Solar-powered O2 delivery for the treatment of children with hypoxaemia in Uganda: a stepped-wedge, cluster randomised controlled trial.

BACKGROUND: Supplemental O2 is not always available at health facilities in low-income and middle-income countries (LMICs). Solar-powered O2 delivery can overcome gaps in O2 access, generating O2 independent of grid electricity. We hypothesized that installation of solar-powered O2 systems on the paediatrics ward of rural Ugandan hospitals would lead to a reduction in mortality among hypoxaemic children. METHODS: In this pragmatic, country-wide, stepped-wedge, cluster randomised controlled trial, solar-powered O2 systems (ie, photovoltaic cells, battery bank, and O2 concentrator) were sequentially installed at 20 rural health facilities in Uganda. Sites were selected for inclusion based on the following criteria: District Hospital or Health Centre IV with paediatric inpatient services; supplemental O2 on the paediatric ward was not available or was unreliable; and adequate space to install solar panels, a battery bank, and electrical wiring. Allocation concealment was achieved for sites up to 2 weeks before installation, but the study was not masked overall. Children younger than 5 years admitted to hospital with hypoxaemia and respiratory signs were included. The primary outcome was mortality within 48 h of detection of hypoxaemia. The statistical analysis used a linear mixed effects logistic regression model accounting for cluster as random effect and calendar time as fixed effect. The trial is registered at ClinicalTrials.gov, NCT03851783. FINDINGS: Between June 28, 2019, and Nov 30, 2021, 2409 children were enrolled across 20 hospitals and, after exclusions, 2405 children were analysed. 964 children were enrolled before site randomisation and 1441 children were enrolled after site randomisation (intention to treat). There were 104 deaths, 91 of which occurred within 48 h of detection of hypoxaemia. The 48 h mortality was 49 (5·1%) of 964 children before randomisation and 42 (2·9%) of 1440 (one individual did not have vital status documented at 48 h) after randomisation (adjusted odds ratio 0·50, 95% CI 0·27-0·91, p=0·023). Results were sensitive to alternative parameterisations of the secular trend. There was a relative risk reduction of 48·7% (95% CI 8·5-71·5), and a number needed to treat with solar-powered O2 of 45 (95% CI 28-230) to save one life. Use of O2 increased from 484 (50·2%) of 964 children before randomisation to 1424 (98·8%) of 1441 children after randomisation (p<0·0001). Adverse events were similar before and after randomisation and were not considered to be related to the intervention. The estimated cost-effectiveness was US$25 (6-505) per disability-adjusted life-year saved. INTERPRETATION: This stepped-wedge, cluster randomised controlled trial shows the mortality benefit of improving O2 access with solar-powered O2. This study could serve as a model for scale-up of solar-powered O2 as one solution to O2 insecurity in LMICs. FUNDING: Grand Challenges Canada and The Women and Children's Health Research Institute.

sTREM-1: A Biomarker of Mortality in Severe Malaria Impacted by Acute Kidney Injury.

BACKGROUND: Malaria is an important cause of mortality in African children. Identification of biomarkers to identify children at risk of mortality has the potential to improve outcomes. METHODS: We evaluated 11 biomarkers of host response in 592 children with severe malaria. The primary outcome was biomarker performance for predicting mortality. Biomarkers were evaluated using receiver operating characteristic (ROC) curve analysis comparing the area under the ROC curve (AUROC). RESULTS: Mortality was 7.3% among children in the study with 72% of deaths occurring within 24 hours of admission. Among the candidate biomarkers, soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) had the highest AUROC (0.78 [95% confidence interval, .70-.86]), outperforming several other biomarkers including C-reactive protein and procalcitonin. sTREM-1 was the top-performing biomarker across prespecified subgroups (malaria definition, site, sex, nutritional status, age). Using established cutoffs, we evaluated mortality across sTREM-1 risk zones. Among children with acute kidney injury, 39.9% of children with a critical-risk sTREM-1 result had an indication for dialysis. When evaluated relative to a disease severity score, sTREM-1 improved mortality prediction (difference in AUROC, P = .016). CONCLUSIONS: sTREM-1 is a promising biomarker to guide rational allocation of clinical resources and should be integrated into clinical decision support algorithms, particularly when acute kidney injury is suspected.

Neurocognitive Impairment in Ugandan Children with Sickle Cell Anemia Compared to Sibling Controls: A cross-sectional study.

Introduction: Neurocognitive function in Ugandan children aged 1-12 years with sickle cell anemia (SCA) were compared to their non-SCA siblings to identify risk factors for disease-associated impairment. Methods: This cross-sectional neurocognitive function study of children with SCA (N=242) and non-SCA siblings (N=127) used age- and linguistically-appropriate standardized tests of cognition, executive function and attention for children ages 1-4 and 5-12 years. Test scores were converted to locally derived age-normalized z-scores. The SCA group underwent standardized stroke examination for prior stroke and transcranial doppler ultrasound (TCD) to determine stroke risk by arterial flow velocity. Results: The SCA group was younger than siblings (mean ages 5.46±3.0 versus 7.11±3.51 years, respectively; p <.001), with lower hemoglobin concentration (7.32±1.02 vs. 12.06±1.42, p <.001). Overall cognitive SCA z-scores were lower: -0.73 ±0.98 vs. siblings -0.25 ±1.12 (p<.001), with comparable findings for executive function of -1.09±0.94 versus -0.84±1.26 (p=0.045), respectively. Attention z-scores for ages 5-12 for the SCA group and controls were similar: -0.37±1.4 vs. -0.11±0.17 (p=.09). Overall differences by SCA status were largely driven by the older age group, as z-scores in the younger sub-sample did not differ from controls. Analyses revealed the strongest predictors of poor neurocognitive outcomes among the SCA sample to be the disease, age and prior stroke (each p<.001). Impact from anemia and SCA were indistinguishable. Discussion: Neurocognitive testing in children with SCA compared to non-SCA siblings revealed poorer SCA-associated functioning in children older than age 4. Results indicate need for trials assessing impact from disease modification for children with SCA.

Blood biomarkers of neuronal injury in paediatric cerebral malaria and severe malarial anaemia.

Persistent neurodisability is a known complication in paediatric survivors of cerebral malaria and severe malarial anaemia. Tau, ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein have proven utility as biomarkers that predict adverse neurologic outcomes in adult and paediatric disorders. In paediatric severe malaria, elevated tau is associated with mortality and neurocognitive complications. We aimed to investigate whether a multi-analyte panel including ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein can serve as biomarkers of brain injury associated with mortality and neurodisability in cerebral malaria and severe malarial anaemia. In a prospective cohort study of Ugandan children, 18 months to 12 years of age with cerebral malaria (n = 182), severe malarial anaemia (n = 158), and asymptomatic community children (n = 118), we measured admission blood levels of ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein. We investigated differences in biomarker levels, associations with mortality, blood-brain barrier integrity, neurodeficits and cognitive Z-scores in survivors up to 24-month follow-up. Admission ubiquitin C-terminal hydrolase-L1 levels were elevated >95th percentile of community children in 71 and 51%, and neurofilament-light chain levels were elevated >95th percentile of community children in 40 and 37% of children with cerebral malaria and severe malarial anaemia, respectively. Glial fibrillary acidic protein was not elevated in disease groups compared with controls. In cerebral malaria, elevated neurofilament-light chain was observed in 16 children who died in hospital compared with 166 survivors (P = 0.01); elevations in ubiquitin C-terminal hydrolase-L1 levels were associated with degree of blood-brain barrier disruption (P = 0.01); and the % predictive value for neurodeficits over follow-up (discharge, 6-, 12-, and 24 months) increased for ubiquitin C-terminal hydrolase-L1 (60, 67, 72, and 83), but not neurofilament-light chain (65, 68, 60, and 67). In cerebral malaria, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse memory scores in children <5 years at malaria episode who crossed to over 5 years old during follow-up cognitive testing [ß -1.13 (95% confidence interval -2.05, -0.21), P = 0.02], and elevated neurofilament-light chain was associated with worse attention in children ≥5 years at malaria episode and cognitive testing [ß -1.08 (95% confidence interval -2.05, -1.05), P = 0.03]. In severe malarial anaemia, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse attention in children <5 years at malaria episode and cognitive testing [ß -0.42 (95% confidence interval -0.76, -0.07), P = 0.02]. Ubiquitin C-terminal hydrolase-L1 and neurofilament-light chain levels are elevated in paediatric cerebral malaria and severe malarial anaemia. In cerebral malaria, elevated neurofilament-light chain is associated with mortality whereas elevated ubiquitin C-terminal hydrolase-L1 is associated with blood-brain barrier dysfunction and neurodeficits over follow-up. In cerebral malaria, both markers are associated with worse cognition, while in severe malarial anaemia, only ubiquitin C-terminal hydrolase-L1 is associated with worse cognition.

Apolipoprotein-E4: risk of severe malaria and mortality and cognitive impairment in pediatric cerebral malaria.

BACKGROUND: The relationship of apolipoprotein-E4 (APOE4) to mortality and cognition after severe malaria in children is unknown. METHODS: APOE genotyping was performed in children with cerebral malaria (CM, n = 261), severe malarial anemia (SMA, n = 224) and community children (CC, n = 213). Cognition was assessed over 2-year follow-up. RESULTS: A greater proportion of children with CM or SMA than CC had APOE4 (n = 162, 31.0%; n = 142, 31.7%; n = 103, 24.2%, respectively, p = 0.02), but no difference was seen in APOE3 (n = 310, 59.4%; n = 267, 59.6%; n = 282, 66.2%, respectively, p = 0.06), or APOE2 (n = 50, 9.6%; n = 39, 8.7%; and n = 41, 9.6%, respectively, p = 0.87). APOE4 was associated with increased mortality in CM (odds ratio, 2.28; 95% CI, 1.01, 5.11). However, APOE4 was associated with better long-term cognition (ß, 0.55; 95% CI, 0.04, 1.07, p = 0.04) and attention (ß 0.78; 95% CI, 0.26, 1.30, p = 0.004) in children with CM < 5 years old, but worse attention (ß, -0.90; 95% CI, -1.69, -0.10, p = 0.03) in children with CM ≥ 5 years old. Among children with CM, risk of post-discharge malaria was increased with APOE4 and decreased with APOE3. CONCLUSIONS: APOE4 is associated with higher risk of CM or SMA and mortality in children with CM, but better long-term cognition in CM survivors <5 years of age.

Renin as a Biomarker of Acute Kidney Injury and Mortality in Children With Severe Malaria or Sickle Cell Disease.

BACKGROUND: Globally, a very high percentage of acute kidney injury (AKI) occurs in low- and middle-income countries (LMICs) where late recognition contributes to increased mortality. There are challenges with using existing biomarkers of AKI in LMICs. Emerging evidence suggests renin may serve as a biomarker of kidney injury that can overcome limitations in creatinine-based diagnostics. METHODS: Two study populations in Uganda were assessed. Cohort #1 was a two-site, prospective cohort study enrolling 600 children with severe malaria (SM). Cohort #2 was a prospective cohort study enrolling 185 children with sickle cell disease (SCD) hospitalized with a vaso-occlusive crisis. Plasma or serum renin concentrations were measured in both cohorts of children at the time of hospital admission using Luminex® (Luminex Corporation, Austin, Texas, United States) or enzyme-linked immunosorbent assay (ELISA), respectively. We assessed the ability of renin to discriminate between children with or without AKI and between children who survived and children who died using receiver operating characteristic curves. RESULTS: In both cohorts, renin concentrations were strongly associated with AKI and mortality. Renin was able to discriminate between children with or without AKI with an area under the curve (AUC) of 0.70 (95%CI, 0.65-0.74) in children with SM and 0.72 (95%CI, 0.6co3-0.81) in children with SCD. Renin was able to discriminate between children who survived and children who died with an AUC of 0.73 (95%CI, 0.63-0.83) in children with SM and 0.94 (95%CI, 0.89-0.99) in children with SCD. In Cohort #2, we compared renin against urine neutrophil gelatinase-associated lipocalin (NGAL) as the leading biomarker of AKI, and it had comparable performance in discriminating AKI and predicting mortality. CONCLUSIONS: In two independent populations of children at risk of AKI with key differences in the etiology of kidney injury, renin was strongly associated with AKI and mortality and had moderate to good diagnostic performance to predict mortality.

Xanthine oxidase levels and immune dysregulation are independently associated with anemia in Plasmodium falciparum malaria.

Severe anemia is an important contributor to mortality in children with severe malaria. Anemia in malaria is a multi-factorial complication, since dyserythropoiesis, hemolysis and phagocytic clearance of uninfected red blood cells (RBCs) can contribute to this syndrome. High levels of oxidative stress and immune dysregulation have been proposed to contribute to severe malarial anemia, facilitating the clearance of uninfected RBCs. In a cohort of 552 Ugandan children with severe malaria, we measured the levels of xanthine oxidase (XO), an oxidative enzyme that is elevated in the plasma of malaria patients. The levels of XO in children with severe anemia were significantly higher compared to children with severe malaria not suffering from severe anemia. Levels of XO were inversely associated with RBC hemoglobin (ρ = - 0.25, p < 0.0001), indicating a relation between this enzyme and severe anemia. When compared with the levels of immune complexes and of autoimmune antibodies to phosphatidylserine, factors previously associated with severe anemia in malaria patients, we observed that XO is not associated with them, suggesting that XO is associated with severe anemia through an independent mechanism. XO was associated with prostration, acidosis, jaundice, respiratory distress, and kidney injury, which may reflect a broader relation of this enzyme with severe malaria pathology. Since inhibitors of XO are inexpensive and well-tolerated drugs already approved for use in humans, the validation of XO as a contributor to severe malarial anemia and other malaria complications may open new possibilities for much needed adjunctive therapy in malaria.

Admission Clinical and EEG Features Associated With Mortality and Long-term Neurologic and Cognitive Outcomes in Pediatric Cerebral Malaria.

BACKGROUND AND OBJECTIVES: For children with cerebral malaria, mortality is high, and in survivors, long-term neurologic and cognitive dysfunctions are common. While specific clinical factors are associated with death or long-term neurocognitive morbidity in cerebral malaria, the association of EEG features with these outcomes, particularly neurocognitive outcomes, is less well characterized. METHODS: In this prospective cohort study of 149 children age 6 months to 12 years who survived cerebral malaria in Kampala, Uganda, we evaluated whether depth of coma, number of clinical seizures, or EEG features during hospitalization were associated with mortality during hospitalization, short-term and long-term neurologic deficits, or long-term cognitive outcomes (overall cognition, attention, memory) over the 2-year follow-up. RESULTS: Higher Blantyre or Glasgow Coma Scores (BCS and GCS, respectively), higher background voltage, and presence of normal reactivity on EEG were each associated with lower mortality. Among clinical and EEG features, the presence of >4 seizures on admission had the best combination of negative and positive predictive values for neurologic deficits in follow-up. In multivariable modeling of cognitive outcomes, the number of seizures and specific EEG features showed independent association with better outcomes. In children younger than 5 years throughout the study, seizure number and presence of vertex sharp waves were independently associated with better posthospitalization cognitive performance, faster dominant frequency with better attention, and higher average background voltage and faster dominant background frequency with better associative memory. In children younger than 5 years at CM episode but 5 years or older at cognitive testing, seizure number, background dominant frequency, and the presence of vertex sharp waves were each associated with changes in cognition, seizure number and variability with attention, and seizure number with working memory. DISCUSSION: In children with cerebral malaria, seizure number is strongly associated with the risk of long-term neurologic deficits, while seizure number and specific EEG features (average background voltage, dominant rhythm frequency, presence of vertex sharp waves, presence of variability) are independently associated with cognitive outcomes. Future studies should evaluate the predictive value of these findings.

Cost-Effectiveness of Hydroxyurea for Sickle Cell Anemia in a Low-Income African Setting: A Model-Based Evaluation of Two Dosing Regimens.

BACKGROUND AND OBJECTIVE: The disease burden of sickle cell anemia (SCA) in sub-Saharan African (SSA) countries is substantial, with many children dying without an established diagnosis or proper treatment. The global burden of SCA is increasing each year, making therapeutic intervention a high priority. Hydroxyurea is the only disease-modifying therapy with proven feasibility and efficacy suitable for SSA; however, no one has quantified the health economic implications of its use. Therefore, from the perspective of the health care provider, we estimated the incremental cost-effectiveness of hydroxyurea as a fixed-dose regimen or maximum tolerated dose (MTD) regimen, versus SCA care without hydroxyurea. METHODS: We estimated the cost of providing outpatient treatment at a pediatric sickle cell clinic in Kampala, Uganda. These estimates were used in a discrete-event simulation model to project mean costs (2021 US$), disability-adjusted life years (DALYs), and consumption of blood products per patient (450 mL units), for patients between 9 months and 18 years of age. We calculated cost-effectiveness as the ratio of incremental costs over incremental DALYs averted, discounted at 3% annually. To test the robustness of our findings, and the impact of uncertainty, we conducted probabilistic and one-way sensitivity analyses, scenario analysis, and price threshold analyses. RESULTS: Hydroxyurea treatment averted an expected 1.37 DALYs and saved US$ 191 per patient if administered at the MTD, compared with SCA care without hydroxyurea. In comparison, hydroxyurea at a fixed dose averted 0.80 DALYs per patient at an incremental cost of US$ 2. The MTD strategy saved 11.2 (95% CI 11.1-11.4) units of blood per patient, compared with 9.1 (95% CI 9.0-9.2) units of blood per patient at the fixed-dose alternative. CONCLUSIONS: Hydroxyurea at MTD is likely to improve quality of life and reduce the consumption of blood products for children with SCA living in Uganda. Compared with a fixed dose regimen, treatment dosing at MTD is likely to be a cost-effective treatment for SCA, using realistic ranges of hydroxyurea costs that are relevant across SSA. Compared with no use of the drug, hydroxyurea could lead to substantial net savings per patient, while reducing the disease morbidity and mortality and increasing quality of life.

Cerebrospinal fluid biomarkers provide evidence for kidney-brain axis involvement in cerebral malaria pathogenesis.

Introduction: Cerebral malaria is one of the most severe manifestations of malaria and is a leading cause of acquired neurodisability in African children. Recent studies suggest acute kidney injury (AKI) is a risk factor for brain injury in cerebral malaria. The present study evaluates potential mechanisms of brain injury in cerebral malaria by evaluating changes in cerebrospinal fluid measures of brain injury with respect to severe malaria complications. Specifically, we attempt to delineate mechanisms of injury focusing on blood-brain-barrier integrity and acute metabolic changes that may underlie kidney-brain crosstalk in severe malaria. Methods: We evaluated 30 cerebrospinal fluid (CSF) markers of inflammation, oxidative stress, and brain injury in 168 Ugandan children aged 18 months to 12 years hospitalized with cerebral malaria. Eligible children were infected with Plasmodium falciparum and had unexplained coma. Acute kidney injury (AKI) on admission was defined using the Kidney Disease: Improving Global Outcomes criteria. We further evaluated blood-brain-barrier integrity and malaria retinopathy, and electrolyte and metabolic complications in serum. Results: The mean age of children was 3.8 years (SD, 1.9) and 40.5% were female. The prevalence of AKI was 46.3% and multi-organ dysfunction was common with 76.2% of children having at least one organ system affected in addition to coma. AKI and elevated blood urea nitrogen, but not other measures of disease severity (severe coma, seizures, jaundice, acidosis), were associated with increases in CSF markers of impaired blood-brain-barrier function, neuronal injury (neuron-specific enolase, tau), excitatory neurotransmission (kynurenine), as well as altered nitric oxide bioavailability and oxidative stress (p < 0.05 after adjustment for multiple testing). Further evaluation of potential mechanisms suggested that AKI may mediate or be associated with CSF changes through blood-brain-barrier disruption (p = 0.0014), ischemic injury seen by indirect ophthalmoscopy (p < 0.05), altered osmolality (p = 0.0006) and through alterations in the amino acids transported into the brain. Conclusion: In children with cerebral malaria, there is evidence of kidney-brain injury with multiple potential pathways identified. These changes were specific to the kidney and not observed in the context of other clinical complications.

Biomarkers of Growth Faltering and Neurodevelopmental Delay in Children who are HIV-Exposed but Uninfected: A Systematic Review.

INTRODUCTION: Children who are HIV-exposed but uninfected (CHEU) are at risk of linear growth faltering and neurodevelopmental delay. Circulating biomarkers associated with these adverse outcomes may elucidate pathways of injury. OBJECTIVE: To identify biomarkers associated with growth faltering and neurodevelopmental delay in CHEU. METHODS: We performed a systematic review of electronic databases MEDLINE (1946-April 2021), EMBASE (1974-April 2021), Scopus (2004-April 2021), and PubMed (1985-April 2021), following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The systematic review was registered on the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42021238363). RESULTS: We found seven studies associating biomarker abnormalities and growth outcomes in CHEUs and two studies on biomarker abnormalities and neurodevelopmental delay. Biomarker abnormalities associated with growth restriction were: C-reactive protein (CRP), tumour necrosis factor (TNF), interferon-gamma (IFN-γ), interleukin (IL)-12p70, IFN-γ-induced protein-10 (CXCL10/IP-10), lipopolysaccharide binding protein (LBP), insulin-like growth factor-1 (IGF-1), and IGF-binding protein-1 (IGFBP-1). Biomarkers associated with motor, language, and cognitive delay were CRP, IFN-γ, IL-1ß, -2, -4, -6, -10, -12p70, neutrophil gelatinase-associated lipocalin (NGAL), granulocyte-macrophage colony-stimulating factor (GM-CSF), and matrix metalloproteinase- 9 (MMP-9). CONCLUSION: Elevated markers of inflammation (acute phase reactants, pro-inflammatory cytokines, chemokines) and intestinal microbial translocation are associated with growth faltering. Elevated markers of inflammation are associated with adverse neurodevelopment.

Pediatric Malaria with Respiratory Distress: Prognostic Significance of Point-of-Care Lactate.

Respiratory distress (RD) in pediatric malaria portends a grave prognosis. Lactic acidosis is a biomarker of severe disease. We investigated whether lactate, measured at admission using a handheld device among children hospitalized with malaria and RD, was predictive of subsequent mortality. We performed a pooled analysis of Ugandan children under five years of age hospitalized with malaria and RD from three past studies. In total, 1324 children with malaria and RD (median age 1.4 years, 46% female) from 21 health facilities were included. Median lactate level at admission was 4.6 mmol/L (IQR 2.6-8.5) and 586 patients (44%) had hyperlactatemia (lactate > 5 mmol/L). The mortality was 84/1324 (6.3%). In a mixed-effects Cox proportional hazard model adjusting for age, sex, clinical severity score (fixed effects), study, and site (random effects), hyperlactatemia was associated with a 3-fold increased hazard of death (aHR 3.0, 95%CI 1.8-5.3, p < 0.0001). Delayed capillary refill time (τ = 0.14, p < 0.0001), hypotension (τ = -0.10, p = 0.00049), anemia (τ = -0.25, p < 0.0001), low tissue oxygen delivery (τ = -0.19, p < 0.0001), high parasite density (τ = 0.10, p < 0.0001), and acute kidney injury (p = 0.00047) were associated with higher lactate levels. In children with malaria and RD, bedside lactate may be a useful triage tool, predictive of mortality.

Effect of Malaria and Malaria Chemoprevention Regimens in Pregnancy and Childhood on Neurodevelopmental and Behavioral Outcomes in Children at 12, 24, and 36 Months: A Randomized Clinical Trial.

BACKGROUND: Malaria in pregnancy has been associated with worse cognitive outcomes in children, but its association with behavioral outcomes and the effectiveness of malaria chemoprevention on child neurodevelopment are not well characterized. METHODS: To determine if more effective malaria chemoprevention in mothers and their children results in better neurodevelopment, 305 pregnant women were randomly assigned to 3 doses of sulfadoxine-pyrimethamine, 3 doses of dihydroartemisinin-piperaquine (DP), or monthly DP during pregnancy, and their 293 children were assigned to DP every 3 months or monthly DP from 2 to 24 months of age. Cognition, language, and motor function were assessed at 12, 24. and 36 months of age, and attention, memory, behavior, and executive function were assessed at 24 and 36 months of age. RESULTS: Children of mothers with versus without malaria in pregnancy had worse scores on cognitive, behavioral, and executive function outcomes at 24 months. Clinical malaria in children within the first 12 months was similarly associated with poorer scores in behavior and executive function at 24 months, language at 24 and 36 months, and motor function scores at 36 months. However, more effective malaria chemoprevention in the mothers and children was not associated with better outcomes. CONCLUSIONS: Malaria in pregnancy was associated with worse cognitive, behavioral, and executive function scores in affected children, but more effective malaria chemoprevention measures did not result in better outcomes. Malaria chemoprevention prior to and early in gestation and with even higher efficacy in mothers and children may be required to prevent neurodevelopmental impairment in children. Clinical Trials Registration. NCT02557425.

Circulating markers of neutrophil activation and lung injury in pediatric pneumonia in low-resource settings.

Diagnostic biomarkers for childhood pneumonia could guide management and improve antibiotic stewardship in low-resource settings where chest x-ray (CXR) is not always available. In this cross-sectional study, we measured chitinase 3-like protein 1 (CHI3L1), surfactant protein D (SP-D), lipocalin-2 (LCN2), and tissue inhibitor of metalloproteinases-1 (TIMP-1) in Ugandan children under the age of five hospitalized with acute lower respiratory tract infection. We determined the association between biomarker levels and primary end-point pneumonia, indicated by CXR consolidation. We included 89 children (median age 11 months, 39% female). Primary endpoint pneumonia was present in 22 (25%). Clinical signs were similar in children with and without CXR consolidation. Broad-spectrum antibiotics (ceftriaxone) were administered in 83 (93%). Levels of CHI3L1, SP-D, LCN2 and TIMP-1 were higher in patients with primary end-point pneumonia compared to patients with normal CXR or other infiltrates. All markers were moderately accurate predictors of primary end-point pneumonia, with area under receiver operator characteristic curves of 0.66-0.70 (p<0.05 for all markers). The probability of CXR consolidation increased monotonically with the number of markers above cut-off. Among 28 patients (31%) in whom all four markers were below the cut-off, the likelihood ratio of CXR consolidation was 0.11 (95%CI 0.015 to 0.73). CHI3L1, SP-D, LCN2 and TIMP-1 were associated with CXR consolidation in children with clinical pneumonia in a low-resource setting. Combinations of quantitative biomarkers may be useful to safely withhold antibiotics in children with a low probability of bacterial infection.

Soluble Urokinase-Type Plasminogen Activator Receptor as a Prognostic Marker of Ugandan Children at Risk of Severe and Fatal Malaria.

BACKGROUND: Current malaria diagnostic tests do not reliably identify children at risk of severe and fatal infection. Host immune and endothelial activation contribute to malaria pathogenesis. Soluble urokinase-type plasminogen activator receptor (suPAR) is a marker of these pathways. We hypothesized that measuring suPAR at presentation could risk-stratify children with malaria. METHODS: Plasma suPAR levels were determined in consecutive febrile children with malaria at presentation to hospital in Jinja, Uganda. We evaluated the accuracy of suPAR in predicting in-hospital mortality, and whether suPAR could improve a validated clinical scoring system (Lambaréné Organ Dysfunction Score [LODS]). RESULTS: Of the 1226 children with malaria, 39 (3.2%) died. suPAR concentrations at presentation were significantly higher in children who went on to die than in those who survived (P < .0001). suPAR levels were associated with disease severity (LODS: 0 vs 1, P = .001; 1 vs 2, P < .001; 2 vs 3, 0 vs 2, 1 vs 3, and 0 vs 3, P < .0001). suPAR concentrations were excellent predictors of in-hospital mortality (area under the receiver operating characteristic curve [AUROC], 0.92 [95% confidence interval {CI}, .91-.94]). The prognostic accuracy of LODS (AUROC, 0.93 [95% CI, .91-.94]) was improved when suPAR was added (AUROC, 0.97 [95% CI, .96-.98]; P < .0001). CONCLUSIONS: Measuring suPAR at presentation can identify children at risk of severe and fatal malaria. Adding suPAR to clinical scores could improve the recognition and triage of children at risk of death. suPAR can be detected with a point-of-care test and can now be evaluated in prospective trials.

Perceptions of orthopaedic medicine students and their supervisors about practice-based learning: an exploratory qualitative study.

BACKGROUND: Practice-based learning is crucial in forming appropriate strategies for improving learning among the medical students that support the country's understaffed health sector. Unsatisfactory learning consequently results in poor performance of students and poor quality of health care workforce in the long run. Exploring the perceptions about the current practice-based learning system and how to improve is thus vital. This study set out to explore the perceptions of Orthopaedic medicine students and their supervisors about practice-based learning at a tertiary training hospital. METHODS: This was an exploratory phenomenological qualitative study that involved in-depth interviews among 10 Orthopedic students during their rotation in the emergency ward of Mulago hospital and 6 of their supervisors. Interviews were audio-recorded, transcribed, and then imported into Atlas ti 8.3 for analysis. The data were coded and grouped into themes relating to perceptions of practice-based learning, general inductive analysis was used. The general inductive approach involved condensing the raw textual data into a brief and summary format. The summarized format was then analyzed to establish clear links between the perceptions of practice-based learning and the summary findings derived from the raw data. RESULTS: The mean age of the students was 23 ± 1.5 years. Four out of the six supervisors were Orthopaedic officers while the remaining two were principal Orthopaedic officers, four out of the six had a university degree while the other two were diploma holders. The main themes arising were hands-on skills, an unconducive learning environment, the best form of learning, and having an undefined training structure. Particularly, the perceptions included the presence of too many students on the wards during the rotation, frequent stock-outs of supplies for learning, and supervisors being overwhelmed caring for a large number of patients. CONCLUSION: Barriers to satisfactory practice-based learning were overcrowding on the wards and insufficient training materials. To improve practice-based learning, adequate learning materials are required and the number of students enrolled needs to be appropriate for the student - supervisor ratio.

Sex as a determinant of disease severity and clinical outcome in febrile children under five presenting to a regional referral hospital in Uganda.

Sex and gender are well-established determinants of health in adult and adolescent populations in low resource settings. There are limited data on sex as a determinant of host response to disease and clinical outcome in febrile children in sub-Saharan Africa, where the risk of infection-related mortality is greatest. We examined sex differences and gender biases in health-seeking behavior, clinical care, biological response to infection, or outcome in a prospective observational cohort of febrile children under 5 years of age presenting to a regional referral hospital in Jinja, Uganda. Main outcomes (stratified by sex) were disease severity at presentation measured by clinical and biological parameters, clinical management (e.g., time to see a physician, treatment by diagnosis), and disease outcome (e.g., mortality). Clinical measures of disease severity included Lambaréné Organ Dysfunction Score (LODS), Signs of Inflammation in Children that Kill (SICK), and the Pediatric Early Death Index for Africa (PEDIA). Biological measures of disease severity were assessed using circulating markers of immune and endothelial activation associated with severe and fatal infections. Differences in outcome by sex were analyzed using bivariate analyses with Bonferroni correction for multiple comparisons. In this cohort of febrile patients admitted to hospital (n = 2049), malaria infection was common (59.2%). 15.9% of children presented with severe disease (LODS score ≥ 2). 97 children (4.7%) died, and most deaths (n = 83) occurred within 48 hours of hospital admission. Clinical measures of disease severity at presentation, clinical management, and outcome (e.g., mortality) did not differ by sex in children under five years of age. Host response to infection, as determined by endothelial and inflammatory mediators (e.g., sTREM1, Ang-2) quantified at hospital presentation, did not differ by sex. In this cohort of children under the age of five, sex was not a principal determinant of disease severity at hospital presentation, clinical management, disease outcome, or biological response to infection (p-values not significant for all comparisons, after Bonferroni correction). The results suggest that health seeking behavior by caregivers and clinical care in the hospital setting did not reflect a gender bias in this cohort.

Plasma Amino Acid Concentrations in Children With Severe Malaria Are Associated With Mortality and Worse Long-term Kidney and Cognitive Outcomes.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 <5 years of age. CONCLUSIONS: Among children with SM, unique amino acid profiles are associated with mortality, CKD, and worse attention.

Intestinal Injury Biomarkers Predict Mortality in Pediatric Severe Malaria.

Severe malaria (SM) increases the risk of invasive bacterial infection, and there is evidence to suggest increased gastrointestinal permeability. Studies have shown sequestration of infected erythrocytes in intestinal microvasculature, and in vivo studies of rectal mucosa have demonstrated disruption of microvascular blood flow. However, the extent of intestinal injury in pediatric malaria is not well characterized. In this study, two serum biomarkers of intestinal injury, trefoil factor 3 (TFF3) and intestinal fatty acid binding protein (I-FABP), were analyzed in 598 children with SM and 120 healthy community children (CC), 6 months to 4 years of age. Serum was collected at enrollment and 1 month for laboratory studies, and participants were monitored for 12 months. Intestinal injury biomarkers were significantly elevated in children with SM, with 18.1% having levels of TFF3 and/or I-FABP greater than the 99th percentile of CC levels. TFF3 levels continued to be elevated at 1 month, while I-FABP levels were comparable to CC levels. Both markers predicted in-hospital mortality {odds ratio (OR) (95% confidence interval [CI]), 4.4 (2.7, 7.3) and 2.3 (1.7, 3.1)} for a natural log increase in TFF3 and I-FABP, respectively. TFF3 was also associated with postdischarge mortality (OR, 2.43 [95% CI, 1.1, 4.8]). Intestinal injury was associated with acute kidney injury (AKI), acidosis (P < 0.001 for both), and angiopoietin 2, a maker of endothelial activation. In conclusion, intestinal injury is common in pediatric severe malaria and is associated with an increased mortality. It is strongly associated with AKI, acidosis, and endothelial activation. IMPORTANCE In children with severe malaria, intestinal injury is a common complication associated with increased mortality. Intestinal injury is associated with acute kidney injury, acidosis, and endothelial activation. Interventions promoting intestinal regeneration and repair represent novel approaches to improve outcomes.

Intestinal Injury in Ugandan Children Hospitalized With Malaria.

BACKGROUND: Severe malaria is associated with multiple organ dysfunction syndrome (MODS), which may involve the gastrointestinal tract. METHODS: In a prospective cohort study in Uganda, we measured markers of intestinal injury (intestinal fatty-acid binding protein [I-FABP] and zonula occludens-1 [ZO-1]) and microbial translocation (lipopolysaccharide binding protein [LBP] and soluble complement of differentiation 14 [sCD14]) among children admitted with malaria. We examined their association with biomarkers of inflammation, endothelial activation, clinical signs of hypoperfusion, organ injury, and mortality. RESULTS: We enrolled 523 children (median age 1.5 years, 46% female, 7.5% mortality). Intestinal FABP was above the normal range (≥400 pg/mL) in 415 of 523 patients (79%). Intestinal FABP correlated with ZO-1 (ρ = 0.11, P = .014), sCD14 (ρ = 0.12, P = .0046) as well as markers of inflammation and endothelial activation. Higher I-FABP levels were associated with lower systolic blood pressure (ρ = -0.14, P = .0015), delayed capillary refill time (ρ = 0.17, P = .00011), higher lactate level (ρ = 0.40, P < .0001), increasing stage of acute kidney injury (ρ = 0.20, P = .0034), and coma (P < .0001). Admission I-FABP levels ≥5.6 ng/mL were associated with a 7.4-fold higher relative risk of in-hospital death (95% confidence interval, 1.4-11, P = .0016). CONCLUSIONS: Intestinal injury occurs commonly in children hospitalized with malaria and is associated with microbial translocation, systemic inflammation, tissue hypoperfusion, MODS, and fatal outcome.