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Identifying genetic risk factors for highly heterogeneous disorders such as epilepsy remains challenging. Here we present, to our knowledge, the largest whole-exome sequencing study of epilepsy to date, with more than 54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies and generalized and focal epilepsies, whereas most other gene discoveries are subtype specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single-nucleotide/short insertion and deletion variants, copy number variants and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies.

AHEAD feasibility trial assessed the feasibility and acceptability of an 8-session group drumming programme aiming to improve executive function, depression and anxiety symptoms, and perceived social support in adolescents living with HIV in a rural low-income South African setting. Sixty-eight 12- to 19-year-old adolescents participated. They were individually randomised. The intervention arm (n = 34) received weekly hour-long group drumming sessions. Controls (n = 34) received no intervention. Feasibility and acceptability were assessed using rates of: enrolment; retention; attendance; logistical problems; adolescent-reported acceptability. Secondary measures included: five Oxford Cognitive Screen-Executive Function (OCS-EF) tasks; two Rapid Assessment of Cognitive and Emotional Regulation (RACER) tasks; the Self-Reporting Questionnaire-20 (SRQ-20) measuring depression and anxiety symptoms; the Multidimensional Scale of Perceived Social Support (MSPSS). All feasibility criteria were within green progression limits. Enrolment, retention, and acceptability were high. There was a positive effect on adolescent depressed mood with signal for a working memory effect. There were no significant effects on executive function or socio-emotional scales. Qualitative findings suggested socio-emotional benefits including: group belonging; decreased internalised stigma; improved mood; decreased anxiety. Group drumming is a feasible and acceptable intervention amongst adolescents living with HIV in rural South Africa. A full-scale trial is recommended.

OBJECTIVE: Epilepsy is a common, chronic neurological disorder that disproportionately affects individuals living in low- and middle-income countries (LMICs), where the treatment gap remains high and adherence to medication remains low. Community health workers (CHWs) have been shown to be effective at improving adherence to chronic medications, yet no study assessing the costs of CHWs in epilepsy management has been reported.

METHODS: Using a Markov model with age- and sex-varying transition probabilities, we determined whether deploying CHWs to improve epilepsy treatment adherence in rural South Africa would be cost-effective. Data were derived using published studies from rural South Africa. Official statistics and international disability weights provided cost and health state values, respectively, and health gains were measured using quality adjusted life years (QALYs).

RESULTS: The intervention was estimated at International Dollars ($) 123 250 per annum per sub-district community and cost $1494 and $1857 per QALY gained for males and females, respectively. Assuming a costlier intervention and lower effectiveness, cost per QALY was still less than South Africa's Gross Domestic Product per capita of $13 215, the cost-effectiveness threshold applied.

SIGNIFICANCE: CHWs would be cost-effective and the intervention dominated even when costs and effects of the intervention were unfavorably varied. Health system re-engineering currently underway in South Africa identifies CHWs as vital links in primary health care, thereby ensuring sustainability of the intervention. Further research on understanding local health state utility values and cost-effectiveness thresholds could further inform the current model, and undertaking the proposed intervention would provide better estimates of its efficacy on reducing the epilepsy treatment gap in rural South Africa.

BACKGROUND: Sub-Saharan Africa is undergoing an epidemiological transition fueled by the interaction between infectious and cardiovascular diseases. Our cross-sectional study aimed to characterize the spectrum of abnormalities suggesting end-organ damage on ECG and transthoracic echocardiograms (TTE) among older adults with cardiovascular diseases in rural South Africa.

METHODS: The prevalence of ECG and TTE abnormalities was estimated; χ2 analyses and multivariable logistic regressions were performed to test their association with sex, hypertension, and other selected comorbidities.

RESULTS: Overall, 729 ECGs and 155 TTEs were completed, with 74 participants completing both. ECG evaluation showed high rates of left ventricular hypertrophy (LVH, 36.5%) and T wave abnormalities (13.6%). TTE evaluation showed high rates of concentric LVH (31.6%), with moderate-severe (56.8%) diastolic dysfunction. Participants with hypertension showed more cardiac remodeling on ECG by LVH (45.4% versus 22.1%, P<0.01), and TTE by concentric LVH (42.5% versus 8.2%, P<0.01) and increased left ventricular mass (58.5% versus 20.4%, P<0.0001). In multivariable logistic regression, systolic blood pressure remained significantly associated with LVH on ECG (adjusted odds ratio, 1.03 per mm Hg [95% CI, 1.03-1.04], P<0.0001) and increased left ventricular mass on TTE (adjusted odds ratio, 1.04 per mm Hg [95% CI, 1.01-1.06], P=0.001). Male participants (n=326, 40.2%) were more likely than females (n=484, 59.8%) to show ECG abnormalities like LVH (45% versus 30.8%, P<0.01), whereas females were more likely to show TTE abnormalities like concentric LVH (40.8% versus 13.5%, P<0.01) and increased left ventricular mass (58.4% versus 23.1%, P<0.0001). Similar results were confirmed in multivariable models.

CONCLUSIONS: Our findings suggest that cardiovascular diseases are widespread in rural South Africa, with a larger burden of hypertensive heart disease than previously appreciated, and define the severity of end-organ damage that is already underway. Local health systems must adapt to face the growing burden of hypertension, as suboptimal rates of hypertension diagnosis and treatment may dramatically increase the heart failure burden.

This review aimed to determine: whether EF is affected in children and adolescents (2–24-years-old) with perinatal HIV infection, perinatal HIV exposure without infection, and behaviourally acquired HIV. A systematic review (PROSPERO number: CRD42017067813) was conducted using 11 electronic databases (01.01.1981–09.07.2019) and 8 conference websites. Primary quantitative studies with EF scores on cognitive tasks and/or behavioural report measures were included. Meta-analyses were performed by EF subtype and subpopulations compared. 1789 records were found. Sixty-one studies were included in the narrative synthesis; 32 (N = 7884 participants) were included in meta-analyses. There was a distinct pattern of reduced EF in those with perinatal HIV infection on antiretroviral therapy compared to controls: pooled effect sizes were largest for verbal and visuospatial working memory, with smaller effects on planning, inhibitory control and set-shifting. Data were limited for other HIV-affected subpopulations. Perinatal HIV infection is associated with reduced EF with varying effect sizes for the different EF subtypes.

Executive function (EF) may predict sexual risk-taking and HIV risk in young women in rural South Africa. We tested associations between EF and seven risky behavioural outcomes: binge drinking, illicit substance use, unprotected vaginal sex, concurrent sexual relationships, transactional sex, herpes simplex virus type 2 (HSV-2) infection, and HIV infection. We compared EF in young women with HIV to matched controls. 1080 young women underwent cognitive assessments. Better verbal short-term memory was associated with a lower risk of HSV-2 (OR 0.77; 95% CI 0.69, 0.86; p < 0.001). Uncorrected trends (p < 0.05) were better verbal working memory being associated with a lower risk of concurrency, better planning with a lower risk of illicit drug use, and better affective inhibition with a lower risk of transactional sex. 78 participants with sexually acquired HIV were matched with 153 HIV-negative controls and had poorer verbal working memory than controls (Hedge's g = -0.38; 95% CI -0.66, -0.10; p = 0.0076), but this was non-significant after adjustment. EF's contribution to young women's risky behaviour in this context does not hold when stringent statistical corrections are applied, with only verbal short term memory reaching statistical significance as predictor. Replication in other samples is recommended.

Background: NCDs are non-infectious, long-term conditions that account for 40 million deaths per annum. 87% of premature NCD mortality occurs in low- and middle-income countries.

Objective: The aims were:develop methods to provide integrated biosocial accounts of NCD mortality; and explore the practical utility of extended mortality data for the primary health care system.

Methods: We drew on data from research programmes in the study area. Data were analysed in three steps: [a]analysis of levels, causes and circumstances of NCD mortality [n = 4,166] from routine census updates including Verbal Autopsy and of qualitative data on lived experiences of NCDs in rural villages from participatory research; [b] identifying areas of convergence and divergence between the analyses; and [c]exploration of the practical relevance of the data drawing on engagements with health systems stakeholders.

Results: NCDs constituted a significant proportion of mortality in this setting [36%]. VA data revealed multiple barriers to access in end-of-life care. Many deaths were attributed to problems with resources and health systems [21%;19% respectively]. The qualitative research provided rich complementary detail on the processes through which risk originates, accumulates and is expressed in access to end-of-life care, related to chronic poverty and perceptions of poor quality care in clinics. The exploration of practical relevance revealed chronic under-funding for NCD services, and an acute need for robust, timely data on the NCD burden.

Conclusions: VA data allowed a significant burden of NCD mortality to be quantified and revealed barriers to access at and around the time of death. Qualitative research contextualised these barriers, providing explanations of how and why they exist and persist. Health systems analysis revealed shortages of resources allocated to NCDs and a need for robust research to provide locally relevant evidence to organise and deliver care. Pragmatic interdisciplinary and mixed method analysis provides relevant renditions of complex problems to inform more effective responses.

Short, reliable, easily administered executive function (EF) assessment tools are needed to measure EF in low- and middle-income countries, particularly in sub-Saharan Africa given the prevalence of human immunodeficiency virus (HIV)-associated neurocognitive disorder. We administered Oxford Cognitive Screen—Executive Function (OCS-EF) to 932 rural South African females (mean age 19.7 years). OCS-EF includes seven tasks: two hot inhibition tasks (a modified Iowa Gambling Task, emotional go/no-go) and five cool EF tasks, two switching tasks (visuospatial rule-finding, geometric trails) and three working memory tasks (digit recall, selection and figure drawing). We performed confirmatory factor analysis testing whether a three-factor, two-factor hot-cool, two-factor working memory and inhibition/switching, or one-factor EF model fitted the data better. The three-factor (switching, inhibition and working memory) model had the best local and global fit (χ2 (11) 24.21, p = 0.012; RMSEA 0.036; CFI 0.920; CD 0.617). We demonstrated the feasibility of OCS-EF administration by trained laypeople, the tripartite structure of EF amongst adolescent females and the factorial validity of OCS-EF in this population and context. OCS-EF tablet-based cognitive assessment tool can be administered by trained laypeople and is a valid tool for assessing cognition at scale amongst adolescents in rural South Africa and similar environments.

Objective: To understand the risk of HIV acquisition through occupational exposure among rural South African traditional healers, notably via the practice of traditional skin incisions with razors.

Design: A random sample of traditional healers living in South Africa participated in a cross-sectional survey that included a rapid HIV test.

Setting: Rural Bushbuckridge district of Mpumalanga, South Africa.

Participants: Traditional healers.

Intervention: Pretest counseling, posttest counseling, and referral to care if HIV seropositive.

Main outcome measure(s): HIV infection.

Results: Among healers who reported a previous positive test result or accepted an HIV test (96%), HIV prevalence was 30% (95% confidence interval: 23–37%). During their careers, 98% of healers reported conducting at least one ‘vaccination’ (as traditional incisions are called), 32% reported always using gloves when conducting these procedures, 29 (14%) reported patient blood touching their bare skin. Healers who reported exposure to patient blood had a higher HIV prevalence than their nonexposed colleagues (adjusted risk ratio: 2.35, 95% confidence interval: 1.55–3.56, P = 0.001).

Conclusion: Nearly all traditional healers are routinely performing minimally invasive skin incisions that could expose them to patient blood. The lack of training and access to personal protective equipment increase their risk of acquisition of blood–borne pathogens, including HIV. Given the widespread practice of traditional skin incisions across southern Africa, and the higher levels of HIV among traditional healers exposed to patient blood, it is likely that traditional healers are a hitherto unrecognized key population at disproportionate risk of acquiring HIV.

Purpose: The percentage of people who are diagnosed with epilepsy (diagnostic gap), access, receive and adhere (treatment gap) to anti-seizure medication (ASM) in low- and middle- income countries remains low. We explored the epilepsy care cascade, measured the diagnostic and treatment gaps, and examined socio-demographic factors associated with adherence to ASMs in rural South Africa.

Methods: Utilizing a population-based cohort of 311 people with active convulsive epilepsy (ACE) residing in rural northeastern South Africa, a questionnaire was administered to examine associations between demographic and socioeconomic factors and the epilepsy treatment gap. Blood was taken to measure levels of ASMs.

Results: Of the 311 individuals diagnosed, 93 % of individuals reported being previously told they had epilepsy and 94 % reported previously attending a health facility for their epilepsy. ASMs were detected in 138 individuals (76 %) and optimal levels were detected in 67 individuals, resulting in a treatment gap of 63 % (95 % confidence interval [95 %CI]: 56 %-70 %). Self-reported specificity of ASM use was 23 % (95 %CI: 12-39 %) and individuals >= 18 years were significantly more likely to report taking ASM than children and were significantly (p = 0.011) more likely to be adherent.

Conclusion: Most people with epilepsy in rural South Africa had been previously diagnosed with epilepsy and had accessed care for epilepsy, yet the level of ASM adherence remained low, significantly lower amongst children. Understanding ways of improving knowledge of and adherence to ASM in rural South Africa is necessary, especially amongst children. The epilepsy care cascade can be useful in identifying gaps in care and targeting interventions to reduce these gaps.