Blood Levels of Environmental Heavy Metals are Associated with Poorer Iron Status in Ugandan Children: A Cross-Sectional Study.

BACKGROUND: Iron deficiency (ID) and environmental exposure to metals frequently co-occur among Ugandan children, but little is known about their associations, although iron and other divalent metals share the same intestinal absorption transporter, divalent metal transporter 1 (DMT1). OBJECTIVES: We examined associations between iron status and blood concentrations of lead, manganese (Mn), cobalt (Co), and cadmium, both singly and as a mixture. METHODS: We used data on sociodemographic status, iron biomarkers, and blood concentrations of heavy metals collected from a cross-sectional survey of 100 children aged 6-59 mo in Kampala, Uganda. We compared blood concentrations of metals in ID with iron-sufficient children. We examined associations between a metal mixture and iron biomarkers using multiple linear regression and weighted quintile sum regression. RESULTS: The median (interquartile range) blood Mn (µg/L) was higher in ID children defined by soluble transferrin receptor (sTfR) and ferritin (ID compared with iron-sufficient children): (sTfR [21.3 {15.1, 28.8}, 11.2 {8.6, 18.5}], ferritin [19.5 {15.0, 27.2}, 11.2 {8.8, 19.6}]; P < 0.001 for both). Similarly, the median (interquartile range) blood Co (µg/L) was higher in ID children by ferritin ([0.5 {0.4, 0.9}, 0.4 {0.3, 0.5}], P = 0.05). Based on the multiple linear regression results, higher blood Co and Mn were associated with poorer iron status (defined by all 4 iron indicators for Co and by sTfR for Mn). The weighted quintile sum regression result showed that higher blood concentrations of a metal mixture were associated with poorer iron status represented by sTfR, ferritin, and hepcidin, mainly driven by Co and Mn. CONCLUSIONS: Our study findings suggest that poorer iron status is associated with overall heavy metal burden, predominantly Co and Mn, among Ugandan children. Further prospective studies should confirm our primary findings and investigate the combined effects of coexposures to neurotoxicants on the neurodevelopment of young children.

Impact of Oxidative Stress on Risk of Death and Readmission in African Children With Severe Malaria: A Prospective Observational Study.

BACKGROUND: We hypothesized that oxidative stress in Ugandan children with severe malaria is associated with mortality. METHODS: We evaluated biomarkers of oxidative stress in children with cerebral malaria (CM, n = 77) or severe malarial anemia (SMA, n = 79), who were enrolled in a randomized clinical trial of immediate vs delayed iron therapy, compared with community children (CC, n = 83). Associations between admission biomarkers and risk of death during hospitalization or risk of readmission within 6 months were analyzed. RESULTS: Nine children with CM and none with SMA died during hospitalization. Children with CM or SMA had higher levels of heme oxygenase-1 (HO-1) (P < .001) and lower superoxide dismutase (SOD) activity than CC (P < .02). Children with CM had a higher risk of death with increasing HO-1 concentration (odds ratio [OR], 6.07 [95% confidence interval {CI}, 1.17-31.31]; P = .03) but a lower risk of death with increasing SOD activity (OR, 0.02 [95% CI, .001-.70]; P = .03). There were no associations between oxidative stress biomarkers on admission and risk of readmission within 6 months of enrollment. CONCLUSIONS: Children with CM or SMA develop oxidative stress in response to severe malaria. Oxidative stress is associated with higher mortality in children with CM but not with SMA. CLINICAL TRIALS REGISTRATION: NCT01093989.

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.

Does mothers' and caregivers' access to information on their child's vaccination card impact the timing of their child's measles vaccination in Uganda?

INTRODUCTION: On-time measles vaccination is essential for preventing measles infection among children as early in life as possible, especially in areas where measles outbreaks occur frequently. Characterizing the timing of routine measles vaccination (MCV1) among children and identifying risk factors for delayed measles vaccination is important for addressing barriers to recommended childhood vaccination and increasing on-time MCV1 coverage. We aim to assess the timing of children's MCV1 vaccination and to investigate the association between demographic and healthcare factors, mothers'/caregivers' ability to identify information on their child's vaccination card, and achieving on-time (vs. delayed) MCV1 vaccination. METHODS: We conducted a population-based, door-to-door survey in Kampala, Uganda, from June-August of 2019. We surveyed mothers/caregivers of children aged one to five years to determine how familiar they were with their child's vaccination card and to determine their child's MCV1 vaccination status and timing. We assessed the proportion of children vaccinated for MCV1 on-time and delayed, and we evaluated the association between mothers'/caregivers' ability to identify key pieces of information (child's birth date, sex, and MCV1 date) on their child's vaccination card and achieving on-time MCV1 vaccination. RESULTS: Of the 999 mothers/caregivers enrolled, the median age was 27 years (17-50), and median child age was 29 months (12-72). Information on vaccination status was available for 66.0% (n = 659) of children. Of those who had documentation of MCV1 vaccination (n = 475), less than half (46.5%; n = 221) achieved on-time MCV1 vaccination and 53.5% (n = 254) were delayed. We found that only 47.9% (n = 264) of the 551 mothers/caregivers who were asked to identify key pieces of information on their child's vaccination card were able to identify the information, but ability to identify the key pieces of information on the card was not independently associated with achieving on-time MCV1 vaccination. CONCLUSION: Mothers'/caregivers' ability to identify key pieces of information on their child's vaccination card was not associated with achieving on-time MCV1 vaccination. Further research can shed light on interventions that may prompt or remind mothers/caregivers of the time and age when their child is due for measles vaccine to increase the chance of the child receiving it at the recommended time.

Parenteral artemisinins are associated with reduced mortality and neurologic deficits and improved long-term behavioral outcomes in children with severe malaria.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Neurocognitive function among HIV-infected children on protease inhibitor -based versus non-protease inhibitor based antiretroviral therapy in Uganda: a pilot study.

BACKGROUND: HIV infection is associated with significant neurocognitive deficits making maximization of cognitive function among children receiving antiretroviral therapy (ART) a public health imperative. Non-protease inhibitors (non-PIs) achieve higher drug levels in the cerebral spinal fluid (CSF) compared to PIs, potentially leading to better neurocognitive function by reducing CSF viral load and inflammation. ART that maximises children's neurodevelopment and school achievement could result in improved quality of life and productivity as adults, but little research to date has examined whether non-PI ART is associated with better neurocognitive outcomes. We compared the neurocognitive function between children living with HIV receiving PI-based and non PI-based ART. METHODS: We recruited a consecutive sample of clinically stable Ugandan children living with HIV aged 5-12 years who received PI-based or non PI-based ART for ≥ 1 year (viral load < 1000 copies). Neurocognitive function was assessed using the Kaufman Assessment Battery for Children, the Test of Variables of Attention, and Bruininks-Oseretsky Test of Motor Proficiency. Age-adjusted neurocognitive z-scores for the two groups were compared using linear regression models in STATA version 13. The Hommel's method was used to adjust for multiple testing. RESULTS: We enrolled 76 children living with HIV; 34 on PI ART and 42 on non-PI ART. Mean (±SD) age was greater in the non-PI vs. PI group (9.5 ± 1.9 vs. 8.5 ± 2.0) years (p = 0.03). Children in the non-PI group had lower socioeconomic scores (5.7 ± 3.3 vs. 7.4 ± 2.8, p = 0.02). There was no difference in neurocognitive function between the groups (adjusted p > 0.05) for KABC and TOVA. Children in the PI group had better total BOT scores than their counterparts (46.07 ± 1.40) vs. 40.51 (1.24), p = 0.03). CONCLUSIONS: We detected no difference in neurocognitive function among children on PI and non PI-based ART therapy based on KABC and TOVA tests. Children on PI based ART had better motor function than their counterparts. We recommend a prospective study with a larger sample size.

The Impact of Undernutrition on Cognition in Children with Severe Malaria and Community Children: A Prospective 2-Year Cohort Study.

BACKGROUND: The frequency of recovery from undernutrition after an episode of severe malaria, and the relationship between undernutrition during severe malaria and clinical and cognitive outcomes are not well characterized. METHODS: We evaluated undernutrition and cognition in children in Kampala, Uganda 18 months to 5 years of age with cerebral malaria (CM), severe malarial anemia (SMA) or community children (CC). The Mullen Scales of Early Learning was used to measure cognition. Undernutrition, defined as 2 SDs below median for weight-for-age (underweight), height-for-age (stunting) or weight-for-height (wasting), was compared with mortality, hospital readmission and cognition over 24-month follow-up. RESULTS: At enrollment, wasting was more common in CM (16.7%) or SMA (15.9%) than CC (4.7%) (both p < 0.0001), and being underweight was more common in SMA (27.0%) than CC (12.8%; p = 0.001), while prevalence of stunting was similar in all three groups. By 6-month follow-up, prevalence of wasting or being underweight did not differ significantly between children with severe malaria and CC. Undernutrition at enrollment was not associated with mortality or hospital readmission, but children who were underweight or stunted at baseline had lower cognitive z-scores than those who were not {underweight, mean difference [95% confidence interval (CI)] -0.98 (-1.66, -0.31), -0.72 (-1.16, -0.27) and -0.61 (-1.08, -0.13); and stunted, -0.70 (-1.25, -0.15), -0.73 (-1.16, -0.31) and -0.61 (-0.96, -0.27), for CM, SMA and CC, respectively}. CONCLUSION: In children with severe malaria, wasting and being underweight return to population levels after treatment. However, being stunted or underweight at enrollment was associated with worse long-term cognition in both CC and children with severe malaria.

The Benefits and Risks of Iron Supplementation in Pregnancy and Childhood.

Iron deficiency is the most common micronutrient deficiency in the world and disproportionately affects pregnant women and young children. Iron deficiency has negative effects on pregnancy outcomes in women and on immune function and neurodevelopment in children. Iron supplementation programs have been successful in reducing this health burden. However, iron supplementation of iron-sufficient individuals is likely not necessary and may carry health risks for iron-sufficient and potentially some iron-deficient populations. This review considers the physiology of iron as a nutrient and how this physiology informs decision-making about weighing the benefits and risks of iron supplementation in iron-deficient, iron-sufficient, and iron-overloaded pregnant women and children.

Delayed iron does not alter cognition or behavior among children with severe malaria and iron deficiency.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. IMPACT: The optimal time to provide iron therapy in children with severe malaria is not known. The present study shows that delay of iron treatment to 28 days after the malaria episode, does not lead to worse cognitive or behavioral outcomes at 12-month follow-up. The study contributes new data to the ongoing discussion of how best to treat ID in children with severe malaria.

Assessment of blood levels of heavy metals including lead and manganese in healthy children living in the Katanga settlement of Kampala, Uganda.

BACKGROUND: Exposure to environmental heavy metals is common among African children. Although many of these metals are known neurotoxicants, to date, monitoring of this exposure is limited, even in countries such as Uganda that are undergoing rapid industrialization. An assessment of the burden and potential causes of metal exposure is a critical first step in gauging the public health burden of metal exposure and in guiding its elimination. METHODS: In May 2016, we enrolled 100 children between the ages of 6 and 59 months living in the Katanga urban settlement of Kampala, Uganda. We measured whole blood concentrations of antimony, arsenic, barium, cadmium, cesium, chromium, cobalt, copper, lead, manganese, nickel, selenium, and zinc. Applying reference cutoffs, we identified metals whose prevalence of elevated blood concentrations was > 10%. We also administered an environmental questionnaire to each child's caregiver to assess potential exposures, including source of drinking water, cooking location and fuel, materials used for roof, walls, and floor, and proximity to potential pollution sources such as main roads, garbage landfills, and fuel stations. We compared log-transformed blood metal concentrations by exposure category, using t-test for dichotomous comparisons and ANOVA for comparisons of three categories, using Tukeys test to adjust for multiple comparisons. RESULTS: The prevalence of high blood levels was elevated for six of the metals: antimony (99%), copper (12%), cadmium (17%), cobalt (19.2%), lead (97%), and manganese (36.4%). Higher blood manganese was significantly associated with having cement walls (p = 0.04) or floors (p = 0.04). Cadmium was greater among children who attended school (< 0.01), and cobalt was higher among children who lived near a garbage landfill (p = 0.01). CONCLUSIONS: Heavy metal exposure is prevalent in the Katanga settlement and may limit neurodevelopment of children living there. Future studies are needed to definitively identify the sources of exposure and to correct potential nutritional deficiencies that may worsen metal absorption.

Nutritional influences on brain development.

There is increasing evidence from preclinical and human studies that nutrition in the late foetal and early neonatal period has a significant impact on neurodevelopment across the lifespan. Certain nutrients have particularly large effects in this time period, and their deficits cause greater long-term risk. The mechanisms by which nutrients influence early brain growth and the sensitive periods for when certain nutrients should be provided are being elucidated. Assessments of nutritional status that index brain growth and predict long-term development are important to assess the efficacy of early life nutritional therapies. CONCLUSION: Optimizing nutrition during foetal and early postnatal life is a golden opportunity to impact neurodevelopment and brain function across the lifespan.

Delaying Iron Therapy until 28 Days after Antimalarial Treatment Is Associated with Greater Iron Incorporation and Equivalent Hematologic Recovery after 56 Days in Children: A Randomized Controlled Trial.

BACKGROUND: Iron therapy begun concurrently with antimalarial treatment may not be well absorbed because of malaria-induced inflammation. Delaying the start of iron therapy may permit better iron absorption and distribution. OBJECTIVE: We compared erythrocyte iron incorporation in children who started iron supplementation concurrently with antimalarial treatment or 28 d later. We hypothesized that delayed iron supplementation would be associated with greater incorporation and better hematologic recovery. METHODS: We enrolled 100 children aged 6-59 mo with malaria and hemoglobin concentrations of 50.0-99.9 g/L who presented to Mulago Hospital, Kampala, into a randomized trial of iron therapy. All children were administered antimalarial treatment. Children with zinc protoporphyrin (ZPP) ≥80 µmol/mol heme were randomly assigned to start iron supplementation concurrently with the antimalarial treatment [immediate iron (I) group] or 28 d later [delayed iron (D) group]. All children were administered iron-stable isotope (57)Fe on day 0 and (58)Fe on day 28. We compared the percentage of iron incorporation at the start of supplementation (I group at day 0 compared with D group at day 28, aim 1) and hematologic recovery at day 56 (aim 2). RESULTS: The percentage of iron incorporation (mean ± SE) was greater at day 28 in the D group (16.5% ± 1.7%) than at day 0 in the I group (7.9% ± 0.5%; P < 0.001). On day 56, concentrations of hemoglobin and ZPP and plasma ferritin, soluble transferrin receptor (sTfR), hepcidin, and C-reactive protein did not differ between the groups. On day 28, the hemoglobin (mean ± SD) and plasma iron markers (geometric mean; 95% CI) reflected poorer iron status in the D group than in the I group at this intervening time as follows: hemoglobin (105 ± 15.9 compared with 112 ± 12.4 g/L; P = 0.04), ferritin (39.3 µg/L; 23.5, 65.7 µg/L compared with 79.9 µg/L; 58.3, 110 µg/L; P = 0.02), sTfR (8.9 mg/L; 7.4, 10.7 mg/L compared with 6.7 mg/L; 6.1, 7.5 mg/L; P = 0.01), and hepcidin (13.3 ng/mL; 8.3, 21.2 ng/mL compared with 38.8 ng/mL; 28.3, 53.3 ng/mL; P < 0.001). CONCLUSIONS: Delaying the start of iron improves incorporation but leads to equivalent hematologic recovery at day 56 in Ugandan children with malaria and anemia. These results do not demonstrate a clear, short-term benefit of delaying iron. This trial was registered at clinicaltrials.gov as NCT01754701.

Safety and efficacy of iron supplementation with 3 months of daily ferrous sulphate in children living with HIV and mild-to-moderate anaemia in Uganda: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Iron deficiency is the most common nutritional deficiency in the world, but iron supplementation can increase risk of opportunistic infections, especially in children living with HIV. We aimed to assess the effect of supplemental iron on haemoglobin concentration in children living with HIV and mild-to-moderate anaemia in Uganda. METHODS: We did a double-blind, randomised, placebo-controlled trial of iron supplementation in children aged 6 months to 12 years living with HIV at two sites (ie, Kampala and Fort Portal, Uganda). Inclusion criteria were confirmed diagnosis of HIV and stable treatment with antiretroviral therapy for at least 6 months. Exclusion criteria were already taking iron supplementation, acute illness, current opportunistic infection, fever, known sickle cell disease, severe undernutrition, or any chronic illness requiring medical attention. Children were randomly assigned (1:1) via simple randomisation to an 84-day course of either ferrous sulphate or identical placebo tablets once per day. Randomisation codes were computer-generated and stratified by age (ie, 6-23 months or 24 months and older) by the Toronto Institute of Pharmaceutical Technology, the tablet manufacturer. Participants and all individuals giving the interventions, assessing outcomes, and analysing data were masked to group assignment. Children aged 6-23 months received tablets of 12·5 mg ferrous sulphate or identical placebo; children aged 24 months or older received tablets of 30·0 mg ferrous sulphate or identical placebo. Caregivers were instructed to give the supplement after a meal, preferably after an evening meal. The primary outcome was mean haemoglobin concentration at day 84. All analyses were intention to treat. This trial is registered at ClinicalTrials.gov (NCT03596996). FINDINGS: Between May 5, 2018, and Nov 6, 2019, 973 children living with HIV were screened, of whom 200 (20%) met all inclusion criteria and were enrolled. 102 (51%) were randomly assigned to receive iron and 98 (49%) to receive placebo. In the iron group, 57 (56%) of 102 children were male and 45 (44%) were female. In the placebo group, 44 (45%) of 98 children were male and 54 (55%) were female. Iron supplementation was associated with improvement in haemoglobin in unadjusted analysis (p=0·029), but not adjusted analysis (p=0·10), and with improvement in ferritin and hepcidin in both adjusted (p=0·0046; p=0·0079) and unadjusted (p<0·0001; p<0·0001) analyses at day 84. There were four hospital admissions, all for children in the iron group; none were fatal: two children were admitted to hospital with pneumonia, one with severe malaria, and one with hepatitis. Frequency of admissions was not significantly different between groups (p=0·12). INTERPRETATION: Iron could have haematological benefit and improve iron status in children living with HIV in Uganda. Future studies powered for morbidity outcomes with longer follow-up are needed, as are those that evaluate the effects of iron supplementation on neurocognitive outcomes. FUNDING: Minnesota Masonic Charities, the Department of Pediatrics at the University of Minnesota, the Hennepin Healthcare Research Institute, and the US National Institutes of Health.

Zinc for infection prevention in children with sickle cell anemia: a randomized double-blind placebo-controlled trial.

Data from small clinical trials in the United States and India suggest zinc supplementation reduces infection in adolescents and adults with sickle cell anemia (SCA), but no studies of zinc supplementation for infection prevention have been conducted in children with SCA living in Africa. We conducted a randomized double-blind placebo-controlled trial to assess zinc supplementation for prevention of severe or invasive infections in Ugandan children 1.00-4.99 years with SCA. Of 252 enrolled participants, 124 were assigned zinc (10 mg) and 126 assigned placebo once daily for 12 months. The primary outcome was incidence of protocol-defined severe or invasive infections. Infection incidence did not differ between treatment arms (282 vs. 270 severe or invasive infections per 100 person-years, respectively, incidence rate ratio of 1.04 [95% confidence interval (CI), 0.81, 1.32, p=0.78]), adjusting for hydroxyurea treatment. There was also no difference between treatment arms in incidence of serious adverse events or SCA-related events. Children receiving zinc had increased serum levels after 12-months, but at study exit, 41% remained zinc deficient (<65 µg/dL). In post-hoc analysis, occurrence of stroke or death was lower in the zinc treatment arm (adjusted hazard ratio (95% CI), 0.22 (0.05, 1.00); p=0.05). Daily 10 mg zinc supplementation for 12 months did not prevent severe or invasive infections in Ugandan children with SCA, but many supplemented children remained zinc deficient. Optimal zinc dosing and the role of zinc in preventing stroke or death in SCA warrant further investigation. This trial was registered at clinicaltrials.gov as #NCT03528434.

Nutrition and Brain Development.

All nutrients are essential for brain development, but pre-clinical and clinical studies have revealed sensitive periods of brain development during which key nutrients are critical. An understanding of these nutrient-specific sensitive periods and the accompanying brain regions or processes that are developing can guide effective nutrition interventions as well as the choice of meaningful circuit-specific neurobehavioral tests to best determine outcome. For several nutrients including protein, iron, iodine, and choline, pre-clinical and clinical studies align to identify the same sensitive periods, while for other nutrients, such as long-chain polyunsaturated fatty acids, zinc, and vitamin D, pre-clinical models demonstrate benefit which is not consistently shown in clinical studies. This discordance of pre-clinical and clinical results is potentially due to key differences in the timing, dose, and/or duration of the nutritional intervention as well as the pre-existing nutritional status of the target population. In general, however, the optimal window of success for nutritional intervention to best support brain development is in late fetal and early postnatal life. Lack of essential nutrients during these times can lead to long-lasting dysfunction and significant loss of developmental potential.

Vitamin D status and associated factors among HIV-infected children and adolescents on antiretroviral therapy in Kampala, Uganda.

BACKGROUND: A high prevalence of suboptimal serum vitamin D has been reported among HIV infected children even in countries with high sunshine abundance throughout the year. Vitamin D is a potent immune modulator of innate and adaptive immune responses. Vitamin D regulates immune responses through the vitamin D receptor on CD4 cells. We aimed to determine the vitamin D status of HIV infected children and factors associated with suboptimal vitamin D. METHODS: This was a cross sectional study. We enrolled children aged between 6 months and 12 years attending an outpatient paediatric HIV clinic. Serum 25-hydroxyvitamin D (25(OH)D) was measured using the electrochemoluminisence method. Suboptimal vitamin D was defined as 25(OH)D <30 ng/ml, vitamin D insufficiency and deficiency were 21-29 ng/ml and <20 ng/ml respectively. Anthropometry, physical exam and medical history were documented. Logistic regression was performed. RESULTS: We enrolled 376 children with mean age (sd) 8.05 years (3.03), a median (IQR) duration of ART of 5.9 years (3.2-8.4). Majority of the children (64%) had been exposed to non nucleoside reverse transcriptase inhibitors (NNRTIs). A third were severely immunosuppressed (CD4% ≤15%) at ART initiation. At the time of the study, the majority (89%) were virologically suppressed (VL <1000 copies/ml). Prevalence of 25(OH)D <30 ng/ml was 49 (13%) of 375 participants and 11 (3%) had 25(OH)D <20 ng/ml. Lopinavir/ritonavir regimen was independently associated with 25(OH)D <30 ng/ml; OR 0.27 CI (0.13-0.57), p value-0.002. Serum 25(OH)D <20 ng/ml was associated with CD4 count ≤15% at ART initiation OR 6.55(1.30-32.9), p value-0.023 and use of NNRTIs; OR 10.9(1.22-96.2), p value-0.03. CONCLUSION: We found a low prevalence of suboptimal vitamin D compared to earlier reports. Severe immunosuppression at ART initiation and use of NNRTIs increases odds of deficiency. Vitamin D supplementation should be considered in severely immunosuppressed children initiating ART.

Maternal HIV and child anthropometric outcomes over time: an analysis of Zimbabwe demographic health surveys.

OBJECTIVES: To understand the association between children's anthropometric measures and maternal HIV status in Zimbabwe and to determine whether these relationships changed over time. DESIGN: Data from Demographic Health Surveys in Zimbabwe rounds 2005, 2010, and 2015 were used to conduct cross-sectional analyses of child anthropometric measures (stunting, underweight, and wasting). METHODS: Using separate logistic regression models for each of the anthropometric measures, we estimated the adjusted prevalence odds ratio (OR) of stunting, underweight, and wasting in children according to maternal HIV status. Moreover, we evaluated an interaction by survey year to evaluate change over time. RESULTS: Children of mothers with HIV had 32% greater odds [OR = 1.32, 95% confidence interval (CI) 1.16-1.5] of stunting, 27% greater odds (OR = 1.27, 95% CI 1.1-1.48) of underweight status and 7% greater odds (OR = 1.07, 95% CI 0.81-1.42) of wasting status, than children of mothers without HIV. These associations between maternal HIV status and child undernutrition did not differ by year (P > 0.05 for all interaction terms). CONCLUSION: In Zimbabwe, having a mother who tested positive for HIV at the time of the survey has been associated with greater child undernutrition over the last two decades with no significant change by survey round. This emphasizes the need for continued programming to address nutritional deficiencies, sanitation, and infectious disease prevention in this high-risk population. The greatest impact of maternal HIV status has been on child stunting and underweight, associated with poor long-term child development.

Meningococcal vaccines and protein-energy undernutrition in children in the African meningitis belt.

BACKGROUND: Vaccines to prevent meningococcal meningitis in the African meningitis belt include PsACWY, a polysaccharide-only vaccine; and PsA-TT, a polysaccharide-protein conjugate vaccine. Protein-energy undernutrition, a condition where children do not receive enough macro- or micronutrients, is related to increased risk of infectious diseases and poor immune function. Reduced immune function could affect vaccine immunogenicity. We investigated connections between protein-energy undernutrition and vaccine immunogenicity and antibody waning to PsACWY and PsA-TT in children in the African meningitis belt. METHODS: This is a secondary analysis of data collected as part of four clinical trials testing the safety and efficacy of PsA-TT in children in Mali, Ghana, and Senegal. We identified whether anthropometric growth indices (low height-for-age, weight-for-height, or weight-for-age Z-score categories) were related to reduced vaccine-elicited antibody (measured with rabbit complement) from pre- to 1 month post-vaccination, in linear regression models. We also identified whether these growth indices were related to increased waning for vaccine-elicited antibody over time, in linear regression models. RESULTS: A total of 697 children were included in our analysis, of which 350 (50.2%) were female; the mean (SD) age was 1.0 (1.1) years, and 578 (83.0%) received PsA-TT. In linear regression models, no consistent statistical relationship was seen between pre-vaccination anthropometric Z-score categories and vaccine immunogenicity, or decline in antibody over time, for either vaccine, although children with low weight-for-height had a greater decline in antibody from 1 to 6 months post-vaccination. CONCLUSIONS: Our analysis did not find protein-energy undernutrition to be associated with immunogenicity or waning of PsACWY- or PsA-TT-elicited antibody in children living in the African meningitis belt. Future studies should consider measuring antibody titers at additional time points post-vaccination, and for longer periods of time, to determine if the rate of antibody waning over a period of several years is associated with protein-energy undernutrition.

Traditional African remedies induce hemolysis in a glucose-6-phopshate dehydrogenase deficient zebrafish model.

Traditional remedies are widely used throughout Africa in routine care for infants. However, such remedies could have detrimental effects. Acute bilirubin encephalopathy (ABE) and kernicterus spectrum disorder (KSD) are common newborn health conditions in the developing world, contributing to substantial neonatal mortality and morbidity. They frequently occur in children with glucose-6-phopshate dehydrogenase (G6PD) deficiency. Using our established zebrafish model of G6PD deficiency, we tested the effects of three traditional compounds used in the care of the newborn umbilical cord: eucalyptus oil, methylated spirits, and Yoruba herbal tea. We found that eucalyptus oil induced a 13.4% increase in a hemolytic phenotype versus control, while methylated spirits showed a 39.7% increase in affected phenotype. Yoruba herbal tea exposure showed no effect. While methylated spirits are already a known pro-oxidant, these data indicate that eucalyptus oil may also be a hemolytic trigger in those with G6PD deficiency. Discovering which agents may contribute to the pathophysiology of G6PD deficiency is critical to eliminate ABE and KSD, especially in countries with a high prevalence of G6PD deficiency. The next step in elucidating the role of these agents is to determine the clinical correlation between the use of these agents and ABE/KSD.