Browsing by Author "Opoka, Robert O."
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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 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 Children’s Oxygen Administration Strategies And Nutrition Trial (COAST-Nutrition): a protocol for a phase II randomised controlled trial(Wellcome open research, 2021) Kiguli, Sarah; Olopot-Olupot, Peter; Alaroker, Florence; Engoru, Charles; Opoka, Robert O.; Tagoola, Abner; Hamaluba, Mainga; Mnjalla, Hellen; Mogaka, Christabel; Nalwanga, Damalie; Nabawanuka, Eva; Nokes, James; Nyaigoti, Charles; Woensel, Job B. M. van; Thomas, Karen; Harrison, David A.; Maitland, KathrynTo prevent poor long-term outcomes (deaths and readmissions) the integrated global action plan for pneumonia and diarrhoea recommends under the 'Treat' element of Protect, Prevent and Treat interventions the importance of continued feeding but gives no specific recommendations for nutritional support. Early nutritional support has been practiced in a wide variety of critically ill patients to provide vital cell substrates, antioxidants, vitamins, and minerals essential for normal cell function and decreasing hypermetabolism. We hypothesise that the excess post-discharge mortality associated with pneumonia may relate to the catabolic response and muscle wasting induced by severe infection and inadequacy of the diet to aid recovery. We suggest that providing additional energy-rich, protein, fat and micronutrient ready-to-use therapeutic feeds (RUTF) to help meet additional nutritional requirements may improve outcome. COAST-Nutrition is an open, multicentre, Phase II randomised controlled trial in children aged 6 months to 12 years hospitalised with suspected severe pneumonia (and hypoxaemia, SpO 2 <92%) to establish whether supplementary feeds with RUTF given in addition to usual diet for 56-days (experimental) improves outcomes at 90-days compared to usual diet alone (control). Primary endpoint is change in mid-upper arm circumference (MUAC) at 90 days and/or as a composite with 90-day mortality. Secondary outcomes include anthropometric status, mortality, readmission at days 28 and 180. The trial will be conducted in four sites in two countries (Uganda and Kenya) enrolling 840 children followed up to 180 days. Ancillary studies include cost-economic analysis, molecular characterisation of bacterial and viral pathogens, evaluation of putative biomarkers of pneumonia, assessment of muscle and fat mass and host genetic studies.Item Co-Trimoxazole Or Multivitamin Multimineral Supplement For Post-Discharge Outcomes After Severe Anaemia In African Children: A Randomised Controlled Trial(The Lancet Global Health, 2019) Maitland, Kathryn; Olupot, Peter Olupot; Kiguli, Sarah; Chagaluka, George; Alaroker, Florence; Opoka, Robert O.; Mpoya, Ayub; Walsh, Kevin; Engoru, Charles; Nteziyaremye, Julius; Mallewa, Machpherson; Nakuya, Margaret; Kennedy, Neil; Namayanja, Cate; Kayaga, Julianne; Nabawanuka, Eva; Sennyondo, Tonny; Aromut, Denis; Kumwenda, Felistas; Musika, Cynthia Williams; Thomason, Margaret J.; Bates, Imelda; Hensbroek, Michael Boele von; Evans, Jennifer A .; Uyoga, Sophie; Williams, Thomas N.; Frost, Gary; George, Elizabeth C.; Gibb, Diana M.; Walker, A. Sarah; the TRACT trial groupSevere anaemia is a leading cause of paediatric admission to hospital in Africa; post-discharge outcomes remain poor, with high 6-month mortality (8%) and re-admission (17%). We aimed to investigate post-discharge interventions that might improve outcomes.Within the two-stratum, open-label, multicentre, factorial randomised TRACT trial, children aged 2 months to 12 years with severe anaemia, defined as haemoglobin of less than 6 g/dL, at admission to hospital (three in Uganda, one in Malawi) were randomly assigned, using sequentially numbered envelopes linked to a second non-sequentially numbered set of allocations stratified by centre and severity, to enhanced nutritional supplementation with iron and folate-containing multivitamin multimineral supplements versus iron and folate alone at treatment doses (usual care), and to co-trimoxazole versus no co-trimoxazole. All interventions were administered orally and were given for 3 months after discharge from hospital. Separately reported randomisations investigated transfusion management. The primary outcome was 180-day mortality. All analyses were done in the intention-to-treat population; follow-up was 180 days. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN84086586, and follow-up is complete.From Sept 17, 2014, to May 15, 2017, 3983 eligible children were randomly assigned to treatment, and followed up for 180 days. 164 (4%) were lost to follow-up. 1901 (95%) of 1997 assigned multivitamin multimineral supplement, 1911 (96%) of 1986 assigned iron and folate, and 1922 (96%) of 1994 assigned co-trimoxazole started treatment. By day 180, 166 (8%) children in the multivitamin multimineral supplement group versus 169 (9%) children in the iron and folate group had died (hazard ratio [HR] 0·97, 95% CI 0·79–1·21; p=0·81) and 172 (9%) who received co-trimoxazole versus 163 (8%) who did not receive co-trimoxazole had died (HR 1·07, 95% CI 0·86–1·32; p=0·56). We found no evidence of interactions between these randomisations or with transfusion randomisations (p>0·2). By day 180, 489 (24%) children in the multivitamin multimineral supplement group versus 509 (26%) children in the iron and folate group (HR 0·95, 95% CI 0·84–1·07; p=0·40), and 500 (25%) children in the co-trimoxazole group versus 498 (25%) children in the no co-trimoxazole group (1·01, 0·89–1·15; p=0·85) had had one or more serious adverse events. Most serious adverse events were re-admissions, occurring in 692 (17%) children (175 [4%] with at least two re-admissions).Neither enhanced supplementation with multivitamin multimineral supplement versus iron and folate treatment or co-trimoxazole prophylaxis improved 6-month survival. High rates of hospital re-admission suggest that novel interventions are urgently required for severe anaemia, given the burden it places on overstretched health services in Africa.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 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 Patients with Nodding Syndrome in Uganda Improve with Symptomatic Treatment: A Cross-Sectional Study(BMJ open, 2014) Idro, Richard; Namusoke, Hanifa; Abbo, Catherine; Mutamba, Byamah B.; Mwesige, Angelina Kakooza; Opoka, Robert O.; Musubire, Abdu K.; Mwaka, Amos D.; Opar, Bernard T.Nodding syndrome (NS) is a poorly understood neurological disorder affecting thousands of children in Africa. In March 2012, we introduced a treatment intervention that aimed to provide symptomatic relief. This intervention included sodium valproate for seizures, management of behaviour and emotional difficulties, nutritional therapy and physical rehabilitation. We assessed the clinical and functional outcomes of this intervention after 12 months of implementation.This was a cross-sectional study of a cohort of patients with NS receiving the specified intervention. We abstracted preintervention features from records and compared these with the current clinical status. We performed similar assessments on a cohort of patients with other convulsive epilepsies (OCE) and compared the outcomes of the two groups.Participants were patients with WHO-defined NS and patients with OCE attending the same centres.The primary outcome was the proportion of patients with seizure freedom (≥1 month without seizures). Secondary outcome measures included a reduction in seizure frequency, resolution of behaviour and emotional difficulties, and independence in basic self-care.Patients with NS had had a longer duration of symptoms (median 5 (IQR 3, 6) years) compared with those with OCE (4 (IQR 2, 6) years), p<0.001. The intervention resulted in marked improvements in both groups; compared to the preintervention state, 121/484 (25%) patients with NS achieved seizure freedom and there was a >70% reduction in seizure frequency; behaviour and emotional difficulties resolved in 194/327 (59%) patients; 193/484 (40%) patients had enrolled in school including 17.7% who had earlier withdrawn due to severe seizures, and over 80% had achieved independence in basic self-care. These improvements were, however, less than that in patients with OCE of whom 243/476 (51.1%) patients were seizure free and in whom the seizure frequency had reduced by 86%.Ugandan children with NS show substantial clinical and functional improvements with symptomatic treatments suggesting that NS is probably a reversible encephalopathy.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 variablesItem Whole blood versus red cell concentrates for children with severe anaemia: a secondary analysis of the Transfusion and Treatment of African Children (TRACT) trial(The Lancet Global Health, 2022) George, Elizabeth C.; Uyoga, Sophie; M’baya, Bridon; Kyeyune Byabazair, Dorothy; Kiguli, Sarah; Olupot-Olupot, Peter; Opoka, Robert O.; Chagaluka, George; Alaroker, Florence; Williams, Thomas N.; Bates, Imelda; Mbanya, Dora; Gibb, Diana M.; Walker, A. Sarah; Maitland, KathrynThe TRACT trial established the timing of transfusion in children with uncomplicated anaemia (haemoglobin 4–6 g/dL) and the optimal volume (20 vs 30 mL/kg whole blood or 10 vs 15 mL/kg red cell concentrates) for transfusion in children admitted to hospital with severe anaemia (haemoglobin <6 g/dL) on day 28 mortality (primary endpoint). Because data on the safety of blood components are scarce, we conducted a secondary analysis to examine the safety and efficacy of different pack types (whole blood vs red cell concentrates) on clinical outcomes. Methods This study is a secondary analysis of the TRACT trial data restricted to those who received an immediate transfusion (using whole blood or red cell concentrates). TRACT was an open-label, multicentre, factorial, randomised trial conducted in three hospitals in Uganda (Soroti, Mbale, and Mulago) and one hospital in Malawi (Blantyre). The trial enrolled children aged between 2 months and 12 years admitted to hospital with severe anaemia (haemoglobin <6 g/dL). The pack type used (supplied by blood banks) was based only on availability at the time. The outcomes were haemoglobin recovery at 8 h and 180 days, requirement for retransfusion, length of hospital stay, changes in heart and respiratory rates until day 180, and the main clinical endpoints (mortality until day 28 and day 180, and readmission until day 180), measured using multivariate regression models. Findings Between Sept 17, 2014, and May 15, 2017, 3199 children with severe anaemia were enrolled into the TRACT trial. 3188 children were considered in our secondary analysis. The median age was 37 months (IQR 18–64). Whole blood was the first pack provided for 1632 (41%) of 3992 transfusions. Haemoglobin recovery at 8 h was significantly lower in those who received packed cells or settled cells than those who received whole blood, with a mean of 1·4 g/dL (95% CI –1·6 to –1·1) in children who received 30 mL/kg and –1·3 g/dL (–1·5 to –1·0) in those who received 20 mL/kg packed cells versus whole blood, and –1·5 g/dL (–1·7 to –1·3) in those who received 30 mL/kg and –1·0 g/dL (–1·2 to –0·9) in those who received 20 mL/kg settled cells versus whole blood (overall p<0·0001). Compared to whole blood, children who received blood as packed or settled cells in their first transfusion had higher odds of receiving a second transfusion (odds ratio 2·32 [95% CI 1·30 to 4·12] for packed cells and 2·97 [2·18 to 4·05] for settled cells; p<0·001) and longer hospital stays (hazard ratio 0·94 [95% CI 0·81 to 1·10] for packed cells and 0·86 [0·79 to 0·94] for settled cells; p=0·0024). There was no association between the type of blood supplied for the first transfusion and mortality at 28 days or 180 days, or readmission to hospital for any cause. 823 (26%) of 3188 children presented with severe tachycardia and 2077 (65%) with tachypnoea, but these complications resolved over time. No child developed features of confirmed cardiopulmonary overload. Interpretation Our study suggests that the use of packed or settled cells rather than whole blood leads to additional transfusions, increasing the use of a scarce resource in most of sub-Saharan Africa. These findings have substantial cost implications for blood transfusion and health services. Nevertheless, a clinical trial comparing whole blood transfusion with red cell concentrates might be needed to inform policy makers.Item A Year-Long Caregiver Training Program to Improve Neurocognition in Preschool Ugandan HIV-Exposed Children(Journal of developmental and behavioral pediatrics, 2013) Boivin, Michael J.; Bangirana, Paul; Nakasujja, Noeline; Page, Connie F.; Shohet, Cilly; Givon, Deborah; Bass, Judith K.; Opoka, Robert O.; Klein, Pnina S.Mediational intervention for sensitizing caregivers (MISC) is a structured program enabling caregivers to enhance their child’s cognitive and emotional development through daily interactions. The principal aim was to evaluate if a year-long MISC caregiver training program produced greater improvement in child cognitive and emotional development compared with a control program. 119 uninfected HIV-exposed preschool children and their caregivers were randomly assigned to one of two treatment arms: biweekly MISC training alternating between home and clinic for one year or a health and nutrition curriculum. All children were evaluated at baseline, 6 months, and 1 year with the Mullen Early Learning Scales, Color-Object Association Test (COAT) for memory, and Achenbach Child Behavior Checklist (CBCL) for psychiatric symptoms. Caregivers were evaluated on the same schedule with the Hopkins Symptoms Checklist (HSCL-25) for depression and anxiety.The treatment arms were compared using repeated-measures ANCOVA with child age, gender, weight, SES, caregiving quality, caregiver anxiety, and caregiver education as covariates. The MISC children had significantly greater gains compared to controls on the Mullen Receptive and Expressive Language development, and on the Mullen composite score of cognitive ability. COAT total memory for MISC children was marginally better than controls. No CBCL differences between the groups were noted. Caldwell HOME scores and observed mediational interaction scores from videotapes measuring caregiving quality also improved significantly more for the MISC group.MISC enhanced cognitive performance, especially in language development. These benefits were possibly mediated by improved caregiving and positive emotional benefit to the caregiver.