{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T01:56:28Z","timestamp":1791510988504,"version":"4.3.4"},"reference-count":134,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,11,30]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Progress in the care of sickle cell disease (SCD) has been hampered by the extreme complexity of the SCD phenotype despite its monogenic inheritance. While epidemiological studies have identified clinical biomarkers of disease severity, with a few exceptions, these have not been routinely incorporated in clinical care algorithms. Furthermore, existing biomarkers have been poorly apt at providing objective parameters to diagnose sickle cell crisis, the hallmark, acute complication of SCD. The repercussions of these diagnostic limitations are reflected in suboptimal care and scarcity of adequate outcome measures for clinical research. Recent progress in molecular and imaging diagnostics has heralded a new era of personalized medicine in SCD. Precision medicine strategies are particularly timely, since molecular therapeutics are finally on the horizon. This chapter will summarize the existing evidence and promising data on biomarkers for clinical care and research in SCD.<\/jats:p>","DOI":"10.1182\/asheducation-2018.1.482","type":"journal-article","created":{"date-parts":[[2019,4,16]],"date-time":"2019-04-16T22:13:59Z","timestamp":1555452839000},"page":"482-492","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":35,"title":["Measuring success: utility of biomarkers in sickle cell disease clinical trials and care"],"prefix":"10.1182","volume":"2018","author":[{"given":"Ram","family":"Kalpatthi","sequence":"first","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology, Department of Pediatrics, Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico M.","family":"Novelli","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology and UPMC Heart, Lung and Blood Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"3","key":"2019111520400015700_B1","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1067\/mcp.2001.113989","article-title":"Biomarkers and surrogate endpoints: preferred definitions and conceptual framework","volume":"69","author":"Biomarkers Definitions Working Group","year":"2001","journal-title":"Clin Pharmacol Ther"},{"issue":"1","key":"2019111520400015700_B2","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1182\/blood.V65.1.183.183","article-title":"Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes","volume":"65","author":"Brittenham","year":"1985","journal-title":"Blood"},{"issue":"24","key":"2019111520400015700_B3","doi-asserted-by":"crossref","first-page":"3892","DOI":"10.1182\/blood-2013-05-498311","article-title":"Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies","volume":"122","author":"Manwani","year":"2013","journal-title":"Blood"},{"issue":"7","key":"2019111520400015700_B4","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1182\/blood-2015-09-618538","article-title":"Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology","volume":"127","author":"Zhang","year":"2016","journal-title":"Blood"},{"issue":"23","key":"2019111520400015700_B5","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1056\/NEJM199406093302303","article-title":"Mortality in sickle cell disease. Life expectancy and risk factors for early death","volume":"330","author":"Platt","year":"1994","journal-title":"N Engl J Med"},{"issue":"1","key":"2019111520400015700_B6","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.blre.2006.07.001","article-title":"Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes","volume":"21","author":"Kato","year":"2007","journal-title":"Blood Rev"},{"issue":"12","key":"2019111520400015700_B7","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1172\/JCI107516","article-title":"Life span of carbamylated red cells in sickle cell anemia","volume":"52","author":"Milner","year":"1973","journal-title":"J Clin Invest"},{"issue":"9","key":"2019111520400015700_B8","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1002\/ajh.24441","article-title":"Determinants of resting cerebral blood flow in sickle cell disease","volume":"91","author":"Bush","year":"2016","journal-title":"Am J Hematol"},{"issue":"4","key":"2019111520400015700_B9","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.jacc.2006.09.038","article-title":"Diastolic dysfunction is an independent risk factor for death in patients with sickle cell disease","volume":"49","author":"Sachdev","year":"2007","journal-title":"J Am Coll Cardiol"},{"issue":"12","key":"2019111520400015700_B10","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1038\/nm1202-799","article-title":"Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease","volume":"8","author":"Reiter","year":"2002","journal-title":"Nat Med"},{"issue":"24","key":"2019111520400015700_B11","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1182\/blood-2014-03-563874","article-title":"Erythroid DAMPs drive inflammation in SCD","volume":"123","author":"Gladwin","year":"2014","journal-title":"Blood"},{"issue":"11","key":"2019111520400015700_B12","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.3324\/haematol.2009.013672","article-title":"Hypercoagulability and thrombotic complications in hemolytic anemias","volume":"94","author":"Ataga","year":"2009","journal-title":"Haematologica"},{"issue":"18","key":"2019111520400015700_B13","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.1182\/blood-2013-09-529420","article-title":"Platelet bioenergetic screen in sickle cell patients reveals mitochondrial complex V inhibition, which contributes to platelet activation","volume":"123","author":"Cardenes","year":"2014","journal-title":"Blood"},{"issue":"6","key":"2019111520400015700_B14","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1182\/blood-2006-12-061697","article-title":"Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin","volume":"110","author":"Villagra","year":"2007","journal-title":"Blood"},{"issue":"1","key":"2019111520400015700_B15","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1001\/jama.294.1.81","article-title":"Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease","volume":"294","author":"Morris","year":"2005","journal-title":"JAMA"},{"issue":"12","key":"2019111520400015700_B16","doi-asserted-by":"crossref","first-page":"e114309","DOI":"10.1371\/journal.pone.0114309","article-title":"Elevated pulse pressure is associated with hemolysis, proteinuria and chronic kidney disease in sickle cell disease","volume":"9","author":"Novelli","year":"2014","journal-title":"PLoS One"},{"issue":"3","key":"2019111520400015700_B17","doi-asserted-by":"crossref","first-page":"464","DOI":"10.3324\/haematol.2012.068965","article-title":"The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe","volume":"98","author":"Nouraie","year":"2013","journal-title":"Haematologica"},{"issue":"1","key":"2019111520400015700_B18","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1111\/j.1365-2141.2010.08520.x","article-title":"Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043)","volume":"153","author":"Ataga","year":"2011","journal-title":"Br J Haematol"},{"issue":"18","key":"2019111520400015700_B19","doi-asserted-by":"crossref","first-page":"3647","DOI":"10.1182\/blood-2012-04-383430","article-title":"Sickle cell pain: a critical reappraisal","volume":"120","author":"Ballas","year":"2012","journal-title":"Blood"},{"issue":"11","key":"2019111520400015700_B20","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1038\/nm.2507","article-title":"Ischemia and reperfusion: from mechanism to translation","volume":"17","author":"Eltzschig","year":"2011","journal-title":"Nat Med"},{"issue":"16","key":"2019111520400015700_B21","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1056\/NEJMra0901217","article-title":"Cell death","volume":"361","author":"Hotchkiss","year":"2009","journal-title":"N Engl J Med"},{"issue":"4","key":"2019111520400015700_B22","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.it.2011.01.005","article-title":"Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation","volume":"32","author":"Krysko","year":"2011","journal-title":"Trends Immunol"},{"issue":"26","key":"2019111520400015700_B23","doi-asserted-by":"crossref","first-page":"3978","DOI":"10.1182\/blood-2014-04-560813","article-title":"Sickle cell disease increases high mobility group box 1: a novel mechanism of inflammation","volume":"124","author":"Xu","year":"2014","journal-title":"Blood"},{"key":"2019111520400015700_B24","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.cyto.2016.03.016","article-title":"Sickle red cells as danger signals on proinflammatory gene expression, leukotriene B4 and interleukin-1 beta production in peripheral blood mononuclear cell","volume":"83","author":"Pitanga","year":"2016","journal-title":"Cytokine"},{"key":"2019111520400015700_B25","doi-asserted-by":"crossref","DOI":"10.1016\/j.cyto.2017.12.001","article-title":"Interleukin-27 and interleukin-37 are elevated in sickle cell anemia patients and inhibit in vitro secretion of interleukin-8 in neutrophils and monocytes","author":"Alagbe","year":"2018","journal-title":"Cytokine"},{"issue":"5","key":"2019111520400015700_B26","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1111\/j.1365-2141.2009.08013.x","article-title":"Increased levels of the inflammatory biomarker C-reactive protein at baseline are associated with childhood sickle cell vasocclusive crises","volume":"148","author":"Krishnan","year":"2010","journal-title":"Br J Haematol"},{"issue":"2","key":"2019111520400015700_B27","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.hoc.2013.11.011","article-title":"Role of the hemostatic system on sickle cell disease pathophysiology and potential therapeutics","volume":"28","author":"Pakbaz","year":"2014","journal-title":"Hematol Oncol Clin North Am"},{"issue":"5","key":"2019111520400015700_B28","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.amjmed.2012.12.016","article-title":"Venous thromboembolism in adults with sickle cell disease: a serious and under-recognized complication","volume":"126","author":"Naik","year":"2013","journal-title":"Am J Med"},{"issue":"1","key":"2019111520400015700_B29","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1161\/01.STR.9.1.45","article-title":"Cerebrovascular disease in sickle cell anemia: a clinical, pathological and radiological correlation","volume":"9","author":"Merkel","year":"1978","journal-title":"Stroke"},{"issue":"2","key":"2019111520400015700_B30","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/ajh.24224","article-title":"Pulmonary platelet thrombi and vascular pathology in acute chest syndrome in patients with sickle cell disease","volume":"91","author":"Anea","year":"2016","journal-title":"Am J Hematol"},{"issue":"5","key":"2019111520400015700_B31","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1111\/j.1538-7836.2012.04697.x","article-title":"Pulmonary embolism in sickle cell disease: a case-control study","volume":"10","author":"Novelli","year":"2012","journal-title":"J Thromb Haemost"},{"issue":"13","key":"2019111520400015700_B32","doi-asserted-by":"crossref","first-page":"3680","DOI":"10.1182\/blood-2010-08-302539","article-title":"The rate of hemolysis in sickle cell disease correlates with the quantity of active von Willebrand factor in the plasma","volume":"117","author":"Chen","year":"2011","journal-title":"Blood"},{"issue":"3","key":"2019111520400015700_B33","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1002\/ajh.22274","article-title":"Plasma thrombospondin-1 is increased during acute sickle cell vaso-occlusive events and associated with acute chest syndrome, hydroxyurea therapy, and lower hemolytic rates","volume":"87","author":"Novelli","year":"2012","journal-title":"Am J Hematol"},{"issue":"11","key":"2019111520400015700_B34","doi-asserted-by":"crossref","first-page":"e132","DOI":"10.3324\/haematol.2013.092635","article-title":"Thrombospondin-1 inhibits ADAMTS13 activity in sickle cell disease","volume":"98","author":"Novelli","year":"2013","journal-title":"Haematologica"},{"issue":"9","key":"2019111520400015700_B35","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1164\/rccm.201105-0783OC","article-title":"Pulmonary artery thrombosis during acute chest syndrome in sickle cell disease","volume":"184","author":"Mekontso Dessap","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"issue":"1","key":"2019111520400015700_B36","doi-asserted-by":"crossref","first-page":"e29786","DOI":"10.1371\/journal.pone.0029786","article-title":"Association of coagulation activation with clinical complications in sickle cell disease","volume":"7","author":"Ataga","year":"2012","journal-title":"PLoS One"},{"issue":"7","key":"2019111520400015700_B37","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1056\/NEJMoa1512021","article-title":"A multinational trial of prasugrel for sickle cell vaso-occlusive events","volume":"374","author":"Heeney","year":"2016","journal-title":"N Engl J Med"},{"issue":"6","key":"2019111520400015700_B38","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1172\/JCI110724","article-title":"Spontaneous oxygen radical generation by sickle erythrocytes","volume":"70","author":"Hebbel","year":"1982","journal-title":"J Clin Invest"},{"issue":"26","key":"2019111520400015700_B39","doi-asserted-by":"crossref","first-page":"15215","DOI":"10.1073\/pnas.221292098","article-title":"Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease","volume":"98","author":"Aslan","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"issue":"11","key":"2019111520400015700_B40","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1182\/blood-2012-07-441188","article-title":"Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease","volume":"121","author":"George","year":"2013","journal-title":"Blood"},{"issue":"3","key":"2019111520400015700_B41","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.bcmd.2011.01.002","article-title":"Assessment of oxidative stress in patients with sickle cell disease: The glutathione system and the oxidant-antioxidant status","volume":"46","author":"Gizi","year":"2011","journal-title":"Blood Cells Mol Dis"},{"issue":"1","key":"2019111520400015700_B42","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1182\/blood-2007-04-081703","article-title":"Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease","volume":"111","author":"Morris","year":"2008","journal-title":"Blood"},{"issue":"3","key":"2019111520400015700_B43","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1056\/NEJMoa1715971","article-title":"A Phase 3 trial of l-glutamine in sickle cell disease","volume":"379","author":"Niihara","year":"2018","journal-title":"N Engl J Med"},{"issue":"4","key":"2019111520400015700_B44","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1172\/JCI106273","article-title":"Abnormal rheology of oxygenated blood in sickle cell anemia","volume":"49","author":"Chien","year":"1970","journal-title":"J Clin Invest"},{"issue":"3","key":"2019111520400015700_B45","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/0026-2862(75)90069-2","article-title":"Effect of deoxygenation on blood rheology in sickle cell disease","volume":"9","author":"Usami","year":"1975","journal-title":"Microvasc Res"},{"key":"2019111520400015700_B46","article-title":"GBT440 improves red blood cell deformability and reduces viscosity of sickle cell blood under deoxygenated conditions [published online ahead of print 13 April 2018]","author":"Dufu","journal-title":"Clin Hemorheol Microcirc"},{"issue":"5 Pt 1","key":"2019111520400015700_B47","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1016\/S0022-5347(17)35817-2","article-title":"Association of sickle cell disease, priapism, exchange transfusion and neurological events: ASPEN syndrome","volume":"150","author":"Siegel","year":"1993","journal-title":"J Urol"},{"issue":"1","key":"2019111520400015700_B48","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJM199107043250103","article-title":"Pain in sickle cell disease. Rates and risk factors","volume":"325","author":"Platt","year":"1991","journal-title":"N Engl J Med"},{"issue":"8","key":"2019111520400015700_B49","doi-asserted-by":"crossref","first-page":"e26455","DOI":"10.1002\/pbc.26455","article-title":"Alpha-thalassaemia promotes frequent vaso-occlusive crises in children with sickle cell anaemia through haemorheological changes","volume":"64","author":"Renoux","year":"2017","journal-title":"Pediatr Blood Cancer"},{"issue":"2","key":"2019111520400015700_B50","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/ajh.10328","article-title":"Role of phlebotomy in the management of hemoglobin SC disease: case report and review of the literature","volume":"73","author":"Markham","year":"2003","journal-title":"Am J Hematol"},{"issue":"3","key":"2019111520400015700_B51","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1002\/ajh.10140","article-title":"Outcome in hemoglobin SC disease: a four-decade observational study of clinical, hematologic, and genetic factors","volume":"70","author":"Powars","year":"2002","journal-title":"Am J Hematol"},{"key":"2019111520400015700_B52","first-page":"573","article-title":"Hyperviscosity and hemolysis biomarkers in sickle cell ocular microangiopathy","volume":"55","author":"Agarwal","year":"2014","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2019111520400015700_B53","first-page":"84","volume-title":"Role of adhesion molecules and vascular endothelium in the pathogenesis of sickle cell disease","author":"Telen","year":"2007"},{"issue":"4","key":"2019111520400015700_B54","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1182\/blood.V98.4.966","article-title":"The nonexpression of CD36 on reticulocytes and mature red blood cells does not modify the clinical course of patients with sickle cell anemia","volume":"98","author":"Lee","year":"2001","journal-title":"Blood"},{"issue":"5","key":"2019111520400015700_B55","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1056\/NEJMoa1611770","article-title":"Crizanlizumab for the prevention of pain crises in sickle cell disease","volume":"376","author":"Ataga","year":"2017","journal-title":"N Engl J Med"},{"issue":"17","key":"2019111520400015700_B56","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1182\/blood-2014-06-583351","article-title":"Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use","volume":"125","author":"Telen","year":"2015","journal-title":"Blood"},{"issue":"3","key":"2019111520400015700_B57","first-page":"273","article-title":"Effects of hydroxyurea on the membrane of erythrocytes and platelets in sickle cell anemia","volume":"89","author":"Covas","year":"2004","journal-title":"Haematologica"},{"issue":"2","key":"2019111520400015700_B58","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/j.1600-0609.2006.00788.x","article-title":"Therapy with hydroxyurea is associated with reduced adhesion molecule gene and protein expression in sickle red cells with a concomitant reduction in adhesive properties","volume":"78","author":"Gambero","year":"2007","journal-title":"Eur J Haematol"},{"issue":"7","key":"2019111520400015700_B59","doi-asserted-by":"crossref","first-page":"e101301","DOI":"10.1371\/journal.pone.0101301","article-title":"Phase 1 study of the E-selectin inhibitor GMI 1070 in patients with sickle cell anemia [published correction appears in PLoS One. 2014;9(10):e111690]","volume":"9","author":"Wun","year":"2014","journal-title":"PLoS One"},{"issue":"1","key":"2019111520400015700_B60","first-page":"288","article-title":"Cerebrovascular accidents in sickle cell disease: rates and risk factors","volume":"91","author":"Ohene-Frempong","year":"1998","journal-title":"Blood"},{"issue":"6","key":"2019111520400015700_B61","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1182\/blood.V63.6.1353.1353","article-title":"Effects of thalassemia and microcytosis on the hematologic and vasoocclusive severity of sickle cell anemia","volume":"63","author":"Steinberg","year":"1984","journal-title":"Blood"},{"issue":"4","key":"2019111520400015700_B62","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1002\/(SICI)1096-8652(199604)51:4<296::AID-AJH8>3.0.CO;2-R","article-title":"Disturbance of plasma and platelet thrombospondin levels in sickle cell disease","volume":"51","author":"Browne","year":"1996","journal-title":"Am J Hematol"},{"issue":"2","key":"2019111520400015700_B63","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.bcmd.2014.11.016","article-title":"Modulation of pain in pediatric sickle cell disease: understanding the balance between endothelin mediated vasoconstriction and apelin mediated vasodilation","volume":"54","author":"Smith","year":"2015","journal-title":"Blood Cells Mol Dis"},{"issue":"19","key":"2019111520400015700_B64","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1182\/bloodadvances.2017007211","article-title":"Pharmacotherapeutical strategies in the prevention of acute, vaso-occlusive pain in sickle cell disease: a systematic review","volume":"1","author":"Sins","year":"2017","journal-title":"Blood Adv"},{"issue":"14","key":"2019111520400015700_B65","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1182\/blood-2015-05-647107","article-title":"A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children","volume":"126","author":"Brousseau","year":"2015","journal-title":"Blood"},{"issue":"1","key":"2019111520400015700_B66","doi-asserted-by":"crossref","first-page":"37","DOI":"10.3945\/ajcn.112.036319","article-title":"Effect of omega-3 (n-3) fatty acid supplementation in patients with sickle cell anemia: randomized, double-blind, placebo-controlled trial","volume":"97","author":"Daak","year":"2013","journal-title":"Am J Clin Nutr"},{"issue":"4","key":"2019111520400015700_B67","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1002\/pbc.25399","article-title":"Vitamin D deficiency and acute vaso-occlusive complications in children with sickle cell disease","volume":"62","author":"Lee","year":"2015","journal-title":"Pediatr Blood Cancer"},{"issue":"2","key":"2019111520400015700_B68","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/bjh.12019","article-title":"High dose vitamin D therapy for chronic pain in children and adolescents with sickle cell disease: results of a randomized double blind pilot study","volume":"159","author":"Osunkwo","year":"2012","journal-title":"Br J Haematol"},{"issue":"2","key":"2019111520400015700_B69","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1097\/MPH.0000000000000783","article-title":"The association of serum 25-hydroxyvitamin D with biomarkers of hemolysis in pediatric patients with sickle cell disease","volume":"40","author":"Adegoke","year":"2018","journal-title":"J Pediatr Hematol Oncol"},{"key":"2019111520400015700_B70","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cyto.2017.03.010","article-title":"Relationship between serum 25-hydroxyvitamin D and inflammatory cytokines in paediatric sickle cell disease","volume":"96","author":"Adegoke","year":"2017","journal-title":"Cytokine"},{"issue":"3","key":"2019111520400015700_B71","doi-asserted-by":"crossref","first-page":"e0119908","DOI":"10.1371\/journal.pone.0119908","article-title":"Prevalence of vitamin D deficiency in sickle cell disease: a systematic review [published correction appears in PLoS One. 2015;10(5):e0128853]","volume":"10","author":"Nolan","year":"2015","journal-title":"PLoS One"},{"issue":"7","key":"2019111520400015700_B72","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1002\/ajh.24742","article-title":"Inhaled steroids reduce pain and sVCAM levels in individuals with sickle cell disease: a triple-blind, randomized trial","volume":"92","author":"Glassberg","year":"2017","journal-title":"Am J Hematol"},{"issue":"suppl 1","key":"2019111520400015700_B73","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1182\/blood.V130.Suppl_1.689.689","article-title":"Initial results from a cohort in a phase 2a study (GBT440-007) evaluating adolescents with sickle cell disease treated with multiple doses of GBT440, a HbS polymerization inhibitor [abstract]","volume":"130","author":"Hoppe","year":"2017","journal-title":"Blood"},{"issue":"2","key":"2019111520400015700_B74","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1182\/blood.V84.2.643.643","article-title":"The acute chest syndrome in sickle cell disease: incidence and risk factors","volume":"84","author":"Castro","year":"1994","journal-title":"Blood"},{"issue":"25","key":"2019111520400015700_B75","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1056\/NEJM200006223422502","article-title":"Causes and outcomes of the acute chest syndrome in sickle cell disease","volume":"342","author":"Vichinsky","year":"2000","journal-title":"N Engl J Med"},{"issue":"6","key":"2019111520400015700_B76","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1097\/01.md.0000189089.45003.52","article-title":"Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients","volume":"84","author":"Powars","year":"2005","journal-title":"Medicine (Baltimore)"},{"issue":"10037","key":"2019111520400015700_B77","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1016\/S0140-6736(16)00145-8","article-title":"The intersection between asthma and acute chest syndrome in children with sickle-cell anaemia","volume":"387","author":"DeBaun","year":"2016","journal-title":"Lancet"},{"issue":"4","key":"2019111520400015700_B78","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/bjh.15076","article-title":"Aeroallergen sensitization predicts acute chest syndrome in children with sickle cell anaemia","volume":"180","author":"Willen","year":"2018","journal-title":"Br J Haematol"},{"issue":"9","key":"2019111520400015700_B79","doi-asserted-by":"crossref","first-page":"3276","DOI":"10.1182\/blood.V96.9.3276","article-title":"Secretory phospholipase A(2) predicts impending acute chest syndrome in sickle cell disease","volume":"96","author":"Styles","year":"2000","journal-title":"Blood"},{"issue":"2","key":"2019111520400015700_B80","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/j.1365-2141.2006.06409.x","article-title":"Transfusion prevents acute chest syndrome predicted by elevated secretory phospholipase A2","volume":"136","author":"Styles","year":"2007","journal-title":"Br J Haematol"},{"issue":"5","key":"2019111520400015700_B81","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1111\/j.1365-2141.2012.09105.x","article-title":"Refining the value of secretory phospholipase A2 as a predictor of acute chest syndrome in sickle cell disease: results of a feasibility study (PROACTIVE)","volume":"157","author":"Styles","year":"2012","journal-title":"Br J Haematol"},{"issue":"8","key":"2019111520400015700_B82","doi-asserted-by":"crossref","first-page":"3384","DOI":"10.1182\/blood-2004-12-4676","article-title":"Serum C-reactive protein parallels secretory phospholipase A2 in sickle cell disease patients with vasoocclusive crisis or acute chest syndrome","volume":"105","author":"Bargoma","year":"2005","journal-title":"Blood"},{"issue":"1","key":"2019111520400015700_B83","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1179\/1607845413Y.0000000092","article-title":"Plasma PTX3 levels in sickle cell disease patients, during vaso occlusion and acute chest syndrome (data from Saudi population)","volume":"19","author":"Elshazly","year":"2014","journal-title":"Hematology"},{"key":"2019111520400015700_B84","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.cyto.2017.05.017","article-title":"Association of plasma CD40L with acute chest syndrome in sickle cell anemia","volume":"97","author":"Garrido","year":"2017","journal-title":"Cytokine"},{"issue":"11","key":"2019111520400015700_B85","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1002\/ppul.23698","article-title":"Exosomes contribute to endothelial integrity and acute chest syndrome risk: Preliminary findings","volume":"52","author":"Lapping-Carr","year":"2017","journal-title":"Pediatr Pulmonol"},{"issue":"2","key":"2019111520400015700_B86","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0002-9343(94)90136-8","article-title":"Acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes","volume":"96","author":"Hassell","year":"1994","journal-title":"Am J Med"},{"issue":"5","key":"2019111520400015700_B87","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1111\/j.1365-2141.2010.08271.x","article-title":"Outcome of adults with sickle cell disease admitted to critical care - experience of a single institution in the UK","volume":"150","author":"Gardner","year":"2010","journal-title":"Br J Haematol"},{"issue":"5","key":"2019111520400015700_B88","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/ncpneuro0495","article-title":"Therapy insight: stroke risk and its management in patients with sickle cell disease","volume":"3","author":"Kirkham","year":"2007","journal-title":"Nat Clin Pract Neurol"},{"issue":"1","key":"2019111520400015700_B89","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1056\/NEJM199807023390102","article-title":"Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography","volume":"339","author":"Adams","year":"1998","journal-title":"N Engl J Med"},{"issue":"26","key":"2019111520400015700_B90","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.1056\/NEJMoa050460","article-title":"Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease","volume":"353","author":"Adams","year":"2005","journal-title":"N Engl J Med"},{"issue":"10019","key":"2019111520400015700_B91","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/S0140-6736(15)01041-7","article-title":"Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial","volume":"387","author":"Ware","year":"2016","journal-title":"Lancet"},{"issue":"11","key":"2019111520400015700_B92","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1007\/s00277-016-2789-5","article-title":"Reticulocyte count is the most important predictor of acute cerebral ischemia and high-risk transcranial Doppler in a newborn cohort of 395 children with sickle cell anemia","volume":"95","author":"Belis\u00e1rio","year":"2016","journal-title":"Ann Hematol"},{"issue":"9","key":"2019111520400015700_B93","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1002\/ajh.23777","article-title":"Reticulocytosis and anemia are associated with an increased risk of death and stroke in the newborn cohort of the Cooperative Study of Sickle Cell Disease","volume":"89","author":"Meier","year":"2014","journal-title":"Am J Hematol"},{"issue":"4","key":"2019111520400015700_B94","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1182\/blood-2010-06-293514","article-title":"Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort","volume":"117","author":"Bernaudin","year":"2011","journal-title":"Blood"},{"issue":"8","key":"2019111520400015700_B95","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1056\/NEJMoa1401731","article-title":"Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia","volume":"371","author":"DeBaun","year":"2014","journal-title":"N Engl J Med"},{"issue":"3","key":"2019111520400015700_B96","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1067\/mpd.2001.117580","article-title":"Silent infarction as a risk factor for overt stroke in children with sickle cell anemia: a report from the Cooperative Study of Sickle Cell Disease","volume":"139","author":"Miller","year":"2001","journal-title":"J Pediatr"},{"issue":"8","key":"2019111520400015700_B97","doi-asserted-by":"crossref","first-page":"3014","DOI":"10.1182\/blood.V99.8.3014","article-title":"Longitudinal changes in brain magnetic resonance imaging findings in children with sickle cell disease","volume":"99","author":"Pegelow","year":"2002","journal-title":"Blood"},{"issue":"3","key":"2019111520400015700_B98","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1067\/mpd.2001.116935","article-title":"Neuropsychologic performance in school-aged children with sickle cell disease: a report from the Cooperative Study of Sickle Cell Disease","volume":"139","author":"Wang","year":"2001","journal-title":"J Pediatr"},{"issue":"16","key":"2019111520400015700_B99","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1182\/blood-2011-05-349621","article-title":"Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure","volume":"119","author":"DeBaun","year":"2012","journal-title":"Blood"},{"issue":"7","key":"2019111520400015700_B100","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1182\/blood-2015-09-618579","article-title":"Central nervous system complications and management in sickle cell disease","volume":"127","author":"DeBaun","year":"2016","journal-title":"Blood"},{"issue":"18","key":"2019111520400015700_B101","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1001\/jama.2010.562","article-title":"Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia","volume":"303","author":"Vichinsky","year":"2010","journal-title":"JAMA"},{"issue":"2","key":"2019111520400015700_B102","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1177\/08830738050200020301","article-title":"Cognitive deficits in children with sickle cell disease","volume":"20","author":"Steen","year":"2005","journal-title":"J Child Neurol"},{"issue":"21","key":"2019111520400015700_B103","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1182\/bloodadvances.2017008219","article-title":"Disease severity and slower psychomotor speed in adults with sickle cell disease","volume":"1","author":"Jorgensen","year":"2017","journal-title":"Blood Adv"},{"issue":"9","key":"2019111520400015700_B104","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1056\/NEJMoa035477","article-title":"Pulmonary hypertension as a risk factor for death in patients with sickle cell disease","volume":"350","author":"Gladwin","year":"2004","journal-title":"N Engl J Med"},{"issue":"12","key":"2019111520400015700_B105","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1001\/jama.2012.358","article-title":"Mortality in adults with sickle cell disease and pulmonary hypertension","volume":"307","author":"Mehari","year":"2012","journal-title":"JAMA"},{"issue":"9","key":"2019111520400015700_B106","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1513\/AnnalsATS.201408-405CME","article-title":"Pulmonary hypertension in sickle cell disease","volume":"11","author":"Hayes","year":"2014","journal-title":"Ann Am Thorac Soc"},{"issue":"1","key":"2019111520400015700_B107","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/ajh.21058","article-title":"Pulmonary hypertension associated with sickle cell disease: clinical and laboratory endpoints and disease outcomes","volume":"83","author":"De Castro","year":"2008","journal-title":"Am J Hematol"},{"issue":"10","key":"2019111520400015700_B108","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1002\/ajh.21838","article-title":"Leg ulcers in sickle cell disease","volume":"85","author":"Minniti","year":"2010","journal-title":"Am J Hematol"},{"issue":"4","key":"2019111520400015700_B109","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1182\/blood-2010-09-306167","article-title":"Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity","volume":"118","author":"Machado","year":"2011","journal-title":"Blood"},{"issue":"6","key":"2019111520400015700_B110","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s004670050491","article-title":"Prevalence of microalbuminuria in children with sickle cell disease","volume":"12","author":"Dharnidharka","year":"1998","journal-title":"Pediatr Nephrol"},{"issue":"14","key":"2019111520400015700_B111","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1056\/NEJM199204023261402","article-title":"Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme","volume":"326","author":"Falk","year":"1992","journal-title":"N Engl J Med"},{"issue":"10","key":"2019111520400015700_B112","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1001\/jama.2014.10517","article-title":"Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members","volume":"312","author":"Yawn","year":"2014","journal-title":"JAMA"},{"issue":"5","key":"2019111520400015700_B113","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1111\/bjh.12690","article-title":"Haemoglobinuria is associated with chronic kidney disease and its progression in patients with sickle cell anaemia","volume":"164","author":"Saraf","year":"2014","journal-title":"Br J Haematol"},{"issue":"7","key":"2019111520400015700_B114","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/ajh.22045","article-title":"Biomarkers for early detection of sickle nephropathy","volume":"86","author":"Sundaram","year":"2011","journal-title":"Am J Hematol"},{"issue":"8","key":"2019111520400015700_B115","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1007\/s00467-010-1536-8","article-title":"Prevalence and clinical correlates of microalbuminuria in children with sickle cell disease","volume":"25","author":"Becton","year":"2010","journal-title":"Pediatr Nephrol"},{"issue":"1","key":"2019111520400015700_B116","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s00467-012-2275-9","article-title":"Masked hypertension is prevalent in children with sickle cell disease: a Midwest Pediatric Nephrology Consortium study","volume":"28","author":"Shatat","year":"2013","journal-title":"Pediatr Nephrol"},{"issue":"3","key":"2019111520400015700_B117","first-page":"305","article-title":"Sickle cell disease","volume":"377","author":"Piel","year":"2017","journal-title":"N Engl J Med"},{"issue":"8","key":"2019111520400015700_B118","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1002\/ajh.23232","article-title":"Genetic modifiers of sickle cell disease","volume":"87","author":"Steinberg","year":"2012","journal-title":"Am J Hematol"},{"issue":"5","key":"2019111520400015700_B119","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1111\/bjh.12590","article-title":"Impact of glucose-6-phosphate dehydrogenase deficiency on sickle cell anaemia expression in infancy and early childhood: a prospective study","volume":"163","author":"Benkerrou","year":"2013","journal-title":"Br J Haematol"},{"issue":"2","key":"2019111520400015700_B120","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/j.1365-2141.2010.08215.x","article-title":"Association of G6PD with lower haemoglobin concentration but not increased haemolysis in patients with sickle cell anaemia","volume":"150","author":"Nouraie","year":"2010","journal-title":"Br J Haematol"},{"issue":"5","key":"2019111520400015700_B121","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1056\/NEJM198202043060504","article-title":"Concurrent sickle-cell anemia and alpha-thalassemia: effect on severity of anemia","volume":"306","author":"Embury","year":"1982","journal-title":"N Engl J Med"},{"issue":"2","key":"2019111520400015700_B122","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1111\/j.1365-2141.2007.06643.x","article-title":"The linear effects of alpha-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease","volume":"138","author":"Vasavda","year":"2007","journal-title":"Br J Haematol"},{"issue":"7","key":"2019111520400015700_B123","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1007\/s00277-014-2016-1","article-title":"Influence of the \u03b2s haplotype and \u03b1-thalassemia on stroke development in a Brazilian population with sickle cell anaemia","volume":"93","author":"Domingos","year":"2014","journal-title":"Ann Hematol"},{"issue":"4","key":"2019111520400015700_B124","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1111\/j.1365-2141.2005.05799.x","article-title":"Windy weather and low humidity are associated with an increased number of hospital admissions for acute pain and sickle cell disease in an urban environment with a maritime temperate climate","volume":"131","author":"Jones","year":"2005","journal-title":"Br J Haematol"},{"issue":"9","key":"2019111520400015700_B125","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.3324\/haematol.2014.120030","article-title":"Environmental determinants of severity in sickle cell disease","volume":"100","author":"Tewari","year":"2015","journal-title":"Haematologica"},{"issue":"2","key":"2019111520400015700_B126","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1056\/NEJM200001133420203","article-title":"Prediction of adverse outcomes in children with sickle cell disease","volume":"342","author":"Miller","year":"2000","journal-title":"N Engl J Med"},{"issue":"2","key":"2019111520400015700_B127","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1182\/blood-2007-07-100719","article-title":"Prediction of adverse outcomes in children with sickle cell anemia: a study of the Dallas Newborn Cohort","volume":"111","author":"Quinn","year":"2008","journal-title":"Blood"},{"issue":"10","key":"2019111520400015700_B128","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1002\/ajh.21846","article-title":"Development and validation of a pediatric severity index for sickle cell patients","volume":"85","author":"van den Tweel","year":"2010","journal-title":"Am J Hematol"},{"issue":"1","key":"2019111520400015700_B129","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/j.1600-0609.2011.01705.x","article-title":"The alpha-globin genotype does not influence sickle cell disease severity in a retrospective cross-validation study of the pediatric severity score","volume":"88","author":"Joly","year":"2012","journal-title":"Eur J Haematol"},{"issue":"7","key":"2019111520400015700_B130","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1182\/blood-2007-04-084921","article-title":"A network model to predict the risk of death in sickle cell disease","volume":"110","author":"Sebastiani","year":"2007","journal-title":"Blood"},{"key":"2019111520400015700_B131","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.bcmd.2017.01.014","article-title":"A systematic review of the literature for severity predictors in children with sickle cell anemia","volume":"65","author":"Meier","year":"2017","journal-title":"Blood Cells Mol Dis"},{"issue":"4","key":"2019111520400015700_B132","doi-asserted-by":"crossref","first-page":"626","DOI":"10.3324\/haematol.2016.153791","article-title":"Risk factors for mortality in adult patients with sickle cell disease: a meta-analysis of studies in North America and Europe","volume":"102","author":"Maitra","year":"2017","journal-title":"Haematologica"},{"issue":"22","key":"2019111520400015700_B133","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1182\/blood-2016-11-752279","article-title":"Association of circulating transcriptomic profiles with mortality in sickle cell disease","volume":"129","author":"Desai","year":"2017","journal-title":"Blood"},{"key":"2019111520400015700_B134","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bcmd.2018.05.001","article-title":"Biomarker signatures of sickle cell disease severity","volume":"72","author":"Du","year":"2018","journal-title":"Blood Cells Mol Dis"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/hematology\/article-pdf\/2018\/1\/482\/1251520\/hem01866.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/hematology\/article-pdf\/2018\/1\/482\/1251520\/hem01866.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T23:32:51Z","timestamp":1721172771000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2018\/1\/482\/277561\/Measuring-success-utility-of-biomarkers-in-sickle"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,30]]},"references-count":134,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2018,11,30]]}},"URL":"https:\/\/doi.org\/10.1182\/asheducation-2018.1.482","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,30]]}}}