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Papers by David Bearden

The American Journal of Tropical Medicine and Hygiene

ABSTRACT. Lumbar puncture (LP) and cerebrospinal fluid (CSF) diagnostics are critical for evaluat... more ABSTRACT. Lumbar puncture (LP) and cerebrospinal fluid (CSF) diagnostics are critical for evaluating central nervous system infections but are often not conducted, resulting in the “Tap Gap.” To investigate patient, provider, and health systems factors contributing to the Tap Gap in Zambia, we conducted focus group discussions with adult caregivers of hospitalized inpatients and in-depth interviews with nurses, clinicians, pharmacy workers, and laboratory staff. Transcripts were independently thematically categorized by two investigators using inductive coding. We identified seven patient-related factors: 1) alternative understandings of CSF; 2) alternative information about LPs, including misinformation; 3) mistrust of doctors; 4) consent delays; 5) fear of blame; 6) peer pressure against consent; and 7) association between LP and stigmatized conditions. Four clinician-related factors were identified: 1) limited LP knowledge and expertise, 2) time constraints, 3) delays in LP reque...

AIDS and Behavior

The objective of this study was to validate the NIH Toolbox Cognition Battery (NIHTB-CB) in Zambi... more The objective of this study was to validate the NIH Toolbox Cognition Battery (NIHTB-CB) in Zambian children with and without HIV-infection. Children living with HIV and HIV-exposed, uninfected (HEU) children completed traditional neuropsychological and NIHTB-CB tasks. Using pairwise correlation and a linear regression model we measured associations between traditional measure composite scores and parental ratings of children’s abilities, and NIHTB-CB scores. A Receiver Operating Characteristic (ROC) curve was developed to identify participants with impairment. 389 children, 8–17 years old participated. NIHTB-CB and traditional measures converged well as a whole and when comparing analogous individual tests across the two batteries. The NIHTB-CB composite score discriminated between the groups and was positively associated with external criteria for cognitive function: parental ratings of intelligence and school performance. Some English vocabulary and/or an unfamiliar cultural context presented challenges. NIHTB-CB was associated with children’s everyday cognitive abilities, though future use may require linguistic and cultural adaptation.

Pediatric Neurology, 2020

BACKGROUND: High rates of cerebrovascular disease (CVD) have previously been described in pediatr... more BACKGROUND: High rates of cerebrovascular disease (CVD) have previously been described in pediatric Human Immunodeficiency Virus (HIV). However, little is known about pediatric CVD in

Epilepsia Open, 2022

ObjectiveThis study describes clinical profiles including human immunodeficiency virus (HIV) dise... more ObjectiveThis study describes clinical profiles including human immunodeficiency virus (HIV) disease history and seizure etiology among children living with HIV presenting with new‐onset seizure during the era of antiretroviral therapy (ART) in Zambia. 30‐day mortality and cause of death are also reported.MethodsChildren living with HIV (CLWHIV) with new‐onset seizures were prospectively evaluated at one large urban teaching hospital and two non‐urban healthcare facilities. Interviews with family members, review of medical records, and where needed, verbal autopsies were undertaken. Two clinicians who were not responsible for the patients' care independently reviewed all records and assigned seizure etiology and cause of death with adjudication as needed.ResultsFrom April 2016 to June 2019, 73 children (49 urban, 24 rural) were identified. Median age was 6 years (IQR 2.2‐10.0) and 39 (53%) were male children. Seizures were focal in 36 (49%) and were often severe, with 37% presen...

ABSTRACTApproximately 10% of youth in sub-Saharan Africa are infected with the Human Immunodefici... more ABSTRACTApproximately 10% of youth in sub-Saharan Africa are infected with the Human Immunodeficiency Virus. In Zambia, it is estimated that over 72,000 children have HIV infection, and despite access to combination antiretroviral therapy, many will experience HIV-associated neurocognitive deficits (HAND) encompassing cognitive and psychiatric sequelae such as global intellectual delay, executive dysfunction, and depressed mood. However, little is known about the neurocognitive profile of such children, the long-term outcomes and impacts of HAND, or the predictors and risk factors for HAND-related impairment. We have initiated the first-ever prospective, longitudinal study of neurocognition in children with HIV-infection in Zambia. Our overarching study goals are to validate cognitive and psychiatric testing tools in children with HIV infection in Zambia, and to determine if inflammatory biomarkers and brain imaging can prospectively identify children at high risk of developing HAND...

Seminars in neurology, 2018

Neurologic disorders contribute significantly to both morbidity and mortality among children in r... more Neurologic disorders contribute significantly to both morbidity and mortality among children in resource-limited settings, but there are a few succinct studies summarizing the epidemiology of neurologic disorders in these settings. A review of available literature was performed to identify data on the prevalence, etiology, outcomes, and treatment of neurologic disorders in children in resource-limited settings. The burden of neurologic disorders in children is high in resource-limited settings. Barriers to optimal care include lack of trained personnel, limited access to diagnostic technology, and limited availability of drugs used to treat common conditions. Several solutions have been suggested to deal with these challenges including increased collaborations to train neurologists willing to practice in resource-limited settings and increased training of physician extenders or community health workers. Further studies are necessary to improve our understanding of the epidemiology o...

JAIDS Journal of Acquired Immune Deficiency Syndromes

Objective: To describe longitudinal outcomes and predictors of cognitive outcomes in children wit... more Objective: To describe longitudinal outcomes and predictors of cognitive outcomes in children with HIV in Zambia. Background: Multiple studies have shown that children with HIV are at risk for impaired cognition. However, there are limited data on longitudinal cognitive outcomes in children with HIV. Methods: We conducted a prospective cohort study of 208 perinatally infected children with HIV ages 8–17 years, all treated with antiretroviral therapy, and 208 HIV-exposed uninfected controls. Participants were followed for 2 years. Cognition was assessed with a custom NIH Toolbox Cognition Battery, and tests were combined to generate a Summary Cognition Score (SCS). The contribution of potential risk factors to outcomes was explored using regression models and group-based trajectory modeling. Results: HIV was strongly associated with lower SCS at baseline [β-14, 95% confidence interval (CI): −20 to −7, P < 0.001]. Change scores over time were similar between groups, but poorer aver...

Journal of Acquired Immune Deficiency Syndromes, 2022

Background:Multiple prior studies have identified a detrimental effect of pediatric HIV on cognit... more Background:Multiple prior studies have identified a detrimental effect of pediatric HIV on cognitive function. Socioeconomic status (SES) is one of the strongest predictors of cognitive performance, and may affect the relationship between HIV and cognition.Methods:As part of the ongoing HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) study, a prospective cohort study, we recruited 208 participants with HIV and 208 HIV-exposed uninfected controls, all aged 8–17 years. A standardized questionnaire was administered to assess SES, and all participants had comprehensive neuropsychological testing. An NPZ8 score was derived as a summary measure of cognitive function. Logistic and linear regression were utilized to model the relationship between SES and cognitive function, and mediation analysis was used to identify specific pathways by which SES may affect cognition.Results:Children with HIV performed significantly worse on a composite measure of cognitive function (NPZ8 score −0.19 vs. 0.22, p <0.001) and were more likely to have cognitive impairment (33% vs. 19%, p=0.001). Higher SES was associated with reduced risk of cognitive impairment (OR 0.8, 95% CI 0.75–0.92, p<0.001) in both groups, with similar effects in children with HIV and HEU groups. SES was more strongly correlated with NPZ8 score in children with HIV than in uninfected controls (Pearson’s R 0.39 vs 0.28), but predicted NPZ8 in both groups. Mediation analysis suggested that the effect of SES on cognition was most strongly mediated through malnutrition.Conclusion:Cognitive function is strongly correlated with SES in children with HIV, suggesting a synergistic effect of HIV and poverty on cognitive function.

Journal of Acquired Immune Deficiency Syndromes, 2022

Background:Multiple prior studies have identified a detrimental effect of pediatric HIV on cognit... more Background:Multiple prior studies have identified a detrimental effect of pediatric HIV on cognitive function. Socioeconomic status (SES) is one of the strongest predictors of cognitive performance, and may affect the relationship between HIV and cognition.Methods:As part of the ongoing HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) study, a prospective cohort study, we recruited 208 participants with HIV and 208 HIV-exposed uninfected controls, all aged 8–17 years. A standardized questionnaire was administered to assess SES, and all participants had comprehensive neuropsychological testing. An NPZ8 score was derived as a summary measure of cognitive function. Logistic and linear regression were utilized to model the relationship between SES and cognitive function, and mediation analysis was used to identify specific pathways by which SES may affect cognition.Results:Children with HIV performed significantly worse on a composite measure of cognitive function (NPZ8 score −0.19 vs. 0.22, p <0.001) and were more likely to have cognitive impairment (33% vs. 19%, p=0.001). Higher SES was associated with reduced risk of cognitive impairment (OR 0.8, 95% CI 0.75–0.92, p<0.001) in both groups, with similar effects in children with HIV and HEU groups. SES was more strongly correlated with NPZ8 score in children with HIV than in uninfected controls (Pearson’s R 0.39 vs 0.28), but predicted NPZ8 in both groups. Mediation analysis suggested that the effect of SES on cognition was most strongly mediated through malnutrition.Conclusion:Cognitive function is strongly correlated with SES in children with HIV, suggesting a synergistic effect of HIV and poverty on cognitive function.

AIDS and Behavior, 2021

Depression is common among people living with HIV. Multiple studies demonstrate a link between de... more Depression is common among people living with HIV. Multiple studies demonstrate a link between depression and cognitive dysfunction in adults with HIV, but the association has been minimally investigated in children and adolescents with HIV in Africa. We conducted a cross-sectional analysis as part of the HIV-associated Neurocognitive Disorders in Zambia study, a prospective cohort study in Lusaka, Zambia. We included 208 perinatally-infected children with HIV ages 8-17 taking antiretroviral therapy and 208 HIV-exposed uninfected (HEU) controls. Cognition was assessed with a comprehensive neuropsychological battery. Depressive symptoms were evaluated using self-report and parent-report versions of the NIH Toolbox Sadness module and the Patient Health Questionnaire-9 (PHQ-9). Risk factors for depression and associations between depressive symptoms and cognition were evaluated in bivariable and multivariable regression models. Participants with HIV demonstrated higher levels of depressive symptoms than controls (mean NIH Toolbox Sadness T-Score 50 vs. 44, p < 0.01; mean PHQ-9 score 2.0 vs. 1.5, p = 0.03), and were more likely to have cognitive impairment (30% vs. 13%, p < 0.001). Risk factors for depressed mood included self-reported poor health (OR 7.8, p < 0.001) and negative life events (OR 1.3, p = 0.004) Depressed mood was associated with cognitive impairment in participants with HIV (OR = 2.9, 95% CI 1.2-7.2, p = 0.02) but not in HEU participants (OR 1.7, 95% CI 0.18-15.7, p = 0.6). In conclusion, depressed mood is common among youth with HIV in Zambia, and is associated with cognitive impairment. Depression may be a result of HIV-related stress and stigma, or may be part of the spectrum of HIV-associated neurocognitive disorders. The causal relationship between depressed mood and cognitive impairment is unclear and should be evaluated in future longitudinal studies.

Journal of the Pediatric Infectious Diseases Society, 2021

Background Place-based inequalities, such as exposure to violence and access to nutritious food a... more Background Place-based inequalities, such as exposure to violence and access to nutritious food and clean water, may contribute to human immunodeficiency virus (HIV)-associated cognitive impairment. In this study, we investigated neighborhood effects on cognition in children and adolescents with HIV in Lusaka, Zambia. Methods We conducted a prospective cohort study of 208 children with perinatally acquired HIV (ages 8–17) and 208 HIV-exposed uninfected controls. Participants underwent neuropsychological testing and interviews assessing socioeconomic status. Geographic regions with clusters of participants with HIV and cognitive impairment were identified using quantitative geographic information systems (QGIS) and SaTScan. Associations between location of residence and cognitive function were evaluated in bivariable and multivariable regression models. Mediation analysis was performed to assess direct and indirect effects of location of the residence on cognitive impairment. Results...

BackgroundWe aimed to define the clinical and mutational spectrum, and to provide novel molecular... more BackgroundWe aimed to define the clinical and mutational spectrum, and to provide novel molecular insights into DHX30-associated neurodevelopmental disorder.MethodsClinical and genetic data from affected individuals were collected through family support group, GeneMatcher and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays.ResultsWe identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe...

Pediatric Neurology, 2019

Background: Neurocysticercosis is the most common parasitic infection of the brain and a leading ... more Background: Neurocysticercosis is the most common parasitic infection of the brain and a leading cause of epilepsy in resource-limited settings. Although neurocysticercosis and human immunodeficiency virus coinfections have commonly been reported, there are few data on how they interact. As part of an observational study of human immunodeficiency virus and cognition in Lusaka, Zambia, we identified a cluster of subjects with neurocysticercosis. We hypothesized that the neighborhood of residence may be an important factor driving clustering of neurocysticercosis and used a geographic information systems approach to investigate this association. Methods: A total of 34 subjects with human immunodeficiency virus and 13 subjects without human immunodeficiency virus (aged eight to 17 years) enrolled in the HIV-Associated Neurocognitive Disorders in Zambia study, had magnetic resonance imaging of the brain performed, and were evaluated for neurocysticercosis. Quantitative geographic information systems was utilized to investigate the relationship between neighborhood of residence, HIV, and neurocysticercosis. Results: Three of 34 subjects with human immunodeficiency virus (8.82%) and one of 13 controls were found to have neurocysticercosis. Geographic cluster analysis demonstrated that all subjects with neurocysticercosis were clustered in two adjacent neighborhoods (Chawama and Kanyama) with lower rates of piped water (Chawama: 22.8%, Kanyama: 26.7%) and flush toilets (Chawama: 14.0%, Kanyama: 14.0%) than the surrounding neighborhoods. Conclusion: We describe a cluster of patients with both neurocysticercosis and human immunodeficiency virus in Lusaka. Cases of neurocysticercosis clustered in neighborhoods with low rates of piped water and limited access to flush toilets. Geographic information systems may be a useful approach for studying the relationship between human immunodeficiency virus and neurocysticercosis. Larger studies are necessary to further investigate this association.

AIDS (London, England), Jan 15, 2018

Neurological conditions associated with HIV remain major contributors to morbidity and mortality ... more Neurological conditions associated with HIV remain major contributors to morbidity and mortality and are increasingly recognized in the aging population on long-standing combination antiretroviral therapy (cART). Importantly, growing evidence shows that the central nervous system (CNS) may serve as a reservoir for viral replication, which has major implications for HIV eradication strategies. Although there has been major progress in the last decade in our understanding of the pathogenesis, burden, and impact of neurological conditions associated with HIV infection, significant scientific gaps remain. In many resource-limited settings, antiretrovirals considered second or third line in the United States, which carry substantial neurotoxicity, remain mainstays of treatment, and patients continue to present with severe immunosuppression and CNS opportunistic infections. Despite this, increased global access to cART has coincided with an aging HIV-positive population with cognitive sequelae, cerebrovascular disease, and peripheral neuropathy. Further neurological research in low-income and middle-income countries (LMICs) is needed to address the burden of neurological complications in HIV-positive patients, particularly regarding CNS viral reservoirs and their effects on eradication.

American journal of human genetics, May 3, 2018

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic hetero... more Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic r...

American journal of human genetics, Jan 2, 2017

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification ... more Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 varian...

Journal of Child Neurology, 2014

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

Seminars in Pediatric Neurology, 2014

Cerebral palsy is a common neurologic problem in children and is reported as occurring in approxi... more Cerebral palsy is a common neurologic problem in children and is reported as occurring in approximately 2-2.5 of 1000 live births globally. As is the case with many pediatric neurologic conditions, very little has been reported on this condition in the African context. Resourcelimited settings such as those found across the continent are likely to result in a different spectrum of etiologies, prevalence, severity as well as management approaches. This review aims to establish what has been reported on this condition from the African continent so as to better define key clinical and research questions.

The American Journal of Tropical Medicine and Hygiene

ABSTRACT. Lumbar puncture (LP) and cerebrospinal fluid (CSF) diagnostics are critical for evaluat... more ABSTRACT. Lumbar puncture (LP) and cerebrospinal fluid (CSF) diagnostics are critical for evaluating central nervous system infections but are often not conducted, resulting in the “Tap Gap.” To investigate patient, provider, and health systems factors contributing to the Tap Gap in Zambia, we conducted focus group discussions with adult caregivers of hospitalized inpatients and in-depth interviews with nurses, clinicians, pharmacy workers, and laboratory staff. Transcripts were independently thematically categorized by two investigators using inductive coding. We identified seven patient-related factors: 1) alternative understandings of CSF; 2) alternative information about LPs, including misinformation; 3) mistrust of doctors; 4) consent delays; 5) fear of blame; 6) peer pressure against consent; and 7) association between LP and stigmatized conditions. Four clinician-related factors were identified: 1) limited LP knowledge and expertise, 2) time constraints, 3) delays in LP reque...

AIDS and Behavior

The objective of this study was to validate the NIH Toolbox Cognition Battery (NIHTB-CB) in Zambi... more The objective of this study was to validate the NIH Toolbox Cognition Battery (NIHTB-CB) in Zambian children with and without HIV-infection. Children living with HIV and HIV-exposed, uninfected (HEU) children completed traditional neuropsychological and NIHTB-CB tasks. Using pairwise correlation and a linear regression model we measured associations between traditional measure composite scores and parental ratings of children’s abilities, and NIHTB-CB scores. A Receiver Operating Characteristic (ROC) curve was developed to identify participants with impairment. 389 children, 8–17 years old participated. NIHTB-CB and traditional measures converged well as a whole and when comparing analogous individual tests across the two batteries. The NIHTB-CB composite score discriminated between the groups and was positively associated with external criteria for cognitive function: parental ratings of intelligence and school performance. Some English vocabulary and/or an unfamiliar cultural context presented challenges. NIHTB-CB was associated with children’s everyday cognitive abilities, though future use may require linguistic and cultural adaptation.

Pediatric Neurology, 2020

BACKGROUND: High rates of cerebrovascular disease (CVD) have previously been described in pediatr... more BACKGROUND: High rates of cerebrovascular disease (CVD) have previously been described in pediatric Human Immunodeficiency Virus (HIV). However, little is known about pediatric CVD in

Epilepsia Open, 2022

ObjectiveThis study describes clinical profiles including human immunodeficiency virus (HIV) dise... more ObjectiveThis study describes clinical profiles including human immunodeficiency virus (HIV) disease history and seizure etiology among children living with HIV presenting with new‐onset seizure during the era of antiretroviral therapy (ART) in Zambia. 30‐day mortality and cause of death are also reported.MethodsChildren living with HIV (CLWHIV) with new‐onset seizures were prospectively evaluated at one large urban teaching hospital and two non‐urban healthcare facilities. Interviews with family members, review of medical records, and where needed, verbal autopsies were undertaken. Two clinicians who were not responsible for the patients' care independently reviewed all records and assigned seizure etiology and cause of death with adjudication as needed.ResultsFrom April 2016 to June 2019, 73 children (49 urban, 24 rural) were identified. Median age was 6 years (IQR 2.2‐10.0) and 39 (53%) were male children. Seizures were focal in 36 (49%) and were often severe, with 37% presen...

ABSTRACTApproximately 10% of youth in sub-Saharan Africa are infected with the Human Immunodefici... more ABSTRACTApproximately 10% of youth in sub-Saharan Africa are infected with the Human Immunodeficiency Virus. In Zambia, it is estimated that over 72,000 children have HIV infection, and despite access to combination antiretroviral therapy, many will experience HIV-associated neurocognitive deficits (HAND) encompassing cognitive and psychiatric sequelae such as global intellectual delay, executive dysfunction, and depressed mood. However, little is known about the neurocognitive profile of such children, the long-term outcomes and impacts of HAND, or the predictors and risk factors for HAND-related impairment. We have initiated the first-ever prospective, longitudinal study of neurocognition in children with HIV-infection in Zambia. Our overarching study goals are to validate cognitive and psychiatric testing tools in children with HIV infection in Zambia, and to determine if inflammatory biomarkers and brain imaging can prospectively identify children at high risk of developing HAND...

Seminars in neurology, 2018

Neurologic disorders contribute significantly to both morbidity and mortality among children in r... more Neurologic disorders contribute significantly to both morbidity and mortality among children in resource-limited settings, but there are a few succinct studies summarizing the epidemiology of neurologic disorders in these settings. A review of available literature was performed to identify data on the prevalence, etiology, outcomes, and treatment of neurologic disorders in children in resource-limited settings. The burden of neurologic disorders in children is high in resource-limited settings. Barriers to optimal care include lack of trained personnel, limited access to diagnostic technology, and limited availability of drugs used to treat common conditions. Several solutions have been suggested to deal with these challenges including increased collaborations to train neurologists willing to practice in resource-limited settings and increased training of physician extenders or community health workers. Further studies are necessary to improve our understanding of the epidemiology o...

JAIDS Journal of Acquired Immune Deficiency Syndromes

Objective: To describe longitudinal outcomes and predictors of cognitive outcomes in children wit... more Objective: To describe longitudinal outcomes and predictors of cognitive outcomes in children with HIV in Zambia. Background: Multiple studies have shown that children with HIV are at risk for impaired cognition. However, there are limited data on longitudinal cognitive outcomes in children with HIV. Methods: We conducted a prospective cohort study of 208 perinatally infected children with HIV ages 8–17 years, all treated with antiretroviral therapy, and 208 HIV-exposed uninfected controls. Participants were followed for 2 years. Cognition was assessed with a custom NIH Toolbox Cognition Battery, and tests were combined to generate a Summary Cognition Score (SCS). The contribution of potential risk factors to outcomes was explored using regression models and group-based trajectory modeling. Results: HIV was strongly associated with lower SCS at baseline [β-14, 95% confidence interval (CI): −20 to −7, P < 0.001]. Change scores over time were similar between groups, but poorer aver...

Journal of Acquired Immune Deficiency Syndromes, 2022

Background:Multiple prior studies have identified a detrimental effect of pediatric HIV on cognit... more Background:Multiple prior studies have identified a detrimental effect of pediatric HIV on cognitive function. Socioeconomic status (SES) is one of the strongest predictors of cognitive performance, and may affect the relationship between HIV and cognition.Methods:As part of the ongoing HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) study, a prospective cohort study, we recruited 208 participants with HIV and 208 HIV-exposed uninfected controls, all aged 8–17 years. A standardized questionnaire was administered to assess SES, and all participants had comprehensive neuropsychological testing. An NPZ8 score was derived as a summary measure of cognitive function. Logistic and linear regression were utilized to model the relationship between SES and cognitive function, and mediation analysis was used to identify specific pathways by which SES may affect cognition.Results:Children with HIV performed significantly worse on a composite measure of cognitive function (NPZ8 score −0.19 vs. 0.22, p <0.001) and were more likely to have cognitive impairment (33% vs. 19%, p=0.001). Higher SES was associated with reduced risk of cognitive impairment (OR 0.8, 95% CI 0.75–0.92, p<0.001) in both groups, with similar effects in children with HIV and HEU groups. SES was more strongly correlated with NPZ8 score in children with HIV than in uninfected controls (Pearson’s R 0.39 vs 0.28), but predicted NPZ8 in both groups. Mediation analysis suggested that the effect of SES on cognition was most strongly mediated through malnutrition.Conclusion:Cognitive function is strongly correlated with SES in children with HIV, suggesting a synergistic effect of HIV and poverty on cognitive function.

Journal of Acquired Immune Deficiency Syndromes, 2022

Background:Multiple prior studies have identified a detrimental effect of pediatric HIV on cognit... more Background:Multiple prior studies have identified a detrimental effect of pediatric HIV on cognitive function. Socioeconomic status (SES) is one of the strongest predictors of cognitive performance, and may affect the relationship between HIV and cognition.Methods:As part of the ongoing HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) study, a prospective cohort study, we recruited 208 participants with HIV and 208 HIV-exposed uninfected controls, all aged 8–17 years. A standardized questionnaire was administered to assess SES, and all participants had comprehensive neuropsychological testing. An NPZ8 score was derived as a summary measure of cognitive function. Logistic and linear regression were utilized to model the relationship between SES and cognitive function, and mediation analysis was used to identify specific pathways by which SES may affect cognition.Results:Children with HIV performed significantly worse on a composite measure of cognitive function (NPZ8 score −0.19 vs. 0.22, p <0.001) and were more likely to have cognitive impairment (33% vs. 19%, p=0.001). Higher SES was associated with reduced risk of cognitive impairment (OR 0.8, 95% CI 0.75–0.92, p<0.001) in both groups, with similar effects in children with HIV and HEU groups. SES was more strongly correlated with NPZ8 score in children with HIV than in uninfected controls (Pearson’s R 0.39 vs 0.28), but predicted NPZ8 in both groups. Mediation analysis suggested that the effect of SES on cognition was most strongly mediated through malnutrition.Conclusion:Cognitive function is strongly correlated with SES in children with HIV, suggesting a synergistic effect of HIV and poverty on cognitive function.

AIDS and Behavior, 2021

Depression is common among people living with HIV. Multiple studies demonstrate a link between de... more Depression is common among people living with HIV. Multiple studies demonstrate a link between depression and cognitive dysfunction in adults with HIV, but the association has been minimally investigated in children and adolescents with HIV in Africa. We conducted a cross-sectional analysis as part of the HIV-associated Neurocognitive Disorders in Zambia study, a prospective cohort study in Lusaka, Zambia. We included 208 perinatally-infected children with HIV ages 8-17 taking antiretroviral therapy and 208 HIV-exposed uninfected (HEU) controls. Cognition was assessed with a comprehensive neuropsychological battery. Depressive symptoms were evaluated using self-report and parent-report versions of the NIH Toolbox Sadness module and the Patient Health Questionnaire-9 (PHQ-9). Risk factors for depression and associations between depressive symptoms and cognition were evaluated in bivariable and multivariable regression models. Participants with HIV demonstrated higher levels of depressive symptoms than controls (mean NIH Toolbox Sadness T-Score 50 vs. 44, p < 0.01; mean PHQ-9 score 2.0 vs. 1.5, p = 0.03), and were more likely to have cognitive impairment (30% vs. 13%, p < 0.001). Risk factors for depressed mood included self-reported poor health (OR 7.8, p < 0.001) and negative life events (OR 1.3, p = 0.004) Depressed mood was associated with cognitive impairment in participants with HIV (OR = 2.9, 95% CI 1.2-7.2, p = 0.02) but not in HEU participants (OR 1.7, 95% CI 0.18-15.7, p = 0.6). In conclusion, depressed mood is common among youth with HIV in Zambia, and is associated with cognitive impairment. Depression may be a result of HIV-related stress and stigma, or may be part of the spectrum of HIV-associated neurocognitive disorders. The causal relationship between depressed mood and cognitive impairment is unclear and should be evaluated in future longitudinal studies.

Journal of the Pediatric Infectious Diseases Society, 2021

Background Place-based inequalities, such as exposure to violence and access to nutritious food a... more Background Place-based inequalities, such as exposure to violence and access to nutritious food and clean water, may contribute to human immunodeficiency virus (HIV)-associated cognitive impairment. In this study, we investigated neighborhood effects on cognition in children and adolescents with HIV in Lusaka, Zambia. Methods We conducted a prospective cohort study of 208 children with perinatally acquired HIV (ages 8–17) and 208 HIV-exposed uninfected controls. Participants underwent neuropsychological testing and interviews assessing socioeconomic status. Geographic regions with clusters of participants with HIV and cognitive impairment were identified using quantitative geographic information systems (QGIS) and SaTScan. Associations between location of residence and cognitive function were evaluated in bivariable and multivariable regression models. Mediation analysis was performed to assess direct and indirect effects of location of the residence on cognitive impairment. Results...

BackgroundWe aimed to define the clinical and mutational spectrum, and to provide novel molecular... more BackgroundWe aimed to define the clinical and mutational spectrum, and to provide novel molecular insights into DHX30-associated neurodevelopmental disorder.MethodsClinical and genetic data from affected individuals were collected through family support group, GeneMatcher and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays.ResultsWe identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe...

Pediatric Neurology, 2019

Background: Neurocysticercosis is the most common parasitic infection of the brain and a leading ... more Background: Neurocysticercosis is the most common parasitic infection of the brain and a leading cause of epilepsy in resource-limited settings. Although neurocysticercosis and human immunodeficiency virus coinfections have commonly been reported, there are few data on how they interact. As part of an observational study of human immunodeficiency virus and cognition in Lusaka, Zambia, we identified a cluster of subjects with neurocysticercosis. We hypothesized that the neighborhood of residence may be an important factor driving clustering of neurocysticercosis and used a geographic information systems approach to investigate this association. Methods: A total of 34 subjects with human immunodeficiency virus and 13 subjects without human immunodeficiency virus (aged eight to 17 years) enrolled in the HIV-Associated Neurocognitive Disorders in Zambia study, had magnetic resonance imaging of the brain performed, and were evaluated for neurocysticercosis. Quantitative geographic information systems was utilized to investigate the relationship between neighborhood of residence, HIV, and neurocysticercosis. Results: Three of 34 subjects with human immunodeficiency virus (8.82%) and one of 13 controls were found to have neurocysticercosis. Geographic cluster analysis demonstrated that all subjects with neurocysticercosis were clustered in two adjacent neighborhoods (Chawama and Kanyama) with lower rates of piped water (Chawama: 22.8%, Kanyama: 26.7%) and flush toilets (Chawama: 14.0%, Kanyama: 14.0%) than the surrounding neighborhoods. Conclusion: We describe a cluster of patients with both neurocysticercosis and human immunodeficiency virus in Lusaka. Cases of neurocysticercosis clustered in neighborhoods with low rates of piped water and limited access to flush toilets. Geographic information systems may be a useful approach for studying the relationship between human immunodeficiency virus and neurocysticercosis. Larger studies are necessary to further investigate this association.

AIDS (London, England), Jan 15, 2018

Neurological conditions associated with HIV remain major contributors to morbidity and mortality ... more Neurological conditions associated with HIV remain major contributors to morbidity and mortality and are increasingly recognized in the aging population on long-standing combination antiretroviral therapy (cART). Importantly, growing evidence shows that the central nervous system (CNS) may serve as a reservoir for viral replication, which has major implications for HIV eradication strategies. Although there has been major progress in the last decade in our understanding of the pathogenesis, burden, and impact of neurological conditions associated with HIV infection, significant scientific gaps remain. In many resource-limited settings, antiretrovirals considered second or third line in the United States, which carry substantial neurotoxicity, remain mainstays of treatment, and patients continue to present with severe immunosuppression and CNS opportunistic infections. Despite this, increased global access to cART has coincided with an aging HIV-positive population with cognitive sequelae, cerebrovascular disease, and peripheral neuropathy. Further neurological research in low-income and middle-income countries (LMICs) is needed to address the burden of neurological complications in HIV-positive patients, particularly regarding CNS viral reservoirs and their effects on eradication.

American journal of human genetics, May 3, 2018

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic hetero... more Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic r...

American journal of human genetics, Jan 2, 2017

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification ... more Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 varian...

Journal of Child Neurology, 2014

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

Seminars in Pediatric Neurology, 2014

Cerebral palsy is a common neurologic problem in children and is reported as occurring in approxi... more Cerebral palsy is a common neurologic problem in children and is reported as occurring in approximately 2-2.5 of 1000 live births globally. As is the case with many pediatric neurologic conditions, very little has been reported on this condition in the African context. Resourcelimited settings such as those found across the continent are likely to result in a different spectrum of etiologies, prevalence, severity as well as management approaches. This review aims to establish what has been reported on this condition from the African continent so as to better define key clinical and research questions.