Background: Lung function assessments have become the cornerstone of understanding the ever-increasing burden of non-communicable respiratory conditions worldwide. The introduction of pulmonary function testing (PFT) has made maximal expiratory flow/volume (MEFV) measurements the basis of lung function assessments and spirometry the most widely used diagnostic tool for lung function testing. The effectiveness of spirometry to distinguish between normal and abnormal lung function has been realised in adults; however, there is an observed history of misinterpretation in children. The quality of measurements remains a major concern in children and good quality measurements are critical in the diagnosis of any health condition as well as understanding the burden of abnormal lung function in children in low and middleincome countries (LMICs). Objective: This study describes the quality and variation of spirometry reads for evaluating lung function in children in a Malawian population. Methods: This study was conducted according to a protocol developed and granted ethical approval by the Faculty of Health Sciences Human Research Ethics Committee, University of Cape Town (HREC REF 669/2018). The protocol describes the parent study data collection, project analysis plans and ethical and other considerations. Current literature on lung function using spirometry was systematically reviewed and synthesised. The literature review included primary studies and review articles that included spirometry measurement in children from settings in Africa and other low- and middle- income countries. The descriptive study involves secondary analysis of data contributed by the Children Lung Health study, a cross-sectional survey conducted in Malawi. Spirometry measurements from 802 healthy children aged 6-8 years, inexperienced in performing MEFV manoeuvres, are evaluated. Data in the primary study were collected by means of a structured questionnaire which included items on socio-demographic characteristics and spirometry was performed according to the American Thoracic Society and European Respiratory Society (ATS/ERS) guidelines using an Easy on-PC spirometer in the participant‘s home. The ATS/ERS standards for adults and the modified recommendations for children were applied to evaluate quality. Descriptive statistics were used to describe the quality of spirometry indices and univariable logistic regression to identify and describe variables that are predictors of quality. Results: The findings of the study were that many children (34%) failed to reach the complete ATS/ERS quality standards. The end-of-test criteria (forced expiratory time) was the most difficult to meet for children and if this is not met (i.e. exhalation is not complete), the forced vital capacity (FVC) will be underestimated leading to it being misinterpreted. More than 30% of the children failed to meet the repeatability criteria when the relative differences for FVC and forced expiratory volume in the first second (FEV1) was used, yet they are the most appropriate in paediatric practice as compared to absolute differences. Young children were more likely to produce poor quality spirometry as compared to older children. Conclusion: Young children may perform acceptable spirometry according to the modified ATS/ERS recommendations; however, the quality remains suboptimal. Further modification of the already lowered quality standards, seems to be the viable option, but the implications of this clinically has not been evaluated. Other alternatives need to be explored for this group.

Over 1.3 million individuals die each year from preventable violence. Many of these violent acts are perpetrated by youths. Despite several initiatives, the prevalence of youth violence remains high. Early life lead exposure is a possible cause of aggressive and violent behaviour in young adults. Several aggregate-level and individual-level studies report an increase in risk of violent behaviour with increasing lead exposure. However, the evidence base for the role of lead in violence is conflicting as many other studies did not support this claim. No systematic synthesis of current evidence at the individual level exists to critically assess this association. Therefore, we planned to conduct a systematic review and meta-analysis of studies examining the relationship between lead exposure in early life and the later development of aggressive and violent behaviour in young adulthood at the individual level. Extensive literature searches, including of grey literature, were performed to identify potentially relevant articles. Studies for inclusion were screened by two reviewers and selected using pilot-tested eligibility form. The two reviewers independently assessed risk of bias and carried out data extraction before analysis. A systematic review and meta-analysis of currently available evidence was carried out. Searches were conducted between September 2019 and October 2019. We identified a total of 2182 reports, out of which six studies in 7 publications were eligible. All of the studies were conducted in high income countries, though a few recruited participants from low-income communities. There were varying definitions of violence, ranging from very narrow to wide and the outcomes were measured as either a count or binary variable. Despite the diversity in study settings, the direction of findings was remarkably homogenous. For studies reporting dichotomous variable, the odds of being arrested or convicted for violent behaviour increases with increasing blood lead level (OR 1.13 to 1.16 with each 5µg/dl rise in blood lead) after controlling for other variables. For the studies reporting count outcome, blood lead may explain up to 63% of the variability in arrest or conviction rates after adjusting for co-variates (IRR for each 5µg/dl rise in blood lead level:1.1 to 1.13). Overall, using a random-effect model with restricted maximum likelihood estimation method, blood lead was associated with a higher risk of exhibiting violent behaviour (OR 1.16; 95% CI 1.10 – 1.23). There was insufficient data to perform sensitivity analyses based on study design, quality of studies or conduct a dose response meta-analysis. We found that an increased exposure to lead in childhood is associated with a higher risk of being arrested or convicted for violent behaviour in young adulthood. In this context, environmental lead control may help to reduce the prevalence of aggressive and violent behaviour in young adults and should be integrated into violence prevention strategies. Despite the ubiquity of environmental lead, the importance of violence as a public health and social concern and the considerable debate their association has generated, we found very few good quality studies that reported enough methodological detail for evidence synthesis. More studies with better quality and from different settings need to be conducted.

Background: Sustained engagement in HIV care, including adherence to antiretroviral therapy (ART) and retention in HIV services, is essential to optimize maternal health and prevent perinatal, postnatal and sexual HIV transmission. However, engagement in care remains a substantial challenge for pregnant and postpartum women. Women’s experience of and response to barriers to engagement in care, including ART side effects, transfer of care and mobility, may be altered by the transitions experienced in pregnancy and motherhood, and there have been few quantitative analyses of these risk factors in maternal ART cohorts. The way engagement in HIV care is measured also varies widely and no gold standard measures of ART adherence or retention exist. Composite assessments of adherence and retention, including drug concentrations, longitudinal self-reported adherence, and interlinked routine electronic health data, have not been thoroughly evaluated among African women living with HIV. To address these gaps in knowledge, this thesis investigates novel measures of ART adherence, and evaluates interlinked routine electronic health data to measure retention in a South African maternal ART cohort. It describes maternal engagement in HIV care, and examines barriers to engagement that require consideration specific to maternal ART. Methods: This research included women who initiated ART during pregnancy in a large integrated antenatal care and ART clinic in Gugulethu, South Africa (2013-2014). Until July 2013, only women who met certain clinical criteria (CD4 cell count <350 cells/µL or disease stage III or IV) were eligible for lifelong ART, thereafter guidelines changed to recommend lifelong ART for all pregnant women living with HIV. In this setting, all women receive ART and antenatal care in an integrated clinic during pregnancy and are required to transfer to a general ART clinic postpartum. Data were obtained from questionnaires (including demographics, self-reported ART adherence and self-reported side effects) and blood specimens (for HIV viral load) collected at study visits approximately every three months from pregnancy through 18 months postpartum. One additional visit took place 3-4 years postpartum where blood specimens for drug concentrations were also collected. In parallel, routine electronic data, linked across clinics and data sources including HIV clinical visits, laboratory testing and pharmacy dispensing data, were obtained through 30 months on ART. Findings: Substantial disengagement from care, both non-adherence and non-retention, was observed in all analyses. At least one ART side effect was reported by 97% of women during pregnancy and high overall side effect burden was associated with reported missed ART doses. Retention worsened over the first two years on ART and 21% of women were lost immediately after transfer from the integrated clinic. Women who linked to care spread to multiple different ART clinics after transfer; 21% moved clinics two or more times. Using combined routine medical records, only 59% of women had evidence of accessing routine HIV care in consecutive 12-month windows through 24 months on ART. Among women with viral loads available, attending ≥2 clinics was associated with viraemia. In analyses of ART adherence, TFV-DP in DBS provided a more nuanced adherence measure but plasma efavirenz and tenofovir assays had similar ability to predict viral suppression. Areas under the Receiver Operating Curve were higher for all drug concentrations (all >0.850) compared to self-reported adherence using a cross-sectional three-item scale (0.756). Longitudinal measurement of the same self-reported adherence scale showed that reporting worse adherence on any of three items over consecutive visits could predict viremia (>50 and >1000 copies/mL), particularly among women who were suppressed at the initial visit. Measuring retention using routine interlinked electronic data facilitated tracing of women beyond transfer from the integrated clinic to any clinic where they accessed HIV care postpartum. Estimates of retention varied widely using different retention definitions and data sources. Overall, electronic primary health care data, linked across clinics, performed better than laboratory data alone and was a robust measure for monitoring retention in HIV care. Conclusions: Taken together, these findings underscore a concerning level of disengagement from HIV care during and after pregnancy. Potential ART side effects, required transfer of care, the potential challenges of mobility and the importance of sustained engagement in care beyond pregnancy and breastfeeding, should be emphasised in ART counselling. Drug concentrations in DBS and plasma strongly predict viral suppression, but these data on longitudinal self-reported adherence provide a proof of concept for a low resource interim adherence measure that warrants further investigation in routine care settings with limited resources for viral load or drug concentration testing. Transfer of care and postpartum mobility mean that interlinked data sources are essential to obtain accurate estimates of retention postpartum. Further evaluation of the optimal approaches to transferring maternal ART care and the development of interventions to support engagement both in and beyond the clinic of ART initiation will be critical to sustain maternal engagement in HIV care in the long term.

Hepatitis A is a vaccine preventable disease caused by the Hepatitis A Virus (HAV). Currently, South Africa is classified by the World Health Organization (WHO) as a high hepatitis A endemic region where 90% of children are assumed to be “naturally immunised” following HAV exposure before the age of 10 years old. In high hepatitis A endemic settings, routine vaccination against HAV is not necessary due to high rates of “natural immunization”. Recent data suggest a possible shift from high to intermediate HAV endemicity may be occurring in South Africa. Countries with intermediate HAV endemicity and no routine hepatitis A vaccination program have a high risk of experiencing hepatitis A outbreaks and high costs associated with care. Currently, there is no routine vaccination program against HAV in South Africa. The aim of this PhD was to generate evidence for decision making on whether a routine vaccination program against HAV should be considered for introduction into the South African Expanded Program on Immunizations (EPI-SA). The objectives included gathering context-specific evidence on the epidemiologic features of hepatitis A, clinical characteristics of the disease, hepatitis A vaccine characteristics and cost of case management. Using this evidence, the PhD estimated the future epidemiology of hepatitis A and impacts of routine hepatitis A vaccination scenarios in the country. The PhD's overall methods were informed by the principles of Evidence-Based Vaccinology for developing vaccine recommendations. The project included a mixed-methods approach: systematic reviews, a retrospective clinical folder review, mathematical modelling, and economic evaluation. A dynamic transmission model was built to forecast the future epidemiology of hepatitis A and to simulate the impacts of several different childhood hepatitis A vaccination strategies in South Africa. Selected findings have been published in relevant peer-reviewed journals. In addition, a technical dossier was prepared to submit to the South African National Advisory Group on Immunization (NAGI) on behalf of the Hepatitis A Working Group for considerations of introducing hepatitis A vaccination into the South African EPI.