{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T20:30:21Z","timestamp":1777321821446,"version":"3.51.4"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005416","name":"Norges Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["196403"],"award-info":[{"award-number":["196403"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006095","name":"Helse S\u00f8r-\u00d8st RHF","doi-asserted-by":"publisher","award":["2008046"],"award-info":[{"award-number":["2008046"]}],"id":[{"id":"10.13039\/501100006095","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005366","name":"University of Oslo","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005366","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Infection"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>The mechanisms that control inflammation in scrub typhus are not fully elucidated. The Notch pathways are important regulators of inflammation and infection, but have not been investigated in scrub typhus.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Plasma levels of the canonical Notch ligand Delta-like protein 1 (DLL1) were measured by enzyme immunoassay and RNA expression of the Notch receptors (<jats:italic>NOTCH1<\/jats:italic>, <jats:italic>NOTCH2<\/jats:italic> and <jats:italic>NOTCH4<\/jats:italic>) in whole blood was analyzed by real-time PCR in patients with scrub typhus (<jats:italic>n<\/jats:italic>\u2009=\u2009129), in patients with similar febrile illness without <jats:italic>O. tsutsugamushi<\/jats:italic> infection (<jats:italic>n<\/jats:italic>\u2009=\u200931) and in healthy controls (<jats:italic>n<\/jats:italic>\u2009=\u200931); all from the same area of South India.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Our main results were: (i) plasma DLL1 was markedly increased in scrub typhus patients at hospital admission with a significant decrease during recovery. (ii) RNA expression of <jats:italic>NOTCH4<\/jats:italic> was decreased at admission in whole blood. (iii) A similar pattern for DLL1 and <jats:italic>NOTCH4<\/jats:italic> was seen in febrile disease controls. (iv) Admission DLL1 in plasma was associated with disease severity and short-term survival. (vi) Regulation of Notch pathways in <jats:italic>O. tsutsugamushi-<\/jats:italic>infected monocytes as evaluated by public repository data revealed enhanced canonical Notch activation with upregulation of DLL1 and downregulation of <jats:italic>NOTCH4<\/jats:italic>.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our findings suggest that scrub typhus patients are characterized by enhanced canonical Notch activation. Elevated plasma levels of DLL1 were associated with organ dysfunction and poor outcomes in these patients.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s15010-024-02192-2","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T07:02:43Z","timestamp":1710831763000},"page":"1357-1365","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Canonical notch activation in patients with scrub typhus: association with organ dysfunction and poor outcome"],"prefix":"10.1007","volume":"52","author":[{"given":"Jan K.","family":"Dam\u00e5s","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kari","family":"Otterdal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"Astrup","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tove","family":"Lekva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeshina","family":"Janardhanan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annika","family":"Michelsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P\u00e5l","family":"Aukrust","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George M.","family":"Varghese","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thor","family":"Ueland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,3,19]]},"reference":[{"key":"2192_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/tropicalmed3010011","author":"J Jiang","year":"2018","unstructured":"Jiang J, Richards AL. Scrub typhus: no longer restricted to the tsutsugamushi triangle. Trop Med Infect Dis. 2018. https:\/\/doi.org\/10.3390\/tropicalmed3010011.","journal-title":"Trop Med Infect Dis"},{"key":"2192_CR2","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1093\/trstmh\/trx017","volume":"111","author":"S Rajapakse","year":"2017","unstructured":"Rajapakse S, Weeratunga P, Sivayoganathan S, Fernando SD. Clinical manifestations of scrub typhus. Trans R Soc Trop Med Hyg. 2017;111:43\u201354. https:\/\/doi.org\/10.1093\/trstmh\/trx017.","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"2192_CR3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0006062","volume":"11","author":"G Xu","year":"2017","unstructured":"Xu G, Walker DH, Jupiter D, Melby PC, Arcari CM. A review of the global epidemiology of scrub typhus. PLoS Negl Trop Dis. 2017;11: e0006062. https:\/\/doi.org\/10.1371\/journal.pntd.0006062.","journal-title":"PLoS Negl Trop Dis"},{"key":"2192_CR4","doi-asserted-by":"publisher","DOI":"10.1128\/cmr.00076-17","author":"FE D\u00edaz","year":"2018","unstructured":"D\u00edaz FE, Abarca K, Kalergis AM. An update on host-pathogen interplay and modulation of immune responses during orientia tsutsugamushi infection. Clin Microbiol Rev. 2018. https:\/\/doi.org\/10.1128\/cmr.00076-17.","journal-title":"Clin Microbiol Rev"},{"key":"2192_CR5","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.micpath.2012.10.001","volume":"55","author":"W Tantibhedhyangkul","year":"2013","unstructured":"Tantibhedhyangkul W, Ben Amara A, Textoris J, Gorvel L, Ghigo E, Capo C, et al. Orientia tsutsugamushi, the causative agent of scrub typhus, induces an inflammatory program in human macrophages. Microb Pathog. 2013;55:55\u201363. https:\/\/doi.org\/10.1016\/j.micpath.2012.10.001.","journal-title":"Microb Pathog"},{"key":"2192_CR6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001028","volume":"5","author":"W Tantibhedhyangkul","year":"2011","unstructured":"Tantibhedhyangkul W, Prachason T, Waywa D, El Filali A, Ghigo E, Thongnoppakhun W, et al. Orientia tsutsugamushi stimulates an original gene expression program in monocytes: relationship with gene expression in patients with scrub typhus. PLoS Negl Trop Dis. 2011;5: e1028. https:\/\/doi.org\/10.1371\/journal.pntd.0001028.","journal-title":"PLoS Negl Trop Dis"},{"key":"2192_CR7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001789","volume":"6","author":"BA Cho","year":"2012","unstructured":"Cho BA, Ko Y, Kim YS, Kim S, Choi MS, Kim IS, et al. Phenotypic characterization of peripheral T cells and their dynamics in scrub typhus patients. PLoS Negl Trop Dis. 2012;6: e1789. https:\/\/doi.org\/10.1371\/journal.pntd.0001789.","journal-title":"PLoS Negl Trop Dis"},{"key":"2192_CR8","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1016\/j.jinf.2014.06.018","volume":"69","author":"K Otterdal","year":"2014","unstructured":"Otterdal K, Janardhanan J, Astrup E, Ueland T, Prakash JA, Lekva T, et al. Increased endothelial and macrophage markers are associated with disease severity and mortality in scrub typhus. J Infect. 2014;69:462\u20139. https:\/\/doi.org\/10.1016\/j.jinf.2014.06.018.","journal-title":"J Infect"},{"key":"2192_CR9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002648","volume":"8","author":"E Astrup","year":"2014","unstructured":"Astrup E, Janardhanan J, Otterdal K, Ueland T, Prakash JA, Lekva T, et al. Cytokine network in scrub typhus: high levels of interleukin-8 are associated with disease severity and mortality. PLoS Negl Trop Dis. 2014;8: e2648. https:\/\/doi.org\/10.1371\/journal.pntd.0002648.","journal-title":"PLoS Negl Trop Dis"},{"key":"2192_CR10","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/nri3445","volume":"13","author":"F Radtke","year":"2013","unstructured":"Radtke F, MacDonald HR, Tacchini-Cottier F. Regulation of innate and adaptive immunity by Notch. Nat Rev Immunol. 2013;13:427\u201337. https:\/\/doi.org\/10.1038\/nri3445.","journal-title":"Nat Rev Immunol"},{"key":"2192_CR11","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.10334","volume":"8","author":"D Vlachakis","year":"2020","unstructured":"Vlachakis D, Papageorgiou L, Papadaki A, Georga M, Kossida S, Eliopoulos E. An updated evolutionary study of the Notch family reveals a new ancient origin and novel invariable motifs as potential pharmacological targets. PeerJ. 2020;8: e10334. https:\/\/doi.org\/10.7717\/peerj.10334.","journal-title":"PeerJ"},{"key":"2192_CR12","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.imlet.2019.01.004","volume":"206","author":"SV Chiplunkar","year":"2019","unstructured":"Chiplunkar SV, Gogoi D. The multifaceted role of Notch signal in regulating T cell fate. Immunol Lett. 2019;206:59\u201364. https:\/\/doi.org\/10.1016\/j.imlet.2019.01.004.","journal-title":"Immunol Lett"},{"key":"2192_CR13","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1007\/s00011-021-01442-5","volume":"70","author":"RC Castro","year":"2021","unstructured":"Castro RC, Goncales RA, Zambuzi FA, Frantz FG. Notch signaling pathway in infectious diseases: role in the regulation of immune response. Inflamm Res. 2021;70:261\u201374. https:\/\/doi.org\/10.1007\/s00011-021-01442-5.","journal-title":"Inflamm Res"},{"key":"2192_CR14","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/s41569-018-0100-2","volume":"15","author":"D MacGrogan","year":"2018","unstructured":"MacGrogan D, Munch J, de la Pompa JL. Notch and interacting signalling pathways in cardiac development, disease, and regeneration. Nat Rev Cardiol. 2018;15:685\u2013704. https:\/\/doi.org\/10.1038\/s41569-018-0100-2.","journal-title":"Nat Rev Cardiol"},{"key":"2192_CR15","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1172\/jci35647","volume":"119","author":"T Ito","year":"2009","unstructured":"Ito T, Schaller M, Hogaboam CM, Standiford TJ, Sandor M, Lukacs NW, et al. TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4. J Clin Invest. 2009;119:33\u201346. https:\/\/doi.org\/10.1172\/jci35647.","journal-title":"J Clin Invest"},{"key":"2192_CR16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002560","volume":"8","author":"F Auderset","year":"2012","unstructured":"Auderset F, Schuster S, Coutaz M, Koch U, Desgranges F, Merck E, et al. Redundant Notch1 and Notch2 signaling is necessary for IFN\u03b3 secretion by T helper 1 cells during infection with Leishmania major. PLoS Pathog. 2012;8: e1002560. https:\/\/doi.org\/10.1371\/journal.ppat.1002560.","journal-title":"PLoS Pathog"},{"key":"2192_CR17","doi-asserted-by":"publisher","first-page":"e1002341","DOI":"10.1371\/journal.ppat.1002341","volume":"7","author":"T Ito","year":"2011","unstructured":"Ito T, Allen RM, Carson WFT, Schaller M, Cavassani KA, Hogaboam CM, et al. The critical role of Notch ligand Delta-like 1 in the pathogenesis of influenza A virus (H1N1) infection. PLoS Pathog. 2011;7:e1002341. https:\/\/doi.org\/10.1371\/journal.ppat.1002341.","journal-title":"PLoS Pathog"},{"key":"2192_CR18","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00672-16","author":"TT Lina","year":"2016","unstructured":"Lina TT, Dunphy PS, Luo T, McBride JW. Ehrlichia chaffeensis TRP120 activates canonical notch signaling to downregulate TLR2\/4 expression and promote intracellular survival. MBio. 2016. https:\/\/doi.org\/10.1128\/mBio.00672-16.","journal-title":"MBio"},{"key":"2192_CR19","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1172\/JCI76468","volume":"125","author":"J Xu","year":"2015","unstructured":"Xu J, Chi F, Guo T, Punj V, Lee WN, French SW, et al. NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J Clin Invest. 2015;125:1579\u201390. https:\/\/doi.org\/10.1172\/JCI76468.","journal-title":"J Clin Invest"},{"key":"2192_CR20","doi-asserted-by":"publisher","DOI":"10.3390\/cells9010111","author":"E Keewan","year":"2020","unstructured":"Keewan E, Naser SA. The role of notch signaling in macrophages during inflammation and infection: implication in rheumatoid arthritis? Cells. 2020. https:\/\/doi.org\/10.3390\/cells9010111.","journal-title":"Cells"},{"key":"2192_CR21","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1007\/s12032-014-0945-0","volume":"31","author":"E Kontomanolis","year":"2014","unstructured":"Kontomanolis E, Panteliadou M, Giatromanolaki A, Pouliliou S, Efremidou E, Limberis V, et al. Delta-like ligand 4 (DLL4) in the plasma and neoplastic tissues from breast cancer patients: correlation with metastasis. Med Oncol. 2014;31:945. https:\/\/doi.org\/10.1007\/s12032-014-0945-0.","journal-title":"Med Oncol"},{"key":"2192_CR22","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1038\/nrmicro1866","volume":"6","author":"DH Walker","year":"2008","unstructured":"Walker DH, Ismail N. Emerging and re-emerging rickettsioses: endothelial cell infection and early disease events. Nat Rev Microbiol. 2008;6:375\u201386. https:\/\/doi.org\/10.1038\/nrmicro1866.","journal-title":"Nat Rev Microbiol"},{"key":"2192_CR23","doi-asserted-by":"publisher","first-page":"519","DOI":"10.4103\/ijmr.IJMR_4098_20","volume":"157","author":"A Jain","year":"2023","unstructured":"Jain A, Jain P, Rebello SC, Todaria M, Kaur H, Gupta N, et al. Determination of a cut-off value for the serological diagnosis of scrub typhus by detecting anti-Orientia tsutsugamushi immunoglobulin M. Indian J Med Res. 2023;157:519\u201323. https:\/\/doi.org\/10.4103\/ijmr.IJMR_4098_20.","journal-title":"Indian J Med Res"},{"key":"2192_CR24","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.3389\/fimmu.2018.01230","volume":"9","author":"MP Steinbuck","year":"2018","unstructured":"Steinbuck MP, Winandy S. A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells. Front Immunol. 2018;9:1230. https:\/\/doi.org\/10.3389\/fimmu.2018.01230.","journal-title":"Front Immunol"},{"key":"2192_CR25","doi-asserted-by":"publisher","first-page":"2556","DOI":"10.1002\/eji.200838722","volume":"39","author":"E Monsalve","year":"2009","unstructured":"Monsalve E, Ruiz-Garcia A, Baladron V, Ruiz-Hidalgo MJ, Sanchez-Solana B, Rivero S, et al. Notch1 upregulates LPS-induced macrophage activation by increasing NF-kappaB activity. Eur J Immunol. 2009;39:2556\u201370. https:\/\/doi.org\/10.1002\/eji.200838722.","journal-title":"Eur J Immunol"},{"key":"2192_CR26","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.642352","volume":"9","author":"A Akil","year":"2021","unstructured":"Akil A, Gutierrez-Garcia AK, Guenter R, Rose JB, Beck AW, Chen H, et al. Notch signaling in vascular endothelial cells, angiogenesis, and tumor progression: an update and prospective. Front Cell Dev Biol. 2021;9: 642352. https:\/\/doi.org\/10.3389\/fcell.2021.642352.","journal-title":"Front Cell Dev Biol"},{"key":"2192_CR27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0007675","volume":"14","author":"B Trent","year":"2020","unstructured":"Trent B, Liang Y, Xing Y, Esqueda M, Wei Y, Cho NH, et al. Polarized lung inflammation and Tie2\/angiopoietin-mediated endothelial dysfunction during severe Orientia tsutsugamushi infection. PLoS Negl Trop Dis. 2020;14: e0007675. https:\/\/doi.org\/10.1371\/journal.pntd.0007675.","journal-title":"PLoS Negl Trop Dis"},{"key":"2192_CR28","doi-asserted-by":"publisher","first-page":"241","DOI":"10.3389\/fcimb.2018.00241","volume":"8","author":"D Hildebrand","year":"2018","unstructured":"Hildebrand D, Uhle F, Sahin D, Krauser U, Weigand MA, Heeg K. The interplay of Notch signaling and STAT3 in TLR-activated human primary monocytes. Front Cell Infect Microbiol. 2018;8:241. https:\/\/doi.org\/10.3389\/fcimb.2018.00241.","journal-title":"Front Cell Infect Microbiol"},{"key":"2192_CR29","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.766713","volume":"12","author":"M Moll","year":"2021","unstructured":"Moll M, Reichel K, Nurjadi D, Former S, Krall LJ, Heeg K, et al. Notch ligand delta-like 1 is associated with loss of vascular endothelial barrier function. Front Physiol. 2021;12: 766713. https:\/\/doi.org\/10.3389\/fphys.2021.766713.","journal-title":"Front Physiol"},{"key":"2192_CR30","doi-asserted-by":"publisher","first-page":"11657","DOI":"10.1074\/jbc.M312102200","volume":"279","author":"F MacKenzie","year":"2004","unstructured":"MacKenzie F, Duriez P, Wong F, Noseda M, Karsan A. Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and -independent pathways. J Biol Chem. 2004;279:11657\u201363. https:\/\/doi.org\/10.1074\/jbc.M312102200.","journal-title":"J Biol Chem"},{"key":"2192_CR31","doi-asserted-by":"publisher","first-page":"2258","DOI":"10.1161\/ATVBAHA.108.174995","volume":"28","author":"T Quillard","year":"2008","unstructured":"Quillard T, Coupel S, Coulon F, Fitau J, Chatelais M, Cuturi MC, et al. Impaired Notch4 activity elicits endothelial cell activation and apoptosis: implication for transplant arteriosclerosis. Arterioscler Thromb Vasc Biol. 2008;28:2258\u201365. https:\/\/doi.org\/10.1161\/ATVBAHA.108.174995.","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2192_CR32","doi-asserted-by":"publisher","first-page":"734966","DOI":"10.3389\/fimmu.2021.734966","volume":"12","author":"S Lopez-Lopez","year":"2021","unstructured":"Lopez-Lopez S, Romero de Avila MJ, Hernandez de Leon NC, Ruiz-Marcos F, Baladron V, Nueda ML, et al. NOTCH4 exhibits anti-inflammatory activity in activated macrophages by interfering with interferon-gamma and TLR4 signaling. Front Immunol. 2021;12:734966. https:\/\/doi.org\/10.3389\/fimmu.2021.734966.","journal-title":"Front Immunol"}],"container-title":["Infection"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s15010-024-02192-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s15010-024-02192-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s15010-024-02192-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T18:49:09Z","timestamp":1722365349000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s15010-024-02192-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,19]]},"references-count":32,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["2192"],"URL":"https:\/\/doi.org\/10.1007\/s15010-024-02192-2","relation":{},"ISSN":["0300-8126","1439-0973"],"issn-type":[{"value":"0300-8126","type":"print"},{"value":"1439-0973","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,19]]},"assertion":[{"value":"4 December 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 March 2024","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"}},{"value":"There are no conflict of interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Blood samples from patients and controls were collected after obtaining informed and written consent from each participant. The study was approved by the local ethic committees; in India by the CMC, IRB & EC (Institutional Review Board & Ethic Committee, Christian Medical College, Vellore) and the Health Ministry Screening Committee, ICMR (Indian Council of Medical Research), in Norway by the Regional Committee for Medical and Health Research Ethics. The study was conducted according to the ethical guidelines from the Helsinki declaration.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}