This ethnographic dissertation argues for reflexive labour practices at Triggerfish Animation Studios in Cape Town, South Africa. Affect is used both as an analytical lens to examine the various social labour processes at Triggerfish, as well as a vitalising medium in reflexivity, which is a form of affect itself. Research was conducted over two months at Triggerfish during January and February 2018, where participant observation was practiced to collect data, along with focus groups and visual diaries collated from participants. The analysis centres on engaging the affective dimension of labour, as well as the ways that affect animates the different relationships that the studio embodies. Employees and management engage with each other through the affective notion of ‘care', and this sustains relationships within a neoliberal labour environment. This sets the context of an affective workplace whose care-economy is carefully balanced and regulated through ‘caring about' and ‘caring for', which has the potential to hide power dynamics, as well as gendered labour expectations. Triggerfish's claims of difference, as well as making a difference, allows them to sell the idea of ‘Africa' through identity claimed as well as identity distanced from. Recognising Triggerfish as a white, historically settler colonial company with an elitist history in a still-segregated society is important, even as the company is also located geographically in the Global South. There is thus the need for reflexivity within the geopolitical relationships involved in creating and selling media. Self-awareness is folded in on itself as an affective medium for understanding the ways that individuals conceptualise service work provided for the Global North, as well as service work provided by the Global North for Triggerfish. This uncovers and allows multiple, sometimes oxymoronic definitions and lived experiences to coexist. I argue that reflexivity at Triggerfish should be encouraged just as it is in Social Anthropology as a discipline. It allows for a multi-dimensional studio that is aware of its history and context, and can therefore make better-informed business decisions and produce better content.

Includes abstract. / Includes bibliographical references. / Pedometers have been demonstrated as a practical tool for measurement and motivation of ambulatory physical activity, typically providing information on volume of steps/day. Recent developments in steps/day research have, however, emphasised the importance of intensity-based steps as part of steps/day recommendations. Such steps/day recommendations are also directed towards current physical activity guidelines, so as to provide further options for achieving guidelines. To complement these developments in steps/day recommendations, technological advancements in pedometry afford the opportunity to provide information on intensity-based steps/day. We therefore use this application to provide further insight into the association between pedometer-based physical activity and fitness and health outcomes. Particular reference is made to intensity-based steps/day, through a series of studies.

Bibliography: leaves 243-298.

Total shoulder arthroplasty (TSA) is the most common surgical solution, that helps in restoring the structural and functional integrity of a diseased glenohumeral (GH) joint with intact rotator-cuff. A 300% increase in the usage of TSA has been observed since 2007, along with 2.5% increase in revision rate. Aseptic glenoid loosening accounts for 37% of postsurgical failures in TSA. Eccentric loading of the prosthetic glenoid cup, leading to the “rocking horse” effect, is one of the prevalent causes of aseptic glenoid loosening. Current anatomical total shoulder prosthesis (ATSP) geometry does not consider all the GH morphometric features, for example the elliptical shape of the humeral head. Moreover, the morphometric studies leading to the initial ATSP design did not consider the GH morphology of any sub-Saharan population. Hence, there exists a gap in understanding of the implications of certain morphometric features on the functionality of a post-TSA GH joint. This thesis had two primary aims to address this gap in knowledge. Firstly, to study the GH morphometric variations between cohorts representing native European (Swiss) and native sub-Saharan (South African) populations. Secondly, to develop anatomically inspired ATSP design concepts and test them using biomechanical and finite element (FE) models, insilico, under standardised testing protocols. The morphometric analysis suggested that an average Swiss humeral head radius of curvature was larger (P<0.05) than the average South African humeral head. By comparing the biological head sizes, across both the populations, with the dimensions of the commercially available humeral heads, it can be inferred that suitable humeral prostheses are currently not available for individuals with head sizes >28mm or <19mm. Considering both the populations, the inherent shape of an average humeral head was found to be elliptical. The thickest region of the head was found to lie in the posterior region and not at the geometric center. Hertzian contact theory was applied to calculate the GH stresses produced by symmetric and asymmetric elliptical heads. Higher concentric stresses (P<0.001), within the acceptable limit for polyethylene, were observed to be imparted by the asymmetric heads. Population-specific musculoskeletal models were developed to study the post-TSA kinematic variation. When an identical range of motion (RoM) was performed by these models, population-specific variation in muscle moment arms was observed. The novel glenoid designs were not found to alter the post-surgical kinematics. FE models of the biradial, compartmental and pear-shaped glenoid implant designs were subjected to compressive and shear loading according to the American Society for Testing and Materials (ASTM). Using the bi-radial the glenoid cup, with thickened posterior-superior surface, anatomically relevant force distribution patterns could be replicated. Compartmentalising the glenoid prosthesis into concentric and eccentric regions with the gaps, proved to be highly beneficial. When compared to a commercially available glenoid prosthesis, the compartmental prosthesis was able to contain the GH forces to the concentric region for longer, delaying the eccentric loading and therefore potentially reducing the “rocking horse” effect. In the light of the above observations, two conclusions can be drawn from this thesis. Firstly, it would be beneficial if population-specific ATSP were made available for natives of certain geographic locations. Secondly, glenoid prosthesis designs could be compartmentalised to contain the GH joint forces within the concentric regions of the cup which might aid in the reduction of post-TSA complications.

Introduction: Substantial research has shown that the inclusion of exercise in cardiac rehabilitation has a favourable effect on many outcome variables, and that exercise should be considered a vital and central component for cardiovascular disease (CVD) rehabilitation. South Africans are facing a growing epidemic of CVD, which has major implications for healthcare services and has placed increasing strain on the already grabbling South African healthcare system. Cost-effective primary and secondary prevention and management strategies are needed to slow down the growing CVD epidemic and relieve strain on health-care systems. The need exists for more evidence to demonstrate that cardiac exercise rehabilitation programmes (CRPs) can significantly reduce readmissions, mortality, comorbidities, and improve quality of life. Aims: The aims of this study were to determine the partial feasibility of a novel CRP in a South African public hospital setting by evaluating the following: 1) The recruitment potential and sample population characteristics of those considered eligible to partake in the exercise component of a novel CRP; and 2) The testretest reliability of the tools utilized for the safe monitoring of the exercise intensity during the prospective CRP. Methods: The recruitment potential and sample population characteristics of the target population were determined via retrospective analysis of a hospital admission patient database spreading over three months. The database was searched for demographic data including age, sex, height, weight, waist circumference and BMI, the admission diagnosis, patient co-morbidities and medications. The test-retest reliability of the monitoring tools was conducted on apparently healthy participants who underwent a series of monitoring measures before and after a 6-min motion test on two separate occasions. The test-retest reliability of each monitoring tool was determined using intraclass correlation coefficients (ICCs), effect size calculation and Bland-Altman plots. Results: One hundred and nine patients (52.2%) were considered ineligible for a CRP, whereas 100 individuals (47.8%) were considered eligible. Significant differences were identified between the eligible and ineligible populations were for four comorbidities and two medications. Twenty-two outcome measures were assessed for reliability, five of which were classified as having “poor” reliability, nine as “moderate”, three as “good” and five as “excellent' according to ICCs. Eighteen measures revealed excellent test-retest reliability, and the remaining 8 measures (Baseline Systolic Blood Pressure; Baseline Diastolic Blood Pressure; Baseline Oxygen Saturation; Immediately Post-Exercise Oxygen Saturation; Immediately Post-Exercise RPE; 5-Minutes Post-Exercise Systolic Blood Pressure; 5-Minutes Post-Exercise Oxygen Saturation; and 5-Minutes Post-Exercise RPE) had showed small effect sizes between 0.2-0.5, which was considered acceptable. Conclusion: The results from the analysis of the recruitment potential from a public hospital setting reveal that approximately 33 patients (100 patients/3 months) will be eligible per CRP intake, and the recruitment potential of eligible patients currently exceeds the prospective resource and staff capacity of the CRP. Further investigation is required to address and resolve the shortcoming in resources to offer the CRP to all eligible participants. The results from the test-retest reliability of the monitoring tools used within the CRP revealed that most of the equipment and measures achieved sound reliability, except for the blood pressure monitors, pulse oximeters and RPE scale. Alternative devices for monitoring blood pressure, oxygen saturation and RPE are recommended.

The challenge of preventing and treating noncommunicable diseases (NCDs) has become a global issue of paramount importance. Climbing obesity rates among children could become a major contributor to the burden of NCDs. While there are numerous factors that contribute to the development of obesity and NCDs, an abundance of research suggests that “sustained inflammation is the common denominator of all chronic disease” (Noland, 2017). Low-grade inflammation is characterized by raised concentrations of inflammatory biomarkers without any overt symptoms (Bonaccio et al., 2017). To date, many studies have demonstrated that unhealthy eating patterns contribute to the development and/or maintenance of low-grade inflammation with particular eating patterns having been categorized as either pro-inflammatory or anti-inflammatory; however, information on the inflammatory potential of the diet of children is sparse, specifically in South Africa. To assess the overall inflammatory potential of an individual's diet, researchers first attempted to provide a tool to classify the inflammatory potential of diets in 2009, with the development of the Dietary Inflammatory Index (DII) tool (Cavicchia et al., 2009). This tool has since been revised and adapted. Key values used in the calculation of the DII include the inflammatory score for each of the 45 parameters in the tool, the mean±SD intake of the population (adults in this case) of each parameter and the mean±SD intake of the actual study sample (Shivappa et al., 2014); however, there is no version of the DII that is suitable for use in children in the South African setting. The aims of this research are: 1) to adapt the DII for application in South African children (the South African Child Dietary Inflammatory Index: the SACDII) (sub-study 1) 2) to apply the SACDII in the investigation of the inflammatory potential of the diet of 1–9-year-old children in two urbanized and economically active provinces in South Africa and the association thereof with sociodemographic, anthropometric, and dietary diversity variables (sub-study 2) SUB-STUDY 1: Adaptation of the DII for use in South African Children Aim: To adapt the DII for application in South Africa by generating a mean±SD intake value for the food parameters on the adult DII (Shivappa et al., 2014) for South African children. Objectives: To identify quantified dietary surveys that involved 1 – 10-year-old South African children published over the last three decades; to obtain the raw data sets (food codes and grams consumed for each food parameter) of identified surveys from the principal investigators (PIs); to generate a nutrient/food data base that includes values for the majority of the 45 food parameters included in the DII (Shivappa et al., 2014); and to combine all raw data obtained and reanalyse the combined data to derive the mean±SD intake of each food parameter using the generated data base.

The ageing process is inevitable and is associated with a progressive decline in physical fitness, functional ability as well as cognitive performance due to the deterioration of the various biological, neuro-physiological and social systems. This may lead to an increased vulnerability for age-related diseases and a dependent lifestyle. In addition to the ageing process, sedentary behaviour is a contributing factor that can lead to decreased functional independence. The decline in physical, functional and cognitive performance with age, along with the increased possibility of becoming sedentary as one gets older may highlight the importance of participating in physical activity to acquire health and wellness benefits as well as to maintain independence. The health and wellness benefits of physical activity have been widely studied within the ageing population. Physical activity can be defined as any bodily movement produced by skeletal muscles that will lead to an increase in resting energy expenditure. According to the World Health Organization guidelines on physical activity, adults should accumulate at least 150 minutes of moderate levels of physical activity or at least 75 minutes of vigorous levels of physical activity throughout the week or an equal combination of both levels. Much of the existing research to date has utilized more conventional physical activity interventions, including the use of various training components such as cardiorespiratory, motor coordination, agility, flexibility, balance and strength. These interventions have been shown to improve physical and cognitive parameters in older adults. In recent times, alternative forms of physical activity interventions such as Tai Chi, Yoga, and Interactive Video Games (IVG) have become increasingly popular among older adults. However, there is limited research on the effectiveness of IVG interventions in older adults, particularly for those with memory complaints. IVG involves combining physical activity and exercise with video game play. It allows the individual to control the “avatar” on screen by using various body movements (e.g. if the individual moves to the right, the onscreen character will also move to the right). This provides an opportunity for individuals to increase their energy expenditure by actively participating in these video games. In addition to increasing energy expenditure, IVG incorporates cognitive skills such as executive function, visuospatial skills, attention, working memory and coordination (hand and eye / foot and eye). Recent review articles have identified that a combination of physical and cognitive training intervention's show greater effects on cognitive performance than single-domain physical and cognitive training and subsequently applied physical and cognitive training. IVG has been shown to intensify the effects of physical exercise by controlling neuroplastic changes via additional cognitive exercise. These neuroplastic changes identified after participation in IVG are referred to as improvements in a specialized neural network and a lower dependency on compensational support. Therefore, IVG combines physical skills and abilities with cognitive skills, creating a cognitively stimulating type of physical activity, which may be different to more conventional physical activity. While these positive neuroplastic changes have been identified in some research studies, the underlying neurophysiological mechanism of IVG on cognitive performance and brain function is still poorly understood. Although some research studies have been conducted showing the potential benefits of IVG on physical function and cognitive performance in different population groups over various time frames, not many studies have investigated whether IVG can improve cognitive function in older persons with memory complaints. In addition, to our knowledge, no other studies have compared IVG to conventional multimodal supervised standing and seated exercise in individuals with memory complaints. Therefore, the aim of this thesis was to determine the effects of a 12-week IVG intervention using the X-Box 360 gaming console with Kinect Sports and Adventures games on cognitive performance in older adults, and specifically, in South African older adults, some with memory complaints. The IVG intervention was compared to a conventional multimodal supervised exercise intervention. We hypothesized that the IVG intervention would show greater improvements in measures of cognitive performance and functional ability than the conventional multimodal exercise intervention. The results showed a significant relationship between the number of the correct responses on the Modified Stroop task and scores on the 6-Item Cognitive Impairment test (r=-0.52, p< 0.001) and Grip Strength (r=0.42, p< 0.01). In addition, a significant inverse association was found between incorrect responses on the Modified Stroop task and Functional Reach (r=-0.45, p< 0.01). The final multivariate regression model included age, Functional Reach and right arm Grip Strength, and described 28% of the variance in performance of the Modified Stroop task. In summary, the study illustrated that measures of physical function were related to cognitive performance in high functioning independent living South African older adults. The extent to which a physical exercise intervention can improve these physical function parameters and its effects on cognitive performance warranted further research within South African older adults. Study 2: The aim of the second study was to explore the feasibility of IVG in South African, normal functioning, healthy older adults. We hypothesized that those individuals with lower functional and cognitive performance would perceive the IVG as more difficult. Twenty normal functioning, healthy community-dwelling older adults with a mean age of 70.5 ±5.5 years were invited to participate in the study. Functional ability was assessed using the Dynamic Balance, ‘Timed Up and Go', Functional Reach and Grip Strength tests while cognitive ability was assessed using the Modified Stroop task. Participants played in an IVG session using the X-Box Kinect Adventures software package which comprised of 5 games, including: 20000 leaks, River Rush, Rally Ball, Reflex Ridge and Halo Popper. Heart rate was recorded throughout the session to measure the intensity while playing the game. An interviewer-administered questionnaire was completed after the IVG session, in which participants reported on their levels of enjoyment and the perceived difficulty of each game during the gaming session, using a Likert scale. The mean resting heart rate for the gaming session was 73.4bpm ±12.6. Rally Ball produced the highest average heart rate of 88.0bpm ±14.4 with 20000 Leaks producing the lowest average heart rate of 82.6bpm ±12.3. The average heart rate response for all games was between 55.2% and 58.7% of age-predicted maximum heart rate, suggesting IVG equates to moderate intensity physical activity according to the American College of Sports Medicine criteria. Non-dominant handgrip strength (kg) was inversely associated with the perceived level of difficulty, (High perceived level of difficulty = 19.5kg; Moderate perceived level of difficulty = 27.0kg; Low perceived level of difficulty = 29.1kg; p=0.034). There were significant relationships between some components of functional ability and cognitive performance with the perceived difficulty of the gaming session. Individuals that perceived the game as more difficult had significantly lower cognitive performance scores than those reporting moderate and low levels of difficulty. Most (95%) participants reported that they were interested in participating in IVG in the future. They perceived the games as fun and enjoyable, as a form of stress reduction and a means to improve physical well-being. In addition, our results indicate that older adults enjoyed the IVG and showed interest in participating regularly. In summary, the study showed that IVG was an enjoyable activity for older adults and associated with functional and physical well-being. Future research is needed to determine if IVG can result in improved health, functional ability and cognitive performance in older adults. Study 3: Therefore, the aim of the third study was to measure the effects of a 12- week IVG intervention, using the X-Box 360 Kinect gaming console on cognitive performance and functional ability in healthy older adults, without any known diagnosis of cognitive impairment. A total of 41 healthy participants with a mean age of 72.7 ±6.6 years were recruited from 4 different retirement homes and clusterrandomized into either the IVG group (n=21) or the Cognitively Stimulating Table Games group (n=20). The IVG group participated in moderate intensity X-Box Kinect Adventure games twice a week for one hour while the comparison group participated in Cognitively Stimulating Table games (Board and Card games) for the same duration. Both groups had high attendance rates with all participants completing all 24 of their respective sessions. Baseline physical activity level was assessed using the Yale Physical Activity Survey. Pre-post measures included the 6-Minute Walk test, Dynamic Balance, Timed Up and Go, Grip Strength, Functional Reach, 6-Item Cognitive Impairment test and the Modified Stroop task. Most participants' highest level of education was at primary school level and the most frequent medical condition was hypertension in both groups. More than half of the participants were prescribed medication for various chronic diseases. Functional Reach was the only significant improvement post intervention in favour of the IVG group (p=0.049). The comparison group's average reaction time for all correct responses improved significantly on the Modified Stroop task post intervention compared to the intervention group. After the variables were log transformed, the comparison group showed significant improvement in average reaction time for all correct responses on the Modified Stroop task (p=0.028). The IVG group showed a significant improvement in balance, measured by the Functional Reach test. Cognitively Stimulating Table Games showed significant improvements in reaction time measures of the Modified Stroop task illustrating benefits of such games on improving cognitive performance. In summary, functional ability and cognitive performance improved for most outcomes in both groups, however, many changes were not statistically significant. Therefore, IVG as an intervention program could serve to preserve cognitive and physical function, especially in high functioning, healthy older adults. The results of the first three studies (chapters 2, 3 and 4) showed that physical function was related to cognitive performance in high functioning, independently living older adults. IVG was identified as a fun and enjoyable activity, a means to improve physical health and it equated to moderate intensity physical activity. Furthermore, a 12-week IVG intervention using the X-Box 360 Kinect gaming console and Kinect Adventures games significantly improved balance in healthy older adults when compared to Cognitively Stimulating Table Games. Cognitively Stimulating Table Games significantly improved executive function measured by the Modified Stroop task post intervention. We also found that most functional ability and cognitive performance outcomes improved after 12-weeks of IVG however, many did not reach a level of significance in our cognitively healthy older adult participants. In South Africa, the prevalence of diagnosed MCI is 27% while research on the prevalence of subjective memory complaints is scares. Previous research from systematic reviews and meta-analysis has shown positive effects of physical activity and exercise on cognitive performance in older adults with MCI and memory complaints. This led us to my fourth study, which aimed to examine the efficacy of IVG in older adults with self-reported and objectively determined memory complaints. A few studies have investigated whether active gaming can improve cognitive performance in older adults with subjective memory complaints, however, to our knowledge; no study has been conducted comparing the benefits of IVG to conventional multimodal supervised exercise in older adults with memory complaints. Study 4: The aim of the fourth study was to determine the effects of a 12-week IVG intervention, using the X-Box 360 gaming console with Kinect Sports games, on cognitive performance in South African older adults with subjective and objectively determined memory complaints. This intervention was compared to a conventional multimodal supervised exercise program that served as the comparison group. We hypothesized that the individuals in the intervention group would show greater improvements in measures of cognitive function and functional ability than the comparison group. Forty-five participants with a mean age of 72.4 ±5.4 years were recruited and screened from 6 retirement homes and cluster-randomized into the IVG group (n=23) or the Conventional Multimodal Supervised Exercise (CM; n=22) group. All participants from both groups completed all 24 of their respective exercise sessions. An interviewer-administered questionnaire was conducted to determine demographic, health and physical activity levels at baseline for each participant. Prepost measurements for physical function included the 6-Minute Walk test, Dynamic Balance, Timed Up and Go and Functional Reach. Cognitive performance was measured by the Mini-Mental State Examination (global cognitive function), N-Back task (working memory) and the Modified Stroop task (executive function). The IVG group demonstrated significant improvements in the total number correct responses on the Modified Stroop task (p=0.028) and for average reaction time of correct colour-words (p=0.024), compared to the CM group. Furthermore, the IVG group showed significant improvements in global cognitive function (p=0.005) measured by the Mini-Mental State Examination (MMSE) when compared to the CM group. Functional ability improved significantly in the IVG group, including the 6-Minute walk (p=0.017), Dynamic Balance (p=0.03), Timed Up and Go (p< 0.001) and Functional Reach (p< 0.001). We concluded that the IVG intervention was more effective than 36 Conventional Multimodal Supervised exercise in improving executive and global cognitive performance and functional capacity in older adults with subjective memory complaints. In summary, measures of physical function which included functional reach, grip strength and dynamic balance were associated with cognitive performance in high functioning older adults. Furthermore, older adults enjoyed participating in IVG as a form of physical activity which was also associated with physical well-being. The feasibility and acceptability of the IVG among older adults prompted the study comparing IVG to table games over a 12-week period in healthy older adults. Both, the IVG intervention and table games were effective in improving functional and cognitive measures in healthy older adults but did not reach a level of statistical significance. Therefore, we conducted a similar study using IVG in older adults with subjective and objectively determined memory complaints to determine its effectiveness on cognitive performance and functional ability. In conclusion, IVG was more effective than conventional multimodal supervised exercise in improving measures of cognitive performance and functional ability in older persons with memory complaints. IVG is recommended to help preserve and maintain quality of life and independent living in healthy older adults residing in low-to-middle income countries such as South Africa while greater cognitive and functional benefits may be achieved in those with some level of memory complaints.

Successful prevention of mother-to-child HIV transmission (PMTCT) programs have reduced the risk of infant HIV infection in South Africa from 8% in 2008 to an estimated 1.4% in 2015, resulting in an increasing population of HIV-exposed uninfected (HEU) children. However, the long-term effects of HIV and antiretroviral therapy (ART) exposure on the developing brain is not well understood. While HEU children perform better than their counterparts living with HIV, they continue to demonstrate greater neurodevelopmental delay than HIV-unexposed uninfected (HUU) children. As a result, neuroimaging studies have looked at the developing brain in this population, however there is little consensus about typical exposure related effects. In addition, it is unclear whether previously reported exposure-related results are directly related to in utero exposure to HIV, or indirectly via family and/or environmental factors. Research focused on newborns allows one to eliminate possible contributions from other factors, clarifying the influence of ART and HIV exposure on the developing brain. This dissertation employs neuroimaging and neurocognitive data in a well-characterized infant cohort to better understand the influence of maternal HIV infection on the uninfected brain. HEU infants were exposed to ART in utero between 3 and 9 months, allowing for the study of potential ART exposure effects of as well as HIV exposure. This dissertation will identify HIV and ART exposure effects on brain structure. In addition, the relationship between neonate brain structural outcomes and cognitive abilities at 9-12 months will be determined to identify potential functional consequences of early structural abnormalities. Chapter two presents an analysis of manually traced subcortical volumes in 120 unexposed uninfected (HUU) and exposed uninfected (HEU) neonates. HEU neonates demonstrated significantly reduced mean caudate volumes bilaterally and left mean putamen volumes relative to HUU neonates. Further analysis revealed the observed differences in basal nuclei volumes were related to duration of ART in utero. Infants exposed to ART throughout pregnancy had similar caudate and putamen volumes compared to their HU counterparts. While infants exposed to ART post conception (from 3 - 8 months in utero) had significantly smaller mean caudate volumes bilaterally, and a trending smaller left putamen volume compared to HUU infants. Chapter three examines the potential functional consequences of HIV/ART volumetric reductions. We modelled manually traced neonatal subcortical volumes with neuropsychological outcomes at 9 - 12 months. Among HUU infants, bilateral pallidum volumes predicted neuropsychological measures across all domains. All volumes, with the exception of bilateral thalamus and vermis, predicted the general quotient score in HUU infants. In contrast, among the HEU infants, volumes did not relate to neuropsychological outcomes with the exception of the caudate, putamen and vermis predicting locomotion scores in the preconception group. While no HIV exposure differences were present in neuropsychological domains, HEU infants recruit alternative subcortical structures compared to typically developing unexposed infants. Chapter four presents a DTI-tractographic analysis of white matter connections between subcortical structures manually traced. HEU demonstrate white matter alterations in two tracts - higher FA between right putamen and left thalamus and higher MD between caudate and thalamus on the right hemisphere. The WM alterations observed in HEU appear to be from roles of both HIV and ART exposure. In contrast to ART dependent subcortical grey matter reductions, the observed white matter alterations are independent of maternal treatment initiation. In addition, we also find associations between unaltered white matter connections and both maternal immune health and ART duration during pregnancy. These results suggest white matter is influenced to varying degrees by HIV and ART exposure, as well as maternal health in pregnancy. Chapter five looks at the possible functional consequences of the reported alterations in white matter integrity. We modelled white matter connections between manually traced neonatal subcortical volumes with neuropsychological outcomes at 9 - 12 months. Similar to chapter 3, within HUU infants, we observed a number of white matter connections predictive of neuropsychological outcomes across all domains. And almost no white matter tracts predicted neuropsychological measures in HEU infants. These results again point to HEU infants recruiting different pathways to perform basic tasks. In conclusion, the results documented in this thesis points to the influence of HIV exposure, ART duration and maternal immune health on fetal brain development. However, these factors impact grey and white matter differently. ART initiated pre-conception was protective of caudate volumes but did not protect two white matter connections, the WM tract between right thalamus and right caudate, and WM that between left thalamus and right putamen. Within HUU neonates, basal ganglia and cerebellar volumes and white matter connections predicted neuropsychological outcomes in late infancy. However, HEU infants did not demonstrate the same associations suggesting they utilize alternate pathways from their HUU peers. While there were no exposure related differences across neuropsychological domains, the long-term functional consequences of altered structural recruitment is unknown. Finally, this thesis adds to the body of literature that early ART in pregnancy is neuroprotective, and that HIV exposure related structural alterations are evident as early as 2 - 4 weeks after birth.

Background: Diabetes mellitus with uncontrolled hyperglycaemia is a major cause of cardiovascular complications and mortality. The developing foetal heart in-utero is particularly susceptible to hyperglycaemia through pathological remodelling, which results in life-long structural abnormalities such as cardiomyopathy and electrical defects like arrhythmias. However, the underlying mechanisms and potential therapeutic drug targets remain unclear. In this study, a cardiac developmental cellular model was used to study hyperglycaemia-induced remodelling. Methods: Mouse embryonic stem cells (mESCs) were differentiated into pulsatile, cardiac-like cells via embryoid body (EB) formation and cultured under baseline- or high glucose conditions. A Ca2+ -sensitive fluorescent dye Fluo-4 was used to measure calcium transients and a voltage-sensitive dye di-4-ANEPPS was used to record action potentials. Cellular biomarkers were detected using immunocytochemistry, confocal microscopy, and Western blotting as well as terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) and 5-ethynyl-2-deoxyuridine (EdU) assay. Results: Undifferentiated mESCs were positive for pluripotent transcription factors Nanog and Oct3/4, whereas the cardiac differentiated mESCs were positive for cardiac proteins troponin T, α-actinin 2, connexin 43, sarco-endoplasmic reticulum calcium ATPase 2 (SERCA 2) and α- and β-myosin heavy chain. Hyperglycaemia decreased the number of beating EBs, their beating rate, and their amplitude of contraction. It also decreased the calcium transient amplitude and the contractile response to ryanodine receptor stimulation by caffeine but did not alter the SERCA 2 expression. The amplitude and duration of action potentials in beating EBs were not altered by hyperglycaemia. However, structural changes included a decrease in EB size and expression of myofilament proteins, α-actinin and α- and β-myosin heavy chain and a disruption of the striated organization of the myofilaments. Hyperglycaemia increased the proportion of TUNEL-positive cells and the expression of the pro-apoptotic marker cytochrome c and decreased the anti-apoptotic protein Bcell lymphoma 2 but did not alter the mitochondrial staining with Mitotracker. It also increased the oxidative stress marker nitrotyrosine but did not alter the extent of EdU nuclear staining nor the expression of the receptor of advanced glycation end-product. The antioxidant n-acetyl cysteine decreased the fraction of hyperglycaemia-induced TUNEL-positive cells and improved the α-actinin striated pattern. Conclusion: Hyperglycaemia suppressed the cardiac differentiation and contractile activity of mESCs as well as disrupted the cardiac myofilament organisation and expression. These effects of hyperglycaemia were likely mediated by mitochondrial-dependent apoptosis triggered by oxidative stress as well as by the abnormalities in calcium signalling. These results have potential clinical implications in foetal diabetic cardiac disease and add novel insights into the mechanistic factors that represent new therapeutic drug targets in the developing foetal heart.

The anatomy of the orbital region is of great importance for many highly specialised clinical disciplines such as ophthalmology, maxillofacial surgery, and neurosurgery. The main source of arterial blood supply to the orbital region is by the ophthalmic artery, a branch of the internal carotid artery, and to a lesser extent by the anastomotic patterns which are formed through the external carotid artery. A range of arterial variations which may be developmental in origin, or which may develop due to pathologies later in life, may affect the ophthalmic artery in terms of its origin, course, and branching. If clinicians are not aware of the variations occurring in this region, the eye of the patient may be at risk of injury during invasive procedures, which may lead to partial or complete visual loss. Up until the present time, there have been only a few cadaveric studies that revealed some of the variant patterns and the overall frequencies of the recorded anastomotic patterns for the orbital blood supply. Whilst the anatomical variations are known, the frequencies of variations in the population are not. Furthermore, no published data exists regarding the variations in the orbital blood supply in a South African population. Therefore, the aim of this study was to investigate the orbital vascular supply within the South Africans of different age groups, to document and describe any variations in anastomotic patterns and record their frequencies. The current study was conducted through dissections of bodies in the Department of Human Biology, University of Cape Town, and patients' angiograms from Groote Schuur Hospital. The angiograms included data obtained from other hospitals within the Cape Town area and were reviewed retrospectively. The dissection sample included six full term fetuses and 63 adults, and the angiograms accounted for 870 individuals. The ophthalmic artery was studied from the point of origin from the internal carotid artery and its course in relation to the optic nerve, and both sides were compared to note any similarities or differences. Statistical analyses were performed to record the frequencies of the patterns of variations and to note whether there were any associations between sex, age, sidedness, and these variations. The results revealed statistically significant associations between age and sex for the patterns of variation. Several variations were noted in the current study. Among the novel findings were those in the origin of the ophthalmic artery from the internal carotid artery, whereby a lateral and inferior origin were recorded in both samples (dissected bodies and angiograms). In addition, it was noted that the ophthalmic artery may take origin from the A2 segment of the anterior cerebral artery, which is also a novel finding. This study, therefore, adds significantly to the current body of knowledge regarding the patterns of arterial supply to the ophthalmic region in a South African sample.