Neurodevelopment in preschool children exposed and unexposed to Zika virus in utero in Nicaragua: a prospective cohort study.

BACKGROUND: Data on long-term neurodevelopmental outcomes of normocephalic children (born with normal head circumference) exposed to Zika virus in utero are scarce. We aimed to compare neurodevelopmental outcomes in normocephalic children up to age 48 months with and without Zika virus exposure in utero. METHODS: In this prospective cohort study, we included infants from two cohorts of normocephalic children born in León and Managua, Nicaragua during the 2016 Zika epidemic. In León, all women pregnant during the two enrolment periods were eligible. In Managua, mother-child pairs were included from three districts in the municipality of Managua: all women who became pregnant before June 15, 2016, and had a due date of Sept 15, 2016 or later were eligible. Infants were serologically classified as Zika virus-exposed or Zika virus-unexposed in utero and were followed up prospectively until age 48 months. At 36 months and 48 months of age, the Mullen Scales of Early Learning (MSEL) assessment was administered. Primary outcomes were MSEL early learning composite (ELC) scores at 30-48 months in León and 36-48 months in Managua. We used an inverse probability weighting generalised estimating equations model to assess the effect of Zika virus exposure on individual MSEL cognitive domain scores and ELC scores, adjusted for maternal education and age, poverty status, and infant sex. FINDINGS: The initial enrolment period for the León cohort was between Jan 31 and April 5, 2017 and the second was between Aug 30, 2017, and Feb 22, 2018. The enrolment period for the Managua cohort was between Oct 24, 2019, and May 5, 2020. 478 mothers (482 infants) from the León cohort and 615 mothers (609 infants) from the Managua cohort were enrolled, of whom 622 children (303 from the León cohort; 319 from the Managua cohort) were included in the final analysis; four children had microcephaly at birth and thus were excluded from analyses, two from each cohort. 33 (11%) of 303 children enrolled in León and 219 (69%) of 319 children enrolled in Managua were exposed to Zika virus in utero. In both cohorts, no significant differences were identified in adjusted mean ELC scores between Zika virus-exposed and unexposed infants at 36 months (between-group difference 1·2 points [95% CI -4·2 to 6·5] in the León cohort; 2·8 [-2·4 to 8·1] in the Managua cohort) or at 48 months (-0·9 [-10·8 to 8·8] in the León cohort; 0·1 [-5·1 to 5·2] in the Managua cohort). No differences in ELC scores between Zika virus-exposed and unexposed infants exceeded 6 points at any time between 30 months and 48 months in León or between 36 months and 48 months in Managua, which was considered clinically significant in other settings. INTERPRETATION: We found no significant differences in neurodevelopmental scores between normocephalic children with in-utero Zika virus exposure and Zika virus-unexposed children at age 36 months or 48 months. These findings are promising, supporting typical neurodevelopment in Zika virus-exposed normocephalic children, although additional follow-up and research is warranted. FUNDING: National Institute of Child Health and Development, National Institute of Allergy and Infectious Diseases, and Fogarty International Center. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Is Neurodevelopmental Assessment in Early Childhood Predictive of Performance Assessed Later in Childhood and Adolescence in Sub-Saharan Africa? A Systematic Review of the Literature.

BACKGROUND: Most neurodevelopmental tests used to assess child development in sub-Saharan Africa were developed in western or high-income countries, raising the question of their usefulness with African children. OBJECTIVE: This systematic review identified and synthesized key findings from studies measuring development in children in Sub-Saharan Africa in early childhood and again at school age, to assess neurocognitive associations longitudinally from infancy through middle childhood. METHODS: The study was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method, selecting articles referenced in the PubMed, PsycInfo, and Embase databases using the following inclusion criteria: published between 2000 and 2022, written in French or English, and presenting results dealing with the objective assessment of child's neurodevelopment. All articles were registered in the Zotero reference manager and analyzed by title, abstract, and full text. RESULTS: Several of the seven selected studies confirmed that attention and working memory in infancy can predict children's neurocognitive performance, including mathematical ability, at school age. In two of the studies, children with poor mental development at 1 year of age are more likely to present with poorer behavioral development at school age, including learning difficulties in school and risk for grade repetition. CONCLUSION: Cognitive ability assessed in early childhood is strongly associated with performance at school age in cohorts of African children followed longitudinally. Even with assessments adapted cross-culturally, infants and preschoolers at risk for poor developmental outcomes can be identified to better receive strategic early interventions to enhance their development.

Attention Test Assessment from a Cluster Randomized Controlled Trial of Caregiver Training for Ugandan Preschool Children Living with Perinatal HIV.

Fifty-six Ugandan mothers/caregivers received Mediational Intervention for Sensitizing Caregivers (MISC) biweekly for one year; 46 mothers received treatment-as-usual. Preschool PHIV child attention was measured by proportion of time viewing a 7-min animation (early childhood vigilance test or ECVT) at enrollment, 6 and 12 months. Analysis of covariance compared ECVT outcomes for the two intervention groups, controlling for baseline ECVT performance, age and weight-for-age z scores. Differences by trial arm were not significant at any of the three time points. MISC trial-arm children on combination ART during the study period displayed more stable ECVT scores across time points compared to controls.

Caregivers' Perspective on the Psychological Burden of Living with Children Affected by Sickle Cell Disease in Kinshasa, the Democratic Republic of Congo.

There is limited information on knowledge, perceptions, and management of sickle cell disease (SCD) in Africa in general and in the Democratic Republic of the Congo (DRC) in particular. This study explored knowledge, perceptions, and burden of 26 parents/caregivers of children with SCD in three selected hospitals in Kinshasa, DRC. We conducted a focus group with in-depth interviews with parents/caregivers of children affected with SCD. Four themes were discussed, including knowledge and perceptions, diagnosis and management, society's perceptions, and the psychosocial burden and the quality of life of the family affected by SCD. The majority of participants/caregivers felt that society, in general, had negative perceptions of, attitudes toward, and knowledge about SCD. They reported that children with sickle cell are often marginalized, ignored, and excluded from society or school. They face a number of challenges related to care, management, financial difficulties, and a lack of psychological support. The results suggest the need to promote measures and strategies to improve knowledge and management of SCD in Kinshasa, DRC.

Early Antiretroviral Therapy Reduces Severity but Does Not Eliminate Neurodevelopmental Compromise in Children With HIV.

BACKGROUND: Early antiretroviral therapy (ART) during infancy reduces cognitive impairment due to HIV, but the extent of benefit is unclear. SETTING: Children were recruited from hospital and health centers providing HIV care and treatment in Nairobi, Kenya. METHODS: Cognitive, behavioral, and motor outcomes were assessed in children with HIV and early ART (<1 year), children with HIV and late ART (1.5-6 years), and children HIV-unexposed uninfected (CHUU). Domain z scores and odds neurobehavioral impairment (≤15th percentile in CHUU) were compared in adjusted analyses. RESULTS: Children with HIV initiated ART at median ages 0.4 (early ART) and 3.5 years (late ART). Children were assessed at median ages 6.9 (CHUU, N = 61), 6.9 (early ART, N = 54), and 13.5 (late ART; N = 27) years. Children with late ART vs. children with early ART had significantly lower z scores in 7 domains, specifically global cognition, short-term memory, visuospatial processing, learning, nonverbal test performance, executive function, and motor skills (adjusted mean differences, -0.42 to -0.62, P values ≤ 0.05), and had higher odds impairment in 7 domains (adjusted odds ratios [aORs], 2.87 to 16.22, P values ≤ 0.05). Children with early ART vs. CHUU had lower z scores in 5 domains (global cognition, short-term memory, delayed memory, processing speed, and behavioral regulation [adjusted mean differences, -0.32 to -0.88, P values < 0.05]) and higher impairment for 2 domains (short-term memory [aOR, 3.88] and behavioral regulation [aOR 3.46], P values < 0.05). Children with late ART vs. CHUU had lower z scores in 8 domains (adjusted mean differences, -0.57 to -1.05, P values ≤ 0.05), and higher impairment in 7 domains (aORs 1.98 to 2.32, P values ≤ 0.05). CONCLUSION: Early ART in the first year of life attenuates but does not eliminate the neurodevelopmental compromise of HIV.

Predictive validation of Ugandan infant eye-tracking test for memory of human faces.

We provide initial evidence that an eye-tracking based measure of infant attention and working memory (gaze preference for novel human faces) can predict aspects of neurocognitive performance years later among Ugandan children. 49 HIV-exposed/uninfected Ugandan children (22 boys, 27 girls) 6-12 months old were tested with the Mullen Scales of Early Learning and a modified Fagan Test of Infant Intelligence (FTII). Modified FTII measures pertaining to attention are correlated to the KABC-II Mental Processing Index (MPI) (rp = -0.40), p Cognitive assessments adapted to eye-tracking instrumentation can be useful to evaluate attention and working memory in HIV-affected children living in low- and middle-income countries.

Antiretroviral choice and severe disease predict poorer neuropsychological outcomes in HIV+ children from Africa.

Background: The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1104s study evaluated neuropsychological outcomes over 96 weeks in children living with HIV (CLHIV) aged 5-11 years at 6 Sub-Saharan African sites to explore associations between HIV-illness related biomarkers and neuropsychological outcomes. Methods: Children living with HIV had participated in IMPAACT P1060, which compared efficacy of nevirapine versus lopinavir/ritonavir in children initiating ART at <3 years of age. At age 5-11, neuropsychological evaluations of KABC cognitive ability, TOVA attention-impulsivity and BOT-2 motor domains were assessed and repeated after 48 and 96 weeks. Clinical, antiretroviral therapy (ART) and laboratory (immunological and virological) parameters were used to predict neuropsychological outcomes using linear mixed-effects multivariable regression models, controlling for child and caregiver characteristics. Results: 246 CLHIV (45% male, mean age at initial neuropsychological evaluation 7.1 yrs [SD 1.2]) began ART at a median age 14.9 months (IQR 8.2, 25.2). Nadir CD4 percentage was 14.7% (IQR 11.0, 19.5); the median peak viral load (VL) was 750 000 copies/ml (IQR 366 000, 750 000) and 63% had ≥WHO stage 3 clinical disease; 164 (67%) were on lopinavir/ritonavir, 71 (29%) were on nevirapine and 7 (3%) were on efavirenz. Other antiretrovirals were similar. Nevirapine at P1104s study start or later was associated with poorer neuropsychological scores across all domains except Global Executive Composite, even when controlling for nadir CD4 percent and time-varying HIV VL. Other predictors of poorer scores in KABC domains included low birth weight, WHO stage 4 disease and serious illness history and elevated VL was associated with worse BOT-2 scores. Conclusion: Children receiving nevirapine had poorer neuropsychological scores than those on lopinavir/ritonavir. Antiretroviral choice might adversely impact neuropsychological performance. In addition, low birth weight and markers of severe HIV disease: advanced WHO clinical HIV disease, history of serious illness and an elevated VL, were associated with lower neuropsychological scores.

Coordination of inflammatory responses in children with perinatally acquired HIV infection.

OBJECTIVE: We investigated dynamics of inflammatory biomarkers in children with perinatally acquired HIV (PHIV) who started antiretrovirals at age less than 3 years and achieved sustained virologic control (HIV plasma RNA <400 copies/ml). DESIGN: This was a retrospective analysis of inflammatory biomarkers in children enrolled in a randomized trial of early (<3 years of age) PI-based versus NNRTI-based regimens (P1060), who achieved sustained virologic control and participated in a neurodevelopmental follow-up study (P1104s) between ages 5 and 11 years. METHODS: We measured 20 inflammatory biomarkers using ELISA or chemiluminescence at onset of sustained virologic control (Tc) and at P1104s entry (Te). RESULTS: The 213 participants had median ages of 1.2, 1.9, and 7 years at antiretroviral initiation, Tc, and Te, respectively, with 138 on protease inhibitor-based and 74 on NNRTI-based regimens at Tc. Eighteen markers decreased and two increased from Tc to Te (Te-Tc). Biomarker subsets, particularly cytokines, the chemokine IP-10, and adhesion molecules sICAM-1 and sVCAM-1, correlated at Tc, Te, and Te-Tc. At Tc, higher biomarker levels were associated with younger age, female sex, HIV plasma RNA at least 750 000 copies/ml, lower nadir CD4 + %, lower nadir weight z scores, and NNRTI-based treatment. Greater Te-Tc biomarker declines were associated with younger age, male sex, higher Tc biomarker levels, lower nadir CD4 + %, and NNRTI-based treatment. Duration of controlled viremia and nadir height z scores showed mixed associations. CONCLUSION: Biomarker expression showed substantial coordination. Most markers decreased after virologic control. Demographic and clinical variables associated with biomarker patterns were identified. Mechanistic studies of these biomarker patterns are needed to inform interventions to control inflammation.

Lower Neurocognitive Functioning in HIV-Exposed Uninfected Children Compared With That in HIV-Unexposed Children.

BACKGROUND: Perinatal HIV and antiretroviral therapy exposure may influence neurocognitive outcomes, although evidence is mixed and most studies are limited to outcomes in the first 24 months. We compared neurocognitive outcomes in school-aged children who were HIV exposed uninfected (CHEU) with those in children who were HIV unexposed uninfected (CHUU). SETTING: Children were recruited from a health center in Nairobi, Kenya. METHODS: Key inclusion criteria were children aged 5-12 years and confirmed child and maternal HIV status; for CHEU, mothers reported knowing HIV-positive status before or at delivery of the index child. Children underwent a detailed battery of neuropsychological tests and behavioral assessment, and comparisons of scores between CHEU and CHUU were conducted using linear regression. RESULTS: Among 56 CHEU and 65 CHUU, the median age and sex distributions were 6.8 and 7.0 years (P = 0.8) and 48% and 60% girls (P = 0.2), respectively. In analyses adjusted for child's age and sex and caregiver's age, education, and household rent, CHEU had significantly lower mean z scores for global cognitive ability than CHUU [-0.35, 95% confidence interval (CI): -0.64 to -0.05; P = 0.02], short-term memory (-0.44, 95% CI: -0.76 to -0.12; P = 0.008), delayed memory (-0.43, 95% CI: -0.79 to -0.08; P = 0.02), attention (-0.41, 95% CI: -0.78 to -0.05; P = 0.03), and processing speed (-0.76, 95% CI: -1.37 to -0.16; P = 0.01). Models adjusted for child nutritional status, household food security, and orphanhood yielded similar results. CONCLUSIONS: Children exposed to HIV had poorer long-term neurocognitive outcomes than CHUU. These data suggest that long-term studies of neurocognitive and educational attainment in CHEU are warranted.

Early Childhood Vigilance Test (ECVT) of attention in younger HIV-exposed Ugandan children predicts Tests of Variables of Attention (TOVA) at school age.

Objective: Evaluate a computerized-based attention test in early infancy in predicting neurocognitive school-age performance in human immunodeficiency virus (HIV)-exposed uninfected children. Method: Thirty-eight Ugandan HIV-exposed/uninfected children (17 boys, 21 girls) were evaluated with the Early Childhood Vigilance Test (ECVT) of attention between 3 and 5 years of age, which is a 6-min 44 s animation with colorful animals that greet the child and move across the screen. Attention was proportion of total animation time viewing a computer screen, as well as the proportion of time tracking the moving animal using eye tracking. These children were then again tested at least 2 years later (between 5 and 9 years of age) with the Kaufman Assessment Battery for Children, 2nd Edition (KABC-II) and the visual computerized Tests of Variables of Attention (TOVA). Results: Irrespective of whether scored by webcam video scoring or using automated eye tracking to compute proportion of time viewing the animation, ECVT attention was significantly correlated with all TOVA outcomes for vigilance attention. This was still the case when the correlation was adjusted for type of caregiver training for the mother, child gender, socioeconomic status (SES), and quality of Home Observational Measurement Evaluation (HOME) environment-especially for the TOVA response time variability to signal (p = .03). None of the ECVT attention performance measures correlated significantly with any of the KABC-II cognitive ability outcomes. Conclusion: Attention assessment in early childhood is predictive of school-age computer-based measures of attention and can be used to gauge the effects of factors of early risk and resilience in brain/behavior development in African children affected by HIV. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The Impact of Maternal Depression and Parent-Child Interactions on Risk of Parasitic Infections in Early Childhood: A Prospective Cohort in Benin.

OBJECTIVES: Maternal depression occurs in 13-20% of women from low-income countries, which is associated with negative child health outcomes, including diarrheal disease. However, few studies have investigated its impact on child risk of infectious disease. We studied the impacts of maternal depressive symptoms and parent-child interactions, independently, on the risk of Plasmodium falciparum malaria and soil-transmitted helminth infection in Beninese children. METHODS: Our population included mothers and children enrolled in a clinical trial during pregnancy (MiPPAD) in Benin. The Edinburgh Postnatal Depression Scale (EPDS) assessed maternal depressive symptoms and the home observation measurement of the environment (HOME) assessed parent-child interactions. Blood and stool sample analyses diagnosed child malaria and helminth infection at 12, 18, and 24 months. Negative binomial and Poisson regression models with robust variance tested associations. RESULTS: Of the 302 mother-child pairs, 39 (12.9%) mothers had depressive symptoms. Median number of malaria episodes per child was 3 (0-14) and 29.1% children had at least one helminth infection. Higher EPDS scores were associated with lower HOME scores; relative risk (RR) 0.97 (95% confidence interval (CI) 0.95, 0.99), particularly with lower acceptance, involvement, and variety subscales; RR 0.92 (95% CI 0.85, 0.99), RR 0.82 (95% CI 0.77, 0.88), RR 0.93 (95% CI 0.88, 0.99), respectively. However, neither exposure was associated with risk of parasitic infection in children. CONCLUSIONS FOR PRACTICE: Maternal depressive symptoms are associated with poor parent-child interactions, particularly acceptance of behavior, involvement with children, and variety of interactions, but these exposures do not independently impact risk of parasitic infection in children.

Growth deficits in antiretroviral and HIV-exposed uninfected versus unexposed children in Malawi and Uganda persist through 60 months of age.

OBJECTIVE: To compare childhood physical growth among antiretroviral drug and maternal HIV-exposed uninfected (AHEU) compared with HIV-unexposed uninfected (HUU) children. DESIGN: Longitudinal follow-up of PROMISE trial (NCT01061151) AHEU and age-matched and sex-matched HUU children, enrolled (September 2013 to October 2014) in Malawi and Uganda. METHOD: We compared WHO population standardized z-scores [height-for-age (HAZ), weight-for-age (WAZ), weight-for-height (WHZ), head-circumference-for-age (HCAZ) at 12, 24, 36, 48, and 60 months of age]. We evaluated HUU versus AHEU [in-utero combination antiretroviral treatment (cART) versus Zidovudine (ZDV) alone]; stratified by country, using longitudinal linear and generalized linear mixed models. RESULTS: Of 466 Malawian and 477 Ugandan children, median maternal age at enrollment was 24.5 years (Malawi) and 27.8 years (Uganda); more than 90% were breastfed through 12 months except Uganda AHEU (64.0%). HAZ scores (adjusted for maternal age, breastfed, and socioeconomic status) were lower among AHEU versus HUU children at every time point, significant (P < 0.05) among Ugandan but not Malawian children. Similar patterns were seen for WAZ but not for WHZ or HCAZ scores. High stunting was observed in both countries, significantly higher in Malawi; and higher among AHEU versus HUU children through 48 months of age, significantly (P < 0.05) among Ugandan but not Malawian children. We found no differences in childhood growth trajectories with in-utero exposures to ZDV compared with cART. CONCLUSION: AHEU versus HUU children had lower median LAZ and WAZ scores persisting through 60 months of age. However, proportions of children with stunting or underweight decreased after 24 months of age.

The Effects of Malaria in Pregnancy on Neurocognitive Development in Children at 1 and 6 Years of Age in Benin: A Prospective Mother-Child Cohort.

BACKGROUND: Malaria in pregnancy (MiP) contributes significantly to infant mortality rates in sub-Saharan Africa and has consequences on survivors, such as preterm birth and low birth weight. However, its impact on long-term neurocognitive development in children remains unknown. METHODS: Our prospective cohort included pregnant women and their live-born singletons from the Malaria in Pregnancy Preventive Alternative Drugs clinical trial. MiP was assessed using microscopy and real-time quantitative polymerase chain reaction (qPCR). Neurocognitive development in children was assessed using the Mullen Scales of Early Learning and the Kaufman Assessment Battery for Children, 2nd edition (KABC-II), at 1 and 6 years of age, respectively. RESULTS: Of 493 pregnant women, 196 (40%) were infected with malaria at least once: 121 (31%) with placental malaria diagnosed by qPCR. Multiple linear regression B-coefficients showed that impaired gross motor scores were associated with MiP at least once (-2.55; confidence interval [95% CI]: -5.15, 0.05), placental malaria by qPCR (-4.95; 95% CI: -7.65, -2.24), and high parasite density at delivery (-1.92; 95% CI: -3.86, 0.02) after adjustment. Malaria and high parasite density at the second antenatal care visit were associated with lower KABC-II Non-Verbal Index scores at 6 years (-2.57 [95% CI: -4.86, -0.28] and -1.91 [-3.51, -0.32]), respectively. CONCLUSIONS: This prospective cohort study provides evidence that MiP, particularly late term, could have important negative consequences on child development at 1 and 6 years of age. Mechanisms behind this association must be further investigated and diagnostic methods in low-income countries should be strengthened to provide adequate treatment. CLINICAL TRIALS REGISTRATION: NCT00811421.

Health-Related Quality of Life: Longitudinal Analysis From the Time of Breast Biopsy Into the Post-treatment Period.

Background: The physical, psychological, social, and spiritual quality of life (QoL) may be affected by breast cancer diagnosis and treatment, with mixed findings for psychological quality of life and cognitive ability performance. The present study aimed to evaluate QoL in women over 1 year from biopsy for a breast abnormality. Methods: Self-reported measures of physical, psychological, social, and spiritual QoL were obtained after biopsy results but prior to treatment initiation (baseline), 4 and 12 months later. CogState computerized neuropsychological screening battery also provided an evaluation of psychological QoL. Three groups of women including those with benign biopsy results, those with malignancy treated with chemotherapy, and those with malignancy not treated with chemotherapy were compared at 4 and 12 months after adjusting for baseline to isolate the effects of treatment. Additional covariates included are age, level of education, and income. Results: Benign biopsy results group included 72 women, whereas malignancy was found in 87 women of whom 33 were treated with chemotherapy and 54 without chemotherapy. At the time of diagnosis, women with cancer had worse psychological and social QoL but better spiritual QoL than those with benign biopsy results. Only CogState monitoring accuracy was worse for women with cancer compared with the controls at the time of biopsy results. After adjusting for QoL at baseline, women treated for cancer had worse physical and social QoL at 4 and 12 months later. Psychological well-being was worse for women with cancer at 4th month but improved at 1 year. No differences in cognition were found at 4 and 12 months when adjusted for baseline cognition and covariates. Discussion: Breast cancer is a traumatic life event for women, affecting psychological and social QoL domains, yet increasing spiritual QoL. Later, cancer treatment worsens physical, psychological, and social QoL compared with those without cancer. Conclusions: These findings suggest that interventions to improve psychological QoL may be especially important at the time of cancer diagnosis, while interventions to improve physical well-being are the most needed during and following cancer treatment. Support to improve social QoL is needed from the time of diagnosis into post-treatment survivorship.

The Relationship Between Central Auditory Tests and Neurocognitive Domains in Adults Living With HIV.

Objective: Tests requiring central auditory processing, such as speech perception-in-noise, are simple, time efficient, and correlate with cognitive processing. These tests may be useful for tracking brain function. Doing this effectively requires information on which tests correlate with overall cognitive function and specific cognitive domains. This study evaluated the relationship between selected central auditory focused tests and cognitive domains in a cohort of normal hearing adults living with HIV and HIV- controls. The long-term aim is determining the relationships between auditory processing and neurocognitive domains and applying this to analyzing cognitive function in HIV and other neurocognitive disorders longitudinally. Method: Subjects were recruited from an ongoing study in Dar es Salaam, Tanzania. Central auditory measures included the Gap Detection Test (Gap), Hearing in Noise Test (HINT), and Triple Digit Test (TDT). Cognitive measures included variables from the Test of Variables of Attention (TOVA), Cogstate neurocognitive battery, and Kiswahili Montreal Cognitive Assessment (MoCA). The measures represented three cognitive domains: processing speed, learning, and working memory. Bootstrap resampling was used to calculate the mean and standard deviation of the proportion of variance explained by the individual central auditory tests for each cognitive measure. The association of cognitive measures with central auditory variables taking HIV status and age into account was determined using regression models. Results: Hearing in Noise Tests and TDT were significantly associated with Cogstate learning and working memory tests. Gap was not significantly associated with any cognitive measure with age in the model. TDT explained the largest mean proportion of variance and had the strongest relationship to the MoCA and Cogstate tasks. With age in the model, HIV status did not affect the relationship between central auditory tests and cognitive measures. Age was strongly associated with multiple cognitive tests. Conclusion: Central auditory tests were associated with measures of learning and working memory. Compared to the other central auditory tests, TDT was most strongly related to cognitive function. These findings expand on the association between auditory processing and cognitive domains seen in other studies and support evaluating these tests for tracking brain health in HIV and other neurocognitive disorders.

Cognitive outcomes at ages seven and nine years in South African children from the children with HIV early antiretroviral (CHER) trial: a longitudinal investigation.

INTRODUCTION: Many children living with HIV (CLWH) display impaired cognition. Although early combination antiretroviral therapy (ART) produces improved cognitive outcomes, more long-term outcome data are needed. After concluding the Children with HIV Early antiRetroviral (CHER) trial in 2011, we investigated cognitive performance, at seven and nine years of age. Participants had been randomized to deferred ART (ART-Def; n = 22); immediate time-limited ART for 40 weeks (ART-40W; n = 30) and immediate time-limited ART for 96 weeks (ART-96W; n = 18). We also recruited HIV-exposed uninfected (CHEU; n = 28) and HIV-unexposed (CHU; n = 35) children. METHODS: Data were collected between May 2012 and December 2017. Mixed-model repeated-measures ANOVAs assessed differences over time between CLWH (ART-40W, ART-96W and ART-Def) and CHIV- CHEU and CHU between ART-Early (ART-40W and ART-96W), ART-Def, CHEU and CHU; and between ART-40W, ART-96W, ART-Def, CHEU and CHU. RESULTS: All comparisons found significant effects of Time for most outcome variables (better scores at nine than at seven years; ps < 0.05). The first ANOVAs found that for (a) motor dexterity, CLWH performed worse than CHIV- at seven years (p < 0.001) but improved to equivalence at nine years, (b) visual-spatial processing and problem solving, only CLWH (p < 0.04) showed significant performance improvement over time and (c) working memory and executive function, CLWH performed worse than CHIV- at both seven and nine years (p = 0.03 and 0.04). The second ANOVAs found that for (a) working memory, CHU performed better than ART-Early and CHEU (p < 0.01 and <0.04), and (b) motor dexterity, ART-Def performed worse than ART-Early, CHEU and CHU at seven years (p = 0.02, <0.001 and <0.001 respectively) but improved to equivalence at nine years (ps > 0.17). Similarly, for motor dexterity, ART-Def performed worse than ART-96W, CHEU and CHU at seven years (p < 0.04, <0.001 and <0.001) but improved to equivalence at nine years (ps > 0.20). CONCLUSIONS: Although neurocognitive developmental trajectories for treatment groups and controls were largely similar (i.e. performance improvements from 7 to 9), all ART-treated children, regardless of treatment arm, remain at risk for cognitive deficits over early school ages. Although the nature of these deficits may change as cognitive development proceeds, there are potential negative consequences for these children's future learning, reasoning and adaptive functioning.

Attention Test Improvements from a Cluster Randomized Controlled Trial of Caregiver Training for HIV-Exposed/Uninfected Ugandan Preschool Children.

OBJECTIVE: To report vigilance attention outcomes from a cluster randomized controlled trial of early childhood development caregiver training for perinatally HIV-exposed/uninfected preschool-age children in rural Uganda. The Early Childhood Vigilance Test (ECVT) provides a webcam recording of proportion of time a child views an animation periodically moving across a computer screen. STUDY DESIGN: Sixty mothers/caregivers received biweekly year-long training sessions of the Mediational Intervention for Sensitizing Caregivers (MISC), and 59 mothers received biweekly training about nutrition, hygiene, and health care. Children were tested for attention at baseline, 6 months, and 12 months with the ECVT, in terms of proportion of time spent viewing a 6-minute animation of animals greeting the child and moving across the computer monitor screen. Time viewing the animation were scored by trained observers using ProCoder program for webcam scoring of proportion of time the child faced the animation. Mixed-effects modeling was used to compare ECVT outcomes for the 2 intervention groups. RESULTS: Unadjusted and adjusted (for age, sex, height, and ECVT at baseline) group differences on ECVT significantly favored the MISC arm at 6 months (P = .03; 95% CI (0.01, 0.11), effect size = 0.46) but not at 12 months. Both groups made significant gains in sustained attention across the year-long intervention (P = .021) with no significant interaction effects between time and treatment arms or sex. CONCLUSIONS: Caregiver early childhood development training enhanced attention in at-risk Ugandan children, which can be foundational to improved working memory and learning, and perhaps related to previous language benefits reported for this cohort. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00889395.

Plasma biomarker factors associated with neurodevelopmental outcomes in children with perinatal HIV infection and controlled viremia.

OBJECTIVE: We examined relationships between plasma biomarkers and neurodevelopment in children from sub-Saharan Africa with perinatal HIV (PHIV) with controlled viremia on antiretroviral therapy (ART). DESIGN: Longitudinal retrospective cohort study of children with controlled blood HIV replication. METHODS: Children (N = 213; 57% girls) started ART at less than 3 years of age, had neurodevelopmental assessments (cognition, attention/impulsivity, motor proficiency, global executive functions) at 5-11 years, and achieved controlled viremia (HIV-1 RNA <400 copies/ml for ≥9 months before initial assessment). Twenty-three plasma biomarkers were measured at onset of controlled viremia, week 0 (first neurodevelopmental assessment), and week 48 (second neurodevelopmental assessment). Factor analysis was conducted at each time point. Multivariable linear regressions assessed associations between factors and neurodevelopmental scores. RESULTS: Median age at week 0 was 7.0 years. Eighteen biomarkers loaded on six factors: a (L-10, IFNγ, IFNα2, IL-1ß, IL-6, IP-10, TNFα); B (sCD163, sICAM-1, sVCAM-1, CRP); C (sE-selectin, sP-selectin); D [MIP-1ß, vascular endothelial growth factor (VEGF)-A]; E (sCD14, CRP); and F (CX3CL1, MCP-1). Higher factor B scores were consistently associated with worse cognition and attention/impulsivity, and higher factor D scores with better attention/impulsivity. CONCLUSION: These results suggest a detrimental effect of increased endothelial cell activation (sICAM-1, sVCAM-1) and monocyte/macrophage scavenger function (sCD163) and a beneficial effect of increased CCR5 ligand and HIV entry blocker MIP-1ß and angiogenesis stimulant-VEGF concentrations on the neurodevelopment of children with PHIV. The model that emerges is of vascular inflammation leading to neurodevelopmental deficits. The role of persistent HIV replication in the central nervous system also needs to be further explored.

[Formula: see text]Neurodevelopmental assessment at one year of age predicts neuropsychological performance at six years in a cohort of West African Children.

Rural children from Benin, west Africa were evaluated with the Mullen Scales of Early Learning (MSEL) at one year of age and then at six years with the Kaufman Assessment Battery for Children (KABC-II), the visual computerized Tests of Variables of Attention (TOVA), and the Bruininks-Oseretsky Test (BOT-2) of motor proficiency (N = 568). Although both the MSEL and KABC-II were available to the assessors in French, instructions to the mother/child were in local language of Fon. Mothers were evaluated with the Edinburgh Postpartum Depression Scale (EPDS), Caldwell HOME Scale, educational level and literacy, and a Socio-Economic Scale - also in their local language (Fon). After adjusting for maternal factors, MSEL cognitive composite was correlated with KABC-II with moderate effect sizes, but not with TOVA scores. Overall eta-squared effect for the multivariate models were moderately to strongly correlated (.07 to .37). Neurodevelopmental assessments in early childhood adapted cross-culturally are predictive of school-age neuropsychological cognitive ability.