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OBJECTIVE: This study was conducted to assess prospectively the frequency of cognitive deficits in children with cerebral malaria. METHODS: Cognitive testing in the areas of working memory, attention, and learning was performed for Ugandan children 5 to 12 years of age with cerebral malaria (n = 44), children with uncomplicated malaria (n = 54), and healthy community children (n = 89) at admission and 3 and 6 months later. RESULTS: Six months after discharge, 21.4% of children with cerebral malaria had cognitive deficits, compared with 5.8% of community children. Deficits were seen in the areas of working memory (11.9% vs 2.3%) and attention (16.7% vs 2.3%). Children with cerebral malaria had a 3.7-fold increased risk of a cognitive deficit, compared with community children, after adjustment for age, gender, nutritional status, school level, and home environment. Among children with cerebral malaria, those with a cognitive deficit had more seizures before admission (mean: 4.1 vs 2.2) and a longer duration of coma (43.6 vs 30.5 hours), compared with those without a deficit. Children with uncomplicated malaria did not have an increased frequency of cognitive deficits. CONCLUSIONS: Cerebral malaria may be a major cause of cognitive impairment in children in sub-Saharan Africa. Cognitive deficits in children with cerebral malaria are more likely for those who have multiple seizures before effective treatment for cerebral malaria. [ABSTRACT FROM AUTHOR]

Konzo is a neglected paralytic neurological disease associated with food (cassava) poisoning that affects the world's poorest children and women of childbearing ages across regions of sub-Saharan Africa. Despite understanding the dietary factors that lead to konzo, the molecular markers and mechanisms that trigger this disease remain unknown. To identify potential protein biomarkers associated with a disease status, plasma was collected from two independent Congolese cohorts, a discovery cohort (n = 60) and validation cohort (n = 204), sampled 10 years apart and subjected to multiple high-throughput assays. We identified that Glutathione Peroxidase 3 (GPx3), a critical plasma-based antioxidant enzyme, was the sole protein examined that was both significantly and differentially abundant between affected and non-affected participants in both cohorts, with large reductions observed in those affected with konzo. Our findings raise the notion that reductions in key antioxidant mechanisms may be the biological risk factor for the development of konzo, particularly those mediated through pathways involving the glutathione peroxidase family., (© 2024. The Author(s).)

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., Competing Interests: Declaration of interests EWG is supported by the National Eye Institute, the END Fund, and the Task Force for Global Health. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., (© The Author(s) 2023. Published by Oxford University Press.)

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.

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., Competing Interests: All authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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.

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.

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., Competing Interests: LB-M was employed by MU-JHU Care Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fairlie, Chernoff, Cotton, Bwakura-Dangarembizi, Violari, Familiar-Lopez, Barlow-Mosha, Kamthunzi, McCarthy, Jean-Philippe, Laughton, Palumbo and Boivin.)

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., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2021. The Author(s).)

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

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).

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Niemczak, Lichtenstein, Magohe, Amato, Fellows, Gui, Huang, Rieke, Massawe, Boivin, Moshi and Buckey.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Boivin, Sikorskii, Haan, Smith, Symonds, Khattree, Giordani, Blow and Osuch.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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-1β, IL-6, IP-10, TNFα); B (sCD163, sICAM-1, sVCAM-1, CRP); C (sE-selectin, sP-selectin); D [MIP-1β, 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-1β 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., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Cassava cyanide-related neurocognitive impairment may persist for years in Central African children who rely on cassava as a dietary staple. In the Democratic Republic of the Congo, a cassava processing method, the 'wetting method', reduced cyanide in cassava, prevented konzo, and proved a cost-effective intervention to improve children's cognitive development. Scaling up use of the wetting method may help prevent neurocognitive impairment in millions of at-risk children in sub-Saharan Africa., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

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.

A case-control design determined whether konzo, an upper motoneuron disease linked to food (cassava) toxicity was associated with protein carbamoylation and genetic variations. Exon sequences of thiosulfate sulfurtransferase (TST) or mercaptopyruvate sulfurtransferase (MPST), plasma cyanide detoxification rates, and 2D-LC-MS/MS albumin carbamoylation were assessed in 40 children [21 konzo-affected and 19 putatively healthy controls, mean (SD) age: 9.2 (3.0) years] subjected to cognition and motor testing using the Kaufman Assessment Battery and the Bruininks/Oseretsky Test, respectively. Konzo was significantly associated with higher levels of carbamoylated peptides 206-219 (LDELRDEGKASSAK, pep1) after adjusting for age, gender, albumin concentrations and BUN [regression coefficient: 0.03 (95%CI:0.02-0.05), p = 0.01]. Levels of pep1 negatively correlated with performance scores at all modalities of motor proficiency (r = 0.38 to 0.61; all p < 0.01) or sequential processing (memory)(r = - 0.59, p = 0.00) and overall cognitive performance (r = - 0.48, p = 0.00) but positively with time needed for cyanide detoxification in plasma (r = 0.33, p = 0.04). Rare potentially damaging TST p.Arg206Cys (rs61742280) and MPST p.His317Tyr (rs1038542246) heterozygous variants were identified but with no impact on subject phenotypes. Protein carbamoylation appears to be a reliable marker for cassava related neurodegeneration., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The prevalence of cognitive impairment or learning difficulties in HIV-infected children is high despite access to antiretroviral treatment (ART). Several biological mechanisms, including latent HIV reservoir persistence in the brain, local inflammation within the central nervous system (CNS), disruption of neuronal function and integrity, and ongoing infiltration of activated HIV target cells to the CNS during brain development, may each dampen efficacy of ART. Development of therapeutics to target these mechanisms will be crucial, and potential candidates may include chemokine receptor antagonists. Separately, psychosocial approaches to support caregiving may leverage neuroplasticity and support brain development during critical developmental windows in spite of perinatal HIV infection. Multipronged approaches that encompass both approaches are crucial for optimizing neurodevelopmental outcomes in these extraordinarily vulnerable children. Dynamic neuropsychological assessments, such as what can be obtained with the use of computerized cognitive games intervention, may prove more sensitive to the brain/behavior benefits of ART. Dynamic neuropsychological outcomes, neuroinflammatory biomarkers, and brain development neuroprotective factors (BDNFs) may each be used to evaluate brain/behavior integrity of children in response to new treatment options., (© 2019. Springer Nature Switzerland AG.)

Background: Children living with human immunodeficiency virus (HIV) are at neuropsychological risk for cognitive and motor dysfunction. However, few prospective, multi-site studies have evaluated neuropsychological outcomes longitudinally among perinatally infected African children who received early antiretroviral treatment (ART)., Methods: We enrolled 611 children aged 5 to 11 years at 6 sites (South Africa [3], Zimbabwe, Malawi, Uganda). Of these, there were 246 children living with HIV (HIV+) who were initiated on ART before 3 years of age in a prior clinical trial comparing nevirapine to lopinavir/ritonavir (International Maternal Pediatric Adolescent Acquired Immunodeficiency Syndrome Clinical Trials [IMPAACT] P1060); 183 age-matched, exposed but uninfected (HEU) children; and 182 unexposed and uninfected (HUU) children. They were compared across 3 assessment time points (Weeks 0, 48, and 96) on cognitive ability (Kaufman Assessment Battery for Children, second edition [KABC-II]), attention/impulsivity (Tests of Variables of Attention [TOVA]), motor proficiency (Bruininks-Oseretsky Test, second edition [BOT-2]), and on the Behavior Rating Inventory of Executive Function (BRIEF). The cohorts were compared using linear mixed models, adjusting for site, child's age and sex, and selected personal/family control variables., Results: The HIV+ cohort performed significantly worse than the HEU and HUU cohorts for all KABC-II, TOVA, and BOT-2 performance outcomes across all 3 time points (P values < .001). The HUU and HEU cohorts were comparable. For the KABC-II planning/reasoning subtests, the HIV+ children showed less improvement over time than the HUU and HEU groups. The groups did not differ significantly on the BRIEF., Conclusions: Despite initiation of ART in early childhood and good viral suppression at the time of enrollment, the HIV+ group had poorer neuropsychological performance over time, with the gap progressively worsening in planning/reasoning. This can be debilitating for self-management in adolescence., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The feasibility, acceptability and preliminary efficacy of computerized cognitive rehabilitation therapy (CCRT) for mitigating neurocognitive decline was evaluated in African adults ≥50 years old. Eighty-one Ugandans with ( n = 40) and without ( n = 41) chronic human immunodeficiency viruses (HIV) were allocated CCRT-i.e., 20-45-min cognitive training sessions with culturally adapted video games delivered via Captain's Log Software, or standard of care (SOC). Pre and post (i.e., 8-weeks later) intervention performance based neurocognitive tests, quality of life (QOL) and frailty related phenotype (FRP) were determined in all respondents. Multivariable linear regression estimated CCRT- vs. SOC-related differences (β) in neurocognitive batteries, QOL and FRP. Effect sizes (ES) for estimated β were calculated. CCRT protocol was completed by 92.8% of persons allocated to it. Regardless of HIV status, CCRT was associated with higher performance in learning tests than SOC-interference list (β = 1.00, 95%CI: (0.02, 1.98); ES = 0.43) and delayed recall (β = 1.04, 95%CI: (0.06, 2.02); ES = 0.47). CCRT effect on verbal fluency was clinically important (ES = 0.38), but statistical significance was not reached (β = 1.25, 95%CI: (-0.09, 2.58)). Among HIV-positive adults, clinically important post-CCRT improvements were noted for immediate recall (ES = 0.69), working memory (ES = 0.51), verbal fluency (ES = 0.51), and timed gait (ES = -0.44) tasks. Among HIV-negative adults, CCRT resulted in moderate post-intervention improvement in learning tests (ES = 0.45) and large decline in FRP (ES = -0.71), without a positive effect on simple attention and visuomotor coordination tasks. CCRT intervention is feasible among older Ugandan adults with potential benefit for learning and verbal fluency tests regardless of HIV status and lowering FRP in HIV-negative older adults.

Background: The universally adopted 2018 PCOS medical diagnostic and treatment guidelines for Polycystic Ovarian Syndrome (PCOS) cites the need for a brief screening measure that can be easily administered in the clinical care setting. We evaluate a 12-item questionnaire emphasizing the medical symptoms of PCOS with a group of women with PCOS as well as comparison samples of college women not diagnosed with PCOS., Method: Of 120 undergraduate psychology women 18 to 41 years of age, 86 screened negative on a 12-item PCOS symptoms inventory. They were compared to a group of PCOS patients diagnosed medically in a manner consistent with the Teede et al. (2018) evidence-based diagnostic guidelines. The screen-positive, screen-negative, and PCOS-confirmed groups were compared on the PCOS Quality-of-Life (QoL) questionnaire, Zung Self-Rating Depression Scale (ZDS), Spielberg State-Trait Anxiety Inventory (STAI), Fatigue Symptom Inventory (FSI), Spiritual well-being and Spiritual Beliefs Inventories, the computerized Automated Neuropsychological Assessment Metric (ANAM) battery, and an experimental tachistoscopic Bilateral Perceptual Asymmetries Letter and Dots Matching Bilateral Field Advantage (BFA) test (to evaluate the effects of early brain androgenization possible from PCOS). For each questionnaire and neuropsychological performance principal outcome, the Linear Mixed Effects (LME) model was employed to evaluate the predictive significance of demographic characteristics and group membership (confirmed cases, screen negative and screen positive cases) for these outcomes., Results: The PCOS-confirmed women scored more poorly than the screen-negative (reference) and screen-positive groups on all the measures of physical, emotional, social, and spiritual well-being measures. On the ANAM neuropsychological battery, PCOS-confirmed women did more poorly on Sternberg Memory and Stimulus Response throughput measures. They also had slower correct response speed for both the unilateral and bilateral dot- and letter-matching tachistoscopic stimulus presentations. However, the bilateral field advantage throughput performance ratio did not differ among groups, which is a global measure of bilateral versus unilateral brain/behavior asymmetries., Conclusion: PCOS screening can be a feasible and important part of women's healthcare. PCOS-confirmed women should receive not only the medical standard of care from the 2018 guidelines, but also comprehensive psychosocial and neurocognitive support to enhance their quality of life.

Background: Immunological biomarkers were related to quality of life and neuropsychological performance in women recently diagnosed with breast cancer through the first six months of treatment. A comparison group of breast cancer survivors in remission were also evaluated., Method: Twenty women newly diagnosed with breast cancer and 26 breast cancer survivors at least a year after treatment were evaluated four times over a course of six to 8 months. The assessments included quality-of-life, emotional and spiritual well-being, sleep quality, computerized neuropsychological performance, and cytokine immunology biomarkers using flow cytometry. The principal immunological markers examined were the CD4+, CD8+, and CD16+ counts., Results: Although equivalent at enrollment, active treatment women reported higher anxiety, depression, poorer quality-of-life, and poorer processing speed and accuracy on memory, logical processes, and coding neuropsychological tasks. They also had significantly higher CD8+ and CD16+ cell count levels during treatment over the next six to eight months than comparison group women in remission. Women undergoing chemotherapy as well during treatment phase also had a significant decline in CD4+ counts. Higher percent CD8+ levels during treatment was associated with poorer quality of life and more depression, while higher CD4+ and CD8+ were associated with poorer neuropsychological memory and processing speed performance., Conclusion: Significant increases in CD8+ is a sensitive biomarker of a broad range of poorer quality-of-life and neurocognitive functioning outcomes during breast cancer treatment, especially in women undergoing chemotherapy. Quality of life should be monitored in breast cancer patients and psychosocial support made available as a standard of care.

Caregiver's and child's self-reported quality of life (QOL) was defined using standardized questionnaires in a sample (N = 277) of 6-10 years old HIV-infected, HIV-exposed uninfected, and HIV-unexposed uninfected children from Uganda. Psychosocial stress (acute stress and cumulative lifetime adversity) and physiologic stress (dysregulations across 13 biomarkers), perinatal HIV status, and their interaction were related to child QOL via general linear models. Lower child- and caregiver-reported psychosocial stress were dose-dependently associated with higher QOL (acute stress: mean difference coefficient b = 8.1-14.8, effect size [ES] = 0.46-0.83). Lower allostasis was dose-dependently associated with higher QOL (b = 6.1-9.7, ES = 0.34-0.54). Given low caregiver acute stress, QOL for HIV-infected was similar to HIV-uninfected children; however, given high caregiver acute stress, a QOL disadvantage (b = -7.8, 95% CI: -12.8, -2.8; ES = -0.73) was evident for HIV-infected versus uninfected children. Testing of caregiver stress reduction interventions is warranted to increase wellbeing in dependent children., (© 2020 Wiley Periodicals, Inc.)

Cumulative lifetime adversity and social support were investigated as determinants of psychosocial adjustment (esteem, distress, hopefulness, positive outlook/future aspirations, and sense of purpose) over 12 months in 6-10-years-old HIV-infected, HIV-exposed uninfected and HIV-unexposed uninfected children from Uganda. Each determinant and psychosocial adjustment indicator was self-reported using standardized questionnaires administered at baseline, 6, and 12 months. Linear mixed effects models were used to relate time-varying lifetime adversity and social support to psychosocial adjustment over 12 months. Regardless of HIV status, higher adversity predicted lower esteem (coefficient b = -2.98, 95% confidence interval (CI): [-4.62, -1.35]) and increased distress (b =3.96, 95% CI: [1.29, 6.62]) but was not associated with hopefulness, positive outlook or sense of purpose. Low social support predicted higher distress (b =9.05, 95% CI: [7.36, 10.73]), lower positive outlook (b = -10.56, 95% CI: [-2.34, -8.79]) and low sense of purpose (b = -9.90, 95% CI: [-11.44, -8.36]) over 12 months. Pragmatic interventions that enhance coping with adversity and provide emotional/instrumental support should be tested for effectiveness in promoting resilient psychosocial adjustment trajectory in vulnerable children., (© 2020 Wiley Periodicals, Inc.)

Depressive symptoms among HIV-positive (HIV+) women may negatively impact their health and possibly that of their young children through risk of compromised caregiving. We evaluated how depression symptoms in predominantly (97%) female caregivers relate to neurodevelopmental outcomes in their HIV affected children. Data come from the IMPAACT P1104s Study, an observational cohort across six sites in four countries: Zimbabwe, South Africa, Uganda and Malawi. Participants ( n  = 611) were 5-11-year-old children with HIV (HIV), HIV exposed uninfected (HEU), or HIV unexposed uninfected (HUU). Primary caregivers were assessed for depression with the Hopkins Symptom Checklist (HSCL) and children with Behavior Rating Inventory for Executive Function (BRIEF) parent-report, Kauffman Assessment Battery for Children II (KABC), Bruininks-Oseretsky Test of Motor Proficiency 2nd Ed. (BOT-2), Test of Variables of Attention (TOVA), Multiple Indicators Cluster Survey, Child Disability and Development scales (MICS-4). Caregivers with higher depression scores (>1.75 mean HSCL score) reported more executive function problems in their children, regardless of HIV status. All executive function scores were significantly ( p  < 0.001) associated with depressive symptomatology at baseline and across time. Caregiver depressive symptomatology was not associated with other assessed neurocognitive outcomes. These results highlight the potential impact of caregiver depression on child behavioral outcomes.

Objective: Early childhood development (ECD) programs can enhance neurocognitive development outcomes through caregiver training. This study explores whether school-age siblings benefited from a program provided to HIV-infected caregivers and their preschool-aged target children., Methods: Siblings of target 2- to 3-year-old children in ECD intervention households were evaluated at school age (5-12 years) on neurocognitive outcomes with the Kaufman Assessment Battery for Children (KABC), computerized Test of Variables of Attention, Behavior Rating Inventory for Executive Function (BRIEF; parent), and attention-deficit/hyperactivity disorder rating inventory (ADHD-R)-IV (parent). Households from 18 geographic clusters in eastern Uganda were randomized to individualized biweekly sessions of either (1) Mediational Intervention for Sensitizing Caregivers (MISC) training emphasizing cognitive stimulation/enrichment or (2) health/nutrition/development [Uganda Community-Based Association For Women & Children Welfare (UCOBAC)] program. Siblings with baseline and at least 1 follow-up assessment (n = 216) were included in the analysis. Three repeated postbaseline measures of sibling neurocognitive outcomes were analyzed using the linear mixed-effects model while adjusting for socioeconomic status and behavioral outcome at baseline., Results: Siblings in the MISC arm had better performance on KABC sequential processing at 6 months (p = 0.02) and simultaneous processing at 12 months (p = 0.03). MISC mothers rated their children as having significantly more problems on the BRIEF and ADHD-RS-IV (p < 0.01) than UCOBAC mothers across all time points., Conclusion: Mediational Intervention for Sensitizing Caregivers training resulted in some short-term neurocognitive benefits for school-aged siblings, but these differences were not sustained at 1-year follow-up. Exploring potential impacts of parenting programs on other children in the home is an important development for the field.

Objectives: Parenting self-efficacy has been associated with positive parenting behaviors, fewer parental mental health problems, less family dysfunction, and better child development outcomes. The parenting sense of competence (PSOC) scale is commonly used to measure parenting self-efficacy in high-resource settings. This study sought to examine the factor structure, internal consistency, and convergent construct validity of the PSOC in a sample of predominantly HIV-infected women in Uganda., Methods: Using data from 155 HIV-affected caregivers who participated in a randomized controlled trial of a parenting intervention, two and three factor models of a 16-item translated version of the PSOC were tested using confirmatory factor analysis. Multivariable regression models were used to examine relationships between parenting confidence (operationalized using the best-fitting PSOC model), caregiver mental health symptoms (depression and anxiety), social support, family dysfunction, and family wealth, after adjusting for covariates., Results: Neither the two- nor three-factor models of the PSOC demonstrated adequate model fit; however, adequate model fit was demonstrated for a one-factor model that included only items from the PSOC efficacy subscale. Cronbach's alpha was 0.73 for this subscale. Correlates of parenting self-efficacy in this sample included caregiver depression, family dysfunction, and family wealth, but not caregiver anxiety or social support., Conclusions for Practice: These findings lend support for future use of the PSOC efficacy subscale among HIV-affected caregivers of children in low-resource settings such as rural Uganda.

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 < 0.001) and WAZ (P < 0.001) at 12 and 24 months of age and HCAZ (P = 0.016) at 24 months, with similar but not significant differences among Malawian AHEU and HUU children. The risk of stunting (more than two standard deviations below the WHO population LAZ median) was increased among AHEU versus 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. The risk of HCAZ below WHO median was increased among AHEU versus HUU children at 24 months of age, aRR = 1.35 (95% CI 1.02-1.79), P = 0.038 in Uganda; and aRR = 1.35 (95% CI 0.91-2.02), P = 0.139 in Malawi., Conclusion: Perinatal exposures to maternal HIV and antiretroviral drugs were associated with lower LAZ (including stunting), WAZ and HCAZ at 24 months of age compared with HUU children.

Background: Antiretroviral therapy (ART) started between 7 and 12 weeks of age improves neurodevelopmental outcomes in HIV-infected (HIV+) infants, but the impact of even earlier initiation is not yet described., Objectives: We assessed the early neurodevelopment of HIV+ infants who started ART within 21 days of life., Method: Participants were enrolled from the public sector birth HIV-diagnosis programme. Inclusion criteria included the following: birth weight > 2000 g, infant commencing ART < 6 weeks and no infant cytomegalovirus disease. Antiretroviral therapy included Zidovudine/Lamivudine/Nevirapine for the first 2 weeks, the latter then replaced by Lopinavir/Ritonavir. Once body weight > 3 kg and gestational age > 44 weeks, Abacavir replaced Zidovudine. The Griffiths mental development scales (GMDS) were administered at 10-12 months., Results: Of 29 infants assessed, 23 (79%) were girls. Mean birth weight was 3002 ± 501 g. Twenty-four mothers (83%) received ART during pregnancy. Seven (24%) infants were diagnosed HIV+ within 48 h of birth. Median [interquartile range] viral load (VL) at diagnosis was 3904 [259-16 922] copies/mL, age starting ART was 6.0 [3-10] days and age at VL suppression was 19.1 [15-36] weeks. At the GMDS assessment, nine (31%) participants had detectable VL and 26 (90%) had World Health Organization (WHO) clinical stage I disease. The GMDS was performed at a mean age of 11.5 ± 0.8 months. Mean quotients were within the average range: Global Griffiths score was 103.6 ± 10.9 and mean quotients on the subscales ranged from lowest 95.9 ± 13.4 for locomotor to highest 112.8 ± 11.3 for hearing-and-language., Conclusion: Preliminary findings in this small group suggest that early neurodevelopmental scores are within the normal range in infants with perinatal HIV infection who started ART at a median of 6 days., Competing Interests: The authors have declared that no competing interests exist., (© 2019. The Authors.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: We explored 3 immunopathogenic biomarkers collected during acute malaria illness as potential moderators of gains from a computerized cognitive rehabilitation training (CCRT) intervention., Method: Von Willebrand Factor (vWF), tumor necrosis factor (TNF) and Regulated on Activation, Normal T Expressed and Secreted (RANTES) were assayed from plasma and cerebral spinal fluid (CSF) of children during acute severe malaria anemia or cerebral malaria. Two years after acute malaria illness, 150 surviving children and 150 nonmalaria community controls (CCs) from their households 6-12 years old entered a 3-arm randomized controlled trial of titrating and nontitrating CCRT against no CCRT. Tests of cognition [Kaufman Assessment Battery for Children (KABC)], Tests of Variables of Attention and Achenbach Child Behavior Checklist (CBCL) were administered before and after 24 CCRT sessions over a 3-month period, and at 1-year follow-up. Differences in outcomes by trial arms and biomarker levels were evaluated using linear mixed effects models., Results: Severe malaria survivors with lower levels of vWF, lower CSF levels of TNF and higher levels of plasma and CSF RANTES had better KABC cognitive performance after both titrating and nontitrating CCRT compared with no CCRT. For the CBCL, high plasma RANTES was associated with no benefit from either the titrating and nontitrating CCRT, whereas high TNF plasma was predictive of the benefit for both interventions. These biomarker moderating effects were not evident for CC children., Conclusions: Severe malaria immunopathogenic biomarkers may be related to poorer long-term brain/behavior function as evidenced by diminished benefit from a computerized cognitive rehabilitation intervention.

An impact of vitamin D in neurocognitive function has been theorized but it remains unknown whether vitamin-D insufficiency (VDI) is associated with worse socio-emotional adjustment (SEA) in vulnerable early school-aged children. This study examines the thesis that deficits in SEA are related to VDI using longitudinal data from 254 children that are perinatally HIV-infected (PHIV), exposed-uninfected (HEU), or unexposed-uninfected (HUU). In utero/peripartum antiretroviral (IPA) exposure was established per medical record documentation of biological mother's ART regimen in pregnancy. Four caregiver-reported age- and sex-standardized measures of SEA were obtained at months 0, 6, and 12 for dependent children aged 6-10 years: externalizing problems (EPC), internalizing problems (IPC), behavioral symptoms index (BSI), and adaptive skills index (ASI). VDI was highly prevalent (74%, n = 188), and its association with change in SEA measures over 12 months varied by HIV-status (VDI*HIV, all p -values < 0.03). There was further variation in relationship of vitamin-D to SEA by IPA among PHIV (for ASI, BSI, and EPC, vitamin-D*IPA, p -value ≤ 0.01) and HEU (for BSI and EPC, vitamin-D*IPA, p -value ≤ 0.04). Among HUU, BSI (β = -0.32, 95% CI: -0.50, -0.13), IPC (β = -0.28, 95% CI: -0.47, -0.09), and EPC (β = -0.20, 95% CI: -0.37, -0.02) all declined moderately per quartile increment in VD. Among PHIV, on the one hand higher vitamin D predicted ASI gains (moderate vs. low VD, β = 0.52, p = 0.002), but this protective association was absent for BSI, EPC, and IPC (β = 0.36-0.77, p < 0.05). In absence of IPA-exposure, increasing vitamin-D predicted declines in BSI and EPC (moderate vs. low Vitamin D, β = -0.56 to -0.71, p ≤ 0.02) among HEU. However, given IPA exposure among HEU, higher VDI predicted moderate elevation in BSI (β = 0.39, 95% CI: 0.00, 0.78) and IPC (β = 0.48, 95% CI: 0.05, 0.92). Interaction between VD and IPA exposure for SEA outcomes among HEU and PHIV children warrants further investigation. The vitamin-D associated SEA improvement among HUU and HEU without IPA exposure suggests vitamin-D supplementation may remediate behavioral and adaptive deficits in this groups.

Fatty acids (FAs) are crucial in child growth and development. In Uganda, antiretroviral therapy (ART) has drastically reduced perinatal human immunodeficiency virus (HIV) infection of infants, however, the interplay of FAs, ART, and HIV in relation to child growth is not well understood. To investigate this, serum was collected from 240 children between 6-10 years old in Uganda and analyzed for FAs using gas-chromatography mass-spectrometry. HIV status and anthropometric measurements were taken, and relationships with FAs were assessed. No significant differences in growth parameters or serum FAs were found between HIV uninfected children with and without exposure to ART. HIV positive children had significantly lower height-for-age- z -scores (HAZ) than uninfected children ( p < 0.001). HIV-positive children had higher arachidonic acid than uninfected children ( p = 0.003). Total omega-6 FAs were significantly associated with HAZ regardless of HIV status ( p = 0.035). Mean total omega-3 FAs (2.90%) were low in this population compared to other cohorts in Africa. These results provide reference serum FA values for 6-10-year-old children in Uganda and may be used to inform lipid supplementation programs to promote child growth. Future studies should investigate the relationships between child growth trajectories in relation to HIV status and serum FAs.

Objective: Caregiver socio-emotional attributes are major determinants of child well-being. This investigation in vulnerable school-aged Ugandan children estimates relationships between children's well-being and their caregiver's anxiety, depression and social support., Methods: Perinatally HIV-infected, HIV-exposed uninfected and HIV-unexposed Ugandan children and their caregivers were enrolled. Perinatal HIV status was determined by 18 months of age using DNA-polymerase chain-reaction test; status was confirmed via HIV rapid diagnostic test when children were 6-18 years old. Five indicators of child well-being (distress, hopelessness, positive future orientation, esteem and quality of life (QOL)) and caregivers' socioemotional status (depressive symptoms, anxiety and social support) were measured using validated, culturally adapted and translated instruments. Categories based on tertiles of each caregiver psychosocial indicator were defined. Linear regression analyses estimated percent differences (β) and corresponding 95% confidence intervals (CI) for child well-being in relation to caregiver's psychosocial status., Results: As per tertile increment, caregiver anxiety was associated with 2.7% higher distress (95%CI:0.2%, 5.3%) and lower self-esteem/QOL (β = -1.3%/-2.6%; 95%CI: -5.0%,-0.2%) in their children. Child distress/hopelessness increased (β = 3.3%/7.6%; 95%CI:0.4%, 14.7%) and self-esteem/QOL decreased 2.3% (β = -2.3%/-4.4%; 95%CI: -7.2%, -1.3%) as per tertile increment in caregiver depression. Higher caregiver social support was associated with lower distress and higher positive outlook (β = 3%; 95%CI:1.4%, 4.5%) in their children. HIV-infected/exposed children had most caregiver depression-related QOL deficit (β = -5.2%/-6.8%; 95%CI: -12.4%, -0.2%) and HIV-unexposed children had most caregiver social support-related enhancements in positive outlook (β=4.5%; 95%CI:1.9%, 7.1%)., Conclusions: Caregiver anxiety, depressive symptoms and low social support were associated with worse well-being in school-aged and adolescent children. Improvement of caregiver mental health and strengthening caregiver social support systems may be a viable strategy for improving well-being of vulnerable children and adolescents in this setting., (© 2019 John Wiley & Sons Ltd.)

Background: Monocyte activation may contribute to neuronal injury in aviremic HIV-infected adults; data are lacking in children. We examined the relation between monocyte activation markers and early and long-term neurodevelopmental outcomes in early-treated HIV-infected children., Setting: Prospective study of infant and child neurodevelopmental outcomes nested within a randomized clinical trial (NCT00428116) and extended cohort study in Kenya., Methods: HIV-infected infants (N = 67) initiated antiretroviral therapy (ART) at age <5 months. Plasma soluble (s) CD163 (sCD163), sCD14, and neopterin were measured before ART (entry) and 6 months later. Milestone attainment was ascertained monthly during 24 months, and neuropsychological tests were performed at 5.8-8.2 years after initiation of ART (N = 27). The relationship between neurodevelopment and sCD163, sCD14, and neopterin at entry and 6 months after ART was assessed using Cox proportional hazards models and linear regression., Results: Infants with high entry sCD163 had unexpected earlier attainment of supported sitting (5 vs 6 months; P = 0.006) and supported walking (10 vs 12 months; P = 0.02) with trends in adjusted analysis. Infants with high 6-month post-ART sCD163 attained speech later (17 vs 15 months; P = 0.006; adjusted hazard ratio, 0.47; P = 0.02), threw toys later (18 vs 17 months; P = 0.01; adjusted hazard ratio, 0.53; P = 0.04), and at median 6.8 years after ART, had worse neuropsychological test scores (adj. mean Z-score differences, cognition, -0.42; P = 0.07; short-term memory, -0.52; P = 0.08; nonverbal test performance, -0.39, P = 0.05)., Conclusions: Before ART, monocyte activation may reflect transient neuroprotective mechanisms in infants. After ART and viral suppression, monocyte activation may predict worse short- and long-term neurodevelopment outcomes.

We sought to understand social representations of effective parenting and parenting self-efficacy among female HIV-affected caregivers in rural Eastern Uganda. We conducted in-depth interviews (n = 21) to describe parenting experiences and caregivers' perceptions of their own parenting abilities and to create vignettes for use in directed focus groups. We carried out open focus groups (n = 2) to gain social perspectives on parenting, and directed focus groups (n = 2) concentrated on parenting self-efficacy. Analysis involved memoing and inductive and deductive coding of transcripts. Caregivers' perceptions of their own parenting were grounded in parenting values such as providing children with basic needs, having well-behaved children, and having good relationships with children. Caregivers' perceptions were influenced by challenges, including single parenthood, living with HIV, limited family resources, and mental health problems. When facing challenges, caregivers relied on social support and faith as well as their own parenting confidence. Caregivers' perceptions of their parenting abilities were influenced by how they felt others perceived them, their satisfaction in the parenting role, their perseverance despite challenges, and the extent to which they had a vision for their family. Our findings contextualize parenting self-efficacy within parenting values, challenges, and social perceptions among HIV-affected caregivers in rural Uganda., (© 2019 Michigan Association for Infant Mental Health.)

Objective: When testing African children with developmental and cognitive standardized tests from high-income countries (HIC), investigators are uncertain as to whether to apply the HIC norms for these tests when standardizing a child's raw-score performance on the basis of age. The present study compared the construct validity of both raw and HIC-based standardized scores for the Mullen Scales of Early Learning (MSEL) and the Kaufman Assessment Battery in Children - 2nd edition (KABC-II) for Beninese children in a rural setting from three to six years of age., Methods: Seventy-four children 3-4 yrs of age were assessed with the MSEL, and 61 eligible older children (5-6 yrs of age) were assessed with the KABC-II. Assessors spoke the instructions to the children and caregivers for the assessment items in the local language. The developmental quality of the home environment was evaluated with the Caldwell Home Observation for Measurement of the Environment (HOME) inventory, and a material possessions and housing quality checklist was used as a measure of socio-economic status (SES). Children's mothers were given the Raven's Progressive Matrices test (nonverbal cognitive ability), and the Edinburgh Postpartum Depression Scale (EPDS) (emotional wellbeing)., Results: For the MSEL, the 4-yr old group performed significantly better than the 3-yr old group on both the raw and standardized score comparisons for all scales. These differences were attenuated when using standardized scores, although the MSEL standardized cognitive composite score was still highly significant between years of age. When comparing 5- to 6-yr olds on KABC-II subtest and global scale performance, comparisons between the raw and standardized mean score performances were much less consistent. Generally, 6-yr olds performed significantly better than 5-yr olds on the raw score comparisons on the KABC-II subtests, but not so for standardized scores. Parent-child interactions assessed through the HOME measure was associated with both raw and standardized MSEL cognitive composite score outcomes on a multiple regression analysis. SES was the only significant predictor for KABC-II raw and standardized outcomes., Conclusion: Standardization using HIC norms was not optimal, resulting in minimal impact to account for age when using the MSEL, and lower scores for oldest children compared with youngest children when using the KABC2. This is likely due to children in Benin drifting away from HIC-based norms with each passing year of age, systematically lowering standardized performance measures. These findings support the importance of having a local comparison group of reference or control children to allow for adjusted (for age, HOME, and SES) raw score comparisons when using western-based tests for developmental and neuropsychological evaluation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Computerized cognitive rehabilitation training (CCRT) may be beneficial for alleviating persisting neurocognitive deficits in Ugandan severe malaria survivors. We completed a randomized controlled trial of CCRT for both severe malaria and non-malaria cohorts of children., Methods: 150 school-age severe malaria and 150 non-malaria children were randomized to three treatment arms: 24 sessions of Captain's Log CCRT for attention, working memory and nonverbal reasoning, in which training on each of 9 tasks difficulty increased with proficiency; a limited CCRT arm that did not titrate to proficiency but randomly cycled across the simplest to moderate level of training; and a passive control arm. Before and after 2 months of CCRT intervention and one year following, children were tested with the Kaufman Assessment Battery for Children, 2nd edition (KABC-II), computerized CogState cognitive tests, the Behavior Rating Inventory for Executive Function (BRIEF), and the Achenbach Child Behavior Checklist (CBCL)., Results: Malaria children assigned to the limited-CCRT intervention arm were significantly better than passive controls on KABC-II Mental Processing Index (P = 0.04), Sequential Processing (working memory) (P = 0.02) and the Conceptual Thinking subtest (planning/reasoning) (P = 0.02). At one year post-training, the limited CCRT malaria children had more rapid CogState card detection (attention) (P = 0.02), and improved BRIEF Global Executive Index (P = 0.01) as compared to passive controls. Non-malaria children receiving CCRT significantly benefited only on KABC-II Conceptual Thinking (both full- and limited-CCRT; P < 0.01), CogState Groton maze chase and learning (P < 0.01), and CogState card identification (P = 0.05, full CCRT only). Improvements in KABC-II Conceptual Thinking planning subtest for the non-malaria children persisted to one-year follow-up only for the full-CCRT intervention arm., Conclusion: For severe malaria survivors, limited CCRT improved attention and memory outcomes more than full CCRT, perhaps because of the greater repetition and practice on relevant training tasks in the absence of the performance titration for full CCRT. There were fewer significant cognitive and behavior benefits for the non-malaria children, with the exception of the planning/reasoning subtest of Conceptual Thinking, with stronger full- compared to limited-CCRT improvements persisting to one-year follow-up., (Copyright © 2018 Elsevier Inc. All rights reserved.)