.5ri0516-237rr","volume":"101","author":"T Lorenzini","year":"2017","unstructured":"Lorenzini T, Dotta L, Giacomelli M, Vairo D, Badolato R. STAT mutations as program switchers: turning primary immunodeficiencies into autoimmune diseases. J Leukoc Biol. 2017;101:29\u201338. https:\/\/doi.org\/10.1189\/jlb.5ri0516-237rr.","journal-title":"J Leukoc Biol"},{"key":"2054_CR24","doi-asserted-by":"publisher","first-page":"1669688","DOI":"10.3389\/fimmu.2025.1669688","volume":"16","author":"R Djidjik","year":"2025","unstructured":"Djidjik R, Mahammed LL, Berkani LM, Allam I, Benmoussa AH, Gharnaout M, et al. JAK\/STAT in human diseases: a common axis in immunodeficiencies and hematological disorders. Front Immunol. 2025;16:1669688. https:\/\/doi.org\/10.3389\/fimmu.2025.1669688.","journal-title":"Front Immunol"},{"key":"2054_CR25","doi-asserted-by":"publisher","first-page":"1832057","DOI":"10.3389\/fimmu.2026.1832057","volume":"17","author":"JN Posey","year":"2026","unstructured":"Posey JN, Jordan M, Olsen-Dufour A, Nguyen T-TN, Farrell C, Lewis CV, et al. Interferon receptor gene dosage differentially regulates hypoxia-induced platelet activation and pulmonary hypertension in down syndrome. Front Immunol. 2026;17:1832057. https:\/\/doi.org\/10.3389\/fimmu.2026.1832057.","journal-title":"Front Immunol"},{"key":"2054_CR26","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/nrd.2017.267","volume":"17","author":"DM Schwartz","year":"2018","unstructured":"Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O\u2019Shea JJ. Erratum: JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2018;17:78\u201378. https:\/\/doi.org\/10.1038\/nrd.2017.267.","journal-title":"Nat Rev Drug Discov"},{"key":"2054_CR27","doi-asserted-by":"publisher","unstructured":"Rachubinski AL, Wallace E, Gurnee E, Enriquez-Estrada BA, Worek KR, Smith KP, et al. JAK inhibition decreases the autoimmune burden in Down syndrome. eLife. 2024;13. https:\/\/doi.org\/10.7554\/elife.99323.3.","DOI":"10.7554\/elife.99323.3"},{"key":"2054_CR28","doi-asserted-by":"publisher","first-page":"262","DOI":"10.3389\/fimmu.2015.00262","volume":"6","author":"NS Merle","year":"2015","unstructured":"Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement System Part I \u2013 Molecular Mechanisms of Activation and Regulation. Front Immunol. 2015;6:262. https:\/\/doi.org\/10.3389\/fimmu.2015.00262.","journal-title":"Front Immunol"},{"key":"2054_CR29","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1002\/alz.12799","volume":"19","author":"A Veteleanu","year":"2023","unstructured":"Veteleanu A, Pape S, Davies K, Kodosaki E, Hye A, Zelek WM, et al. Complement dysregulation and Alzheimer\u2019s disease in Down syndrome. Alzheimer\u2019s Dement. 2023;19:1383\u201392. https:\/\/doi.org\/10.1002\/alz.12799.","journal-title":"Alzheimer\u2019s Dement"},{"key":"2054_CR30","doi-asserted-by":"publisher","unstructured":"Silva ALTe, de Oliveira PHP, Yokota-Moreno BY, Avila JP, Nakaya HI, Fausto J da S. Complement system alteration in iPSC-derived astrocytes from individuals with Down syndrome. 2024; https:\/\/doi.org\/10.21203\/rs.3.rs-5319960\/v1","DOI":"10.21203\/rs.3.rs-5319960\/v1"},{"key":"2054_CR31","doi-asserted-by":"publisher","first-page":"e2435018","DOI":"10.1001\/jamanetworkopen.2024.35018","volume":"7","author":"E Rubenstein","year":"2024","unstructured":"Rubenstein E, Tewolde S, Michals A, Weuve J, Fortea J, Fox MP, et al. Alzheimer Dementia Among Individuals With Down Syndrome. JAMA Netw Open. 2024;7:e2435018. https:\/\/doi.org\/10.1001\/jamanetworkopen.2024.35018.","journal-title":"JAMA Netw Open"},{"key":"2054_CR32","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1016\/s1474-4422(21)00245-3","volume":"20","author":"J Fortea","year":"2021","unstructured":"Fortea J, Zaman SH, Hartley S, Rafii MS, Head E, Carmona-Iragui M. Alzheimer\u2019s disease associated with Down syndrome: a genetic form of dementia. Lancet Neurol. 2021;20:930\u201342. https:\/\/doi.org\/10.1016\/s1474-4422(21)00245-3.","journal-title":"Lancet Neurol"},{"key":"2054_CR33","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1016\/j.stem.2022.06.007","volume":"29","author":"M Jin","year":"2022","unstructured":"Jin M, Xu R, Wang L, Alam MM, Ma Z, Zhu S, et al. Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer\u2019s disease. Cell Stem Cell. 2022;29:1135\u2013e11538. https:\/\/doi.org\/10.1016\/j.stem.2022.06.007.","journal-title":"Cell Stem Cell"},{"key":"2054_CR34","doi-asserted-by":"publisher","first-page":"1396520","DOI":"10.3389\/fneur.2024.1396520","volume":"15","author":"L Negro-Demontel","year":"2024","unstructured":"Negro-Demontel L, Maleki AF, Reich DS, Kemper C. The complement system in neurodegenerative and inflammatory diseases of the central nervous system. Front Neurol. 2024;15:1396520. https:\/\/doi.org\/10.3389\/fneur.2024.1396520.","journal-title":"Front Neurol"},{"key":"2054_CR35","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1126\/science.1198687","volume":"331","author":"E Vivier","year":"2011","unstructured":"Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or Adaptive Immunity? The Example of Natural Killer Cells. Science. 2011;331:44\u20139. https:\/\/doi.org\/10.1126\/science.1198687.","journal-title":"Science"},{"key":"2054_CR36","doi-asserted-by":"publisher","first-page":"154938","DOI":"10.1016\/j.cyto.2019.154938","volume":"127","author":"D Huggard","year":"2020","unstructured":"Huggard D, Kelly L, Ryan E, McGrane F, Lagan N, Roche E, et al. Increased systemic inflammation in children with Down syndrome. Cytokine. 2020;127:154938. https:\/\/doi.org\/10.1016\/j.cyto.2019.154938.","journal-title":"Cytokine"},{"key":"2054_CR37","doi-asserted-by":"publisher","first-page":"eabi4888","DOI":"10.1126\/scitranslmed.abi4888","volume":"14","author":"K Lambert","year":"2022","unstructured":"Lambert K, Moo KG, Arnett A, Goel G, Hu A, Flynn KJ, et al. Deep immune phenotyping reveals similarities between aging, Down syndrome, and autoimmunity. Sci Transl Med. 2022;14:eabi4888. https:\/\/doi.org\/10.1126\/scitranslmed.abi4888.","journal-title":"Sci Transl Med"},{"key":"2054_CR38","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1002\/ajmg.1320370743","volume":"37","author":"A Cossarizza","year":"1990","unstructured":"Cossarizza A, Monti D, Montagnani G, Ortolani C, Masi M, Zannotti M, et al. Precocious aging of the immune system in Down syndrome: Alteration of b lymphocytes, T-lymphocyte subsets, and cells with natural killer markers. Am J M\u00e9d Genet. 1990;37:213\u20138. https:\/\/doi.org\/10.1002\/ajmg.1320370743.","journal-title":"Am J M\u00e9d Genet"},{"key":"2054_CR39","doi-asserted-by":"publisher","first-page":"3450","DOI":"10.1038\/s41467-025-58662-0","volume":"16","author":"JJ Rodriguez-Sevilla","year":"2025","unstructured":"Rodriguez-Sevilla JJ, Ganan-Gomez I, Kumar B, Thongon N, Ma F, Chien KS, et al. Natural killer cells\u2019 functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes. Nat Commun. 2025;16:3450. https:\/\/doi.org\/10.1038\/s41467-025-58662-0.","journal-title":"Nat Commun"},{"key":"2054_CR40","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/ni.1841","volume":"11","author":"DI Godfrey","year":"2010","unstructured":"Godfrey DI, Stankovic S, Baxter AG. Raising the NKT cell family. Nat Immunol. 2010;11:197\u2013206. https:\/\/doi.org\/10.1038\/ni.1841.","journal-title":"Nat Immunol"},{"key":"2054_CR41","doi-asserted-by":"publisher","first-page":"1443910","DOI":"10.3389\/fimmu.2024.1443910","volume":"15","author":"MR P\u00e9rez","year":"2024","unstructured":"P\u00e9rez MR, Vandenabeele P, Tougaard P. The thymus road to a T cell: migration, selection, and atrophy. Front Immunol. 2024;15:1443910. https:\/\/doi.org\/10.3389\/fimmu.2024.1443910.","journal-title":"Front Immunol"},{"key":"2054_CR42","doi-asserted-by":"publisher","first-page":"3010","DOI":"10.1182\/blood-2025-3010","volume":"146","author":"T Hall","year":"2025","unstructured":"Hall T, Schild A, Li L, Sheppard H, Liu Y, Cotton A, et al. Aberrant thymic architecture and enhanced interferon signaling in down syndrome. Blood. 2025;146:3010. https:\/\/doi.org\/10.1182\/blood-2025-3010.","journal-title":"Blood"},{"key":"2054_CR43","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/1742-4933-2-4","volume":"2","author":"N Prada","year":"2005","unstructured":"Prada N, Nasi M, Troiano L, Roat E, Pinti M, Nemes E, et al. Direct analysis of thymic function in children with Down\u2019s syndrome. Immun Ageing. 2005;2:4. https:\/\/doi.org\/10.1186\/1742-4933-2-4.","journal-title":"Immun Ageing"},{"key":"2054_CR44","doi-asserted-by":"publisher","first-page":"447","DOI":"10.3389\/fimmu.2019.00447","volume":"10","author":"GE Marcovecchio","year":"2019","unstructured":"Marcovecchio GE, Bortolomai I, Ferrua F, Fontana E, Imberti L, Conforti E, et al. Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development. Front Immunol. 2019;10:447. https:\/\/doi.org\/10.3389\/fimmu.2019.00447.","journal-title":"Front Immunol"},{"key":"2054_CR45","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1016\/j.immuni.2016.02.009","volume":"44","author":"S Malchow","year":"2016","unstructured":"Malchow S, Leventhal DS, Lee V, Nishi S, Socci ND, Savage PA. Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage. Immunity. 2016;44:1102\u201313. https:\/\/doi.org\/10.1016\/j.immuni.2016.02.009.","journal-title":"Immunity"},{"key":"2054_CR46","doi-asserted-by":"publisher","first-page":"3422","DOI":"10.4049\/jimmunol.1003053","volume":"187","author":"FA Lima","year":"2011","unstructured":"Lima FA, Moreira-Filho CA, Ramos PL, Brentani H, Lima L, de A, Arrais M, et al. Decreased AIRE Expression and Global Thymic Hypofunction in Down Syndrome. J Immunol. 2011;187:3422\u201330. https:\/\/doi.org\/10.4049\/jimmunol.1003053.","journal-title":"J Immunol"},{"key":"2054_CR47","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.4049\/jimmunol.1400742","volume":"193","author":"G Skogberg","year":"2014","unstructured":"Skogberg G, Lundberg V, Lindgren S, Gudmundsdottir J, Sandstr\u00f6m K, K\u00e4mpe O, et al. Altered Expression of Autoimmune Regulator in Infant Down Syndrome Thymus, a Possible Contributor to an Autoimmune Phenotype. J Immunol. 2014;193:2187\u201395. https:\/\/doi.org\/10.4049\/jimmunol.1400742.","journal-title":"J Immunol"},{"key":"2054_CR48","doi-asserted-by":"publisher","first-page":"4500","DOI":"10.4049\/jimmunol.1001700","volume":"186","author":"BLP Bloemers","year":"2011","unstructured":"Bloemers BLP, Bont L, de Weger RA, Otto SA, Borghans JA, Tesselaar K. Decreased Thymic Output Accounts for Decreased Naive T Cell Numbers in Children with Down Syndrome. J Immunol. 2011;186:4500\u20137. https:\/\/doi.org\/10.4049\/jimmunol.1001700.","journal-title":"J Immunol"},{"key":"2054_CR49","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/ni.3419","volume":"17","author":"Y Xing","year":"2016","unstructured":"Xing Y, Wang X, Jameson SC, Hogquist KA. Late stages of T cell maturation in the thymus involve NF-\u03baB and tonic type I interferon signaling. Nat Immunol. 2016;17:565\u201373. https:\/\/doi.org\/10.1038\/ni.3419.","journal-title":"Nat Immunol"},{"key":"2054_CR50","doi-asserted-by":"publisher","first-page":"eadp1139","DOI":"10.1126\/sciimmunol.adp1139","volume":"9","author":"KM Ashby","year":"2024","unstructured":"Ashby KM, Vobo\u0159il M, Salgado OC, Lee ST, Martinez RJ, O\u2019Connor CH, et al. Sterile production of interferons in the thymus affects T cell repertoire selection. Sci Immunol. 2024;9:eadp1139\u20131139. https:\/\/doi.org\/10.1126\/sciimmunol.adp1139.","journal-title":"Sci Immunol"},{"key":"2054_CR51","doi-asserted-by":"publisher","first-page":"2506","DOI":"10.4049\/jimmunol.149.7.2506","volume":"149","author":"M Murphy","year":"1992","unstructured":"Murphy M, Friend DS, Pike-Nobile L, Epstein LB. Tumor necrosis factor-alpha and IFN-gamma expression in human thymus. Localization and overexpression in Down syndrome (trisomy 21). J Immunol. 1992;149:2506\u201312. https:\/\/doi.org\/10.4049\/jimmunol.149.7.2506.","journal-title":"J Immunol"},{"key":"2054_CR52","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1126\/science.aac9475","volume":"351","author":"SG Hansen","year":"2016","unstructured":"Hansen SG, Wu HL, Burwitz BJ, Hughes CM, Hammond KB, Ventura AB, et al. Broadly targeted CD8\u2009+\u2009T cell responses restricted by major histocompatibility complex E. Science. 2016;351:714\u201320. https:\/\/doi.org\/10.1126\/science.aac9475.","journal-title":"Science"},{"key":"2054_CR53","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1111\/imr.13296","volume":"322","author":"M Ramba","year":"2024","unstructured":"Ramba M, Bogunovic D. The immune system in Down Syndrome: Autoimmunity and severe infections. Immunol Rev. 2024;322:300\u201310. https:\/\/doi.org\/10.1111\/imr.13296.","journal-title":"Immunol Rev"},{"key":"2054_CR54","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1007\/s00281-020-00804-1","volume":"42","author":"N Gensous","year":"2020","unstructured":"Gensous N, Bacalini MG, Franceschi C, Garagnani P. Down syndrome, accelerated aging and immunosenescence. Semin Immunopathol. 2020;42:635\u201345. https:\/\/doi.org\/10.1007\/s00281-020-00804-1.","journal-title":"Semin Immunopathol"},{"key":"2054_CR55","doi-asserted-by":"publisher","first-page":"24231","DOI":"10.1073\/pnas.1908129116","volume":"116","author":"P Araya","year":"2019","unstructured":"Araya P, Waugh KA, Sullivan KD, N\u00fa\u00f1ez NG, Roselli E, Smith KP, et al. Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity. Proc Natl Acad Sci. 2019;116:24231\u201341. https:\/\/doi.org\/10.1073\/pnas.1908129116.","journal-title":"Proc Natl Acad Sci"},{"key":"2054_CR56","doi-asserted-by":"publisher","first-page":"925135","DOI":"10.1155\/2012\/925135","volume":"2012","author":"RV Luckheeram","year":"2012","unstructured":"Luckheeram RV, Zhou R, Verma AD, Xia B. CD4\u2009+\u2009T Cells: Differentiation and Functions. J Immunol Res. 2012;2012:925135. https:\/\/doi.org\/10.1155\/2012\/925135.","journal-title":"J Immunol Res"},{"key":"2054_CR57","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1038\/s41586-023-05736-y","volume":"615","author":"L Malle","year":"2023","unstructured":"Malle L, Patel RS, Martin-Fernandez M, Stewart OJ, Philippot Q, Buta S, et al. Autoimmunity in Down\u2019s syndrome via cytokines, CD4 T cells and CD11c\u2009+\u2009B cells. Nature. 2023;615:305\u201314. https:\/\/doi.org\/10.1038\/s41586-023-05736-y.","journal-title":"Nature"},{"key":"2054_CR58","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1111\/j.1365-2249.2012.04610.x","volume":"169","author":"FP Pellegrini","year":"2012","unstructured":"Pellegrini FP, Marinoni M, Frangione V, Tedeschi A, Gandini V, Ciglia F, et al. Down syndrome, autoimmunity and T regulatory cells. Clin Exp Immunol. 2012;169:238\u201343. https:\/\/doi.org\/10.1111\/j.1365-2249.2012.04610.x.","journal-title":"Clin Exp Immunol"},{"key":"2054_CR59","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1093\/cei\/uxac123","volume":"211","author":"JL Astarita","year":"2022","unstructured":"Astarita JL, Dominguez CX, Tan C, Guillen J, Pauli ML, Labastida R, et al. Treg specialization and functions beyond immune suppression. Clin Exp Immunol. 2022;211:176\u201383. https:\/\/doi.org\/10.1093\/cei\/uxac123.","journal-title":"Clin Exp Immunol"},{"key":"2054_CR60","doi-asserted-by":"publisher","first-page":"268","DOI":"10.3390\/genes12020268","volume":"12","author":"M Ferrari","year":"2021","unstructured":"Ferrari M, Stagi S. Autoimmunity and Genetic Syndromes: A Focus on Down Syndrome. Genes. 2021;12:268. https:\/\/doi.org\/10.3390\/genes12020268.","journal-title":"Genes"},{"key":"2054_CR61","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s13052-018-0478-9","volume":"44","author":"T Aversa","year":"2018","unstructured":"Aversa T, Crisafulli G, Zirilli G, Luca FD, Gallizzi R, Valenzise M. Epidemiological and clinical aspects of autoimmune thyroid diseases in children with Down\u2019s syndrome. Ital J Pediatr. 2018;44:39. https:\/\/doi.org\/10.1186\/s13052-018-0478-9.","journal-title":"Ital J Pediatr"},{"key":"2054_CR62","doi-asserted-by":"publisher","first-page":"3872","DOI":"10.4049\/jimmunol.1400223","volume":"193","author":"M Gim\u00e9nez-Barcons","year":"2014","unstructured":"Gim\u00e9nez-Barcons M, Caster\u00e0s A, Armengol M, del Porta P, Correa E, Mar\u00edn PA. Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of AIRE and Peripheral Antigens. J Immunol. 2014;193:3872\u20139. https:\/\/doi.org\/10.4049\/jimmunol.1400223.","journal-title":"J Immunol"},{"key":"2054_CR63","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/s2171-9748(11)70003-4","volume":"15","author":"F Mu\u00f1oz-L\u00f3pez","year":"2011","unstructured":"Mu\u00f1oz-L\u00f3pez F, Pediatrics. Down\u2019s syndrome and allergic disease. Int M\u00e9d Rev Down Syndr. 2011;15:8\u201313. https:\/\/doi.org\/10.1016\/s2171-9748(11)70003-4.","journal-title":"Int M\u00e9d Rev Down Syndr"},{"key":"2054_CR64","doi-asserted-by":"publisher","first-page":"388","DOI":"10.3390\/nu14020388","volume":"14","author":"F Okazaki","year":"2022","unstructured":"Okazaki F, Wakiguchi H, Korenaga Y, Takahashi K, Yasudo H, Fukuda K, et al. Food Protein-Induced Enterocolitis Syndrome in Children with Down Syndrome: A Pilot Case-Control Study. Nutrients. 2022;14:388. https:\/\/doi.org\/10.3390\/nu14020388.","journal-title":"Nutrients"},{"key":"2054_CR65","doi-asserted-by":"publisher","first-page":"101103","DOI":"10.1016\/j.waojou.2025.101103","volume":"18","author":"F Okazaki","year":"2025","unstructured":"Okazaki F, Wakiguchi H, Korenaga Y, Shimokawa M, Tanabe T, Fukuda K, et al. Non-immunoglobulin E-mediated gastrointestinal food allergies in children with Down syndrome: An epidemiological study. World Allergy Organ J. 2025;18:101103. https:\/\/doi.org\/10.1016\/j.waojou.2025.101103.","journal-title":"World Allergy Organ J"},{"key":"2054_CR66","doi-asserted-by":"publisher","first-page":"4047","DOI":"10.3390\/jcm11144047","volume":"11","author":"V Pecora","year":"2022","unstructured":"Pecora V, Mennini M, Valluzzi R, Fierro V, Villani A, Valentini D, et al. Down Syndrome in FPIES: An Overwhelming and Unexpected Prevalence. J Clin Med. 2022;11:4047. https:\/\/doi.org\/10.3390\/jcm11144047.","journal-title":"J Clin Med"},{"key":"2054_CR67","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1038\/s41390-021-01664-7","volume":"91","author":"ML Vielkind","year":"2022","unstructured":"Vielkind ML, Hamlington KL, Wolter-Warmerdam K, Meier MR, Liu AH, Hickey FJ, et al. Airwave oscillometry to measure lung function in children with Down syndrome. Pediatr Res. 2022;91:1775\u201380. https:\/\/doi.org\/10.1038\/s41390-021-01664-7.","journal-title":"Pediatr Res"},{"key":"2054_CR68","doi-asserted-by":"publisher","first-page":"1963","DOI":"10.1002\/lary.27063","volume":"128","author":"AA Ong","year":"2018","unstructured":"Ong AA, Atwood CM, Nguyen SA, Teufel RJ, Lal C, LaRosa AC, et al. Down syndrome and pediatric obstructive sleep apnea surgery: A national cohort. Laryngoscope. 2018;128:1963\u20139. https:\/\/doi.org\/10.1002\/lary.27063.","journal-title":"Laryngoscope"},{"key":"2054_CR69","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1177\/01945998211023102","volume":"166","author":"CA Abijay","year":"2021","unstructured":"Abijay CA, Tomkies A, Rayasam S, Johnson RF, Mitchell RB. Children With Down Syndrome and Obstructive Sleep Apnea: Outcomes After Tonsillectomy. OtolaryngolHead Neck Surg. 2021;166:557\u201364. https:\/\/doi.org\/10.1177\/01945998211023102.","journal-title":"OtolaryngolHead Neck Surg"},{"key":"2054_CR70","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.3390\/pharmaceutics17111366","volume":"17","author":"B Tielemans","year":"2025","unstructured":"Tielemans B, Llambrich S, Seldeslachts L, Cremer J, Tsui HC, Jonckheere A-C, et al. Cardiopulmonary and Immune Alterations in the Ts65Dn Mouse Model of Down Syndrome and Modulation by Epigallocatechin-3-Gallate-Enriched Green Tea Extract. Pharmaceutics. 2025;17:1366. https:\/\/doi.org\/10.3390\/pharmaceutics17111366.","journal-title":"Pharmaceutics"},{"key":"2054_CR71","doi-asserted-by":"publisher","first-page":"2570","DOI":"10.3324\/haematol.2023.283225","volume":"108","author":"A Baruchel","year":"2023","unstructured":"Baruchel A, Bourquin J-P, Crispino J, Cuartero S, Hasle H, Hitzler J, et al. Down syndrome and leukemia: from basic mechanisms to clinical advances. Haematologica. 2023;108:2570\u201381. https:\/\/doi.org\/10.3324\/haematol.2023.283225.","journal-title":"Haematologica"},{"key":"2054_CR72","doi-asserted-by":"publisher","first-page":"8","DOI":"10.3390\/hemato6020008","volume":"6","author":"E Papakonstantinou","year":"2025","unstructured":"Papakonstantinou E, Tragiannidis A, Ampatzidou M, Katzilakis N, Nikita M, Totikidis G, et al. Acute Leukemia in Children with Down Syndrome: A Report from the Hellenic HESPHO Group. Hemato. 2025;6:8. https:\/\/doi.org\/10.3390\/hemato6020008.","journal-title":"Hemato"},{"key":"2054_CR73","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.1038\/s41598-025-31340-3","volume":"16","author":"C-J Hsu","year":"2025","unstructured":"Hsu C-J, Schraw JM, Rasmussen SA, Chambers TM, Desrosiers TA, Huff CD, et al. Structural birth defects and leukemia risk in children with Down syndrome. Sci Rep. 2025;16:1741. https:\/\/doi.org\/10.1038\/s41598-025-31340-3.","journal-title":"Sci Rep"},{"key":"2054_CR74","doi-asserted-by":"publisher","first-page":"e27459","DOI":"10.1097\/md.0000000000027459","volume":"100","author":"M-P Schmidt","year":"2021","unstructured":"Schmidt M-P, Colita A, Ivanov A-V, Coriu D, Miron I-C. Outcomes of patients with Down syndrome and acute leukemia. Medicine. 2021;100:e27459. https:\/\/doi.org\/10.1097\/md.0000000000027459.","journal-title":"Medicine"},{"key":"2054_CR75","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1159\/000530431","volume":"91","author":"TA Akker","year":"2024","unstructured":"Akker TA, van den, Liu Y-C, Liu H, Chapman J, Levine JM, Weinberg OK, et al. Myeloid Proliferations Associated with Down Syndrome: Clinicopathologic Characteristics of Forty Cases from Five Large Academic Institutions. Pathobiology. 2024;91:89\u201398. https:\/\/doi.org\/10.1159\/000530431.","journal-title":"Pathobiology"},{"key":"2054_CR76","doi-asserted-by":"publisher","first-page":"166","DOI":"10.24287\/j.1072","volume":"25","author":"EG Boychenko","year":"2026","unstructured":"Boychenko EG, Lebedenko EA, Garbuzova IA. Transient abnormal myelopoiesis in children with Down syndrome: a literature review and clinical case presentation. Pediatr HematolOncol Immunopathol. 2026;25:166\u201374. https:\/\/doi.org\/10.24287\/j.1072.","journal-title":"Pediatr HematolOncol Immunopathol"},{"key":"2054_CR77","doi-asserted-by":"publisher","first-page":"636633","DOI":"10.3389\/fonc.2021.636633","volume":"11","author":"J Grimm","year":"2021","unstructured":"Grimm J, Heckl D, Klusmann J-H. Molecular Mechanisms of the Genetic Predisposition to Acute Megakaryoblastic Leukemia in Infants With Down Syndrome. Front Oncol. 2021;11:636633. https:\/\/doi.org\/10.3389\/fonc.2021.636633.","journal-title":"Front Oncol"},{"key":"2054_CR78","doi-asserted-by":"publisher","first-page":"101177","DOI":"10.1016\/j.ymgmr.2024.101177","volume":"42","author":"J Cai","year":"2025","unstructured":"Cai J, Zhou X, Zhou Y, Pi G. Clinical characterization and genetic analysis of transient abnormal myelopoiesis without the down syndrome phenotype. Mol Genet Metab Rep. 2025;42:101177. https:\/\/doi.org\/10.1016\/j.ymgmr.2024.101177.","journal-title":"Mol Genet Metab Rep"},{"key":"2054_CR79","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1016\/j.jaci.2013.01.046","volume":"131","author":"K Pieper","year":"2013","unstructured":"Pieper K, Grimbacher B, Eibel H. B-cell biology and development. J Allergy Clin Immunol. 2013;131:959\u201371. https:\/\/doi.org\/10.1016\/j.jaci.2013.01.046.","journal-title":"J Allergy Clin Immunol"},{"key":"2054_CR80","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/s41586-024-07946-4","volume":"634","author":"AR Marderstein","year":"2024","unstructured":"Marderstein AR, Zuani MD, Moeller R, Bezney J, Padhi EM, Wong S, et al. Single-cell multi-omics map of human fetal blood in Down syndrome. Nature. 2024;634:104\u201312. https:\/\/doi.org\/10.1038\/s41586-024-07946-4.","journal-title":"Nature"},{"key":"2054_CR81","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1016\/j.jaci.2014.07.015","volume":"134","author":"RHJ Verstegen","year":"2014","unstructured":"Verstegen RHJ, Driessen GJ, Bartol SJW, van Noesel CJM, Boon L, Burg M, van der, et al. Defective B-cell memory in patients with Down syndrome. J Allergy Clin Immunol. 2014;134:1346\u2013e13539. https:\/\/doi.org\/10.1016\/j.jaci.2014.07.015.","journal-title":"J Allergy Clin Immunol"},{"key":"2054_CR82","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.clicom.2025.09.001","volume":"8","author":"T Satnarine","year":"2025","unstructured":"Satnarine T, Pundit V, de Almeida AX, Wyke M, Kleiner G, Gans M. Immunologic profiles and infection patterns in patients with down syndrome: A retrospective review. Clin Immunol Commun. 2025;8:54\u20139. https:\/\/doi.org\/10.1016\/j.clicom.2025.09.001.","journal-title":"Clin Immunol Commun"},{"key":"2054_CR83","doi-asserted-by":"publisher","first-page":"1056925","DOI":"10.3389\/fendo.2023.1056925","volume":"14","author":"SL Grace","year":"2023","unstructured":"Grace SL, Mortimer GL, Kozhakhmetova A, Leveret J, Newton R, Reimand K, et al. Increased levels of anti-BSA antibodies in children with Down syndrome. Front Endocrinol. 2023;14:1056925. https:\/\/doi.org\/10.3389\/fendo.2023.1056925.","journal-title":"Front Endocrinol"},{"key":"2054_CR84","doi-asserted-by":"publisher","unstructured":"van Seventer JM, Hochberg NS. International encyclopedia of public health (Second Edition). P Epidemiol Dis Infect Dis 2017;22\u201339. https:\/\/doi.org\/10.1016\/b978-0-12-803678-5.00516-6","DOI":"10.1016\/b978-0-12-803678-5.00516-6"},{"key":"2054_CR85","doi-asserted-by":"publisher","first-page":"246","DOI":"10.3390\/children11020246","volume":"11","author":"M Ghezzi","year":"2024","unstructured":"Ghezzi M, Garancini N, Santis RD, Gianolio L, Zirpoli S, Mandelli A, et al. Recurrent Respiratory Infections in Children with Down Syndrome: A Review. Children. 2024;11:246. https:\/\/doi.org\/10.3390\/children11020246.","journal-title":"Children"},{"key":"2054_CR86","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1002\/ajmg.a.61924","volume":"185","author":"SL Santoro","year":"2021","unstructured":"Santoro SL, Chicoine B, Jasien JM, Kim JL, Stephens M, Bulova P, et al. Pneumonia and respiratory infections in Down syndrome: A scoping review of the literature. Am J M\u00e9d Genet Part A. 2021;185:286\u201399. https:\/\/doi.org\/10.1002\/ajmg.a.61924.","journal-title":"Am J M\u00e9d Genet Part A"},{"key":"2054_CR87","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1016\/s0140-6736(05)71877-8","volume":"365","author":"J Bryce","year":"2005","unstructured":"Bryce J, Boschi-Pinto C, Shibuya K, Black RE. Group the WCHER. WHO estimates of the causes of death in children. Lancet. 2005;365:1147\u201352. https:\/\/doi.org\/10.1016\/s0140-6736(05)71877-8.","journal-title":"Lancet"},{"key":"2054_CR88","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1046\/j.1440-1754.1999.00386.x","volume":"35","author":"J Hilton","year":"1999","unstructured":"Hilton J, Fitzgerald D, Cooper D. Respiratory morbidity of hospitalized children with Trisomy 21. J Paediatr Child Heal. 1999;35:383\u20136. https:\/\/doi.org\/10.1046\/j.1440-1754.1999.00386.x.","journal-title":"J Paediatr Child Heal"},{"key":"2054_CR89","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1007\/s12098-014-1389-4","volume":"81","author":"S Kapoor","year":"2014","unstructured":"Kapoor S, Bhayana S, Singh A, Kishore J. Co-morbidities Leading to Mortality or Hospitalization in Children with Down Syndrome and its Effect on the Quality of Life of their Parents. Indian J Pediatr. 2014;81:1302\u20136. https:\/\/doi.org\/10.1007\/s12098-014-1389-4.","journal-title":"Indian J Pediatr"},{"key":"2054_CR90","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1017\/s104795110700042x","volume":"17","author":"C Medrano","year":"2007","unstructured":"Medrano C, Garcia-Guereta L, Grueso J, Insa B, Ballesteros F, Casaldaliga J, et al. Respiratory infection in congenital cardiac disease. Hospitalizations in young children in Spain during 2004 and 2005: the CIVIC Epidemiologic Study. Cardiol Young. 2007;17:360\u201371. https:\/\/doi.org\/10.1017\/s104795110700042x.","journal-title":"Cardiol Young"},{"key":"2054_CR91","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1097\/inf.0000000000002666","volume":"39","author":"YN L\u00f6wensteyn","year":"2020","unstructured":"L\u00f6wensteyn YN, Phijffer EWEM, Simons JVL, Scheltema NM, Mazur NI, Nair H, et al. Respiratory Syncytial Virus-related Death in Children With Down Syndrome. Pediatr Infect Dis J. 2020;39:665\u201370. https:\/\/doi.org\/10.1097\/inf.0000000000002666.","journal-title":"Pediatr Infect Dis J"},{"key":"2054_CR92","doi-asserted-by":"publisher","first-page":"e1076","DOI":"10.1542\/peds.2007-0788","volume":"120","author":"BLP Bloemers","year":"2007","unstructured":"Bloemers BLP, van Furth AM, Weijerman ME, Gemke RJBJ, Broers CJM, Ende K, van den, et al. Down Syndrome: A Novel Risk Factor for Respiratory Syncytial Virus Bronchiolitis\u2014 A Prospective Birth-Cohort Study. Pediatrics. 2007;120:e1076\u201381. https:\/\/doi.org\/10.1542\/peds.2007-0788.","journal-title":"Pediatrics"},{"key":"2054_CR93","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1016\/j.jpeds.2014.11.058","volume":"166","author":"DR Stagliano","year":"2015","unstructured":"Stagliano DR, Nylund CM, Eide MB, Eberly MD. Children with Down Syndrome Are High-Risk for Severe Respiratory Syncytial Virus Disease. J Pediatr. 2015;166:703\u2013e7092. https:\/\/doi.org\/10.1016\/j.jpeds.2014.11.058.","journal-title":"J Pediatr"},{"key":"2054_CR94","doi-asserted-by":"publisher","first-page":"2047","DOI":"10.1016\/s0140-6736(22)00478-0","volume":"399","author":"Y Li","year":"2022","unstructured":"Li Y, Wang X, Blau DM, Caballero MT, Feikin DR, Gill CJ, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis. Lancet. 2022;399:2047\u201364. https:\/\/doi.org\/10.1016\/s0140-6736(22)00478-0.","journal-title":"Lancet"},{"key":"2054_CR95","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1007\/s00431-025-06596-6","volume":"184","author":"KA Domany","year":"2025","unstructured":"Domany KA, Golan-Tripto I, Burrack N, Masarweh K, Gur M, Rochman M, et al. Risk factors associated with severe RSV disease among hospitalized children in the second year of life: a multicenter study. Eur J Pediatr. 2025;184:799. https:\/\/doi.org\/10.1007\/s00431-025-06596-6.","journal-title":"Eur J Pediatr"},{"key":"2054_CR96","doi-asserted-by":"publisher","first-page":"e20180225","DOI":"10.1542\/peds.2018-0225","volume":"142","author":"AA Beckhaus","year":"2018","unstructured":"Beckhaus AA, Castro-Rodriguez JA. Down Syndrome and the Risk of Severe RSV Infection: A Meta-analysis. Pediatrics. 2018;142:e20180225. https:\/\/doi.org\/10.1542\/peds.2018-0225.","journal-title":"Pediatrics"},{"key":"2054_CR97","doi-asserted-by":"publisher","first-page":"621440","DOI":"10.3389\/fimmu.2021.621440","volume":"12","author":"T Illouz","year":"2021","unstructured":"Illouz T, Biragyn A, Iulita MF, Flores-Aguilar L, Dierssen M, Toma ID, et al. Immune Dysregulation and the Increased Risk of Complications and Mortality Following Respiratory Tract Infections in Adults With Down Syndrome. Front Immunol. 2021;12:621440. https:\/\/doi.org\/10.3389\/fimmu.2021.621440.","journal-title":"Front Immunol"},{"key":"2054_CR98","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1016\/j.jpeds.2011.11.004","volume":"160","author":"P Zachariah","year":"2012","unstructured":"Zachariah P, Ruttenber M, Sim\u00f5es EAF. Down Syndrome and Hospitalizations due to Respiratory Syncytial Virus: A Population-Based Study. J Pediatr. 2012;160:827\u2013e8311. https:\/\/doi.org\/10.1016\/j.jpeds.2011.11.004.","journal-title":"J Pediatr"},{"key":"2054_CR99","doi-asserted-by":"publisher","first-page":"020413","DOI":"10.7189\/jogh.07.020413","volume":"7","author":"M Chan","year":"2017","unstructured":"Chan M, Park JJ, Shi T, Martin\u00f3n\u2013Torres F, Bont L, Nair H, et al. The burden of respiratory syncytial virus (RSV) associated acute lower respiratory infections in children with Down syndrome: A systematic review and meta\u2013analysis. J Glob Heal. 2017;7:020413. https:\/\/doi.org\/10.7189\/jogh.07.020413.","journal-title":"J Glob Heal"},{"key":"2054_CR100","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1111\/irv.12431","volume":"11","author":"M S\u00e1nchez-Luna","year":"2017","unstructured":"S\u00e1nchez-Luna M, Medrano C, Lirio J, Group the RS, Suazo JAH, Pe\u00f1a M, et al. Down syndrome as risk factor for respiratory syncytial virus hospitalization: A prospective multicenter epidemiological study. Influ Other Respir Viruses. 2017;11:157\u201364. https:\/\/doi.org\/10.1111\/irv.12431.","journal-title":"Influ Other Respir Viruses"},{"key":"2054_CR101","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.3390\/medicina60091480","volume":"60","author":"SY Takita","year":"2024","unstructured":"Takita SY, S\u00e9 ABS, Hoffmann GM, Bunduki W, Carvalho LR, Fonseca CRB. Causes of Hospitalization in Children with Down Syndrome. Medicina. 2024;60:1480. https:\/\/doi.org\/10.3390\/medicina60091480.","journal-title":"Medicina"},{"key":"2054_CR102","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1542\/peds.2013-3916","volume":"133","author":"H Yi","year":"2014","unstructured":"Yi H, Lanct\u00f4t KL, Bont L, Bloemers BLP, Weijerman M, Broers C, et al. Respiratory Syncytial Virus Prophylaxis in Down Syndrome: A Prospective Cohort Study. Pediatrics. 2014;133:1031\u20137. https:\/\/doi.org\/10.1542\/peds.2013-3916.","journal-title":"Pediatrics"},{"key":"2054_CR103","doi-asserted-by":"publisher","first-page":"e667","DOI":"10.5001\/omj.2024.111","volume":"39","author":"AS Alharbi","year":"2024","unstructured":"Alharbi AS, Alnemri AR, Abushahin A, Alhammadi E, AlDhanhani HSM, Obaid L, et al. Palivizumab for the Prophylaxis of Respiratory Syncytial Virus Disease: Expert Opinion and Recommendations for the Gulf Cooperation Council Region. Oman M\u00e9d J. 2024;39:e667\u2013667. https:\/\/doi.org\/10.5001\/omj.2024.111.","journal-title":"Oman M\u00e9d J"},{"key":"2054_CR104","doi-asserted-by":"publisher","first-page":"e95336","DOI":"10.7759\/cureus.95336","volume":"17","author":"YK Ameen","year":"2025","unstructured":"Ameen YK. Seasonal Influenza: A Narrative Review of Epidemiology, Clinical Features, and Preventive Strategies. Cureus. 2025;17:e95336. https:\/\/doi.org\/10.7759\/cureus.95336.","journal-title":"Cureus"},{"key":"2054_CR105","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.3201\/eid1608.091931","volume":"16","author":"R P\u00e9rez-Padilla","year":"2010","unstructured":"P\u00e9rez-Padilla R, Fern\u00e1ndez R, Garc\u00eda-Sancho C, Franco-Marina F, Aburto O, L\u00f3pez-Gatell H, et al. Pandemic (H1N1) 2009 Virus and Down Syndrome Patients - 16, Number 8\u2014August 2010 - Emerging Infectious Diseases journal - CDC. Emerg Infect Dis. 2010;16:1312\u20134. https:\/\/doi.org\/10.3201\/eid1608.091931.","journal-title":"Emerg Infect Dis"},{"key":"2054_CR106","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.ss7706a1","volume":"73","author":"A Naquin","year":"2024","unstructured":"Naquin A, O\u2019Halloran A, Ujamaa D, Sundaresan D, Masalovich S, Cummings CN, et al. Laboratory-Confirmed Influenza-Associated Hospitalizations Among Children and Adults \u2014 Influenza Hospitalization Surveillance Network, United States, 2010\u20132023. MMWR Surveill Summ. 2024;73:1\u201318. https:\/\/doi.org\/10.15585\/mmwr.ss7706a1.","journal-title":"MMWR Surveill Summ"},{"key":"2054_CR107","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.3390\/jcm14061785","volume":"14","author":"K Kanecki","year":"2025","unstructured":"Kanecki K, Lewtak K, Tyszko P, Gory\u0144ski P, Rz\u0105d M, Okr\u0119glicka K, et al. Hospitalizations and In-Hospital Fatality Among Influenza Patients in the Pre-Pandemic and COVID-19 Pandemic Periods. J Clin Med. 2025;14:1785. https:\/\/doi.org\/10.3390\/jcm14061785.","journal-title":"J Clin Med"},{"key":"2054_CR108","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1111\/irv.12335","volume":"9","author":"J Puig-Barber\u00e0","year":"2015","unstructured":"Puig-Barber\u00e0 J, Tormos A, Trushakova S, Sominina A, Pisareva M, Ciblak MA, et al. The Global Influenza Hospital Surveillance Network (GIHSN): a new platform to describe the epidemiology of severe influenza. Influ Other Respir Viruses. 2015;9:277\u201386. https:\/\/doi.org\/10.1111\/irv.12335.","journal-title":"Influ Other Respir Viruses"},{"key":"2054_CR109","doi-asserted-by":"publisher","first-page":"e0338519","DOI":"10.1371\/journal.pone.0338519","volume":"21","author":"DB Victorino","year":"2026","unstructured":"Victorino DB, Malheiros JM, Ten-Caten F, Betta VHC, Barbosa FFS, Ghneim K, et al. Elevated mortality and upregulated SARS-CoV-2-associated pathways in innate and adaptive immune cells from individuals with Down syndrome. PLoS ONE. 2026;21:e0338519. https:\/\/doi.org\/10.1371\/journal.pone.0338519.","journal-title":"PLoS ONE"},{"key":"2054_CR110","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1038\/s41436-020-01004-w","volume":"23","author":"L Malle","year":"2021","unstructured":"Malle L, Gao C, Hur C, Truong HQ, Bouvier NM, Percha B, et al. Individuals with Down syndrome hospitalized with COVID-19 have more severe disease. Genet Med. 2021;23:576\u201380. https:\/\/doi.org\/10.1038\/s41436-020-01004-w.","journal-title":"Genet Med"},{"key":"2054_CR111","doi-asserted-by":"publisher","first-page":"100769","DOI":"10.1016\/j.eclinm.2021.100769","volume":"33","author":"A H\u00fcls","year":"2021","unstructured":"H\u00fcls A, Costa ACS, Dierssen M, Baksh RA, Bargagna S, Baumer NT, et al. Medical vulnerability of individuals with Down syndrome to severe COVID-19\u2013data from the Trisomy 21 Research Society and the UK ISARIC4C survey. EClinicalMedicine. 2021;33:100769. https:\/\/doi.org\/10.1016\/j.eclinm.2021.100769.","journal-title":"EClinicalMedicine"},{"key":"2054_CR112","doi-asserted-by":"publisher","first-page":"26","DOI":"10.3201\/eid2901.220530","volume":"29","author":"C Leung","year":"2023","unstructured":"Leung C, Su L, Sim\u00f5es-e-Silva AC, Arocha LS, de Paiva KM, Haas P. Risk for Severe Illness and Death among Pediatric Patients with Down Syndrome Hospitalized for COVID-19, Brazil - 29, Number 1\u2014January 2023 - Emerging Infectious Diseases journal - CDC. Emerg Infect Dis. 2023;29:26\u201335. https:\/\/doi.org\/10.3201\/eid2901.220530.","journal-title":"Emerg Infect Dis"},{"key":"2054_CR113","doi-asserted-by":"publisher","first-page":"3748","DOI":"10.3390\/jcm10163748","volume":"10","author":"DR de Asua","year":"2021","unstructured":"de Asua DR, Mayer MA, Ortega M del, Borrel C, Bermejo JM, de J T, Gonz\u00e1lez-Lamu\u00f1o D, et al. Comparison of COVID-19 and Non-COVID-19 Pneumonia in Down Syndrome. J Clin Med. 2021;10:3748. https:\/\/doi.org\/10.3390\/jcm10163748.","journal-title":"J Clin Med"},{"key":"2054_CR114","doi-asserted-by":"publisher","unstructured":"Joshi AY, Abraham RS, Snyder MR, Boyce TG. Immune evaluation and vaccine responses in Down syndrome: Evidence of immunodeficiency? Vaccine. 2011;29:5040\u20136. https:\/\/doi.org\/10.1016\/j.vaccine.2011.04.060","DOI":"10.1016\/j.vaccine.2011.04.060"},{"key":"2054_CR115","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1093\/infdis\/jiac235","volume":"226","author":"BMM Streng","year":"2022","unstructured":"Streng BMM, Bont M, Delemarre EM, Binnendijk RS, Smit G, Hartog G, den, et al. Decreased Antibody Response After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Patients With Down Syndrome. J Infect Dis. 2022;226:673\u20137. https:\/\/doi.org\/10.1093\/infdis\/jiac235.","journal-title":"J Infect Dis"},{"key":"2054_CR116","doi-asserted-by":"publisher","unstructured":"Sali M, Carf\u00ec A, Paola AD, Boza MP, Zampino G, Sanguinetti M, et al. SARS-CoV-2 vaccine humoral response in adults with Down syndrome. Clin Microbiol Infect. 2022;28. https:\/\/doi.org\/10.1016\/j.cmi.2022.04.008. :1155.e1-1155.e4.","DOI":"10.1016\/j.cmi.2022.04.008"},{"key":"2054_CR117","doi-asserted-by":"publisher","first-page":"e155","DOI":"10.1093\/cid\/ciac590","volume":"76","author":"L Esparcia-Pinedo","year":"2022","unstructured":"Esparcia-Pinedo L, Yarci-Carri\u00f3n A, Mateo-Jim\u00e9nez G, Ropero N, G\u00f3mez-Caba\u00f1as L, Lancho-S\u00e1nchez \u00c1, et al. Development of an Effective Immune Response in Adults With Down Syndrome After Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination. Clin Infect Dis. 2022;76:e155\u201362. https:\/\/doi.org\/10.1093\/cid\/ciac590.","journal-title":"Clin Infect Dis"},{"key":"2054_CR118","first-page":"298","volume":"31","author":"RA Hawkes","year":"1978","unstructured":"Hawkes RA, Boughton CR, Schroeter DR. The antibody response of institutionalized Down\u2019s syndrome patients to seven microbial antigens. Clin Exp Immunol. 1978;31:298\u2013304.","journal-title":"Clin Exp Immunol"},{"key":"2054_CR119","doi-asserted-by":"publisher","first-page":"1587","DOI":"10.1590\/s0100-879x2006005000047","volume":"39","author":"BT Costa-Carvalho","year":"2006","unstructured":"Costa-Carvalho BT, Martinez RMA, Dias ATN, Kubo CA, Barros-Nunes P, Leiva L, et al. Antibody response to pneumococcal capsular polysaccharide vaccine in Down syndrome patients. Braz J M\u00e9d Biol Res. 2006;39:1587\u201392. https:\/\/doi.org\/10.1590\/s0100-879x2006005000047.","journal-title":"Braz J M\u00e9d Biol Res"},{"key":"2054_CR120","doi-asserted-by":"publisher","first-page":"6261","DOI":"10.1016\/j.vaccine.2013.09.070","volume":"31","author":"MAA Kusters","year":"2013","unstructured":"Kusters MAA, Manders NCC, Jong BAW, van de, Hout RWNM, Rijkers GT, de Vries E. Functionality of the pneumococcal antibody response in down syndrome subjects. Vaccine. 2013;31:6261\u20135. https:\/\/doi.org\/10.1016\/j.vaccine.2013.09.070.","journal-title":"Vaccine"},{"key":"2054_CR121","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.jped.2024.06.007","volume":"100","author":"KR Martins","year":"2024","unstructured":"Martins KR, Alves FA, Silva LR, da da, Silva LOA, Segundo GRS. Different immunological patterns of Down syndrome patients with and without recurrent infections. J Pediatr. 2024;100:653\u20139. https:\/\/doi.org\/10.1016\/j.jped.2024.06.007.","journal-title":"J Pediatr"},{"key":"2054_CR122","doi-asserted-by":"publisher","first-page":"2583416","DOI":"10.1080\/21645515.2025.2583416","volume":"21","author":"LCM Hensen","year":"2025","unstructured":"Hensen LCM, Streng BMM, van Wijk F, Nierkens S, van Binnendijk RS, Buisman A-M, et al. T-cell responses to SARS-CoV-2 vaccinations in adults with Down syndrome \u2013 a prospective cohort study. Hum Vaccines Immunother. 2025;21:2583416. https:\/\/doi.org\/10.1080\/21645515.2025.2583416.","journal-title":"Hum Vaccines Immunother"},{"key":"2054_CR123","doi-asserted-by":"publisher","first-page":"530","DOI":"10.3390\/vaccines10040530","volume":"10","author":"A H\u00fcls","year":"2022","unstructured":"H\u00fcls A, Feany PT, Zisman SI, Costa ACS, Dierssen M, Balogh R, et al. COVID-19 Vaccination of Individuals with Down Syndrome\u2014Data from the Trisomy 21 Research Society Survey on Safety, Efficacy, and Factors Associated with the Decision to Be Vaccinated. Vaccines. 2022;10:530. https:\/\/doi.org\/10.3390\/vaccines10040530.","journal-title":"Vaccines"},{"key":"2054_CR124","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.jinf.2022.11.014","volume":"86","author":"A Yarci-Carri\u00f3n","year":"2023","unstructured":"Yarci-Carri\u00f3n A, Esparcia-Pinedo L, Mateo-Jim\u00e9nez G, Alfranca A, de As\u00faa DR, Guti\u00e9rrez-Cobos A. Effect of a SARS-CoV-2 booster vaccine dose on the immune response of adults with Down syndrome. J Infect. 2023;86:154\u2013225. https:\/\/doi.org\/10.1016\/j.jinf.2022.11.014.","journal-title":"J Infect"}],"container-title":["Journal of Clinical Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10875-026-02054-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10875-026-02054-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10875-026-02054-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T07:26:01Z","timestamp":1788247561000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10875-026-02054-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":124,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2054"],"URL":"https:\/\/doi.org\/10.1007\/s10875-026-02054-6","relation":{},"ISSN":["1573-2592"],"issn-type":[{"value":"1573-2592","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]},"assertion":[{"value":"27 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Ethics, Consent to Participate, and Consent to Publish declarations: not applicable.","order":1,"name":"Ethics","label":"Ethics Approval and Consent to Participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"86"}}