{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:39:57Z","timestamp":1787618397526,"version":"build-2736575974"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T00:00:00Z","timestamp":1664496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS055349"],"award-info":[{"award-number":["R01NS055349"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000061","name":"Fogarty International Center","doi-asserted-by":"publisher","award":["D43 TW010928"],"award-info":[{"award-number":["D43 TW010928"]}],"id":[{"id":"10.13039\/100000061","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Global changes in amino acid levels have been described in severe malaria (SM), but the relationship between amino acids and long-term outcomes in SM has not been evaluated.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We measured enrollment plasma concentrations of 20 amino acids using high-performance liquid chromatography in 500 Ugandan children aged 18 months to 12 years, including 122 community children and 378 children with SM. The Kidney Disease: Improving Global Outcomes criteria were used to define acute kidney injury (AKI) at enrollment and chronic kidney disease (CKD) at 1-year follow-up. Cognition was assessed over 2 years of follow-up.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Compared to laboratory-defined, age-specific reference ranges, there were deficiencies in sulfur-containing amino acids (methionine, cysteine) in both community children and children with SM. Among children with SM, global changes in amino acid concentrations were observed in the context of metabolic complications including acidosis and AKI. Increases in threonine, leucine, and valine were associated with in-hospital mortality, while increases in methionine, tyrosine, lysine, and phenylalanine were associated with postdischarge mortality and CKD. Increases in glycine and asparagine were associated with worse attention in children &amp;lt;5 years of age.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Among children with SM, unique amino acid profiles are associated with mortality, CKD, and worse attention.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/infdis\/jiac392","type":"journal-article","created":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T20:15:45Z","timestamp":1664568945000},"page":"2215-2225","source":"Crossref","is-referenced-by-count":11,"title":["Plasma Amino Acid Concentrations in Children With Severe Malaria Are Associated With Mortality and Worse Long-term Kidney and Cognitive Outcomes"],"prefix":"10.1093","volume":"226","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5328-6511","authenticated-orcid":false,"given":"Andrea L","family":"Conroy","sequence":"first","affiliation":[{"name":"Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine , Indianapolis, Indiana , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuan M","family":"Tran","sequence":"additional","affiliation":[{"name":"Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine , Indianapolis, Indiana , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin","family":"Bond","sequence":"additional","affiliation":[{"name":"Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine , Indianapolis, Indiana , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert O","family":"Opoka","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Global Health Uganda , Kampala , Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1693-935X","authenticated-orcid":false,"given":"Dibyadyuti","family":"Datta","sequence":"additional","affiliation":[{"name":"Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine , Indianapolis, Indiana , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward A","family":"Liechty","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Indiana University School of Medicine , Indianapolis, Indiana , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Bangirana","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Makerere University College of Health Sciences, Global Health Uganda , Kampala , Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Namazzi","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Global Health Uganda , Kampala , Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Idro","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Global Health Uganda , Kampala , Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Cusick","sequence":"additional","affiliation":[{"name":"Division of Pediatric Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota , Minneapolis, Minnesota , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M","family":"Ssenkusu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Makerere University School of Public Health , Kampala , Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandy C","family":"John","sequence":"additional","affiliation":[{"name":"Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine , Indianapolis, Indiana , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,30]]},"reference":[{"key":"2023060109500317600_jiac392-B1","author":"World Health Organization (WHO)","year":"2021"},{"key":"2023060109500317600_jiac392-B2","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1093\/cid\/ciu293","article-title":"Severe malarial anemia is associated with long-term neurocognitive impairment","volume":"59","author":"Bangirana","year":"2014","journal-title":"Clin Infect Dis"},{"key":"2023060109500317600_jiac392-B3","doi-asserted-by":"crossref","first-page":"e92","DOI":"10.1542\/peds.2007-3709","article-title":"Cerebral malaria in children is associated with long-term cognitive impairment","volume":"122","author":"John","year":"2008","journal-title":"Pediatrics"},{"key":"2023060109500317600_jiac392-B4","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1136\/adc.2005.077784","article-title":"Risk factors for persisting neurological and cognitive impairments following cerebral malaria","volume":"91","author":"Idro","year":"2006","journal-title":"Arch Dis Child"},{"key":"2023060109500317600_jiac392-B5","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/1756-0500-3-104","article-title":"Severe neurological sequelae and behaviour problems after cerebral malaria in Ugandan children","volume":"3","author":"Idro","year":"2010","journal-title":"BMC Res Notes"},{"key":"2023060109500317600_jiac392-B6","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1203\/PDR.0b013e3181eee738","article-title":"Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome","volume":"68","author":"Idro","year":"2010","journal-title":"Pediatr Res"},{"key":"2023060109500317600_jiac392-B7","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/S1474-4422(10)70270-2","article-title":"Blantyre Malaria Project Epilepsy Study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort study","volume":"9","author":"Birbeck","year":"2010","journal-title":"Lancet Neurol"},{"key":"2023060109500317600_jiac392-B8","doi-asserted-by":"crossref","DOI":"10.1542\/peds.2018-1026","article-title":"Neurodevelopmental impairments 1 year after cerebral malaria","volume":"143","author":"Langfitt","year":"2019","journal-title":"Pediatrics"},{"key":"2023060109500317600_jiac392-B9","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s12916-019-1332-7","article-title":"Acute kidney injury is associated with impaired cognition and chronic kidney disease in a prospective cohort of children with severe malaria","volume":"17","author":"Conroy","year":"2019","journal-title":"BMC Med"},{"key":"2023060109500317600_jiac392-B10","doi-asserted-by":"crossref","DOI":"10.1542\/peds.2016-1965","article-title":"Long-term behavioral problems in children with severe malaria","volume":"138","author":"Ssenkusu","year":"2016","journal-title":"Pediatrics"},{"key":"2023060109500317600_jiac392-B11","first-page":"e41","article-title":"High postdischarge morbidity in Ugandan children with severe malarial anemia or cerebral malaria","volume":"6","author":"Opoka","year":"2017","journal-title":"J Pediatric Infect Dis Soc"},{"key":"2023060109500317600_jiac392-B12","doi-asserted-by":"crossref","first-page":"235","DOI":"10.2147\/IJNRD.S239157","article-title":"Malaria-associated acute kidney injury in African children: prevalence, pathophysiology, impact, and management challenges","volume":"14","author":"Batte","year":"2021","journal-title":"Int J Nephrol Renovasc Dis"},{"key":"2023060109500317600_jiac392-B13","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/s12936-018-2274-9","article-title":"Acidosis and acute kidney injury in severe malaria","volume":"17","author":"Sriboonvorakul","year":"2018","journal-title":"Malar J"},{"key":"2023060109500317600_jiac392-B14","doi-asserted-by":"crossref","first-page":"6197","DOI":"10.3390\/ijms21176197","article-title":"The role of amino acids in neurotransmission and fluorescent tools for their detection","volume":"21","author":"Dalangin","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2023060109500317600_jiac392-B15","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1042\/BCJ20160822","article-title":"Amino acid homeostasis and signalling in mammalian cells and organisms","volume":"474","author":"Br\u00f6er","year":"2017","journal-title":"Biochem J"},{"key":"2023060109500317600_jiac392-B16","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1093\/ajcn\/79.2.185","article-title":"Renal metabolism of amino acids: its role in interorgan amino acid exchange","volume":"79","author":"van de Poll","year":"2004","journal-title":"Am J Clin Nutr"},{"key":"2023060109500317600_jiac392-B17","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/00000658-198901000-00009","article-title":"Plasma-amino acid profiles in sepsis and stress","volume":"209","author":"Vente","year":"1989","journal-title":"Ann Surg"},{"key":"2023060109500317600_jiac392-B18","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.1016\/j.clnu.2021.03.015","article-title":"Comprehensive metabolic amino acid flux analysis in critically ill patients","volume":"40","author":"Deutz","year":"2021","journal-title":"Clin Nutr"},{"key":"2023060109500317600_jiac392-B19","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0175686","article-title":"Extensive alterations of blood metabolites in pediatric cerebral malaria","volume":"12","author":"Gupta","year":"2017","journal-title":"PLoS One"},{"key":"2023060109500317600_jiac392-B20","doi-asserted-by":"crossref","first-page":"3355","DOI":"10.1128\/IAI.02106-05","article-title":"Elevated plasma phenylalanine in severe malaria and implications for pathophysiology of neurological complications","volume":"74","author":"Lopansri","year":"2006","journal-title":"Infect Immun"},{"key":"2023060109500317600_jiac392-B21","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/S0140-6736(03)12564-0","article-title":"Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production","volume":"361","author":"Lopansri","year":"2003","journal-title":"Lancet"},{"key":"2023060109500317600_jiac392-B22","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.1084\/jem.20070819","article-title":"Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria","volume":"204","author":"Yeo","year":"2007","journal-title":"J Exp Med"},{"key":"2023060109500317600_jiac392-B23","doi-asserted-by":"crossref","DOI":"10.1371\/annotation\/e49842d3-ea72-45a4-93d4-2f494baee962","article-title":"Increased asymmetric dimethylarginine in severe falciparum malaria: association with impaired nitric oxide bioavailability and fatal outcome","volume":"6","author":"Yeo","year":"2010","journal-title":"PLoS Pathog"},{"key":"2023060109500317600_jiac392-B24","doi-asserted-by":"crossref","first-page":"29151","DOI":"10.1038\/srep29151","article-title":"Monocyte polarization in children with falciparum malaria: relationship to nitric oxide insufficiency and disease severity","volume":"6","author":"Weinberg","year":"2016","journal-title":"Sci Rep"},{"key":"2023060109500317600_jiac392-B25","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1093\/qjmed\/92.9.495","article-title":"Hyperphenylalaninaemia in children with falciparum malaria","volume":"92","author":"Enwonwu","year":"1999","journal-title":"QJM"},{"key":"2023060109500317600_jiac392-B26","doi-asserted-by":"crossref","first-page":"6602","DOI":"10.1038\/s41598-019-43044-6","article-title":"Amino acid derangements in adults with severe falciparum malaria","volume":"9","author":"Leopold","year":"2019","journal-title":"Sci Rep"},{"key":"2023060109500317600_jiac392-B27","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/s12916-021-02033-1","article-title":"Parenteral artemisinins are associated with reduced mortality and neurologic deficits and improved long-term behavioral outcomes in children with severe malaria","volume":"19","author":"Conroy","year":"2021","journal-title":"BMC Med"},{"key":"2023060109500317600_jiac392-B28","doi-asserted-by":"crossref","DOI":"10.1093\/ofid\/ofx151","article-title":"Plasmodium falciparum histidine-rich protein-2 plasma concentrations are higher in retinopathy-negative cerebral malaria than in severe malarial anemia","volume":"4","author":"Park","year":"2017","journal-title":"Open Forum Infect Dis"},{"key":"2023060109500317600_jiac392-B29","doi-asserted-by":"crossref","first-page":"e360","DOI":"10.1542\/peds.2006-2027","article-title":"Cognitive impairment after cerebral malaria in children: a prospective study","volume":"119","author":"Boivin","year":"2007","journal-title":"Pediatrics"},{"key":"2023060109500317600_jiac392-B30","volume-title":"Mullen scales of early learning","author":"Mullen","year":"1995"},{"key":"2023060109500317600_jiac392-B31","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1080\/09297040601100430","article-title":"The Color Object Association Test (COAT): the development of a new measure of declarative memory for 18- to 36-month-old toddlers","volume":"14","author":"Jordan","year":"2008","journal-title":"Child Neuropsychol"},{"key":"2023060109500317600_jiac392-B32","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1207\/s15326942dn2503_1","article-title":"Measurement of vigilance in 2-year-old children","volume":"25","author":"Goldman","year":"2004","journal-title":"Dev Neuropsychol"},{"key":"2023060109500317600_jiac392-B33","volume-title":"Kaufman assessment battery for children manual","author":"Kaufman","year":"2004","edition":"2nd ed"},{"key":"2023060109500317600_jiac392-B34","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1111\/j.1469-7610.1993.tb01105.x","article-title":"Developmental normative data on the test of variables of attention (T.O.V.A.)","volume":"34","author":"Greenberg","year":"1993","journal-title":"J Child Psychol Psychiatry"},{"key":"2023060109500317600_jiac392-B35","doi-asserted-by":"crossref","DOI":"10.1093\/tropej\/fmab091","article-title":"The impact of undernutrition on cognition in children with severe malaria and community children: a prospective 2-year cohort study","volume":"67","author":"Mburu","year":"2021","journal-title":"J Trop Pediatr"},{"key":"2023060109500317600_jiac392-B36","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3390\/metabo11020061","article-title":"Amino acid metabolism in apicomplexan parasites","volume":"11","author":"Krishnan","year":"2021","journal-title":"Metabolites"},{"key":"2023060109500317600_jiac392-B37","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1172\/JCI109771","article-title":"Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency","volume":"65","author":"Tizianello","year":"1980","journal-title":"J Clin Invest"},{"key":"2023060109500317600_jiac392-B38","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1093\/cid\/cis034","article-title":"Predicting the clinical outcome of severe falciparum malaria in African children: findings from a large randomized trial","volume":"54","author":"von Seidlein","year":"2012","journal-title":"Clin Infect Dis"},{"key":"2023060109500317600_jiac392-B39","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/s12916-017-0906-5","article-title":"Clinical and laboratory predictors of death in African children with features of severe malaria: a systematic review and meta-analysis","volume":"15","author":"Sypniewska","year":"2017","journal-title":"BMC Med"},{"key":"2023060109500317600_jiac392-B40","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1093\/cid\/ciac229","article-title":"Acute kidney injury interacts with coma, acidosis, and impaired perfusion to significantly increase risk of death in children with severe malaria","volume":"75","author":"Namazzi","year":"2022","journal-title":"Clin Infect Dis"},{"key":"2023060109500317600_jiac392-B41","doi-asserted-by":"crossref","first-page":"534","DOI":"10.3389\/fnins.2017.00534","article-title":"Cerebrospinal fluid amino acid profiling of pediatric cases with tuberculous meningitis","volume":"11","author":"Mason","year":"2017","journal-title":"Front Neurosci"},{"key":"2023060109500317600_jiac392-B42","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0226405","article-title":"Acute kidney injury in Ugandan children with severe malaria is associated with long-term behavioral problems","volume":"14","author":"Hickson","year":"2019","journal-title":"PLoS One"},{"key":"2023060109500317600_jiac392-B43","doi-asserted-by":"crossref","first-page":"e734","DOI":"10.1097\/CCM.0000000000004469","article-title":"Endothelial activation, acute kidney injury, and cognitive impairment in pediatric severe malaria","volume":"48","author":"Ouma","year":"2020","journal-title":"Crit Care Med"},{"key":"2023060109500317600_jiac392-B44","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1093\/cid\/ciz325","article-title":"Elevated cerebrospinal fluid tau protein concentrations on admission are associated with long-term neurologic and cognitive impairment in Ugandan children with cerebral malaria","volume":"70","author":"Datta","year":"2019","journal-title":"Clin Infect Dis"},{"key":"2023060109500317600_jiac392-B45","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2021.38515","article-title":"Association of plasma tau with mortality and long-term neurocognitive impairment in survivors of pediatric cerebral malaria and severe malarial anemia","volume":"4","author":"Datta","year":"2021","journal-title":"JAMA Netw Open"},{"key":"2023060109500317600_jiac392-B46","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1743-7075-4-24","article-title":"Are we getting enough sulfur in our diet?","volume":"4","author":"Nimni","year":"2007","journal-title":"Nutr Metab"},{"key":"2023060109500317600_jiac392-B47","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1093\/ajcn\/nqab136","article-title":"Dietary intake of sulfur amino acids and risk of kwashiorkor malnutrition in eastern Democratic Republic of the Congo","volume":"114","author":"Fitzpatrick","year":"2021","journal-title":"Am J Clin Nutr"},{"key":"2023060109500317600_jiac392-B48","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1001339","article-title":"G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: a geostatistical model-based map","volume":"9","author":"Howes","year":"2012","journal-title":"PLoS Med"},{"key":"2023060109500317600_jiac392-B49","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1080\/1028415021000055952","article-title":"The effects of dietary sulfur amino acid deficiency on rat brain glutathione concentration and neural damage in global hemispheric hypoxia-ischemia","volume":"5","author":"Bobyn","year":"2002","journal-title":"Nutr Neurosci"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiac392\/46381779\/jiac392.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/226\/12\/2215\/50499256\/jiac392.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/226\/12\/2215\/50499256\/jiac392.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T09:52:04Z","timestamp":1685613124000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/226\/12\/2215\/6732500"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,30]]},"references-count":49,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,9,30]]},"published-print":{"date-parts":[[2022,12,13]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiac392","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,15]]},"published":{"date-parts":[[2022,9,30]]}}}