Association of in utero HIV exposure with child brain structure and language development: a South African birth cohort study.

BACKGROUND: There is a growing population of children with in utero HIV exposure who are at risk of poor neurodevelopmental outcomes despite avoiding HIV infection. However, the underlying neurobiological pathways are not understood and neuroimaging studies are lacking. We aimed to investigate the cortical brain structure of children who are HIV-exposed and uninfected (HEU) compared to HIV-unexposed (HU) children and to examine the relationship with neurodevelopment. METHODS: The Drakenstein Child Health birth cohort study enrolled pregnant women from a high HIV prevalence area in South Africa with longitudinal follow-up of mother-child pairs. High-resolution magnetic resonance imaging scans from 162 children (70 HEU; 92 HU) were acquired at 2-3 years of age. All HEU children were born to mothers taking antiretroviral therapy. Measures of brain structure (cortical thickness and surface area) in the prefrontal cortex regions were extracted from T1-weighted images and compared between groups using multivariate analysis of variance and linear regression. Child development, assessed using the Bayley Scales of Infant and Toddler Development-III, was correlated with cortical structure, and mediation analyses were performed. RESULTS: Analyses demonstrated an association between HIV exposure and cortical thickness across the prefrontal cortex (p = 0.035). Children who were HEU had thicker cortices in prefrontal regions, with significantly greater cortical thickness in the medial orbitofrontal cortex (mOFC) bilaterally compared to HU children (3.21 mm versus 3.14 mm, p = 0.009, adjusted effect size 0.44 [95% CI 0.12 to 0.75]). Estimates held across multiple sensitivity analyses. There were no group differences in cortical surface area. Language scores, which were lower in HEU versus HU children (81.82 versus 86.25, p = 0.011, effect size - 0.44 [95% CI - 0.78 to - 0.09]), negatively correlated with prefrontal cortical thickness in both groups. Cortical thickness in the mOFC mediated the relationship between HIV exposure and poor language outcomes (Sobel test p = 0.032). CONCLUSIONS: In this cohort study, exposure to HIV during pregnancy was associated with altered cortical structure in early life. Our findings indicate that differences in cortical thickness development in the prefrontal region in children who are HEU may be a pathway leading to language impairment. Longitudinal studies are needed to determine the lasting impact.

Risk factors for sustained virological non-suppression among children and adolescents living with HIV in Zimbabwe and Malawi: a secondary data analysis.

BACKGROUND: We investigated risk factors for sustained virological non-suppression (viral load ≥ 1000 copies/ml on two tests 48 weeks apart) among children and adolescents accessing HIV care in public sector clinics in Harare, Zimbabwe and Blantyre, Malawi. METHODS: Participants were enrolled between 2016 and 2019, were aged 6-19 years, living with HIV, had chronic lung disease (FEV z-score < -1) and had taken antiretroviral therapy (ART) for at least six months. We used multivariate logistic regression to identify risk factors for virological non-suppression after 48 weeks, among participants who were non-suppressed at enrolment. RESULTS: At enrolment 258 participants (64.6%) were on first-line ART and 152/347 (43.8%) had virological non-suppression. After 48 weeks 114/313 (36.4%) were non-suppressed. Participants non-suppressed at baseline had almost ten times higher odds of non-suppression at follow-up (OR = 9.9, 95%CI 5.3-18.4, p < 0.001). Of those who were non-suppressed at enrolment, 87/136 (64.0%) were still non-suppressed at 48 weeks. Among this group non-suppression at 48 weeks was associated with not switching ART regimen (adjusted OR = 5.55; 95%CI 1.41-21.83); p = 0.014) and with older age. Twelve participants switched regimen in Zimbabwe and none in Malawi. CONCLUSIONS: Viral non-suppression was high among this group and many with high viral load were not switched to a new regimen, resulting in continued non-suppression after 48 weeks. Further research could determine whether improved adherence counselling and training clinicians on regimen switches can improve viral suppression rates in this population. TRIAL REGISTRATION: Secondary cohort analysis of data from BREATHE trial (Clinicaltrials.gov NCT02426112 ).

ß-cell dysfunction and insulin resistance in relation to pre-diabetes and diabetes among adults in north-western Tanzania: a cross-sectional study.

OBJECTIVE: Studies on phenotypes of diabetes in Africa are inconsistent. We assessed the role of ß-cell dysfunction and insulin resistance on pre-diabetes and diabetes. METHODS: We included 1890 participants with mean age of 40.6 (SD11.9) years in a cross-sectional study among male and female adults in Tanzania during 2016 to 2017. Data on C-reactive protein (CRP), alpha-acid glycoprotein (AGP), HIV, oral glucose tolerance test (OGTT), body composition and insulin were collected. Insulinogenic index and HOMA-IR were used to derive an overall marker of ß-cell dysfunction and insulin resistance which was categorised as follows: normal ß-cell function and insulin sensitivity, isolated ß-cell dysfunction, isolated insulin resistance, and combined ß-cell dysfunction and insulin resistance. Pre-diabetes and diabetes were defined as 2-hour OGTT glucose between 7.8-11.0 and ≥ 11.1 mmol/L, respectively. Multinomial regression assessed the association of ß-cell dysfunction and insulin resistance with outcome measures. RESULTS: ß-cell dysfunction, insulin resistance, and combined ß-cell dysfunction and insulin resistance were associated with higher pre-diabetes risk. Similarly, isolated ß-cell dysfunction (adjusted relative risk ratio (aRRR) 4.8 (95% confidence interval (CI) 2.5, 9.0), isolated insulin resistance (aRRR 3.2 (95% CI 1.5, 6.9), and combined ß-cell dysfunction and insulin resistance (aRRR 35.9 (95% CI 17.2, 75.2) were associated with higher diabetes risk. CRP, AGP and HIV were associated with higher diabetes risk, but fat mass was not. 31%, 10% and 33% of diabetes cases were attributed to ß-cell dysfunction, insulin resistance, and combined ß-cell dysfunction and insulin resistance, respectively. CONCLUSIONS: ß-cell dysfunction seemed to explain most of diabetes cases compared to insulin resistance in this population. Cohort studies on evolution of diabetes in Africa are needed to confirm these results.

Prevalence and antimicrobial resistance profiles of respiratory microbial flora in African children with HIV-associated chronic lung disease.

BACKGROUND: HIV-associated chronic lung disease (CLD) is common among children living with HIV (CLWH) in sub-Saharan Africa, including those on antiretroviral therapy (ART). However, the pathogenesis of CLD and its possible association with microbial determinants remain poorly understood. We investigated the prevalence, and antibiotic susceptibility of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), and Moraxella catarrhalis (MC) among CLWH (established on ART) who had CLD (CLD+), or not (CLD-) in Zimbabwe and Malawi. METHODS: Nasopharyngeal swabs (NP) and sputa were collected from CLD+ CLWH (defined as forced-expiratory volume per second z-score < - 1 without reversibility post-bronchodilation with salbutamol), at enrolment as part of a randomised, placebo-controlled trial of azithromycin (BREATHE trial - NCT02426112 ), and from age- and sex-matched CLD- CLWH. Samples were cultured, and antibiotic susceptibility testing was conducted using disk diffusion. Risk factors for bacterial carriage were identified using questionnaires and analysed using multivariate logistic regression. RESULTS: A total of 410 participants (336 CLD+, 74 CLD-) were enrolled (median age, 15 years [IQR = 13-18]). SP and MC carriage in NP were higher in CLD+ than in CLD- children: 46% (154/336) vs. 26% (19/74), p = 0.008; and 14% (49/336) vs. 3% (2/74), p = 0.012, respectively. SP isolates from the NP of CLD+ children were more likely to be non-susceptible to penicillin than those from CLD- children (36% [53/144] vs 11% [2/18], p = 0.036). Methicillin-resistant SA was uncommon [4% (7/195)]. In multivariate analysis, key factors associated with NP bacterial carriage included having CLD (SP: adjusted odds ratio (aOR) 2 [95% CI 1.1-3.9]), younger age (SP: aOR 3.2 [1.8-5.8]), viral load suppression (SP: aOR 0.6 [0.4-1.0], SA: 0.5 [0.3-0.9]), stunting (SP: aOR 1.6 [1.1-2.6]) and male sex (SA: aOR 1.7 [1.0-2.9]). Sputum bacterial carriage was similar in both groups (50%) and was associated with Zimbabwean site (SP: aOR 3.1 [1.4-7.3], SA: 2.1 [1.1-4.2]), being on ART for a longer period (SP: aOR 0.3 [0.1-0.8]), and hot compared to rainy season (SP: aOR 2.3 [1.2-4.4]). CONCLUSIONS: CLD+ CLWH were more likely to be colonised by MC and SP, including penicillin-non-susceptible SP strains, than CLD- CLWH. The role of these bacteria in CLD pathogenesis, including the risk of acute exacerbations, should be further studied.

Incidence and Progression of Echocardiographic Abnormalities in Older Children with Human Immunodeficiency Virus and Adolescents Taking Antiretroviral Therapy: A Prospective Cohort Study.

BACKGROUND: A high prevalence of cardiac abnormalities has been reported in children with human immunodeficiency virus (HIV) taking antiretroviral therapy (ART) in sub-Saharan Africa. We investigated the incidence and progression of cardiac abnormalities among children taking ART in Zimbabwe. METHODS: A prospective cohort study was conducted at a pediatric HIV clinic from 2014 to 2017. Children with HIV aged between 6 and 16 years and taking ART ≥6 months were enrolled. Transthoracic echocardiography was performed at baseline and after 18 months. RESULTS: Of 197 participants recruited at baseline, 175 (89%; 48% female; median age 12 years, interquartile range 10-14 years) were followed up. The incidences of left and right heart abnormalities were 3.52 and 5.64 per 100 person-years, respectively. Stunting was associated with the development of any cardiac abnormality (adjusted odds ratio 2.59, 95% confidence interval 1.03-6.49; P = .043). Right ventricular (RV) dilatation persisted at follow-up in 92% of participants and left ventricular (LV) diastolic dysfunction in 88%. Cardiac abnormalities present at baseline reverted to normal over the follow-up period in 11 (6%). There was an overall increase in mean z scores for LV, left atrium (LA), RV, interventricular septum, and LV posterior wall diameters at 18 months (P < .001). CONCLUSIONS: Despite ART, children with HIV have a high incidence of cardiac abnormalities, with only a minority being transient. Mean z scores for LV, LA, RV, interventricular septum, and LV posterior wall diameters increased over a relatively short follow-up period, suggesting the potential for progression of cardiac abnormalities. Longer follow-up is required to understand the clinical implications of these abnormalities.

Neuroimaging young children and associations with neurocognitive development in a South African birth cohort study.

Magnetic resonance imaging (MRI) is an indispensable tool for investigating brain development in young children and the neurobiological mechanisms underlying developmental risk and resilience. Sub-Saharan Africa has the highest proportion of children at risk of developmental delay worldwide, yet in this region there is very limited neuroimaging research focusing on the neurobiology of such impairment. Furthermore, paediatric MRI imaging is challenging in any setting due to motion sensitivity. Although sedation and anesthesia are routinely used in clinical practice to minimise movement in young children, this may not be ethical in the context of research. Our study aimed to investigate the feasibility of paediatric multimodal MRI at age 2-3 years without sedation, and to explore the relationship between cortical structure and neurocognitive development at this understudied age in a sub-Saharan African setting. A total of 239 children from the Drakenstein Child Health Study, a large observational South African birth cohort, were recruited for neuroimaging at 2-3 years of age. Scans were conducted during natural sleep utilising locally developed techniques. T1-MEMPRAGE and T2-weighted structural imaging, resting state functional MRI, diffusion tensor imaging and magnetic resonance spectroscopy sequences were included. Child neurodevelopment was assessed using the Bayley-III Scales of Infant and Toddler Development. Following 23 pilot scans, 216 children underwent scanning and T1-weighted images were obtained from 167/216 (77%) of children (median age 34.8 months). Furthermore, we found cortical surface area and thickness within frontal regions were associated with cognitive development, and in temporal and frontal regions with language development (beta coefficient ≥0.20). Overall, we demonstrate the feasibility of carrying out a neuroimaging study of young children during natural sleep in sub-Saharan Africa. Our findings indicate that dynamic morphological changes in heteromodal association regions are associated with cognitive and language development at this young age. These proof-of-concept analyses suggest similar links between the brain and cognition as prior literature from high income countries, enhancing understanding of the interplay between cortical structure and function during brain maturation.

Chronic lung disease in children and adolescents with HIV: a case-control study.

OBJECTIVE: To describe the features of HIV-associated chronic lung disease (CLD) in older children and adolescents living with HIV and to examine the clinical factors associated with CLD. This is a post hoc analysis of baseline data from the BREATHE clinical trial (ClinicalTrials.gov, NCT02426112). METHODS: Children and adolescents aged 6-19 years were screened for CLD (defined as a FEV1 z-score <-1 with no reversibility post-bronchodilation with salbutamol) at two HIV clinics in Harare, Zimbabwe, and Blantyre, Malawi. Eligible participants with CLD (cases) were enrolled, together with a control group without CLD [frequency-matched by age group and duration on antiretroviral therapy (ART)] in a 4:1 allocation ratio. A clinical history and examination were undertaken. The association between CLD and a priori-defined demographic and clinical covariates was investigated using multivariable logistic regression. RESULTS: Of the 1585 participants screened, 419 (32%) had a FEV1 z-score <-1, of whom 347 were enrolled as cases [median age 15.3 years (IQR 12.7-17.7); 48.9% female] and 74 with FEV1 z-score >0 as controls [median age 15.6 years (IQR 12.1-18.2); 62.2% female]. Among cases, current respiratory symptoms including cough and shortness of breath were reported infrequently (9.3% and 1.8%, respectively). However, 152 (43.8%) of cases had a respiratory rate above the 90th centile for their age. Wasting and taking second-line ART were independently associated with CLD. CONCLUSIONS: The presence of CLD indicates the need to address additional treatment support for youth living with HIV, alongside ART provision, to ensure a healthier adulthood.

OBJECTIF: Décrire les caractéristiques de la maladie pulmonaire chronique (MPC) associée au VIH chez les enfants plus âgés et les adolescents vivant avec le VIH et examiner les facteurs cliniques associés à la MPC. Il s'agit d'une analyse post-hoc des données de référence de l'essai clinique BREATHE (ClinicalTrials.gov, NCT02426112 ). MÉTHODES: Les enfants et adolescents âgés de 6 à 19 ans ont été dépistés pour la MPC (défini comme un score z FEV1 <-1 sans réversibilité post-bronchodilatation avec du salbutamol) dans deux cliniques VIH à Harare, au Zimbabwe et à Blantyre, au Malawi. Les participants éligibles atteints de MPC (cas) ont été inscrits, ainsi qu'un groupe témoin sans MPC (fréquence appariée par groupe d'âge et durée sous ART) dans un rapport d'allocation de 4:1. Une histoire clinique et un examen ont été entrepris. L'association entre la MPC et les covariables démographiques et cliniques définies a priori a été étudiée en utilisant une régression logistique multivariable. RÉSULTATS: Sur les 1.585 participants dépistés, 419 (32%) avaient un score z FEV 1 <-1, dont 347 étaient inscrits comme cas (âge médian 15,3 ans [IQR 12,7 -17,7]; 48,9% de sexe féminin), et 74 avec un score z FEV1 >0 comme témoins (âge médian 15,6 ans [IQR 12,1 -18,2]; 62,2% de sexe féminin). Parmi les cas, les symptômes respiratoires en cours, y compris la toux et l'essoufflement, n'ont pas été rapportés fréquemment (9,3% et 1,8%, respectivement). Cependant, 152 (43,8%) des cas avaient une fréquence respiratoire supérieure au 90e centile pour leur âge. L'émaciation et la prise d'un traitement antirétroviral (ART) de deuxième intention étaient indépendamment associées à la MPC. CONCLUSIONS: La présence de MPC indique la nécessité d'un soutien thérapeutique supplémentaire aux jeunes vivant avec le VIH, à côté de à la fourniture de l'ART, pour assurer un âge adulte en meilleure santé.

The impact of common mental disorders among caregivers living with HIV on child cognitive development in Zimbabwe.

This paper aimed to assess the impact of maternal common mental disorders (CMD) among caregivers living with HIV on the cognitive functioning of their child. Data were collected at baseline and 12 months follow-up from mother-child dyads recruited as part of an ongoing trial in Zimbabwe. Symptoms of CMD were assessed using the Shona Symptom Questionnaire. Mixed-effects linear regression was used to assess child cognitive scores at follow-up (using the Mullen Scales of Early Learning) in relation to caregiver CMD prevalence over 12 months. At baseline, caregivers reporting CMD (n = 230; 40.1%) were less likely to have completed higher education (46.9% vs. 56.9%; p = 0.02), more likely to be unmarried (27.8% vs. 16.0%; p < 0.01), and experience food insecurity (50.0% vs. 29.4%; p < 0.01) compared to the group without CMD (n = 344). There were 4 CMD patterns over time: (i) Emerging CMD (n = 101; 19.7% of caregivers) defined as those who were below the cut-off at baseline, and above it at 12 months; (ii) Improving CMD (n = 76; 14.8%) defined as those who reported CMD at baseline, and were below the cut-off by follow-up; (iii) No CMD (n = 206; 40.1%) defined as those who did not report CMD symptoms at either time point; and (iv) Chronic CMD (n = 131; 25.5%) defined as those who reported CMD above the cut-off at both time points. Children of caregivers with chronic CMD (n = 131, 25.5%) had lower receptive language scores (aMD:-2.81, 95%CI -5.1 to -0.6; p = 0.05) compared to the reference group with no CMD (n = 206, 40.1%). Exposure to caregiver CMD over a prolonged period may affect child receptive vocabulary skills.

Validation of the global lung initiative 2012 multi-ethnic spirometric reference equations in healthy urban Zimbabwean 7-13 year-old school children: a cross-sectional observational study.

BACKGROUND: The 2012 Global Lung Function Initiative (GLI2012) provide multi-ethnic spirometric reference equations (SRE) for the 3-95 year-old age range, but Sub-Saharan African populations are not represented. This study aimed to evaluate the fit of the African-American GLI2012 SRE to a population of healthy urban and peri-urban Zimbabwean school-going children (7-13 years). METHODS: Spirometry and anthropometry were performed on black-Zimbabwean children recruited from three primary schools in urban and peri-urban Harare, with informed consent and assent. Individuals with a history or current symptoms of respiratory disease or with a body mass index-z score (BMI) < - 2 were excluded. Spirometry z-scores were generated from African-American GLI2012 SRE, which adjust for age, sex, ethnicity and height, after considering all GLI2012 modules. Anthropometry z-scores were generated using the British (1990) reference equations which adjust for age and sex. The African-American GLI2012 z-score distribution for the four spirometry measurements (FVC, FEV1, FEV1/FVC and MMEF) were evaluated across age, height, BMI and school (as a proxy for socioeconomic status) to assess for bias. Comparisons between the African-American GLI2012 SRE and Polgar equations (currently adopted in Zimbabwe) on the percent-predicted derived values were also performed. RESULTS: The validation dataset contained acceptable spirometry data from 712 children (344 girls, mean age: 10.5 years (SD 1.81)). The spirometry z-scores were reasonably normally distributed, with all means lower than zero but within the range of ±0.5, indicating a good fit to the African-American GLI2012 SRE. The African-American GLI2012 SRE produced z-scores closest to a normal distribution. Z-scores of girls deviated more than boys. Weak correlations (Pearson's correlation coefficient < 0.2) were observed between spirometry and anthropometry z-scores, and scatterplots demonstrated no systematic bias associated with age, height, BMI or socioeconomic status. The African-American GLI2012 SRE provided a better fit for Zimbabwean paediatric spirometry data than Polgar equations. CONCLUSION: The use of African-American GLI2012 SRE in this population could help in the interpretation of pulmonary function tests.

Incidence of maternal peripartum infection: A systematic review and meta-analysis.

BACKGROUND: Infection is an important, preventable cause of maternal morbidity, and pregnancy-related sepsis accounts for 11% of maternal deaths. However, frequency of maternal infection is poorly described, and, to our knowledge, it remains the one major cause of maternal mortality without a systematic review of incidence. Our objective was to estimate the average global incidence of maternal peripartum infection. METHODS AND FINDINGS: We searched Medline, EMBASE, Global Health, and five other databases from January 2005 to June 2016 (PROSPERO: CRD42017074591). Specific outcomes comprised chorioamnionitis in labour, puerperal endometritis, wound infection following cesarean section or perineal trauma, and sepsis occurring from onset of labour until 42 days postpartum. We assessed studies irrespective of language or study design. We excluded conference abstracts, studies of high-risk women, and data collected before 1990. Three reviewers independently selected studies, extracted data, and appraised quality. Quality criteria for incidence/prevalence studies were adapted from the Joanna Briggs Institute. We used random-effects models to obtain weighted pooled estimates of incidence risk for each outcome and metaregression to identify study-level characteristics affecting incidence. From 31,528 potentially relevant articles, we included 111 studies of infection in women in labour or postpartum from 46 countries. Four studies were randomised controlled trials, two were before-after intervention studies, and the remainder were observational cohort or cross-sectional studies. The pooled incidence in high-quality studies was 3.9% (95% Confidence Interval [CI] 1.8%-6.8%) for chorioamnionitis, 1.6% (95% CI 0.9%-2.5%) for endometritis, 1.2% (95% CI 1.0%-1.5%) for wound infection, 0.05% (95% CI 0.03%-0.07%) for sepsis, and 1.1% (95% CI 0.3%-2.4%) for maternal peripartum infection. 19% of studies met all quality criteria. There were few data from developing countries and marked heterogeneity in study designs and infection definitions, limiting the interpretation of these estimates as measures of global infection incidence. A limitation of this review is the inclusion of studies that were facility-based or restricted to low-risk groups of women. CONCLUSIONS: In this study, we observed pooled infection estimates of almost 4% in labour and between 1%-2% of each infection outcome postpartum. This indicates maternal peripartum infection is an important complication of childbirth and that preventive efforts should be increased in light of antimicrobial resistance. Incidence risk appears lower than modelled global estimates, although differences in definitions limit comparability. Better-quality research, using standard definitions, is required to improve comparability between study settings and to demonstrate the influence of risk factors and protective interventions.

Risk and protective factors for child development: An observational South African birth cohort.

BACKGROUND: Approximately 250 million (43%) children under the age of 5 years in low- and middle-income countries (LMICs) are failing to meet their developmental potential. Risk factors are recognised to contribute to this loss of human potential. Expanding understanding of the risks that lead to poor outcomes and which protective factors contribute to resilience in children may be critical to improving disparities. METHODS AND FINDINGS: The Drakenstein Child Health Study is a population-based birth cohort in the Western Cape, South Africa. Pregnant women were enrolled between 20 and 28 weeks' gestation from two community clinics from 2012 to 2015; sociodemographic and psychosocial data were collected antenatally. Mothers and children were followed through birth until 2 years of age. Developmental assessments were conducted by trained assessors blinded to background, using the Bayley-III Scales of Infant and Toddler Development (BSID-III), validated for use in South Africa, at 24 months of age. The study assessed all available children at 24 months; however, some children were not able to attend, because of loss to follow-up or unavailability of a caregiver or child at the correct age. Of 1,143 live births, 1,002 were in follow-up at 24 months, and a total of 734 children (73%) had developmental assessments, of which 354 (48.2%) were girls. This sample was characterised by low household employment (n = 183; 24.9%) and household income (n = 287; 39.1% earning 1 domain affected, and 75 (10.2%) had delay in all domains. Bivariate and multivariable analyses revealed several factors that were associated with developmental outcomes. These included protective factors (maternal education, higher birth weight, and socioeconomic status) and risk factors (maternal anaemia in pregnancy, depression or lifetime intimate partner violence, and maternal HIV infection). Boys consistently performed worse than girls (in cognition [ß = -0.74; 95% CI -1.46 to -0.03, p = 0.042], receptive language [ß = -1.10; 95% CI -1.70 to -0.49, p < 0.001], expressive language [ß = -1.65; 95% CI -2.46 to -0.84, p < 0.001], and fine motor [ß = -0.70; 95% CI -1.20 to -0.20, p = 0.006] scales). There was evidence that child sex interacted with risk and protective factors including birth weight, maternal anaemia in pregnancy, and socioeconomic factors. Important limitations of the study include attrition of sample from birth to assessment age and missing data in some exposure areas from those assessed. CONCLUSIONS: This study provides reliable developmental data from a sub-Saharan African setting in a well-characterised sample of mother-child dyads. Our findings highlight not only the important protective effects of maternal education, birth weight, and socioeconomic status for developmental outcomes but also sex differences in developmental outcomes and key risk and protective factors for each group.

Unhealthy Snack Food and Beverage Consumption Is Associated with Lower Dietary Adequacy and Length-for-Age z-Scores among 12-23-Month-Olds in Kathmandu Valley, Nepal.

BACKGROUND: Consumption of unhealthy snack foods and beverages (USFBs) in low- and middle-income countries (LMICs) is rising, with global awareness increasing about risks of overnutrition. However, little is known about the relation between USFB consumption and young children's diet/nutritional outcomes in contexts where nutrient density of complementary foods is often low. OBJECTIVES: This study assessed the association of high USFB consumption, compared with low consumption, with nutrient intakes, dietary adequacy, iron status, and growth in young children in Kathmandu Valley, Nepal. METHODS: A cross-sectional survey was conducted in a representative sample of 745 primary caregivers of children aged 12-23 mo. Food consumption was measured through quantitative 24-h recalls, and child anthropometric measurements and capillary blood samples were collected. Using adjusted linear/logistic regression models, nutrient intakes, dietary adequacy, length-for-age and weight-for-length z-scores (LAZ and WLZ, respectively), and iron status were compared between lowest and highest tertiles of consumption based on the contribution of USFBs to total energy intakes (TEIs). Mediation of the relation between USFB consumption and LAZ via lowered dietary adequacy was explored using structural equations modeling. RESULTS: On average, USFBs contributed 46.9% of TEI among the highest tertile of consumers, compared with 5.2% of TEI among the lowest. Compared with low-USFB consumers, high-USFB consumers had lower nutrient intakes and a greater proportion were at risk of inadequate intakes for 8 nutrients. Mean LAZ was nearly 0.3 SD lower among high-USFB consumers than low consumers (P = 0.003), with this relationship partially mediated through dietary adequacy. No associations were found with stunting prevalence or iron status. Prevalence of overweight/obesity was low. CONCLUSIONS: In this LMIC context, high USFB consumption among young children was associated with inadequate micronutrient intakes, which can contribute to poor growth outcomes. Addressing increased availability of USFBs in LMIC food systems should be a priority for policies and programs aiming to safeguard child nutrition.

Intermittent preventive treatment of malaria delivered to primary schoolchildren provided effective individual protection in Jinja, Uganda: secondary outcomes of a cluster-randomized trial (START-IPT).

BACKGROUND: Intermittent preventive treatment (IPT) of malaria is recommended as policy for certain high-risk populations, but not currently for schoolchildren. A cluster-randomized trial was conducted to evaluate the effect of IPT with dihydroartemisinin-piperaquine (DP) on primary schoolchildren in Jinja, Uganda. Results of the impact of IPT of schoolchildren on community-level transmission have been reported previously. Here, secondary outcomes from a school-based survey are presented. METHODS: Eighty-four clusters (one primary school plus 100 households) were randomized to intervention and control (1:1 ratio). Participants from intervention schools received monthly IPT with DP for up to 6 rounds (June-December 2014). At endline (November-December 2014), randomly selected children from all 84 schools were surveyed (13 per school) and thick blood smears were done. Those with fever or history of fever were tested with rapid diagnostic tests (RDTs) for malaria. Haemoglobin was measured in every fifth participant. Outcome measures included prevalence of asexual parasites and gametocytes (by microscopy), and prevalence of anaemia. Prevalence outcomes were analysed using generalized linear Poisson models with log link function, incorporating a cluster-level random intercept and quantified using prevalence risk ratios. RESULTS: Among 23,280 students listed on the 42 intervention school registers, 10,079 (43.3%) aged 5-20 years were enrolled into the IPT intervention and received at least one dose of DP; of these, 9286 (92.1%) received at least one full (3-day) course. In total, 1092 children were enrolled into the final school survey (546 per arm) and had a thick blood smear done; of these, 255 had haemoglobin measured (129 intervention, 126 control). Children in the intervention arm were less likely to have asexual parasites (9.2% intervention vs 44.1% control, adjusted risk ratio [aRR] 0.22 [95% CI 0.16-0.30] p < 0.001), gametocytes (3.1% intervention vs 9.5% control, aRR 0.34 [95% CI 0.20-0.56] p < 0.001), fever (20.2% intervention vs 56.2% control, aRR 0.35 [95% CI 0.25-0.50] p < 0.001), or symptomatic malaria (5.1% intervention vs 35.7% control, aRR 0.14 [95% CI 0.08-0.26] p < 0.001). Prevalence of anaemia and mean haemoglobin were similar in both study arms. CONCLUSIONS: School-aged children are a major reservoir of malaria parasites. Delivering IPT to schoolchildren would benefit individual children and may reduce transmission. School-based IPT could help to intensify malaria control toward elimination, and should be considered for policies and programmes. Trial registration Clinicaltrials.gov (NCT02009215), Registered 11 December 2013. https://clinicaltrials.gov/ct2/show/NCT02009215.

Energy intake from unhealthy snack food/beverage among 12-23-month-old children in urban Nepal.

Unhealthy snack food and beverage (USFB) consumption among young children has been noted in many low-income and middle-income countries (LMIC), however, there is a lack of information on the contribution of these foods to children's diets in these contexts. This study describes the nutrient profiles and costs of snacks consumed by young children in Kathmandu Valley, Nepal, and assesses the proportion of total energy intake from nonbreastmilk foods (%TEI-NBF) contributed by USFB and factors associated with high USFB consumption. A cross-sectional survey was conducted among 745 randomly sampled primary caregivers of children aged 12-23 months. Of 239 unique snack foods and beverages consumed, 180 (75.3%) were classified as unhealthy based on nutrient profiling, with 158 of these being commercially branded. Median cost/100 kcal of USFB was lower as compared with healthy snacks. Ninety-one percent of children had consumed a USFB in the previous 24 hr, with these foods contributing a mean %TEI-NBF of 24.5 ± 0.7 among all children. Biscuits (10.8%), candy/chocolate (3.5%), and savoury snacks (3.4%) provided the largest %TEI-NBF. Children who were older, female, or from the poorest households had significantly higher odds of high USFB consumption, whereas children whose caregivers were of upper caste/ethnicity or had achieved tertiary education had lower odds of consumption than other children. To reduce USFB consumption, interventions should seek to further understand social/cultural drivers of feeding practices, target disadvantaged populations, and ensure caregivers are fully aware of the nutritional quality of food products they choose for their children.

Comparison of an interactive 24-h recall and weighed food record for measuring energy and nutrient intakes from complementary foods among 9-10-month-old Malawian infants consuming lipid-based nutrient supplements.

Fortifying complementary foods with lipid-based nutrient supplements (LNS) may improve energy and nutrient intakes of infants at risk for undernutrition. We aimed to determine the relative validity of an interactive 24-h recall (i-24-HR) for assessing the impact of an LNS intervention on dietary intakes of energy and nutrients among rural Malawian 9-10-month-old infants (n 132) participating in the International Lipid-Based Nutrient Supplements Dose (iLiNS-DOSE) trial. Dietary data were collected for the same day via i-24-HR and weighed food records. Inter-method agreements were estimated overall and by intervention group, using Bland-Altman plots and paired t tests; measurement error models (differential error); and percentage of food omissions and intrusions were estimated. Overall, inter-method differences in mean intakes of energy and most nutrients were not significant. When stratified by group, recalled energy intakes were under-estimated (-368 kJ; P=0·01) in the control but not in the intervention group (-42 kJ; P=0·6). This differential reporting error was related to an over-estimation of recalled LNS (8·1 v. 4·5 g; P30 % eating occasions) omissions were milk/fish/eggs, starchy roots/vegetables and sweetened snacks. Common intrusions were milk/yogurt. Starchy staples and LNS were recalled when consumed (>85 %) (i.e. matched). These results emphasise the importance of considering differential error when interpreting dietary results in LNS trials.

Racial Variation in Echocardiographic Reference Ranges for Left Chamber Dimensions in Children and Adolescents: A Systematic Review.

Echocardiography plays a critical role in the assessment of cardiac disease. Important differences in echocardiographically derived cardiac chamber dimensions have been previously highlighted in different population groups in adult studies, but this has not been systematically studied in children, whose body size changes throughout childhood. The aim of this study was to review the distribution of available reference ranges for the left cardiac chamber dimensions in older children and adolescents. The following electronic data bases were searched: Medline, Embase and Web of Science were searched to identify studies which have established echocardiographic reference ranges of left heart parameters in children and adolescents from 1975 to December 2017. There was no geographical limitation. All results were imported into Endnote. Retrieved articles were screened and data extracted by two independent reviewers. A total of 4398 studies were retrieved, with 36 studies finally included in this review. 29 (81%) references were from North America and European (Caucasians) populations, with only one study each from Africa and South America. Two-dimensional and M-mode techniques were the most commonly used echocardiography techniques. There were methodological variations in techniques and normalisation of references. Comparison of selected cardiac measures showed significant differences for interventricular septal thickness among Black African, Indian, German and US American children. Available echocardiographic references cannot be generalised to all settings and therefore, there is need for locally relevant reference ranges. Africa and South America are particularly under-represented. Future studies should focus on developing comprehensive echocardiographic reference ranges for children from different racial backgrounds and should use standardised techniques.

Lipid-Based Nutrient Supplements Increase Energy and Macronutrient Intakes from Complementary Food among Malawian Infants.

BACKGROUND: Low intakes of good-quality complementary foods (CFs) contribute to undernutrition and consequently negatively affect health, growth, and development. Lipid-based nutrient supplements (LNSs) are designed to ensure dietary adequacy in micronutrients and essential fatty acids and to provide some energy and high-quality protein. In populations in which acute energy deficiency is rare, the dose-dependent effect of LNSs on CF intakes is unknown. OBJECTIVE: The objective of this study was to evaluate the difference in energy and macronutrient intakes from CF between a control (no supplement) group and 3 groups that received 10, 20, or 40 g LNS/d. METHODS: We collected repeated interactive 24-h dietary recalls from caregivers of rural Malawian 9- to 10-mo-old infants (n = 748) to estimate dietary intakes (LNS and all non-breast-milk foods) of energy and macronutrients and their dietary patterns. All infants were participating in a 12-mo randomized controlled trial to investigate the efficacy of various doses of LNS for preventing undernutrition. RESULTS: Dietary energy intakes were significantly higher among infants in the LNS intervention groups than in the control group (396, 406, and 388 kcal/d in the 10-, 20-, and 40-g LNS/d groups, respectively, compared with 345 kcal/d; each pairwise P < 0.05), but no significant differences were found in energy intakes between groups who were administered the different LNS doses (10 g LNS/d compared with 20 g LNS/d: P = 0.72; 10 g LNS/d compared with 40 g LNS/d: P ≥ 0.67; 20 g LNS/d compared with 40 g LNS/d: P = 0.94). Intakes of protein and fat were significantly higher in the LNS intervention groups than in the control group. No significant intergroup differences were found in median intakes of energy from non-LNS CFs (357, 347, and 296 kcal/d in the 10-, 20-, and 40-g LNS/d groups, respectively, compared with 345 kcal/d in the control group; P = 0.11). CONCLUSION: LNSs in doses of 10-40 g/d increase intakes of energy and macronutrients among 9- to 10-mo-old Malawian infants, without displacing locally available CFs. This trial was registered at clinicaltrials.gov as NCT00945698.

Risk factors for mortality among malnourished HIV-infected adults eligible for antiretroviral therapy.

BACKGROUND: A substantial proportion of HIV-infected adults starting antiretroviral therapy (ART) in sub-Saharan Africa are malnourished. We aimed to increase understanding of the factors affecting their high mortality, particularly in the high-risk period before ART initiation. METHODS: We analysed potential risk factors for mortality of Zambian and Tanzanian participants enrolled in the NUSTART clinical trial. Malnourished adults (n = 1815; body mass index [BMI] <18.5 kg/m2) were recruited at referral to ART and randomised to receive different nutritional supplements. Demographics, measures of body composition, blood electrolytes and clinical conditions were investigated as potential risk factors using Poisson regression models. RESULTS: The mortality rate was higher in the period from referral to starting ART (121 deaths/100 person-years; 95 % CI 103, 142) than during the first 12 weeks of ART (66; 95 % CI 57, 76) and was not affected by trial study arm. In adjusted analyses, lower CD4 count, BMI and mid-arm circumference and raised C-reactive protein were associated with an increased risk of mortality throughout the study. Male sex and lower hand-grip strength carried an increased risk in the pre-ART period. Participants on tuberculosis treatment at referral had a lower mortality rate (adjusted Rate Ratio 0.44; 95 % CI 0.31, 0.63). CONCLUSION: Among malnourished ART-eligible adults, pre-ART mortality was twice that in the early post-ART period, suggesting many early ART deaths represent advanced HIV disease rather than treatment-related events. Therefore, more efforts are needed to promote earlier diagnosis and immediate initiation of ART, as recently recommended by WHO for all persons with HIV worldwide. The positive effect of tuberculosis treatment suggests undiagnosed tuberculosis is a contributor to mortality in this population. TRIAL REGISTRATION: Pan African Clinical Trials Registry, PACTR201106000300631 ; registered on 1st June 2011.

A Randomized Trial to Compare the Safety, Tolerability, and Effectiveness of 3 Antimalarial Regimens for the Prevention of Malaria in Nigerian Patients With Sickle Cell Disease.

BACKGROUND: Malaria prophylaxis is recommended for persons with sickle cell disease (SCD), but the value of this has been questioned. The aim of this study was to find out whether intermittent preventive treatment (IPT) with a fixed-dose combination of mefloquine-artesunate (MQAS) or sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) was more effective than daily proguanil for malaria prevention in subjects with SCD. METHODS: Patients with SCD were randomized to receive daily treatment with proguanil or IPT with either MQAS or SPAQ once every 2 months at routine clinic visits. Patients were followed up for 14 months. FINDINGS: A total of 270 patients with SCD were studied, with 90 in each group. Adherence to the IPT regimens was excellent, but 57% of patients took <75% of their daily doses of proguanil. IPT was well tolerated; the most common side effects were vomiting and abdominal pain. Protective efficacy against malaria, compared with daily proguanil, was 61% (95% confidence interval, 3%-84%) for MQAS and 36% (40%-70%) for SPAQ. There were fewer outpatient illness episodes in children who received IPT than those who received proguanil. CONCLUSIONS: IPT with MQAS administered to patients with SCD during routine clinic visits was well tolerated and more effective in preventing malaria than daily prophylaxis with proguanil. CLINICAL TRIALS REGISTRATION: NCT01319448 and ISRCTN46158146.

Effects on mortality of a nutritional intervention for malnourished HIV-infected adults referred for antiretroviral therapy: a randomised controlled trial.

BACKGROUND: Malnourished HIV-infected African adults are at high risk of early mortality after starting antiretroviral therapy (ART). We hypothesized that short-course, high-dose vitamin and mineral supplementation in lipid nutritional supplements would decrease mortality. METHODS: The study was an individually-randomised phase III trial conducted in ART clinics in Mwanza, Tanzania, and Lusaka, Zambia. Participants were 1,815 ART-naïve non-pregnant adults with body mass index (BMI) <18.5 kg/m² who were referred for ART based on CD4 count <350 cells/µL or WHO stage 3 or 4 disease. The intervention was a lipid-based nutritional supplement either without (LNS) or with additional vitamins and minerals (LNS-VM), beginning prior to ART initiation; supplement amounts were 30 g/day (150 kcal) from recruitment until 2 weeks after starting ART and 250 g/day (1,400 kcal) from weeks 2 to 6 after starting ART. The primary outcome was mortality between recruitment and 12 weeks of ART. Secondary outcomes were serious adverse events (SAEs) and abnormal electrolytes throughout, and BMI and CD4 count at 12 weeks ART. RESULTS: Follow-up for the primary outcome was 91%. Median adherence was 66%. There were 181 deaths in the LNS group (83.7/100 person-years) and 184 (82.6/100 person-years) in the LNS-VM group (rate ratio (RR), 0.99; 95% CI, 0.80-1.21; P = 0.89). The intervention did not affect SAEs or BMI, but decreased the incidence of low serum phosphate (RR, 0.73; 95% CI, 0.55-0.97; P = 0.03) and increased the incidence of high serum potassium (RR, 1.60; 95% CI, 1.19-2.15; P = 0.002) and phosphate (RR, 1.23; 95% CI, 1.10-1.37; P <0.001). Mean CD4 count at 12 weeks post-ART was 25 cells/µL (95% CI, 4-46) higher in the LNS-VM compared to the LNS arm (P = 0.02). CONCLUSIONS: High-dose vitamin and mineral supplementation in LNS, compared to LNS alone, did not decrease mortality or clinical SAEs in malnourished African adults initiating ART, but improved CD4 count. The higher frequency of elevated serum potassium and phosphate levels suggests high-level electrolyte supplementation for all patients is inadvisable but the addition of micronutrient supplements to ART may provide clinical benefits in these patients. TRIAL REGISTRATION: PACTR201106000300631, registered on 1st June 2011.