Browsing by Author "John, Chandy C."
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Item Acute Kidney Injury In Ugandan Children With Severe Malaria Is Associated With Long-Term Behavioral Problems(PloS one, 2019) Hickson, Meredith R.; Conroy, Andrea L.; Bangirana, Paul; Opoka, Robert O.; Idro, Richard; Ssenkusu, John M.; John, Chandy C.Acute kidney injury (AKI) is a risk factor for neurocognitive impairment in severe malaria (SM), but the impact of AKI on long-term behavioral outcomes following SM is unknown.We conducted a prospective study on behavioral outcomes of Ugandan children 1.5 to 12 years of age with two forms of severe malaria, cerebral malaria (CM, n = 226) or severe malarial anemia (SMA, n = 214), and healthy community children (CC, n = 173). AKI was defined as a 50% increase in creatinine from estimated baseline. Behavior and executive function were assessed at baseline and 6, 12, and 24 months later using the Child Behavior Checklist and Behavior Rating Inventory of Executive Function, respectively. Age-adjusted z-scores were computed for each domain based on CC scores. The association between AKI and behavioral outcomes was evaluated across all time points using linear mixed effect models, adjusting for sociodemographic variables and disease severity.AKI was present in 33.2% of children with CM or SMA at baseline. Children ≥6 years of age with CM or SMA who had AKI on admission had worse scores in socio-emotional function in externalizing behaviors (Beta (95% CI), 0.52 (0.20, 0.85), p = 0.001), global executive function (0.48 (0.15, 0.82), p = 0.005) and behavioral regulation (0.66 (0.32, 1.01), p = 0.0002) than children without AKI. There were no behavioral differences associated with AKI in children <6 years of age.AKI is associated with long-term behavioral problems in children ≥6 years of age with CM or SMA, irrespective of age at study enrollment.Item Acute Kidney Injury Is Associated With Impaired Cognition And Chronic Kidney Disease In A Prospective Cohort Of Children With Severe Malaria(BMC medicine, 2019) Conroy, Andrea L.; Opoka, Robert O.; Bangirana, Paul; Idro, Richard; Ssenkusu, John M.; Datta, Dibyadyuti; Hodges, James S.; Morgan, Catherine; John, Chandy C.Acute kidney injury (AKI) is a recognized complication of pediatric severe malaria, but its long-term consequences are unknown. Ugandan children with cerebral malaria (CM, n = 260) and severe malaria anemia (SMA, n = 219) or community children (CC, n = 173) between 1.5 and 12 years of age were enrolled in a prospective cohort study. Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to retrospectively define AKI and chronic kidney disease (CKD). Cognitive testing was conducted using the Mullen Scales of Early Learning in children < 5 and Kaufman Assessment Battery for Children (K-ABC) second edition in children ≥ 5 years of age.The prevalence of AKI was 35.1%, ranging from 25.1% in SMA to 43.5% in CM. In-hospital mortality was 11.9% in AKI compared to 4.2% in children without AKI (p = 0.001), and post-discharge mortality was 4.7% in AKI compared to 1.3% in children without AKI (p = 0.030) corresponding to an all-cause adjusted hazard ratio of 2.30 (95% CI 1.21, 4.35). AKI was a risk factor for short- and long-term neurocognitive impairment. At 1 week post-discharge, the frequency of neurocognitive impairment was 37.3% in AKI compared to 13.5% in children without AKI (adjusted odds ratio (aOR) 2.31 [95% CI 1.32, 4.04]); at 1-year follow-up, it was 13.3% in AKI compared to 3.4% in children without AKI (aOR 2.48 [95% CI 1.01, 6.10]), and at 2-year follow-up, it was 13.0% in AKI compared to 3.4% in children without AKI (aOR 3.03 [95% CI 1.22, 7.58]). AKI was a risk factor for CKD at 1-year follow-up: 7.6% of children with severe malaria-associated AKI had CKD at follow-up compared to 2.8% of children without AKI (p = 0.038) corresponding to an OR of 2.81 (95% CI 1.02, 7.73). The presenting etiology of AKI was consistent with prerenal azotemia, and lactate dehydrogenase as a marker of intravascular hemolysis was an independent risk factor for AKI in CM and SMA (p < 0.0001). In CM, AKI was associated with the presence and severity of retinopathy (p < 0.05) and increased cerebrospinal fluid albumin suggestive of blood-brain barrier disruption.AKI is a risk factor for long-term neurocognitive impairment and CKD in pediatric severe malaria.Item The Association between Cognition and Academic Performance in Ugandan Children Surviving Malaria with Neurological Involvement(PLoS One, 2013) Bangirana, Paul; Menk, Jeremiah; John, Chandy C.; Boivin, Michael J.; Hodges, James S.The contribution of different cognitive abilities to academic performance in children surviving cerebral insult can guide the choice of interventions to improve cognitive and academic outcomes. This study's objective was to identify which cognitive abilities are associated with academic performance in children after malaria with neurological involvement.62 Ugandan children with a history of malaria with neurological involvement were assessed for cognitive ability (working memory, reasoning, learning, visual spatial skills, attention) and academic performance (reading, spelling, arithmetic) three months after the illness. Linear regressions were fit for each academic score with the five cognitive outcomes entered as predictors. Adjusters in the analysis were age, sex, education, nutrition, and home environment. Exploratory factor analysis (EFA) and structural equation models (SEM) were used to determine the nature of the association between cognition and academic performance. Predictive residual sum of squares was used to determine which combination of cognitive scores was needed to predict academic performance.In regressions of a single academic score on all five cognitive outcomes and adjusters, only Working Memory was associated with Reading (coefficient estimate = 0.36, 95% confidence interval = 0.10 to 0.63, p<0.01) and Spelling (0.46, 0.13 to 0.78, p<0.01), Visual Spatial Skills was associated with Arithmetic (0.15, 0.03 to 0.26, p<0.05), and Learning was associated with Reading (0.06, 0.00 to 0.11, p<0.05). One latent cognitive factor was identified using EFA. The SEM found a strong association between this latent cognitive ability and each academic performance measure (P<0.0001). Working memory, visual spatial ability and learning were the best predictors of academic performance.Academic performance is strongly associated with the latent variable labelled “cognitive ability” which captures most of the variation in the individual specific cognitive outcome measures. Working memory, visual spatial skills, and learning together stood out as the best combination to predict academic performance.Item Cerebral Malaria in Children Is Associated With Long-term Cognitive Impairment(Pediatrics, 2008) John, Chandy C.; Bangirana, Paul; Byarugaba, Justus; Opoka, Robert O.; Idro, Richard; Jurek, Anne M.; Wu, Baolin; Boivin, Michael J.Cerebral malaria affects >785000 African children every year. We previously documented an increased frequency of cognitive impairment in children with cerebral malaria 6 months after their initial malaria episode. This study was conducted to determine the long-term effects of cerebral malaria on the cognitive function of these children.Children who were 5 to 12 years of age and presented to Mulago Hospital, Kampala, Uganda, with cerebral malaria (n = 44) or uncomplicated malaria (n = 54), along with healthy, asymptomatic community children (n = 89), were enrolled in a prospective cohort study of cognition. Cognitive testing was performed at enrollment and 2 years later. The primary outcome was presence of a deficit in ≥1 of 3 cognitive areas tested.At 2-year follow-up testing, 26.3% of children with cerebral malaria and 12.5% with uncomplicated malaria had cognitive deficits in ≥1 area, as compared with 7.6% of community children. Deficits in children with cerebral malaria were primarily in the area of attention (cerebral malaria, 18.4%, vs community children, 2.5%). After adjustment for age, gender, nutrition, home environment, and school level, children with cerebral malaria had a 3.67-fold increased risk for a cognitive deficit compared with community children. Cognitive impairment at 2-year follow-up was associated with hyporeflexia on admission and neurologic deficits 3 months after discharge.Cerebral malaria is associated with long-term cognitive impairments in 1 of 4 child survivors. Future studies should investigate the mechanisms involved so as to develop interventions aimed at prevention and rehabilitation.Item Cognition, Behaviour And Academic Skills After Cognitive Rehabilitation In Ugandan Children Surviving Severe Malaria: A Randomised Trial(BMC neurology, 2011) Bangirana, Paul; Allebeck, Peter; Boivin, Michael J.; John, Chandy C.; Page, Connie; Ehnvall, Anna; Musisi, SegganeInfection with severe malaria in African children is associated with not only a high mortality but also a high risk of cognitive deficits. There is evidence that interventions done a few years after the illness are effective but nothing is known about those done immediately after the illness. We designed a study in which children who had suffered from severe malaria three months earlier were enrolled into a cognitive intervention program and assessed for the immediate benefit in cognitive, academic and behavioral outcomes.This parallel group randomised study was carried out in Kampala City, Uganda between February 2008 and October 2010. Sixty-one Ugandan children aged 5 to 12 years with severe malaria were assessed for cognition (using the Kaufman Assessment Battery for Children, second edition and the Test of Variables of Attention), academic skills (Wide Range Achievement Test, third edition) and psychopathologic behaviour (Child Behaviour Checklist) three months after an episode of severe malaria. Twenty-eight were randomised to sixteen sessions of computerised cognitive rehabilitation training lasting eight weeks and 33 to a non-treatment group. Post-intervention assessments were done a month after conclusion of the intervention. Analysis of covariance was used to detect any differences between the two groups after post-intervention assessment, adjusting for age, sex, weight for age z score, quality of the home environment, time between admission and post-intervention testing and pre-intervention score. The primary outcome was improvement in attention scores for the intervention group. This trial is registered with Current Controlled Trials, number ISRCTN53183087.Significant intervention effects were observed in the intervention group for learning mean score (SE), [93.89 (4.00) vs 106.38 (4.32), P = 0.04] but for working memory the intervention group performed poorly [27.42 (0.66) vs 25.34 (0.73), P = 0.04]. No effect was observed in the other cognitive outcomes or in any of the academic or behavioural measures.In this pilot study, our computerised cognitive training program three months after severe malaria had an immediate effect on cognitive outcomes but did not affect academic skills or behaviour. Larger trials with follow-up after a few years are needed to investigate whether the observed benefits are sustained.Item Cognitive Impairment After Cerebral Malaria In Children: A Prospective Study(Pediatrics, 2007) Boivin, Michael J.; Bangirana, Paul; Byarugaba, Justus; Opoka, Robert O.; Idro, Richard; Jurek, Anne M.; John, Chandy C.This study was conducted to assess prospectively the frequency of cognitive deficits in children with cerebral malaria.Cognitive testing in the areas of working memory, attention, and learning was performed for Ugandan children 5 to 12 years of age with cerebral malaria (n = 44), children with uncomplicated malaria (n = 54), and healthy community children (n = 89) at admission and 3 and 6 months later.Six months after discharge, 21.4% of children with cerebral malaria had cognitive deficits, compared with 5.8% of community children. Deficits were seen in the areas of working memory (11.9% vs 2.3%) and attention (16.7% vs 2.3%). Children with cerebral malaria had a 3.7-fold increased risk of a cognitive deficit, compared with community children, after adjustment for age, gender, nutritional status, school level, and home environment. Among children with cerebral malaria, those with a cognitive deficit had more seizures before admission (mean: 4.1 vs 2.2) and a longer duration of coma (43.6 vs 30.5 hours), compared with those without a deficit. Children with uncomplicated malaria did not have an increased frequency of cognitive deficits.Cerebral malaria may be a major cause of cognitive impairment in children in sub-Saharan Africa. Cognitive deficits in children with cerebral malaria are more likely for those who have multiple seizures before effective treatment for cerebral malaria.Item Delayed Iron Does Not Alter Cognition Or Behavior Among Children With Severe Malaria And Iron Deficiency(Pediatric research, 2020) Ssemata, Andrew S.; Hickson, Meredith; Ssenkusu, John M.; Cusick, Sarah E.; Nakasujja, Noeline; Opoka, Robert O.; Kroupina, Maria; Georgieff, Michael K.; Bangirana, Paul; John, Chandy C.Malaria and iron deficiency (ID) in childhood are both associated with cognitive and behavioral dysfunction. The current standard of care for children with malaria and ID is concurrent antimalarial and iron therapy. Delaying iron therapy until inflammation subsides could increase iron absorption but also impair cognition.In this study, Ugandan children 18 months to 5 years old with cerebral malaria (CM, n = 79), severe malarial anemia (SMA, n = 77), or community children (CC, n = 83) were enrolled and tested for ID. Children with ID were randomized to immediate vs. 28-day delayed iron therapy. Cognitive and neurobehavioral outcomes were assessed at baseline and 6 and 12 months (primary endpoint) after enrollment.All children with CM or SMA and 35 CC had ID (zinc protoporphyrin concentration ≥80 μmol/mol heme). No significant differences were seen at 12-month follow-up in overall cognitive ability, attention, associative memory, or behavioral outcomes between immediate and delayed iron treatment (mean difference (standard error of mean) ranged from −0.2 (0.39) to 0.98 (0.5), all P ≥ 0.06).Children with CM or SMA and ID who received immediate vs. delayed iron therapy had similar cognitive and neurobehavioral outcomes at 12-month follow-up.Item Endothelial Activation, Acute Kidney Injury, and Cognitive Impairment in Pediatric Severe Malaria(Critical care medicine, 2020) Ouma, Benson J.; Ssenkusu, John M.; Shabani, Estela; Datta, Dibyadyuti; Opoka, Robert O.; Idro, Richard; Bangirana, Paul; Park, Gregory; Joloba, Moses L.; Kain, Kevin C.; John, Chandy C.; Conroy, Andrea L.Evaluate the relationship between endothelial activation, malaria complications, and long-term cognitive outcomes in severe malaria survivors.Prospectively cohort study of children with cerebral malaria, severe malarial anemia, or community children. Mulago National Referral Hospital in Kampala, Uganda.Children 18 months to 12 years old with severe malaria (cerebral malaria, n = 253 or severe malarial anemia, n = 211) or community children (n = 206) were followed for 24 months.Children underwent neurocognitive evaluation at enrollment (community children) or a week following hospital discharge (severe malaria) and 6, 12, and 24 months follow-up. Endothelial activation was assessed at admission on plasma samples (von Willebrand factor, angiopoietin-1 and angiopoietin-2, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, soluble E-Selectin, and P-Selectin). False discovery rate was used to adjust for multiple comparisons. Severe malaria was associated with widespread endothelial activation compared with community children (p < 0.0001 for all markers). Acute kidney injury was independently associated with changes in von Willebrand factor, soluble intercellular adhesion molecule-1, soluble E-Selectin, P-Selectin, and angiopoietin-2 (p < 0.0001 for all). A log10 increase in angiopoietin-2 was associated with lower cognitive z scores across age groups (children < 5, β −0.42, 95% CI, −0.69 to −0.15, p = 0.002; children ≥ 5, β −0.39, 95% CI, −0.67 to −0.11, p = 0.007) independent of disease severity (coma, number of seizures, acute kidney injury) and sociodemographic factors. Angiopoietin-2 was associated with hemolysis (lactate dehydrogenase, total bilirubin) and inflammation (tumor necrosis factor-α, interleukin-10). In children with cerebral malaria who had a lumbar puncture performed, angiopoietin-2 was associated with blood-brain barrier dysfunction, and markers of neuroinflammation and injury in the cerebrospinal fluid (tumor necrosis factor-α, kynurenic acid, tau).These data support angiopoietin-2 as a measure of disease severity and a risk factor for long-term cognitive injury in children with severe malaria.Item High Plasma Erythropoietin Levels are Associated With Prolonged Coma Duration and Increased Mortality in Children With Cerebral Malaria(Clinical Infectious Diseases, 2015) Shabani, Estela; Opoka, Robert O.; Idro, Richard; Schmidt, Robert; Park, Gregory S.; Bangirana, Paul; Vercellotti, Gregory M.; Hodges, James S.; Widness, John A.; John, Chandy C.Elevated endogenous plasma erythropoietin (EPO) levels have been associated with protection from acute neurologic deficits in Kenyan children with cerebral malaria (CM). Based on these findings and animal studies, clinical trials of recombinant human EPO (rHuEPO) have been started in children with CM. Recent clinical trials in adults with acute ischemic stroke have demonstrated increased mortality with rHuEPO treatment. We conducted a study in children with CM to assess the relationship of endogenous plasma and cerebrospinal fluid (CSF) EPO levels with mortality and acute and long-term neurologic outcomes.A total of 210 children between 18 months and 12 years of age with a diagnosis of CM, were enrolled at Mulago Hospital, Kampala, Uganda. Plasma (n = 204) and CSF (n = 147) EPO levels at admission were measured by radioimmunoassay and compared with mortality and neurologic outcomes. After adjustment for age and hemoglobin level, a 1-natural-log increase in plasma EPO level was associated with a 1.74-fold increase in mortality (95% confidence interval, 1.09–2.77, P = .02). Plasma and CSF EPO levels also correlated positively with coma duration (P = .05 and P = .02, respectively). Plasma and CSF EPO levels did not differ in children with vs those without acute or long-term neurologic deficits. Plasma EPO levels correlated positively with markers of endothelial and platelet activation and histidine-rich protein-2 levels, but remained associated with mortality after adjustment for these factors.High endogenous plasma EPO levels are associated with prolonged coma duration and increased mortality in children >18 months of age with CM.Item Immediate Neuropsychological And Behavioral Benefits Of Computerized Cognitive Rehabilitation In Ugandan Pediatric Cerebral Malaria Survivors(Journal of developmental and behavioral pediatrics, 2009) Bangirana, Paul; Giordani, Bruno; John, Chandy C.; Page, Connie; Opoka, Robert O.; Boivin, Michael J.Our earlier studies on Ugandan children surviving cerebral malaria showed cognitive deficits mainly in attention and memory. We now present the first study in sub-Saharan Africa to investigate the feasibility and potential benefits of computerized cognitive rehabilitation training on neuropsychological and behavioural functioning of children surviving cerebral malaria.A randomized trial in which 65 children admitted 45 months earlier with cerebral malaria were recruited at Mulago Hospital, Kampala, Uganda. For eight weeks, 32 of the children received weekly training sessions using Captain’s Log cognitive training software and the other 33 were assigned to a non treatment condition. Pre- and post-intervention assessments were completed using CogState, a computerized neuropsychological battery, measuring Visuomotor Processing Speed, Working Memory, Learning, Attention and Psychomotor Speed and the Child Behavior Checklist measuring Internalising Problems, Externalising Problems and Total Problems.Pre-intervention scores were similar between both groups. Treatment effects were observed on Visual Spatial Processing Speed (group effect (standard error) 0.14 (0.03); p< 0.001); on a Working Memory and Learning task (0.08 (0.02); p< 0.001), Psychomotor Speed (0.14 (0.07); p= 0.04) and on Internalising Problems (−3.80 (1.56); p= 0.02) after controlling for age, sex, school grade, quality of the home environment and weight for age z scores. Similar treatment effects were observed when no adjustments for the above covariates were made.Computerized cognitive training long after the cerebral malaria episode has immediate benefit on some neuropsychological and behavioral functions in African children. The long-term benefit of this intervention needs to be investigated.Item Inpatient Mortality in Children With Clinically Diagnosed Malaria As Compared With Microscopically Confirmed Malaria(The Pediatric infectious disease journal, 2008) Opoka, Robert O.; Xia, Zongqi; Bangirana, Paul; John, Chandy C.Inpatient treatment for malaria without microscopic confirmation of the diagnosis occurs commonly in sub-Saharan Africa. Differences in mortality in children who are tested by microscopy for Plasmodium falciparum infection as compared with those not tested are not well characterized.A retrospective chart review was conducted of all children up to 15 years of age admitted to Mulago Hospital, Kampala, Uganda from January 2002 to July 2005, with a diagnosis of malaria and analyzed according to microscopy testing for P. falciparum.A total of 23,32 children were treated for malaria during the study period, 991 (4.2%) of whom died. Severe malarial anemia in 7827 (33.5%) and cerebral malaria in 1912 (8.2%) were the 2 common causes of malaria-related admissions. Children who did not receive microscopy testing had a higher case fatality rate than those with a positive blood smear (7.5% versus 3.2%, P < 0.001). After adjustment for age, malaria complications, and comorbid conditions, children who did not have microscopy performed or had a negative blood smear had a higher risk of death than those with a positive blood smear [odds ratio (OR): 3.49, 95% confidence interval (CI): 2.88–4.22, P < 0.001; and OR: 1.59, 95% CI: 1.29–1.96, P < 0.001, respectively].Diagnosis of malaria in the absence of microscopic confirmation is associated with significantly increased mortality in hospitalized Ugandan children. Inpatient diagnosis of malaria should be supported by microscopic or rapid diagnostic test confirmation.Item Malaria parasitemia among blood donors in Uganda(Transfusion, 2020) Murphy, Kristin J.; Conroy, Andrea L.; Ddungu, Henry; Shrestha, Ruchee; Kyeyune-Byabazaire, Dorothy; Petersen, Molly R.; Musisi, Ezra; Patel, Eshan U.; Kasirye, Ronnie; Bloch, Evan M.; Lubega, Irene; John, Chandy C.; Hume, Heather A.; Tobian, Aaron A.R.Malaria remains a leading transfusion associated infectious risk in endemic areas. However, the prevalence of malaria parasitemia has not been well characterized in blood donor populations. This study sought to determine the prevalence of Plasmodium in red blood cell (RBC) and whole blood (WB) units after the rainy season in Uganda. METHODS AND MATERIALS: Between May and July 2018, blood was collected from the sample diversion pouch of 1000 WB donors in Kampala and Jinja, Uganda. The RBC pellet from ethylenediamine tetraacetic acid (EDTA) anticoagulated blood was stored at −80°C until testing. DNA was extracted and nested PCR was used to screen samples at the genus level for Plasmodium, with positive samples further tested for species identification. RESULTS: Malaria parasitemia among asymptomatic, eligible blood donors in two regions of Uganda was 15.4%; 87.7% (135/154) of infections were with P. falciparum, while P. malariae and P. ovale were also detected. There were 4.3% of blood donors who had mixed infection with multiple species. Older donors (>30 years vs. 17-19 years; aPR = 0.31 [95% CI = 0.17-0.58]), females (aPR = 0.60 [95% CI = 0.42-0.87]), repeat donors (aPR = 0.44 [95% CI = 0.27-0.72]) and those donating near the capital city of Kampala versus rural Jinja region (aPR = 0.49 [95% CI = 0.34-0.69]) had a lower prevalence of malaria parasitemia. CONCLUSIONS: A high proportion of asymptomatic blood donors residing in a malaria endemic region demonstrate evidence of parasitemia at time of donation. Further research is needed to quantify the risk and associated burden of transfusion-transmitted malaria (TTM) in order to inform strategies to prevent TTM.Item Malaria With Neurological Involvement In Ugandan Children: Effect On Cognitive Ability, Academic Achievement And Behaviour(Malaria journal, 2011) Bangirana, Paul; Musisi, Seggane; Boivin, Michael J.; Ehnvall, Anna; John, Chandy C.; Bergemann, Tracy L.; Allebeck, PeterMalaria is a leading cause of ill health and neuro-disability in children in sub-Saharan Africa. Impaired cognition is a common outcome of malaria with neurological involvement. There is also a possibility that academic achievement may be affected by malaria with neurological involvement given the association between cognitive ability and academic achievement. This study investigated the effect of malaria with neurological involvement on cognitive ability, behaviour and academic achievement.This prospective case-control study was carried out in Kampala City, Uganda between February 2008 and October 2010. Sixty-two children with a history of malaria with neurological involvement were followed up and given assessments for cognitive ability (working memory, reasoning, learning, visual spatial skills and attention), behaviour (internalizing and externalizing problems) and academic achievement (arithmetic, spelling and reading) three months after the illness. Sixty-one community controls recruited from the homes or neighbouring families of the cases were also given the same assessments. Tests scores of the two groups were compared using analysis of covariance with age, sex, level of education, nutritional status and quality of the home environment as covariates. This study was approved by the relevant ethical bodies and informed consent sought from the caregivers.Children in the malaria group had more behavioural problems than the community controls for internalizing problems (estimated mean difference = -3.71, 95% confidence interval (CI), = -6.34 to -1.08, p = 0.007). There was marginal evidence of lower attention scores (0.40, CI = -0.05 to 0.86, p = 0.09). However, excluding one child from the analyses who was unable to perform the tests affected the attention scores to borderline significance (0.32, CI, = 0.01 to 0.62, p = 0.05). No significant differences were observed in other cognitive abilities or in academic achievement scores.Malaria with neurological involvement affects behaviour, with a minimal effect on attention but no detectable effect on academic achievement at three months post discharge. This study provides evidence that development of cognitive deficits after malaria with neurological involvement could be gradual with less effect observed in the short term compared to the long term.Item Parenteral Artemisinins Are Associated With Reduced Mortality And Neurologic Deficits And Improved Long-Term Behavioral Outcomes In Children With Severe Malaria(BMC medicine, 2021) Conroy, Andrea L.; Opoka, Robert O.; Bangirana, Paul; Namazzi, Ruth; Okullo, Allen E.; Georgieff, Michael K.; Cusick, Sarah; Idro, Richard; Ssenkusu, John M.; John, Chandy C.In 2011, the World Health Organization recommended injectable artesunate as the first-line therapy for severe malaria (SM) due to its superiority in reducing mortality compared to quinine. There are limited data on long-term clinical and neurobehavioral outcomes after artemisinin use for treatment of SM.From 2008 to 2013, 502 Ugandan children with two common forms of SM, cerebral malaria and severe malarial anemia, were enrolled in a prospective observational study assessing long-term neurobehavioral and cognitive outcomes following SM. Children were evaluated a week after hospital discharge, and 6, 12, and 24 months of follow-up, and returned to hospital for any illness. In this study, we evaluated the impact of artemisinin derivatives on survival, post-discharge hospital readmission or death, and neurocognitive and behavioral outcomes over 2 years of follow-up.346 children received quinine and 156 received parenteral artemisinin therapy (artemether or artesunate). After adjustment for disease severity, artemisinin derivatives were associated with a 78% reduction in in-hospital mortality (adjusted odds ratio, 0.22; 95% CI, 0.07–0.67). Among cerebral malaria survivors, children treated with artemisinin derivatives also had reduced neurologic deficits at discharge (quinine, 41.7%; artemisinin derivatives, 23.7%, p=0.007). Over a 2-year follow-up, artemisinin derivatives as compared to quinine were associated with better adjusted scores (negative scores better) in internalizing behavior and executive function in children irrespective of the age at severe malaria episode. After adjusting for multiple comparisons, artemisinin derivatives were associated with better adjusted scores in behavior and executive function in children <6 years of age at severe malaria exposure following adjustment for child age, sex, socioeconomic status, enrichment in the home environment, and the incidence of hospitalizations over follow-up. Children receiving artesunate had the greatest reduction in mortality and benefit in behavioral outcomes and had reduced inflammation at 1-month follow-up compared to children treated with quinine.Treatment of severe malaria with artemisinin derivatives, particularly artesunate, results in reduced in-hospital mortality and neurologic deficits in children of all ages, reduced inflammation following recovery, and better long-term behavioral outcomes. These findings suggest artesunate has long-term beneficial effects in children surviving severe malaria.Item Patterns Of Traumatic Brain Injury And Six-Month Neuropsychological Outcomes In Uganda(BMC neurology, 2019) Bangirana, Paul; Giordani, Bruno; Kobusingye, Olive; Murungyi, Letisia; Mock, Charles; John, Chandy C.; Idro, RichardTraumatic brain injuries in Uganda are on the increase, however little is known about the neuropsychological outcomes in survivors. This study characterized patients with traumatic brain injury (TBI) and the associated six-month neuropsychological outcomes in a Ugandan tertiary hospital.Patients admitted at Mulago Hospital with head injury from November 2015 to April 2016 were prospectively enrolled during admission and followed up at six months after discharge to assess cognition, posttraumatic stress symptoms (PTSS), depression symptoms and physical disability. The outcomes were compared to a non-head-injury group recruited from among the caretakers, siblings and neighbours of the patients with age and sex entered as covariates.One hundred and seventy-one patients and 145 non-head injury participants were enrolled. The age range for the whole sample was 1 to 69 years with the non-head injury group being older (mean age (SD) 33.34 (13.35) vs 29.34 (14.13) years of age, p = 0.01). Overall, motorcycle crashes (36/171, 38.6%) and being hit by an object (58/171, 33.9%) were the leading causes of TBI. Head injury from falls occurred more frequently in children < 18 years (13.8% vs 2.8%, p = 0.03). In adults 18 years and older, patients had higher rates of neurocognitive impairment (28.4% vs 6.6%, p < 0.0001), PTSS (43.9% vs 7.9%, p < 0.0001), depression symptoms (55.4% vs 10%, p < 0.0001) and physical disability (7.2% vs 0%, p = 0.002). Lower Glasgow Coma Score (GCS) on admission was associated with neurocognitive impairment (11.6 vs 13.1, p = 0.04) and physical disability (10 vs 12.9, p = 0.01) six months later.This first such study in the East-African region shows that depth of coma on admission in TBI is associated with neurocognitive impairment and physical disability.Item Rehabilitation for cognitive impairments after cerebral malaria in African children: strategies and limitations(Tropical Medicine & International Health, 2006) Bangirana, Paul; Idro, Richard; John, Chandy C.; Boivin, Michael J.Cerebral malaria results in short- to long-term cognitive impairments in many of its child survivors. Although some of the risk factors for impairments have been identified, no attempts have been made to address the plight of those who develop cognitive impairments. This paper discusses the burden of cognitive impairment caused by cerebral malaria and suggests some rehabilitation strategies based on brain injury and cognitive rehabilitation studies. Potential cognitive rehabilitation solutions such as cognitive exercises, environmental enrichment, nutritional supplementation, physical therapy and speech therapy are highlighted. The limitations of implementing these interventions and solutions are discussed in light of the limited human resources and infrastructure of the developing countries that are malaria endemic.Item Reliability of the Luganda version of the Child Behaviour Checklist in measuring behavioural problems after cerebral malaria(Child and adolescent psychiatry and mental health, 2009) Bangirana, Paul; Nakasujja, Noeline; Giordani, Bruno; Opoka, Robert O.; John, Chandy C.; Boivin, Michael J.No measure of childhood behaviour has been validated in Uganda despite the documented risks to behaviour. Cerebral malaria in children poses a great risk to their behaviour, however behavioural outcomes after cerebral malaria have not been described in children. This study examined the reliability of the Luganda version of the Child Behaviour Checklist (CBCL) and described the behavioural outcomes of cerebral malaria in Ugandan children.The CBCL was administered to parents of 64 children aged 7 to 16 years participating in a trial to improve cognitive functioning after cerebral malaria. These children were assigned to the treatment or control group. The CBCL parent ratings were completed for the children at baseline and nine weeks later. The CBCL was translated into Luganda, a local language, prior to its use. Baseline scores were used to calculate internal consistency using Cronbach Alpha. Correlations between the first and second scores of the control group were used to determine test-retest reliability. Multicultural norms for the CBCL were used to identify children with behavioural problems of clinical significance.The test-retest reliability and internal consistency of the Internalising scales were 0.64 and 0.66 respectively; 0.74 and 0.78 for the Externalising scale and 0.67 and 0.83 for Total Problems. Withdrawn/Depressed (15.6%), Thought Problems (12.5%), Aggressive Behaviour (9.4%) and Oppositional Defiant Behaviour (9.4%) were the commonly reported problems.The Luganda version of the CBCL is a fairly reliable measure of behavioural problems in Ugandan children. Depressive and thought problems are likely behavioural outcomes of cerebral malaria in children. Further work in children with psychiatric diagnoses is required to test its validity in a clinical setting.Item Seizure Activity And Neurological Sequelae In Ugandan Children Who Have Survived An Episode Of Cerebral Malaria(African health sciences, 2009) Opoka, Robert O.; Bangirana, Paul; Boivin, Michael J.; John, Chandy C.; Justus Byarugaba, JustusSeizures are a common presenting feature in children with cerebral malaria (CM) and neurologic deficits have been described in survivors of CM. However few prospective studies have described the frequency of seizure activity and neurologic deficits in survivors of CM over time.Eighty-two children aged 3 to 12 years who survived an episode of CM were followed up and monitored for seizure activity and neurologic deficits at discharge, 3, 6 and 24 months. Seventy six children with uncomplicated malaria (UM) and 105 healthy community controls (CC) age 3 to 12 years were recruited as comparison groups and the frequency of seizures in the 6 to 24 month follow-up period was compared in the 3 groups.Cumulative incidence of seizures increased over time in children with CM, with a total of 2 of 76 children (2.6%) reporting seizures at 3 months, 3 of 74 children (4.1%) at 6 months and 11 of 68 children (16.2%) at 24 months (Chi square for trend = 9.36, P=0.002). In contrast, neurologic deficits almost completely resolved over time, occurring in 19 of 76 children with CM (25%) at discharge, 2 of 74 children (2.7%) at 6 months, and 1 of 68 (1.5%) children at 24 months.During the 24 months following a CM episode, neurologic deficits resolve but the cumulative incidence of seizures increases in children with CM. Neurologic impairment after an episode of CM may not be limited to the neurologic deficits seen at discharge.Item Socioeconomic Predictors of Cognition in Ugandan Children: Implications for Community Interventions(PloS one, 2009) Bangirana, Paul; John, Chandy C.; Idro, Richard; Opoka, Robert O.; Byarugaba, Justus; Jurek, Anne M.; Boivin, Michael J.Several interventions to improve cognition in at risk children have been suggested. Identification of key variables predicting cognition is necessary to guide these interventions. This study was conducted to identify these variables in Ugandan children and guide such interventions.A cohort of 89 healthy children (45 females) aged 5 to 12 years old were followed over 24 months and had cognitive tests measuring visual spatial processing, memory, attention and spatial learning administered at baseline, 6 months and 24 months. Nutritional status, child's educational level, maternal education, socioeconomic status and quality of the home environment were also measured at baseline. A multivariate, longitudinal model was then used to identify predictors of cognition over the 24 months.A higher child's education level was associated with better memory (p = 0.03), attention (p = 0.005) and spatial learning scores over the 24 months (p = 0.05); higher nutrition scores predicted better visual spatial processing (p = 0.002) and spatial learning scores (p = 0.008); and a higher home environment score predicted a better memory score (p = 0.03).Cognition in Ugandan children is predicted by child's education, nutritional status and the home environment. Community interventions to improve cognition may be effective if they target multiple socioeconomic variables