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Background Severe anaemia (haemoglobin Methods Secondary analyses of the trial examined 3894 children from Uganda and Malawi surviving a hospital episode of severe anaemia. Predictors of all-cause readmission within 180 days of discharge were identified using multivariable regression with death as a competing risk. Groups of children with similar characteristics were identified using hierarchical clustering. Results Of the 3894 survivors 682 (18%) were readmitted; 403 (10%) had ≥2 re-admissions over 180 days. Three main causes of readmission were identified: severe anaemia (n = 456), malaria (n = 252) and haemoglobinuria/dark urine syndrome (n = 165). Overall, factors increasing risk of readmission included HIV-infection (hazard ratio 2.48 (95% CI 1.63–3.78), p p p = 0.005); and missing ≥1 trial medication dose (proxy for care quality) (1.43 (1.21–1.69), p p = 0.04). Malaria (among children with no prior history of transfusion) (0.60(0.47–0.76), p p p = 0.001) also decreased risk of readmission. For anaemia re-admissions, gross splenomegaly and enlarged spleen increased risk by 1.73(1.23–2.44) and 1.46(1.18–1.82) respectively compared to no splenomegaly. Clustering identified four groups of children with readmission rates from 14 to 20%. The cluster with the highest readmission rate was characterised by very low haemoglobin (mean 3.6 g/dL). Sickle Cell Disease (SCD) predominated in two clusters associated with chronic repeated admissions or severe, acute presentations in largely undiagnosed SCD. The final cluster had high rates of malaria (78%), severity signs and very low platelet count, consistent with acute severe malaria. Conclusions Younger age, HIV infection and history of previous hospital admissions predicted increased risk of readmission. However, no obvious clinical factors for intervention were identified. As missing medication doses was highly predictive, attention to care related factors may be important. Trial registration ISRCTN ISRCTN84086586.

ObjectivesMortality during acute illness among children in low- and middle-income settings remain unacceptably high and there is increasing recognition of the importance of post-discharge mortality. A comprehensive understanding of pathways underlying mortality among acutely ill children is needed to develop interventions and improve guidelines. We aimed to determine the incidence, timing and contributions of proximal and underlying exposures for mortality among acutely ill young children from admission to hospital until 6 months after discharge in sub-Saharan Africa and South Asia in the context of guideline-based care.DesignA prospective stratified cohort study recruiting acutely ill children at admission to hospital with follow up until 180 days after discharge from hospital (November 2016-July 2019).SettingNine urban and rural hospitals in sub-Saharan Africa and South Asia across a range of facility levels, and local prevalences of HIV and malaria.ParticipantsInclusion criteria were age 2-23 months, admission to hospital with acute, non-traumatic medical illness and stratified into three groups by anthropometry. Children were excluded if currently receiving pulmonary resuscitation, had a known condition requiring surgery within 6 months or known terminal illness with death expected within 6 months.Main outcome measuresAcute mortality occurring within 30-days from admission; post-discharge mortality within 180-days from discharge; characteristics with direct and indirect associations with mortality within a multi-level a priori framework including demographic, clinical, anthropometric characteristics at admission and discharge from hospital, and pre-existing child-, caregiver- and household-level characteristics.ResultsOf 3101 participants (median age 11 months), 1218 were severely wasted/kwashiorkor, 763 moderately wasted and 1120 were not wasted. Of 350 deaths, 182 (52%) occurred during index admission, 234 (67%) within 30-days of admission and 168 (48%) within 180-days post-discharge. Ninety (54%) post-discharge deaths occurred at home. The ratio of inpatient to post-discharge mortality was consistent across anthropometric strata and sites. Large high and low risk groups could be disaggregated for both early and post-discharge mortality. Structural equation models identified direct pathways to mortality and multiple socioeconomic, clinical and nutritional domains acting indirectly through anthropometric status.ConclusionsAmong diverse sites in Africa and South Asia, almost half of mortality occurs post-discharge. Despite being highly predictable, these deaths are not addressed in current guidelines. A fundamental shift to a risk-based approach to inpatient and post-discharge management is needed to further reduce childhood mortality and clinical trials of these approaches with outcomes of mortality, readmission and cost are warranted.Trial RegistrationClinicalTrials.gov: NCT03208725

Background Malnutrition is highly prevalent in HIV-exposed perinatally uninfected infants (HEUs) increasing the risk of morbidity and mortality throughout the life course. We set out to compare the effect of postnatal exposure to maternal antiretroviral therapy (mART) in breastmilk versus infant Nevirapine prophylaxis (iNVP) on somatic growth of HEUs in the randomized PROMISE trial. Methods and findings We randomized 2431 mothers with HIV and their 2444 HEUs from six African countries and India 6–14 days after delivery to mART or iNVP for prevention of breastmilk HIV transmission. The mART regimen contained tenofovir/emtricitabine (99%) plus lopinavir/ritonavir. Infant growth parameters were compared at postnatal week 10, 26, 74 and 104 using World Health Organization (WHO) z-scores for length-for-age (LAZ), weight-for-age (WAZ), and head circumference-for-age (HCAZ). Week 26 LAZ was the primary endpoint measure. Student T-tests compared mean LAZ, WAZ, and HCAZ; estimated mean and 95% confidence interval (CI) are presented. Maternal and infant baseline characteristics were comparable between study arms. The estimated median breastfeeding duration was 70 weeks. After a mean follow-up of 88 weeks, mean LAZ and WAZ were below the WHO reference population mean at all timepoints, whereas mean HCAZ was not. The mART and iNVP arms did not differ for the primary outcome measure of LAZ at week 26 (p-value = 0.39; estimated mean difference (95%CI) of -0.05 (-0.18, 0.07)) or any of the other secondary growth outcome measures or timepoints (all p-values≥0.16). Secondary analyses of the primary outcome measure adjusting for week 0 LAZ and other covariates did not change these results (all p-values≥0.09). However, infants assigned to mART were more likely to have stunting compared to iNVP infants at week 26 (odds ratio (95% CI): 1.28 (1.05, 1.57)). Conclusions In HEUs, growth effects from postnatal exposure to mART compared to iNVP were comparable for measures on length, weight and head circumference with no clinically relevant differences between the groups. Despite breastfeeding into the second year of life, length and weight were below reference population means at all ages in both arms. Further investment is needed to optimize postnatal growth of infants born to women with HIV. Clinical trial registration ClinicalTrials.gov number NCT01061151.

Summary Background Antiretroviral medication during pregnancy and breastfeeding substantially decreases the risk of HIV transmission from mothers to infants, but its effects on the child's neurodevelopment are unknown. This study compared neurodevelopmental outcomes of ante-partum and post-partum antiretroviral exposure in HIV-exposed and uninfected children with HIV-unexposed and uninfected children at ages 12, 24, 48, and 60 months. Methods For this study, a prospective cohort of HIV-exposed and uninfected children was identified from two research sites in the PROMISE-BF trial (at Blantyre, Malawi, and Kampala, Uganda), in which pregnant HIV-infected mothers were randomly assigned to triple antiretroviral prophylaxis (lopinavir–ritonavir plus either lamivudine and zidovudine or emtricitabine and tenofovir), versus zidovudine alone. Post partum, the mother–infant pairs were randomly assigned to maternal triple antiretroviral treatment or infant nevirapine during breastfeeding. HIV-unexposed and uninfected children matched for age, sex, and socioeconomic background were enrolled at vaccination and well-child clinics at the study sites. We included only children without a history of documented brain infection or injury or substantial malnutrition, and whose mothers were randomly assigned and maintained within their assigned ante-partum and post-partum phases throughout their treatment arm periods. Primary outcomes were the Mullen Scales of Early Learning (MSEL) cognitive composite score at age 12 months, 24 months, and 48 months; and the mental processing index for the Kaufman Assessment Battery for Children, second edition (KABC-II) global score at 48 months and 60 months. Repeated measures were analysed using a linear mixed-effects model controlling for data collection site. Findings Between Aug 23, 2013, and Dec 17, 2014, we co-enrolled 861 children. For MSEL assessments, 738 were eligible for inclusion at age 12 months, 790 at age 24 months, and 692 at age 48 months. For KABC-II assessments, 685 were eligible for inclusion at age 48 months and 445 at age 60 months. There were no differences in MSEL cognitive composite scores according to exposure at age 12 and 24 months (p=0·19 and 0·24, respectively, for comparison of all groups). At 48 months, MSEL cognitive composite scores were worse for children of mothers who did not remain on triple antiretroviral treatment throughout both the ante-partum and post-partum treatment phases (adjusted means 80·64 [95% CI 77·74–83·54] and 81·34 [78·19–84·48], respectively), compared with those who did remain on triple treatment (adjusted mean 85·93, 95% CI 83·05–88·80; p=0·0486 for the comparison of all groups). The KABC-II composite scores (mental processing index) did not differ at 48 or 60 months according to exposure (p=0·81 and 0·89, respectively, for comparison of all groups). Scores for MSEL and KABC-II for children of mothers on triple antiretrovirals in both the ante-partum and post-partum treatment phases were similar to those for children in the HIV-unexposed and uninfected reference group at all timepoints. Interpretation Maternal triple antiretroviral exposure during both the ante-partum and post-partum phases did not result in greater developmental risks for the mothers' HIV-exposed and uninfected children through age 60 months, compared with children who were HIV-unexposed and uninfected. This might be because ante-partum triple antiretroviral protection of the health of mothers with HIV during pregnancy might be neuroprotective for the child, and when continued post partum, could enhance the quality of caregiving for the child through better clinical care for the mother. Funding National Institutes of Health and Eunice Kennedy Shriver National Institute of Child Health and Human Development.

BACKGROUND: The World Health Organization recommends not performing transfusions in African children hospitalized for uncomplicated severe anemia (hemoglobin level of 4 to 6 g per deciliter and no signs of clinical severity). However, high mortality and readmission rates suggest that less restrictive transfusion strategies might improve outcomes.METHODS: In this factorial, open-label, randomized, controlled trial, we assigned Ugandan and Malawian children 2 months to 12 years of age with uncomplicated severe anemia to immediate transfusion with 20 ml or 30 ml of whole-blood equivalent per kilogram of body weight, as determined in a second simultaneous randomization, or no immediate transfusion (control group), in which transfusion with 20 ml of whole-blood equivalent per kilogram was triggered by new signs of clinical severity or a drop in hemoglobin to below 4 g per deciliter. The primary outcome was 28-day mortality. Three other randomizations investigated transfusion volume, postdischarge supplementation with micronutrients, and postdischarge prophylaxis with trimethoprim-sulfamethoxazole.RESULTS: A total of 1565 children (median age, 26 months) underwent randomization, with 778 assigned to the immediate-transfusion group and 787 to the control group; 984 children (62.9%) had malaria. The children were followed for 180 days, and 71 (4.5%) were lost to follow-up. During the primary hospitalization, transfusion was performed in all the children in the immediate-transfusion group and in 386 (49.0%) in the control group (median time to transfusion, 1.3 hours vs. 24.9 hours after randomization). The mean (±SD) total blood volume transfused per child was 314±228 ml in the immediate-transfusion group and 142±224 ml in the control group. Death had occurred by 28 days in 7 children (0.9%) in the immediate-transfusion group and in 13 (1.7%) in the control group (hazard ratio, 0.54; 95% confidence interval [CI], 0.22 to 1.36; P = 0.19) and by 180 days in 35 (4.5%) and 47 (6.0%), respectively (hazard ratio, 0.75; 95% CI, 0.48 to 1.15), without evidence of interaction with other randomizations (P>0.20) or evidence of between-group differences in readmissions, serious adverse events, or hemoglobin recovery at 180 days. The mean length of hospital stay was 0.9 days longer in the control group.CONCLUSIONS: There was no evidence of differences in clinical outcomes over 6 months between the children who received immediate transfusion and those who did not. The triggered-transfusion strategy in the control group resulted in lower blood use; however, the length of hospital stay was longer, and this strategy required clinical and hemoglobin monitoring. (Funded by the Medical Research Council and Department for International Development; TRACT Current Controlled Trials number, ISRCTN84086586.).

BACKGROUND. Adverse pregnancy outcomes such as preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA) remain major global problems. We compared pregnancy outcomes among HIV-infected women receiving antiretroviral treatment (ART) and with CD4 ≥350 cells, and HIV-uninfected women to assess if disparities associated with HIV infection have been eliminated through use of ART. SETTING: Observational study conducted at five health facilities in Blantyre, Malawi during 2016–2017. METHODS. HIV-infected women receiving the national ART regimen (efavirenz+lamuvidine+tenfovir) and HIV-uninfected women were consented and enrolled at delivery. Data collected included sociodemographic and clinical; gestational age (GA); birth weight (BW); infant/maternal anthropometry; and laboratory results. We defined PTB as GA0·05). Of 231 SGA infants, 78·8% were proportionate and 21% were disproportionate. Of the 614 HIV-infected women on ART, 75% had undetectable virus at delivery. CONCLUSION. ART use has reduced the high rates of adverse pregnancy outcomes among HIV-infected women. However, the rates remain high irrespective of HIV infection and require appropriate interventions.

A comprehensive evidence-based framework is needed to guide policies and programmes that enable children and adolescents to accrue the human capital required to meet the Sustainable Development Goals (SDGs). This paper proposes a comprehensive, multisectoral, multilevel life-course conceptualisation of human capital development by building on the Nurturing Care Framework (NCF), originally developed for the foundational period of growth and development through the age 3 years. Nurturing care (NC) comprises stable environments that promote children’s health and nutrition, protect from threats, and provide opportunities for learning and responsive, emotionally supportive and developmentally enriching relationships. NC is fostered by families, communities, services, national policies and beyond. The principles apply across the life course, endorse equity and human rights, and promote long-term human capital. This paper presents an evidence-based argument for the extension of the NCF from preconception through adolescence (0–20 years), organised into six developmental periods: preconception/prenatal, newborn/birth, infancy/toddlerhood, preschool, middle childhood and adolescence. The proposed framework advances human capital within each developmental period by promoting resilience and adaptive developmental trajectories while mitigating negative consequences of adversities. Attaining the SDGs depends on strengthening human capital formation, extending throughout childhood and adolescence and supported by NC. Embedded in enabling laws, policies and services, the dynamic NCF components can mitigate adversities, enhance resilience and promote the well-being of marginalised groups. The life-course extension of the NCF is strategically positioned to enhance human capital, to attain the SDGs and to ensure that children or adolescents are not left behind in reaching their developmental potential.

BackgroundWe sought to identify perceptions of neurorehabilitation challenges for paediatric cerebral malaria (CM) survivors post-hospital discharge at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi.MethodsAn exploratory approach was used to qualitatively investigate the perceived neurorehabilitation challenges for paediatric CM survivors. Data were collected through semi-structured in-depth interviews (IDIs) and focus group discussions (FGDs). Eighteen data-gathering sessions were conducted with 38 total participants, including 3 FGDs with 23 primary caregivers, 11 IDIs with healthcare workers at QECH, and 4 IDIs with community-based rehabilitation workers (CRWs).ResultsFGDs revealed that caregivers lack important knowledge about CM and fear recurrence of CM in their children. Post-CM children and families experience substantial stigma and sociocultural barriers to integrating into their community and accessing neurorehabilitative care. At a community-level, rehabilitation infrastructure, including trained staff, equipment, and programmes, is extremely limited. Rehabilitation services are inequitably accessible, and community-based rehabilitation remains largely unavailable.ConclusionsThere is an urgent need to establish further training of rehabilitation personnel at all levels and to build accessible rehabilitation infrastructure in Malawi for post-CM patients. Additional work is required to expand this study across multiple regions for a holistic understanding of neurorehabilitation needs.

IntroductionSevere acute malnutrition (SAM) and disability are major global health issues. Although they can cause and influence each other, data on their co-existence are sparse. We aimed to describe the prevalence and patterns of disability among a cohort of children with SAM.MethodsA longitudinal cohort study in Malawi followed SAM survivors up to 7 years postdischarge. Clinical and anthropometric profiles were compared with sibling and community controls. Disability at original admission was identified clinically; at 7-year follow-up a standardised screening tool called ‘the Washington Group Questionnaire’ was used.Results60/938 (6.4%) of admissions to SAM treatment had clinically obvious disability at admission. Post-treatment mortality was high, with only 11/60 (18%) surviving till 7-year follow-up. SAM children with a disability at admission had 6.99 (95% CI 3.49 to 14.02; pThe Washington Group Questionnaire confirmed disability in all who had been identified clinically, and identified many who had not been previously flagged.ConclusionDisability is common among children affected by SAM. Those with disability-associated SAM have greatly increased risk of dying even if they survive the initial episode of malnutrition. Survivors have poorer growth, physical strength and school achievement. To enable all children to survive and thrive post-SAM, it is vital to focus more on those with disabilities. SAM treatment programmes should consider using not just clinical assessment but structured assessments to better identify at-risk individuals as well as understand the population of children for which they are developing services.

Background In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling, and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling. Methods We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain magnatic resonance imaging (MRI), and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. Results Three types of retinal leakage were seen: large focal leak (LFL), punctate leak (PL), and vessel leak. The LFL and PL were associated with death (odds ratio [OR] = 13.20, 95% confidence interval [CI] = 5.21–33.78 and OR = 8.58, 95% CI = 2.56–29.08, respectively) and brain swelling (P Conclusions Blood-retina barrier breakdown occurs in 3 patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak, from barrier dysfunction, and nonperfusion were not associated with severe brain swelling but with neurological deficits, suggesting hypoxic injury in survivors.

We aimed to identify the contribution of central nervous system (CNS) viral coinfection to illness in African children with retinopathy-negative or retinopathy-positive cerebral malaria (CM). We collected cerebrospinal fluid (CSF) from 272 children with retinopathy-negative or retinopathy-positive CM and selected CSF from 111 of these children (38 retinopathy positive, 71 retinopathy negative, 2 retinopathy unknown) for analysis by metagenomic next-generation sequencing. We found CSF viral coinfections in 7/38 (18.4%) retinopathy-positive children and in 18/71 (25.4%) retinopathy-negative children. Excluding HIV-1, human herpesviruses (HHV) represented 61% of viruses identified. Excluding HIV-1, CNS viral coinfection was equally likely in children who were retinopathy positive and retinopathy negative (P = 0.1431). Neither mortality nor neurological morbidity was associated with the presence of virus (odds ratio [OR] = 0.276, 95% CI: 0.056-1.363). Retinopathy-negative children with a higher temperature, lower white blood cell count, or being dehydrated were more likely to have viral coinfection. Level of consciousness at admission was not associated with CNS viral coinfection in retinopathy-negative children. Viral CNS coinfection is unlikely to contribute to coma in children with CM. The herpesviruses other than herpes simplex virus may represent incidental bystanders in CM, reactivating during acute malaria infection.

Background - The World Health Organization recommends benzylpenicillin and gentamicin as antimicrobial treatment of infants with sepsis in low income settings (LICs), and ceftriaxone or cefotaxime as an alternative. In a meta-analysis from 13 LICs, Staphylococcus aureus, Klebsiella spp. and E.coli accounted for 55% of infants with sepsis. In a review of bacterial meningitis, resistance to third generation cephalosporins was >50% of all isolates, and 44% of Gram-negative isolates were gentamicin resistant. However, ceftriaxone may cause neonatal jaundice and gentamicin may cause deafness. Therefore, we compared parenteral benzylpenicillin plus gentamicin to ceftriaxone as first line treatment, assessing outcome and adverse events.\ud \ud Methods - This was an open randomized trial carried out in the Queen Elizabeth Central Hospital, Blantyre, Malawi from 2010 to 2013. Infants < 60 days of age with possible severe sepsis received either benzylpenicillin and gentamicin or ceftriaxone. Adverse events and outcomes were recorded until 6 months post discharge.\ud \ud Results - 348 infants were included in analyses. Outcome in the benzylpenicillin and gentamicin or ceftriaxone groups was similar; deaths were 13.7% and 16.5% and sequelae 14.5% and 11.2% respectively. More infants in the penicillin/gentamicin group required phototherapy: 15% v 5%, p=0.03. Thirteen (6%) survivors had bilateral hearing loss. There was no difference between the treatment groups. By 6 months post discharge 11 more infants had died and 17 more children were found to have sequelae.\ud \ud Conclusions - Ceftriaxone and gentamicin are safe for infants in our setting. Infants should receive long term follow up as many poor outcomes occurred after hospital discharge.

Background Acute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression. We undertook studies of enteral levetiracetam (eLVT) to evaluate pharmacokinetics (PK), safety and efficacy including an open-label, randomized controlled trial (RCT) comparing eLVT to phenobarbital. Methods Children 24–83 months old with CM were enrolled in an eLVT dose-finding study starting with standard dose (40 mg/kg load, then 30 mg/kg Q12 hours) titrated upward until seizure freedom was attained in 75% of subjects. The RCT that followed randomized children to eLVT vs. phenobarbital for acute seizures and compared the groups on minutes with seizures based upon continuous electroencephalogram. Due to safety concerns, midway through the study children allocated to phenobarbital received the drug only if they continued to have seizures (either clinically or electrographically) after benzodiazepine treatment. Secondary outcomes were treatment failure requiring cross over, coma duration and neurologic sequelae at discharge. PK and safety assessments were also undertaken. Results Among 30 comatose CM children, eLVT was rapidly absorbed and well-tolerated. eLVT clearance was lower in patients with higher admission serum creatinine (SCr), but overall PK parameters were similar to prior pediatric PK studies. Within 4 h of the first dose, 90% reached therapeutic levels (> 20 μg/mL) and all were above 6 μg/mL. 7/7 children achieved seizure freedom on the initial eLVT dose. Comparing 23 eLVT to 21 phenobarbital patients among whom 15/21 received phenobarbital, no differences were seen for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death, but eLVT was safer (p = 0.019). Phenobarbital was discontinued in 3/15 due to respiratory side effects. Conclusion Enteral LVT offers an affordable option for seizure control in pediatric CM and is safer than phenobarbital. Trial registration NCT01660672. NCT01982812.

OBJECTIVE To compare growth among antiretroviral drug and maternal HIV-exposed uninfected (AHEU) versus age-matched and sex-matched HIV-unexposed uninfected (HUU) children. DESIGN Prospective cohort of AHEU children identified from the PROMISE trial (NCT01061151: clinicaltrials.gov registry) and age-matched and sex-matched HUU controls from child-wellness clinics, enrolled (September 2013 to October 2014) in Malawi and Uganda. METHODS Weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), and head-circumference-for-age (HCAZ) z-scores were derived at 12 months and 24 months of age. Wilcoxon Rank-Sum and Fisher's exact tests were used for unadjusted exposure group comparisons. Generalized Estimating Equations models estimated adjusted relative risks (aRR) for poor growth outcomes. RESULTS Overall, 471 (50.5%) AHEU and 462 (49.5%) HUU children were assessed. Ugandan AHEU compared with HUU children had significantly lower mean LAZ (P

Background: Antiretroviral drug and HIV exposed uninfected (AHEU) children were associated with growth deficits in some but not all previous studies which had considerable limitations. Objective: To compare anthropometric outcomes among AHEU, and HIV unexposed uninfected (HUU) children at 12 and 24-months-of-age. Design: Prospective cohort of AHEU children co-enrolled from the PROMISE randomized clinical trial (NCT01061151: clinicaltrials.gov registry); and age-and-sex-matched HUU controls enrolled from child-wellness clinics, between 09/2013-10/2014 in Malawi and Uganda. Methods: Standardized anthropometric and clinical data were collected at 12 and 24-months-of-age. We used WHO-population (2006) growth-standards to derive weight-for-age (WAZ); length-for-age (LAZ); weight-for-length (WLZ); and head-circumference-for-age (HCAZ) z-scores. Wilcoxon Rank-Sum/Fischer's exact tests were used for AHEU and HUU comparisons; and Generalized-Estimating-Equations models controlling for maternal-age, tap-water, electricity/gas, and breastfeeding status were used to estimate adjusted relative risk (aRR). Findings: Overall, 472 (50.5%) AHEU and 462 (49.5%) HUU children were assessed. Ugandan AHEU compared to HUU children had significantly lower mean-Z-scores: LAZ (p 0.05). The risk of stunting (more than two standard deviations below the WHO-population LAZ median) was increased among AHEU compared to HUU children: aRR=2.13 (95% confidence interval (CI): 1.36, 3.33), p=0.001, at 12-months, and aRR=1.67 (95% CI: 1.16, 2.41), p=0.006, at 24-months-of-age, in Uganda; and aRR=1.32 (95% CI: 1.10, 1.66), p=0.018, at 24-months-of-age, in Malawi. Relative-risk of HCAZ below WHO median was increased among AHEU children at 24-months-of-age, aRR = 1.35 (95% CI: 1.02, 1.79), p=0.038, in Uganda; and in similar direction but not significant, aRR=1.35 (95% CI: 0.91, 2.02), p=0.139, in Malawi. Interpretation: Perinatal maternal-HIV and ARV exposures were associated with lower LAZ (including stunting), WAZ and HCAZ at 24 months-of-age compared to sex and age-matched HUU children from similar socioeconomic backgrounds. Funding Statement: The study was funded by the US National Institute of Child Health and Human Development (HD 073296). Declaration of Interests: The authors do not have financial, consultant, institutional or other relationships that might lead to a bias or conflict of interest. Ethics Approval Statement: Regulatory oversight was provided by Institutional Review Boards in Malawi and Uganda, and the Johns Hopkins Medical Institute.

Summary Background Fever with reduced consciousness is an important cause of hospital admission of children in sub-Saharan Africa, with high mortality. Cerebral malaria, diagnosed when acute Plasmodium falciparum infection and coma are recorded with no other apparent reason, is one important cause. We investigated whether viruses could also be an important cause of CNS infection in such patients, and examined the relative contribution of viral pathogens and malaria parasitaemia. Methods We did a prospective cohort study in Blantyre, Malawi. From March 1, 2002, to Aug 31, 2004, we enrolled children aged between 2 months and 15 years who were admitted to hospital with suspected non-bacterial CNS infections. Children with a cerebrospinal fluid (CSF) white cell count of less than 1000 cells per μL and negative bacterial microscopy and culture were deemed to have suspected viral CNS infection. Blood was examined for asexual forms of P falciparum. PCR was done on CSF or on post-mortem brain biopsy specimens to detect 15 viruses known to cause CNS infection. Findings Full outcome data were available for 513 children with suspected viral CNS infection, of whom 94 (18%) died. 163 children (32%) had P falciparum parasitaemia, of whom 34 (21%) died. At least one virus was detected in the CNS in 133 children (26%), of whom 43 (33%) died. 12 different viruses were detected; adenovirus was the most common, affecting 42 children; mumps, human herpes virus 6, rabies, cytomegalovirus, herpes simplex virus 1, and enterovirus were also important. 45 (9%) of the 513 children had both parasitaemia and viral infection, including 27 (35%) of 78 diagnosed clinically with cerebral malaria. Children with dual infection were more likely to have seizures than were those with parasitaemia alone, viral infection only, or neither (p

Cerebral malaria, defined as an otherwise unexplained coma in a patient with Plasmodium falciparum parasitemia, affects up to 1 million people per year, the vast majority of them being children living in sub-Saharan Africa. Despite optimal treatment, this condition kills 15% of those affected and leaves 30% of survivors with neurologic sequelae. The clinical diagnosis is hampered by its poor specificity, but the presence or absence of a malarial retinopathy in cerebral malaria has proven to be important in the differentiation of underlying coma etiology. Both antimalarials and intense supportive care are necessary for optimal treatment. As of yet, clinical trials of adjunctive therapies have not improved the high rates of mortality and morbidity. Survivors are at high risk of neurologic sequelae including epilepsy, neurodisabilities and cognitive–behavioral problems. The neuroanatomic and functional bases of these sequelae are being elucidated. Although adjunctive therapy trials continue, the best hope for African children may lie in disease prevention. Strategies include bednets, chemoprophylaxis and vaccine development.

Background Salmonella enterica serovar Typhi causes an estimated 22 million cases of typhoid fever and 216 000 deaths annually worldwide. We investigated an outbreak of unexplained febrile illnesses with neurologic findings, determined to be typhoid fever, along the Malawi-Mozambique border. Methods The investigation included active surveillance, interviews, examinations of ill and convalescent persons, medical chart reviews, and laboratory testing. Classification as a suspected case required fever and ≥1 other finding (eg, headache or abdominal pain); a probable case required fever and a positive rapid immunoglobulin M antibody test for typhoid (TUBEX TF); a confirmed case required isolation of Salmonella Typhi from blood or stool. Isolates underwent antimicrobial susceptibility testing and subtyping by pulsed-field gel electrophoresis (PFGE). Results We identified 303 cases from 18 villages with onset during March-November 2009; 214 were suspected, 43 were probable, and 46 were confirmed cases. Forty patients presented with focal neurologic abnormalities, including a constellation of upper motor neuron signs (n = 19), ataxia (n = 22), and parkinsonism (n = 8). Eleven patients died. All 42 isolates tested were resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole; 4 were also resistant to nalidixic acid. Thirty-five of 42 isolates were indistinguishable by PFGE. Conclusions The unusual neurologic manifestations posed a diagnostic challenge that was resolved through rapid typhoid antibody testing in the field and subsequent blood culture confirmation in the Malawi national reference laboratory. Extending laboratory diagnostic capacity, including blood culture, to populations at risk for typhoid fever in Africa will improve outbreak detection, response, and clinical treatment.

The first African Child Neurology Association meeting identified key challenges that the continent faces to improve the health of children with neurology disorders. The capacity to diagnose common neurologic conditions and rare disorders is lacking. The burden of neurologic disease on the continent is not known, and this lack of knowledge limits the ability to lobby for better health care provision. Inability to practice in resource-limited settings has led to the migration of skilled professionals away from Africa. Referral systems from primary to tertiary are often unpredictable and chaotic. There is a lack of access to reliable supplies of basic neurology treatments such as antiepileptic drugs. Few countries have nationally accepted guidelines either for the management of epilepsy or status epilepticus. There is a great need to develop better training capacity across Africa in the recognition and management of neurologic conditions in children, from primary health care to the subspecialist level.

Plasmodium falciparum and other human malaria parasites can cause a variety of life-threatening syndromes. Diagnosis is difficult because none of these syndromes is unique to malaria, and parasitemia may be incidental rather than responsible for the illness. Malaria must be considered in the differential diagnosis of each of the severe syndromes it can cause – severe anemia, coma and convulsions, acidosis, hypoglycemia, shock, acute renal failure, intravascular hemolysis, acute respiratory distress syndrome and disseminated intravascular coagulation. The possibility of an alternative or additional infection must be considered and, in many circumstances, covered by initial emergency treatment. In the comatose patient the presence of a distinctive retinopathy is suggestive that malaria is the cause of the disease. Management must begin with emergency measures to ensure vital functions, followed by prompt provision of supportive measures (airway protection, glucose, fluids, oxygen, blood, antipyresis and ant...

In 1891, Winter1 described the first 4 cases of tuberculous meningitis (TBM), in which “paracenteses of the theca vertebralis was performed to relieve cerebrospinal fluid (CSF) fluid pressure.” Since this original description of the lumbar puncture (LP) procedure, neurologists worldwide have relied on LPs for both diagnostic and therapeutic purposes. In resource-limited settings, LPs are often the only neurologic test available to aid the clinician in neurologic diagnosis. In sub-Saharan Africa, a large number of patients present to hospitals with acute neurologic symptoms, including those who are HIV-infected and have opportunistic infections such as cryptococcal meningitis and TBM. In these clinical scenarios, LPs are an essential point-of-care diagnostic and therapeutic procedure.2 The benefits of the LP as a diagnostic tool are well-known, but it is important to emphasize that therapeutic LPs are a low-cost measure to monitor and treat intracranial pressure (ICP) due to nonobstructive hydrocephalus in regions of the world where more sophisticated testing and treatment are unavailable due to limitations of medical equipment, medication supplies, and clinical personnel, including specialized neurologists and neurosurgeons.

Cerebral palsy is the most common cause of physical disability in children worldwide. However, little is reported on this condition in the African context. Doctors from 22 countries in Africa, and representatives from a further 5 countries outside Africa, met to discuss the challenges in the evaluation and management of children with cerebral palsy in Africa and to propose service needs and further research. Basic care is limited by the poor availability of diagnostic facilities or medical personnel with experience and expertise in managing cerebral palsy, exacerbated by lack of available interventions such as medications, surgical procedures, or even regular therapy input. Relevant guidelines are lacking. In order to guide services for children with existing disabilities, to effectively target the main etiologies and to develop preventive strategies for the continent, research priorities must include multicenter collaborative studies looking at the prevalence, risk factors, and treatment of cerebral palsy.

In addition to encountering most of the conditions treated by clinicians in the West, clinicians in the tropics are faced with unique tropical encephalopathies. These are largely but not entirely infectious in nature. Despite the relatively low cost of EEG technology, it remains unavailable in many low-income tropical settings even at the tertiary care level. Where available, the EEG recordings and interpretation are often of unacceptable quality. Nonetheless, there are existing data on the EEG patterns seen in malaria and a number of tropical viral, bacterial, and parasitic infestations.

This article presents key findings from the International Child Neurology Association/African Child Neurology Association Workshop. The viability of international guidelines for the management of children with epilepsy should be reviewed within each African country, and adapted to comply with the regional capacity. Such recommendations can be used to lobby for resources. More training centers should be developed in Africa, so that specialists can be trained within Africa, in skills relevant to the continent, in collaboration with “out of Africa” visiting-specialists to develop the concept of “train the trainers.” At least 1 child neurology specialist per 100 000 of the population is required. Specific to Africa are the challenges from stigma, prejudice, and misconceptions. “Epilepsy teams,” inclusive of the traditional healers, would enable management of increased numbers of children, and challenge policy such that it is the right of the child with epilepsy to have reliable access to appropriate antiepileptic drugs, support, and health care equity between the rural and urban settings.

Objective To collect normative MRI data for effective clinical and research applications. Such data may also offer insights into common neurological insults. Methods We identified a representative, community-based sample of children aged 9–14 years. Children were screened for neurodevelopmental problems. Demographic data, medical history and environmental exposures were ascertained. Eligible children underwent the Neurologic Examination for Subtle Signs (NESS) and a brain MRI. Descriptive findings and analyses to identify risk factors for MRI abnormalities are detailed. Results One hundred and two of 170 households screened had age-appropriate children. Two of 102 children had neurological problems – one each with cerebral palsy and epilepsy. Ninety-six of 100 eligible children were enrolled. Mean age was 11.9 years (SD 1.5), and 43 (45%) were boys. No acute MRI abnormalities were seen. NESS abnormalities were identified in 6 of 96 children (6%). Radiographic evidence of sinusitis in 29 children (30%) was the most common MRI finding. Brain abnormalities were found in 16 (23%): mild diffuse atrophy in 4 (4%), periventricular white matter changes/gliosis in 6 (6%), multifocal punctuate subcortical white matter changes in 2 (2%), vermian atrophy in 1 (1%), empty sella in 3 (3%) and multifocal granulomas with surrounding gliosis in 1 (1%). Having an abnormal MRI was not associated with age, sex, antenatal problems, early malnutrition, febrile seizures, an abnormal neurological examination or housing quality (all P values >0.05). No predictors of radiographic sinusitis were identified. Conclusion Incidental brain MRI abnormalities are common in normal Malawian children. The incidental atrophy and white matter abnormalities seen in this African population have not been reported among incidental findings from US populations, suggesting Malawi-specific exposures may be the cause. Objectif Recueillir des donnees IRM normatives pour des applications cliniques et de recherche efficaces. De telles donnees peuvent egalement offrir un apercu sur les affections neurologiques courantes. Methodes Nous avons identifie un echantillon representatif, base sur la communaute d'enfants âges de 9 a 14 ans. Les enfants ont ete examines pour des problemes de developpement neurologique. Les donnees demographiques, les antecedents medicaux et les expositions environnementales ont ete constates. Les enfants eligibles ont subi l'examen neurologique pour les signes subtils (ENSS) et une IRM du cerveau. Les resultats descriptifs et analyses pour l'identification des facteurs de risque d'anomalies IRM sont detailles. Resultats 102/170 menages echantillonnes avaient des enfants d’âge approprie. 2/102 enfants avaient des problemes neurologiques, un avec une paralysie cerebrale et un avec l’epilepsie. 96/100 enfants eligibles ont ete inscrits a l’etude. L’âge moyen etait de 11.9 ans (DS: 1.5), 43 (45%) etaient de sexe masculin. Aucune anomalie IRM aigue n'a ete observee. Des anomalies ENSS ont ete identifiees chez 6/96 (6%) enfants. Des signes radiologiques de sinusite 29 (30%) representaient le resultat IRM le plus courant. Des anomalies cerebrales ont ete trouvees chez 16 (23%) enfants: atrophie diffuse benigne chez 4 (4%), changements de la matiere blanche peri ventriculaire/gliose chez 6 (6%), changements multifocaux ponctues de la substance blanche sous-corticale chez 2 (2%), atrophie du vermis chez 1 (1%), selle turcique vide chez 3 (3%) et des granulomes multifocaux avec gliose environnante chez 1 (1%). Avoir une IRM anormale n’etait pas associe a l’âge, au sexe, a des problemes prenataux, a la malnutrition precoce, a des convulsions febriles, a un examen neurologique anormal ni a la qualite des logements (tous les P > 0.05). Aucun predicteurs de la sinusite radiographique n'a ete identifie. Conclusion Les anomalies IRM cerebrales fortuites sont communes chez les enfants du Malawi. L'atrophie fortuite et des anomalies de la substance blanche observees dans cette population africaine n'ont pas ete rapportees parmi les decouvertes fortuites dans les populations americaines, ce qui suggere que des expositions specifiques au Malawi pourraient en etre la cause. Objetivo Recoger datos de imagenes por resonancia magnetica (IRM) normales para aplicaciones clinicas efectivas e investigacion. Estos datos podrian tambien ofrecer una vision de lesiones neurologicas comunes. Metodos Hemos identificado una muestra representativa, basada en la comunidad, de ninos con edades entre los 9–14 anos. Los ninos se evaluaron en busca de problemas de desarrollo neurologico. Se determinaron los datos demograficos, la historia medica y la exposicion ambiental. A los ninos elegibles se les realizo en Examen Neurologico para Signos Sutiles (NESS) y una IRM del cerebro. Se detallan los hallazgos descriptivos y el analisis para identificar los factores de riesgo de anormalidades en las IRM. Resultados 102/170 hogares evaluados tenian ninos en edad apropiada. 2/102 ninos tenian problemas neurologicos — uno con paralisis cerebral y otro con epilepsia. Se incluyeron 96/100 ninos elegibles. La edad media era de 11.9 anos (SD 1.5), 43 (45%) eran hombre. No se observaron anormalidades agudas en las IRM. Se identificaron anormalidades en NESS en 6/96 (6%). La evidencia radiografica de sinusitis 29 (30%) era el hallazgo por IRM mas comun. Se encontraron anormalidades en el cerebro en 16 (23%): atrofia difusa leve en 4 (4%), cambios periventriculares en la sustancia blanca /gliosis en 6 (6%), cambios multifocales en la sustancia blanca subcortical en 2 (2%), atrofia vermiana en 1 (1%), silla turca vacia en 3 (3%), y granulomas multifocales con gliosis circundante en 1 (1%). El tener una IRM anormal no estaba asociada con la edad, el sexo, los problemas prenatales, una desnutricion temprana, convulsiones febriles, un examen neurologico anormal o la calidad del hogar (todos los P's > 0.05). No se identificaron vaticinadores de sinusitis radiografica. Conclusion Las anomalias incidentales en IMR del cerebro son comunes en ninos normales de Malawi. La atrofia incidental y anormalidades de la materia blanca observadas en esta poblacion Africana no se han reportado entre los hallazgos incidentales de poblaciones de Estado Unidos, sugiriendo que las exposiciones especificas para Malawi podrian ser la causa.

Objective\ud High mortality burden from Acute Bacterial Meningitis (ABM) in resource-poor settings has been frequently blamed on delays in treatment seeking. We explored treatment-seeking pathways from household to primary health care and referral for ABM in Malawi.\ud \ud Design\ud A cross-sectional qualitative study using narrative in-depth interviews, semi-structured interviews and focus group discussions.\ud \ud Participants\ud Adults and children with proven and probable acute bacterial meningitis and/or their carers; adults from urban and peri-urban communities; and primary health care workers (HCW).\ud \ud Setting\ud Queen Elizabeth Central Hospital (QECH), urban and peri-urban private and government primary health centres and communities in Blantyre District, Malawi.\ud \ud Results\ud Whilst communities associated meningitis with a stiff neck, in practice responses focused on ability to recognise severe illness. Misdiagnosis of meningitis as malaria was common. Subsequent action by families depended on the extent to which normal social life was disrupted by the illness and depended on the age and social position of the sufferer. Seizures and convulsions were considered severe symptoms but were often thought to be malaria. Presumptive malaria treatment at home often delayed formal treatment seeking. Further delays in treatment seeking were caused by economic barriers and perceptions of inefficient or inadequate primary health services.\ud \ud Conclusions\ud Given the difficulties in diagnosis of meningitis where malaria is common, any intervention for ABM at primary level must focus on recognising severe illness, and encouraging action at the household, community and primary health levels. Overcoming barriers to recognition and social constraints at community level require broad community-based strategies and may provide a route to addressing poor clinical outcomes.

Rabies is an acute infection of the central nervous system (CNS) and caused by rabies virus or related members of the genus Lyssavirus , family Rhabdoviridae.1 The virus is usually transmitted through a dog bite and produces one of the most important viral encephalitides worldwide, with at least 40 000 deaths reported annually.2 However, it is rare in the United Kingdom, where just 12 cases have been reported since 19773: 11 were imported from overseas, and one occurred in a bat handler infected in Scotland with European bat lyssavirus type 2a.4 Most UK patients presented with furious rabies, which is characterised by hydrophobia and spasms. We report a case of paralytic rabies in a tourist after a two week holiday in Goa, India. Fig 2 Phylogenetic tree depicting the relation between the rabies virus sequence amplified from our patient (RV1964—boxed) and other viruses originating in Asia. The horizontal branch lengths represent the extent of difference between the strains (expressed as nucleotide substitutions per nucleotide site), and the closer viruses are on the tree, the more closely they are related A woman in her late 30s was admitted to her local general hospital under the orthopaedic surgeons, with lower back pain radiating to the left leg. The pain had started four days earlier, was severe and shooting in nature, and was getting worse. She had been seen twice in casualty in the preceding days, and by the time of admission she was unable to walk. She also had a headache and had vomited once. Three and a half months before admission, during a two week holiday to Goa, India, she had been bitten by a dog; she was walking in the street when a puppy on a lead nipped her on the left leg. There was a slight …

In this article, British neurologists share their experiences of neurology in Malawi - as educators and researchers. Malawi is a resource-poor country in Central Africa. The spectrum of neurological illnesses is varied and primarily related to HIV and neuroinfections. Structured overseas training programmes for residents can lead to aca- demic exchange with mutual benefit. New links can be established which can then be used to launch international health initiatives. Such visits can also lead to the develop- ment of institutional links, the fostering of which can have a role in the achievement of the global health agenda.

Aims Rehabilitation services in Malawi are limited despite the burden of paediatric neurodisability secondary to conditions such as cerebral malaria, meningitis, encephalitis and traumatic brain injury. This hospital-based study aims to explore the perceptions and experiences of parent/carers and health-workers caring for children with neurodisability following brain injury, in order to inform the development of a capacity-building programme to improve rehabilitation services. Methods The study was conducted in the Paediatrics department of an urban tertiary hospital in Malawi and utilised qualitative methodology. Sampling was purposive with recruitment via Paediatrics staff. Fourteen interviews were completed with parents/carers of children affected by recent brain injuries, and ten interviews and four focus-groups with health-workers. Analysis involved a thematic framework approach. Results Health-workers With limited resources, management of acute conditions is prioritised over rehabilitation. Lack of confidence, knowledge, and a sense of ‘there’s nothing we can do’ hampers health-workers’ rehabilitation efforts, despite many suggesting that simple things make a difference. Bias exists towards managing physical disability rather than impairments of cognition, speech or behaviour. Concerns were raised about the wider impact of neurodisability on the family, including the risk of child abuse and neglect. Counselling, including information giving, was identified as a priority. Health-workers recognised that effective rehabilitation could not be achieved unless parents/carers first understood and accepted their child’s condition. Parents/Carers Reports of poor communication between health-workers and parents/carers were common. Parents often had not understood or been adequately informed about investigations, diagnosis or management of their child’s condition. This contributed to unrealistic expectations about prognosis, misunderstanding about underlying causes, and lack of continued rehabilitation in the community. The burden of caring for a child with neurodisability, and the financial and opportunity costs this entails was strongly evident. Main issues were lack of mobility in their child, feeding, continence and speech difficulties. Religion was a key source of support. Conclusion Limited resources, lack of health-worker training, bias towards physical disability, and poor communication, are key factors inhibiting rehabilitation of children with brain injury in a hospital-setting in Malawi. A programme to improve rehabilitation services should address these issues as priority.

BACKGROUND: The bacterium Salmonella enterica serovar Typhi causes typhoid fever, which is typically associated with fever and abdominal pain. An outbreak of typhoid fever in Malawi-Mozambique in 2009 was notable for a high proportion of neurologic illness. OBJECTIVE: Describe neurologic features complicating typhoid fever during an outbreak in Malawi-Mozambique METHODS: Persons meeting a clinical case definition were identified through surveillance, with laboratory confirmation of typhoid by antibody testing or blood/stool culture. We gathered demographic and clinical information, examined patients, and evaluated a subset of patients 11 months after onset. A sample of persons with and without neurologic signs was tested for vitamin B6 and B12 levels and urinary thiocyanate. RESULTS: Between March - November 2009, 303 cases of typhoid fever were identified. Forty (13%) persons had objective neurologic findings, including 14 confirmed by culture/serology; 27 (68%) were hospitalized, and 5 (13%) died. Seventeen (43%) had a constellation of upper motor neuron findings, including hyperreflexia, spasticity, or sustained ankle clonus. Other neurologic features included ataxia (22, 55%), parkinsonism (8, 20%), and tremors (4, 10%). Brain MRI of 3 (ages 5, 7, and 18 years) demonstrated cerebral atrophy but no other abnormalities. Of 13 patients re-evaluated 11 months later, 11 recovered completely, and 2 had persistent hyperreflexia and ataxia. Vitamin B6 levels were markedly low in typhoid fever patients both with and without neurologic signs. CONCLUSIONS: Neurologic signs may complicate typhoid fever, and the diagnosis should be considered in persons with acute febrile neurologic illness in endemic areas.

Sept 28 marks World Rabies Day, launched in 2007 to increase public health awareness and reduce the incidence of this fatal but preventable disease. 5 years on, our experience in Malawi suggests that rabies incidence is rising and control measures are inadequate. We have seen ten cases of rabies in children at the Queen Elizabeth Central Hospital in Blantyre, Malawi, over a 9-month period (June, 2011, to February, 2012). This is the largest number of paediatric rabies cases described from a single institution in Africa and a threefold increase in the number of cases reported between 2002 and 2005 at the same hospital. All the patients had clear evidence of rabies encephalitis and all died. In the eight patients for whom history of exposure was obtained, all were secondary to a dog bite. A third of the patients did not report the exposure to their guardian; another third sought medical attention but there was unavailable or inadequate vaccine; one patient was denied treatment because they did not have a vet’s certifi cate. These cases presented to a tertiary referral hospital and the true incidence will be much higher. Current reporting systems in Africa have been shown to underestimate true numbers of rabies cases by up to 100-fold. Of the 14 rabies cases previously reported from Queen Elizabeth Central Hospital, four were misdiagnosed as cerebral malaria or meningitis. Anti-rabies vaccine in Malawi is often limited or unavailable. This is despite investment in its provision having been shown to be highly cost eff ective even if only 1% of those receiving anti-rabies vaccine were at actual risk of developing rabies. Additionally, the adoption of intradermal regimens can signifi cantly reduce the volume and thereby the cost of delivering antirabies vaccines. Our experience is that medical practitioners continue to use intramuscular regimens. Mass dog immunisation programmes are essential to control rabies spread, but often perceived as too expensive and logistically diffi cult to implement. Nevertheless, it has been shown than these barriers are surmountable and elimination of canine rabies in Africa is feasible, with initiatives such as the Rabies Blueprint website off ering practical support and guidance. Our recent experience highlights the ongoing burden from this terrible disease. Greater advocacy of intradermal regimens, better education and training of ground-level healthcare professionals, and governmental commitment to dog vaccination programmes are needed urgently if we are to stop these needless deaths from continuing to occur.

Background HIV-1 Tat protein is implicated in HIV-neuropathogenesis. Tat C31S polymorphism (TatCS) has been associated with milder neuropathology in vitro and in animal models but this has not been addressed in a cohort of HIV-infected adults or children. Methods HIV viral load (VL) in plasma and cerebrospinal fluid (CSF) were determined and plasma HIV tat gene was sequenced. Neurodevelopmental assessment was performed using Bayley Scales of Infant Development III (BSID-III), with scores standardized to Malawian norms. The association between TatCS and BSID-III scores was evaluated using multivariate linear regression. Results Neurodevelopmental assessment and HIV tat genotyping were available for 33 children. Mean age was 19.4 (SD 7.1) months, mean log VL was 5.9 copies/mL (SD 0.1) in plasma and 3.9 copies/mL (SD 0.9) in CSF. The prevalence of TatCC was 27 %. Z-scores for BSID-III subtests ranged from −1.3 to −3.9. TatCC was not associated with higher BSID-III z-scores. Conclusions The hypothesis of milder neuropathology in individuals infected with HIV TatCS was not confirmed in this small cohort of Malawian children. Future studies of tat genotype and neurocognitive disorder should be performed using larger sample sizes and investigate if this finding is due to differences in HIV neuropathogenesis between children and adults.