The increasing prevalence of type 2 diabetes mellitus (T2DM) poses a major threat to the health and well-being of South Africans. Effective interventions to inform health planning and policy are hampered by the paucity of accurate national epidemiological data. Although several prevalence studies have been conducted, these estimates are not representative of the South African population or are sub-optimal due to the diagnostic methods employed. To address the lack of accurate and representative prevalence data, the aim of this dissertation is to use robust systematic review methods to collate, synthesise and summarise all T2DM prevalence data in South Africa. The dissertation comprises of four parts. Part A contains the study protocol that was published in BMJ Open in 2018. The protocol outlines the problem statement, motivation and rationale, aim, search strategy and robust systematic methods that were used to conduct the study. Part B provides an overview of T2DM enabling a broader understanding of the disease, with a focus on South Africa and the challenges of obtaining accurate T2DM prevalence estimates. We also describe prevention and management strategies for T2DM, and point to priority actions and approaches to achieve such prevention and management of T2DM. Part C consists of a manuscript that has been formatted for submission to BMJ Open and Part D is an Appendix with supporting information. This part addresses the aim of the dissertation and presents the systematic review "The prevalence of type 2 diabetes in South Africa: A systematic review". The manuscript outlines the rationale and methodologies, together with presenting and discussing the results of the systematic review. Our literature search, which included PubMed, Scopus, Web of Science and African Index Medicus, grey literature and references of included studies identified 1782 articles published in South Africa between January 1997 and May 2019. Of these, 15 met the inclusion criteria and were included in the systematic review. Heterogeneity across studies did not allow for a meta-analysis and a pooled estimate, thus results are described narratively. Some studies failed to report key methodological elements, which limited our ability to accurately appraise study quality. In conclusion, the systematic review highlights the high prevalence of glucose intolerance in South Africa and confirms the paucity of accurate and representative T2DM prevalence data. There is a need for well-designed epidemiological studies that use best-practice, uniform diagnostic methods to assess prevalence. Collaboration between public health scientists, diabetes specialists and policy makers is recommended to enable the collection of reliable national epidemiological data which can guide policy and planning towards effective diabetes prevention and management strategies.

During aetiology of respiratory illnesses, it is widely accepted that infection is preceded by nasopharyngeal (NP) colonisation with bacteria and that NP flora develop early in childhood (during the first year of life). The presence of multiple NP bacteria results in competitive and synergistic associations, however temporal organism interactions have rarely been explored due to limited availability of longitudinal data sets, and the complex statistical methods needed. This study aimed to identify, describe and quantify the temporal interactions existing between selected key bacteria colonizing the nasopharynx in young children (up to 1 year old), and to further compare these patterns in children who go on to develop pneumonia compared to those who do not. The significance of the study, as well as the objectives of the study, methods and data analysis plan are outlined in the study protocol (Part A). A summary of what is currently known about NP bacterial species interactions is presented as part of the literature review (Part B). The primary aim of the literature review was to describe the prevalence of NP carriage of four NP colonizing bacteria of interest: S. pneumoniae, S. aureus, H. influenzae and M. catarrhalis in children, as well as identify any risk factors or confounding associations. The literature review furthermore aimed to identify previously described NP bacterial species interaction patterns, as well as providing a summary of statistical approaches previously employed in the studying bacterial interactions. A manuscript presenting the subsequent analysis of these data is included as Part C. This study was a secondary data analysis of 760 infants enrolled in a birth cohort with NP swabs collected every two weeks for the first year of life and additionally at episodes of lower respiratory tract infections (LRTI). Kaplan-Meier estimates were used to visualize time to first carriage. Generalised estimating equations with a logit link and adjusted for repeated measures were used to estimate the time varying association of NP bacteria carriage with development of pneumonia, while enabling adjustment by key confounders. Markov multi state models (MSMs) were used to describe NP bacterial acquisition with age and estimation of clearance probabilities, new acquisition or persistent acquisition. There were 760 individuals included in the analysis, with a total of 16,346 NP samples available and a median 364 person-days (IQR 346 – 365 person-days). S. pneumoniae was predominant, found in >55% of all samples and demonstrating carriage in >95% of individuals at least once by 12 months of age. S. aureus was both less common (25% of samples and 88% of individuals) but also had a strikingly different pattern of first acquisition compared to the other three organisms, demonstrating a rapid increase in carriage prevalence until approximately four weeks and subsequently decreasing. S. pneumoniae had the highest co-carriage prevalence overall with H. influenzae and M. catarrhalis (both 25%) but this varied by age category. In contrast, co-carriage with S. aureus was less prevalent with either S. pneumoniae (12%), H. influenzae (5%) or M. catarrhalis (6%). Co-carriage frequencies differed considerably by age category, at least partially reflecting the relative prevalence of carriage by age. Carriage and co-carriage rates were similar among those children that experienced LRTI compared to those that did not. Seasonal carriage varied, but to a small extent compared to variance by age. Models adjusting for sex, site, season of birth and age found temporally sustained positive associations between the co-carriages of S. pneumoniae with H. influenzae, and M. catarrhalis, but no association with S. aureus. Clear differences occur in the co-carriage patterns of S. pneumoniae with other organisms. The probability of acquisition of S. pneumoniae is modified by earlier carriage of H. influenzae or M. catarrhalis. Positive H. influenzae carriage increases the probability of acquisition of S. pneumoniae with transition probabilities from 0.15 (95% CI 0.14-0.17) to 0.36 (95% CI 0.17, 0.54) after 28 days of age, compared to the same period probability of acquisition of S. pneumoniae alone at 0.015 (95% CI 0.043-0.076) to 0.088 (95% CI 0.075- 0.10). There is no difference in the clearance of S. pneumoniae related to H. influenzae carriage, but clearance of H. influenzae before 6 months of age is far less likely if coming from a state of co-carriage (probability between 0.04 - 0.07) compared to sole carriage (probability 0.23 - 0.12). The only evidence of differences in clearance probability in the models investigating S. pneumoniae and M. catarrhalis are in the probability of M. catarrhalis clearance before 28d which is 0.24 (95% CI 0.15 - 0.38) if carried alone and only 0.058 (55%CI 0.01 - 0.30) if carried with S. pneumoniae, though these confidence intervals overlap.Through this modelling we found positive sustained interactions between S. pneumoniae and both H. influenzae, and M. catarrhalis, where models indicated that preceding carriage or colonisation with either H. influenzae, and M. catarrhalis may increase the risk of colonisation with S. pneumonia. Timing of carriage and overall prevalence of carriage are in line with other findings in similar populations with overall high exposure to S. pneumoniae, H. influenzae, M. catarrhalis during the first year of life and rapid and early exposure to S. aureus. Carriage, co-carriage and transition frequency did not vary appreciably when comparing children who experienced LRTI in the first year of life compared to those who did not, suggesting that overall exposures are similar, but that further modelling is required to understand the specific timing of associations in relations to LRTI.

Includes bibliographical references. / [Background] Prenatal alcohol exposure can result in a range of permanent birth defects known as Fetal Alcohol Spectrum Disorders (FASD). Fetal Alcohol Syndrome (FAS), which detrimentally affects the neurodevelopmental, physical, and social capabilities of children, is the most severe diagnosis on this scale of disorders. Research suggests that FASD rates exceed FAS in various populations. South Africa’s Western Cape region has one of the highest rates of FAS in the world. [Hypothesis] In populations where the prevalence of full-blown FAS is already known to be high, such as the Western Cape, other, less severe childhood developmental and behavioural disorders may be due to prenatal alcohol exposure. Objectives The aim of this research was to determine the odds of maternal alcohol use in children with behavioural and/or developmental disorders (BDD) in comparison to children free from behavioural disorders. This project also examined the average utilisation of health services by children with BDD as an arm of a larger study on the economic burden of FAS in South Africa. [Methods] Opportunistic sampling was employed to select parents or caretakers of 110 children aged 4 to 12 for interviews at a tertiary children’s public hospital in Cape Town. Health service utilization and maternal alcohol consumption habits were compared between 55 cases, children with BDD and 55 controls, children free from such disorders. Univariate analyses and logistic regression methods were used to determine these associations. [Ethics] The University of Cape Town Research Ethics Committee approved this study. Dr. T. Blake, Senior Medical Superintendent of Red Cross War Memorial Children’s Hospital granted access to Red Cross Hospital. Before each study interview was conducted, informed consent, which emphasized confidentiality of responses and the right to refuse to answer a question or withdraw from the interview, was taken from the adult respondent. We also explained to participants that they would remain anonymous and that their answers would not affect their child’s treatment in the clinics. [Results] BDD were significantly associated with current maternal alcohol consumption, maternal binge drinking in the last six months, and maternal alcohol use six months before pregnancy, but not significantly with reported maternal gestational drinking. The median number of visits to a clinic in the last six months was significantly higher for cases than for controls. [Conclusions] Childhood BDD among our study participants were not attributed to prenatal alcohol exposure. Current maternal alcohol consumption has a significant impact on BDD in children, possibly serving as a proxy for unstable home environments. The competing environmental factors that influence childhood BDD warrants further research.

Staphylococcus aureus is a major human pathogen found worldwide, causing a wide variety of clinical infections. This ranges from skin and soft tissue infections to lifethreatening invasive disease, such as S. aureus bacteraemia (SAB). Despite being a common cause of both community-acquired and hospital-acquired infections, limited evidence exists on the management and outcomes of Staphylococcus aureus bacteraemia (SAB) in resource-limited settings. The aim of this study was to describe a cohort of South African patients with SAB, and explore the factors associated with complicated infection and death. A prospective observational study was performed of patients over the age of 13 years admitted to a South African referral hospital with SAB. Data were analysed using Kaplan Meier survival models and linear regression models. One hundred consecutive SAB infection episodes in 98 patients were included. SAB was healthcare-associated in 68.4%, with 57.6% of these linked to drip site infection; 24.0% of all cases were caused by methicillin-resistant S. aureus (MRSA). Ninety-day mortality was 47.0%, with 83.3% of deaths attributable to SAB. Predictors of 90-day mortality were MRSA (odds ratio (OR) 1.28; 95% confidence interval (CI) 1.0 to 15.1) and the presence of co-morbidities (OR 4.1; 95% CI 1.0 to 21.6). The risk of complicated infection was higher with suboptimal antibiotic therapy (OR 8.5; 95% CI 1.8 to 52.4), female sex (OR 3.8; 95% CI 1.1 to 16.3) and community-acquired infection (OR 7.4; 95% CI 2.0 to 33.1). Definitive antibiotic therapy was suboptimal in 22.6% of all cases. Overall, SAB-related mortality was high. A large proportion of SAB episodes may be preventable, and there is a need for improved antibiotic management in this setting. Part A. The study protocol, as submitted for departmental and ethical approval, is presented here. It includes the background, rationale and methodology of the research done for this mini-dissertation. Part B. A structured literature review is presented of articles pertaining to SAB epidemiology and treatment, with the aim to place this research study in context and identify gaps in research. Part C. A journal-ready manuscript according to the requirements of the International Journal of Infectious Diseases. Appendix. All additional documentation necessary as addendums in the presentation of this mini-dissertation.

Background: The increase in access and coverage of ART, including through prevention of mother-to-child transmission (PMTCT) programmes in Africa, has resulted in the reduction of vertical transmission, which has led to >95% of infants born to women living with HIV (WLHIV) in South Africa being born HIV uninfected. Concerns have however been raised regarding the health and development of HIV exposed and uninfected (HEU) infants. WLHIV in South Africa are more likely to have an unintended pregnancy compared HIV negative women. Unintended pregnancies continue to be a challenge towards the on-going strides and achievement of PMTCT goals. There is however a paucity of data on the investigations in research for the effect of unplanned pregnancy and early child development in South Africa. This research study focused on early infant development health outcomes of HIV exposed but uninfected (HEU).The aim of the study was to investigate the association between the intention of pregnancy among pregnant WLHIV, and the subsequent early child development of their HEU infants in Gugulethu, South Africa. Methods: This study used data from the “Long-term Adherence and Care Engagement” study (LACE; May 2017-Apr 2018), which provided long-term data from women who had initiated antiretroviral therapy (ART) during pregnancy. During pregnancy, the London Measure of Unplanned Pregnancy was used to assess pregnancy intentions. At 36-60 months postpartum, child development was assessed across six developmental domains using the Ages & Stages questionnaire (ASQ). Multivariate Linear regression models were used to examine the association between pregnancy intentions and subsequent child development, with results reported as regression coefficients (β) with 95% confidence intervals (CI). Results: A total of 250 mother-infant pairs completed assessments and were included in analysis. At enrolment, the median age for the women was 28.3 years, and 38% were married and/or cohabiting. Overall, based on the women's responses 58% of pregnancies were categorised as unplanned. Upon analysis, no associations were observed between pregnancy intention and all early child development domains p>0.05. Overall, infants with evidence of early developmental delay that scored below threshold (ASQ-3) were 8% for the gross motor domain, 19% for fine motor, 4% for communication, 15% for problem solving, and 7% for personal social domain. Whilst for the social emotional domain (ASQ: SE-2), two percent of infants scored above threshold and hence, had evidence of early developmental delay. Conclusions: Among women initiating ART during pregnancy, we observed no significant association between pregnancy intention and the early child development of their HEU infants. The findings of this research accentuate the need for targeted strategies towards psychosocial issues, and educational interventions for WLHIV and, for informed fertility decisions. Furthermore, the need for exploration of interventions to encourage infant-parent attachment and interaction for development, as well as the impact of pregnancy intentions on parenting behaviours.

By the 1950s, poliomyelitis (polio) was a major public health and medical issue as it became one of the most communicable diseases for children in the United States and globally. Following the widespread use of vaccinations in the 1950s, and an increased global effort in the late 1980s, cases of polio reduced exponentially in countries that were able to enroll widespread vaccination to their citizens. The elementary pathogenic process includes central nervous system (CNS) involvement which may lead to paralysis in extreme rare circumstances. Through mass-vaccination campaigns and global efforts led by the World Health Organization (WHO), United Nations Children’s Fund (UNICEF), and the Bill & Melinda Gates Foundation, the number of new cases has remained minimal in most of the developed world except in three countries: Pakistan, Afghanistan, and Nigeria. There are multiple reasons why this disease continues to spread in these countries including vaccine-derived disease associated with mutations, geographical logistics, and the presence of anti-vaccine terrorist groups. While this review aims to explore the history, pathogenesis, and epidemiology of polio, a focus will also be placed on why the disease is still prevalent in Pakistan and novel methods that can be taken to ensure that polio is eradicated in the country. The goal should be for poliomyelitis to join the ranks of smallpox and rinderpest, the only two diseases that have ever been completely eradicated through the use of vaccinations and global cooperation.

Introduction Universal access to antiretroviral therapy (ART) during pregnancy and breastfeeding has implications for retention in HIV care and adherence to ART. Retention and adherence may be especially challenging during antenatal and postnatal periods, where women living with HIV have competing responsibilities between infant care, self-care and personal responsibilities. Lifelong ART also highlights the role interconception care (ICC) and preconception care (PCC) interventions can play in improving maternal outcomes. While the latter exist for other health topics, ICC and PCC interventions targeting women living with HIV has the potential to maintain retention in care and adherence to ART during, after, and in between pregnancies. This systematic review evaluates interventions that aim to improve retention and adherence in pregnant and postpartum women. Methods The Cochrane Library; MEDLINE via PubMed; Web of Science; and EBSCOHOST (Africa Wide, Academic Search Premier, CINAHL, PsychArticles, Health Source Nursing Academic, PsychInfo) and conference databases were searched for articles in English published between 1990 to 2020. All study designs, intervention types and geographic locations were included. Data were extracted using a standardized tool, and effect sizes recalculated for all studies. Risk of bias was conducted using tools suited to specific study designs, and the PRECIS-2 tool assessed intervention applicability in real-world settings. The protocol was registered with PROSPERO (ID: CRD42020185196). Results Thirty-one studies were identified, of which 31 and 16 provided retention and adherence data, respectively. No interconception or preconception care interventions were found. Interventions were predominantly from Sub-Saharan Africa, except one from the USA. Intervention types varied and included integration of services, peer support, mhealth and multicomponent interventions. The definitions of retention and adherence used for outcome assessment varied widely across studies, but almost all were scored as pragmatic in real-world settings. Due to high heterogeneity, a narrative approach was used based on study reported data and the effect sizes. Conclusion Overall, heterogeneity of identified studies make definitive recommendations for interventions scale up difficult. Future interventions will benefit from consistent study designs, outcome definitions, outcome measurements, validated tools, and longer retention time points will strengthen the evidence base. Ongoing studies being conducted show promise in addressing some of these points.

Cartas al editor. / Revisión por pares

INTRODUCTION: The effects of maternal subclinical hypothyroidism on pregnancy outcomes are not clear. We performed a cohort study to assess potential associations between maternal thyrotropin (TSH) levels in pregnancy and obstetric and perinatal outcomes. METHODS: Women aged ≥18 years with a singleton gestation seen for prenatal care at Boston Medical Center from 1/1/2007 through 5/22/2014 and their fetuses and infants were included. Women with known thyroid disease or use of thyroid medication or lithium were excluded. Maternal demographics, pertinent medical and obstetric histories, and initial serum TSH levels during pregnancy were assessed in relation to adverse obstetric and perinatal outcomes. Normal TSH values were defined as ≤4mIU/L, low birth weight (LBW) as ≤2500g, and prematurity as gestational age (GA) at birth <37weeks. RESULTS: A total of 8,413 pregnant women (mean age 29.1years, 15% white, 60% black, 13% Hispanic) and their fetuses and infants (mean GA at birth 38.5wks, 52% male, mean birth weight 3.2kg) were included in the analyses. The median (range) TSH level was 1.06 (<0.01–106.41) mIU/L, and 130 women (1.6%) had TSH >4mIU/L. Maternal TSH levels >4mIU/L were associated with increased risks of prematurity (risk ratio (RR) 2.15; 95% confidence interval (CI) 1.14–4.03) and neonatal respiratory distress syndrome (RDS) (RR 2.80; 95% CI 1.01, 7.78) compared to maternal TSH levels ≤4mIU/L. Although not statistically significant, there were increased risks of fetal loss, preeclampsia/eclampsia, and low birth weight associated with TSH levels >4mIU/L (RR 1.54, 95% CI 0.61–3.90; RR 1.45, 95% CI 0.70–2.99; and RR 2.16, 95% CI 0.76–6.13, respectively). TSH levels >4mIU/L were not associated with preterm labor, placental abruption, cesarean section, gestational hypertension, gestational diabetes, or neonatal intensive care unit admission CONCLUSION: Maternal serum TSH concentration >4mIU/L in pregnancy was associated with approximately 2-fold increased risks of prematurity and RDS in offspring. Elevated TSH was also associated with unstable increases in the risk of fetal loss, preeclampsia/eclampsia, and low birth weight. However, more interventional studies are needed to ascertain the benefit of treatment of maternal subclinical hypothyroidism in pregnancy. / 2020-09-28T00:00:00Z

Background: Recent gains in TB control in South Africa are being reversed by drug-resistant tuberculosis (MDR-TB and XDR-TB), which has a high mortality, is a threat to health care workers, and is prohibitively costly to treat. MDR-TB has been supplanted by XDR-TB, resistance beyond XDR-TB, and programmatically incurable TB. Short-term treatment-related outcomes of XDR-TB patients are known to be poor. However, there are no prospective data to inform longterm treatment-related outcomes, design of effective XDR-TB treatment regimens, and public health interventions required to interrupt transmission. In particular, the utility of certain costly drugs, e.g. capreomycin, for the treatment of XDR-TB remain unclear. There are also few data about how these characteristics differ in HIV-infected persons. Finally, little is known about the experiences of patients living with XDR-TB. This thesis aims to provide best practice evidence to promote drug-resistant TB control in high burden TB and HIV syndemic countries. Methods: We prospectively followed two cohorts of adult South African XDR-TB patients who received hospital and community treatment, which included a capreomycin and PAS-based regimen: (i) cohort A (n=107) from 3 provinces were diagnosed between August 2002 and February 2008 (retrospectively identified) and then prospectively followed up till August 2012; (ii) cohort B (n=273) from 2 provinces were prospectively identified between October 2008 and October 2012 and followed up till October 2014. Strain typing and drug susceptibility testing were performed and treatment-related outcomes were determined. In-depth interviews were conducted with therapeutically destitute patients from cohort B (n=12) and were home-discharged from hospital back to the community.