Includes bibliographical references. / The aim of the first study was to measure validity and reliability of two PA questionnaires, the Yale Physical Activity Survey for older adults (YPAS) and the short version of the International Physical Activity Questionnaire (IPAQ), in a group of South African older adults.

Includes abstract. Includes bibliographical references.

Includes bibliographical references. / Heart rate variability (HRV) biofeedback is effective in reducing stress as well as managing chronic disease. It facilitates easy manipulation of HRV, and, therefore, potentially provides a valuable intervention for altering the activity of the autonomic nervous system. The aim of this thesis was to examine the effects of a single 10 minute episode of HRV biofeedback on measures of HRV and EEG during and immediately after the intervention, measures of HRV and cognitive performance during laboratory induced cognitive stress and subjective feelings of anxiety and relaxation states after testing. Eighteen healthy male volunteers (34 ± 6 years) exposed to work-related stress, were randomised into an HRV biofeedback intervention (BIO) and a comparative intervention group (COM).

The Black River Cemetery, located in modern day Athlone (a suburb of Cape Town), was open for burials from 1867 - 1951, serving three Anglican Churches. The recent (2017) excavation of the historic site allowed for the analysis of the exhumed skeletal remains. The outcome of the skeletal analysis is valuable as the lives documented on the skeleton of a past group of people can write the story of individuals and communities that may have otherwise been omitted from the history books. The aim of this study is to describe demography, lifestyle and disease for a group of people living at the Cape between the 18th and early 20th centuries. The excavation of the cemetery yielded 1,305 graves of which 1,050 contained skeletal remains. Skeletal preservation was varied due to taphonomic influences, but overall it was poor with high fragmentation and taphonomic loss of skeletal material. The skeletal analysis performed utilised several well-established methodologies used in bioarchaeological and forensic anthropological disciplines and produced a body of information encompassing the demographics for this historic skeletal sample. Historical research on the Colonial Cape, coupled with the Black River Cemetery history and burial registers was employed to provide the context to the results of the skeletal analysis. The historic research suggests that the community and people buried there were most likely hardworking people of the poorer communities at the Cape in the 18th and 19th century with a division of labour between men and women. In the period of time that the cemetery was receiving burials, multiple social, political and economic changes occurred including; the bubonic (black) plague, Spanish influenza epidemic, the Boer War, the First World War and the Diamond Rush. It also saw the beginnings of racially segregated living and forced relocations. This backdrop provides an interesting landscape on which to view the skeletal analysis. The data analyses showed that the mortality profiles were skewed from the normal profiles determined by Weiss (1973). The sex ratio was skewed toward males indicating a greater mortality risk for men while the age mortality profiles showed a higher child and juvenile mortality and lower old adult mortality than is typically expected in a cemetery assemblage. This is an indicator of the effects of the epidemics and other factors reducing survivability of individuals. The low frequencies of periosteal reactions also may point to the poor survival capability as individuals may have succumbed to infections before the effect would be exhibited on the skeletal material. Pathological and stress indicators also show a sexually dimorphic trend with males exhibiting greater frequencies of degenerative joint disease, fractures, osteophytic growths and rates of dental attrition. Stature analysis showed a sexually homogenous group of people suggesting a lower health status and likely malnourishment or undernutrition. The social environment in which people lived likely contributed to a weakened immune system, and the generally poor health status of the people. The experience of the people living in Black River and the surrounding areas appears to be one of hard, repetitive labour and nutritional stress within an everchanging urban setting.

It is well established that the brain changes dramatically in appearance during gestation and even after birth. Due to the multi-channelled origins and the number of developmental options, the adult venous system is characterised by a higher incidence of anatomical variations than the arterial system. Limited information is available on anatomical variation of the complete cerebral venous system. It is important to have an understanding of the usual drainage pattern the cerebral venous system and its anatomical variations to provide a foundation for future studies on anomalous venous structures. The extent to which fetal drainage patterns persist postnatally has yet to be established. The goal of the current study was to accurately describe the cerebral venous drainage patterns, including persistence of fetal drainage patterns in children, adolescents and adults in order to understand anatomical variations and the clinical impact during cerebrovascular interventions. For the current study 302 magnetic resonance images with contrast medium from the Groote Schuur and Red Cross Children's War Memorial Hospitals were retrospectively reviewed. The volumes of the dural venous sinuses were traced using a novel approach developed for the study. The approach included constructing 3D models of the dural venous sinuses and using the tracings for statistical and morphological analyses. No images of children met the inclusion criteria and therefore further analyses of the subset was not possible. Statistical analyses were performed to determine if there are any associations between venous sinus volume and sex, age, cerebral dominance and/or variations. Significant differences were noted for sex, dominance and variations of the cerebral venous system. The confluence of sinuses (CS) showed the most abundant number of variations. Although many studies and classifications have been made regarding the variations of these structures, there is a lack of a comprehensive classification that includes all variations. The goal of the current study was to determine the anatomical variations more comprehensively particularly at the level of the superior sagittal sinus (SSS) and confluence of sinuses. The study improved on the current literature by using contrast enhanced images as opposed to nonenhanced images or results obtained at autopsy. It is also the first study to establish a tracing protocol for venous volume to determine cerebral dominance and describe variations of the dural venous sinuses.

Background: Although sickle cell anaemia (SCA) is genetically characterised by a single point mutation, patients can manifest varying degrees of clinical severity due to various genetic modulators that affect the phenotype of this disease. The co-inheritance of alpha-thalassemia (α-thalassemia) has been associated with a milder phenotype in SCA patients (e.g. lower stoke rate), but could also result in the increase of vaso-occlusive (VOC) pain episodes. There is a scarcity of data on the co-inheritance of α-thalassemia and SCA in Cameroon. The present study explored the correlation between α-thalassemia, haematological indices, and clinical events in Cameroonian SCA patients. Materials and Methods: For this cross-sectional study, a full blood count and clinical phenotype profile was collected for 262 Cameroonian individuals. Restriction fragment length polymorphism - polymerase chain reaction (RFLP-PCR) was performed for the molecular diagnosis of SCA and for the study of the β-globin (HBB) gene cluster haplotypes. Multiplex Gap-PCR was performed to investigate the 3.7kb and 4.2kb α-thalassemia gene deletions.

P. falciparum malaria remains one of the leading public health problems worldwide. The global tally of malaria in 2018 was estimated at 228 million cases and 405, 000 deaths worldwide. African countries disproportionately carry the global burden of malaria accounting for 93% and 94% of cases and deaths, respectively. Even though most infected children recover from P. falciparum malaria, a small subset (~1%) of cases progresses to severe disease and death. Over the last decade, several genome-wide association studies (GWASs) have been conducted in diverse malaria endemic populations to understand the natural host protective immunity against severe malaria that can provide clues for the development of new vaccines and therapeutics. However, beyond identifying association variants, conventional GWAS approaches can't inform the underpinning biological functions. To bridge this gap, we applied various contemporary statistical genetic analytic approaches to malaria GWAS datasets of diverse malaria endemic populations. First, we accessed malaria resistance GWAS datasets of three African populations (N=~11,000) including Kenya, Gambia and Malawi from European Genome Phenome Archive (EGA) through MalariaGEN consortium standard data accession procedures. We explored the challenges of GWAS approaches in the genetically diverse Africa populations and figured out how various advanced statistical genetic methods can be implemented to address these challenges. We investigated single nucleotide polymorphism (SNP) heritability (h2 g) of malaria resistance in the Gambian populations and determined appropriate quality (QC) thresholds to accurately estimate the h2 g in our dataset. Second, we estimated h2 g in the three populations and partitioned the h2 g into chromosomes, allele frequencies and annotations using the genetic relationship-matrix restricted maximum likelihood approaches. We further created African specific reference panel from African population datasets obtained from 1000 Genomes Project and African Genome Variation Project dataset and computed linkage disequilibrium (LD). We used LD information obtained from these reference panels to compute cell-type specific and none cell-type specific enrichments for GWAS-summary statistics meta-analyzed across the three populations. Our results showed for the first time that malaria resistance is polygenic trait with h2 g of ~20% and that the causal variants are overrepresented around protein coding regions of the genome. We further showed that the h2 g is disproportionately concentrated on three chromosomes (chr 5, 11 and 20), suggesting cost-effectiveness of targeting these chromosomes in future malaria genomic sequencing studies. Third, we systematically predicted plausible candidate genes and pathways from functional analysis of severe malaria resistance GWAS summary statistics (N = 17,000) meta-analyzed across eleven populations in malaria endemic regions in Africa, Asia and Oceania. We applied positional mapping, expression quantitative trait locus (eQTL), chromatin interaction mapping and gene-based association analyses to identify candidate severe malaria resistance genes. We performed network and pathway analyses to investigate their shared biological functions. We further applied rare variant analysis to raw GWAS datasets of three malaria endemic populations including Kenya, Malawi and Gambia and performed various population genetic structures of the identified genes in the three endemic populations and 20 world-wide ethnics. Our functional mapping analysis identified 57 genes located in the known malaria genomic loci while our gene-based GWAS analysis identified additional 125 genes across the genome. The identified genes were significantly enriched in malaria pathogenic pathways including multiple overlapping pathways in erythrocyte-related functions, blood coagulations, ion channels, adhesion molecules, membrane signaling elements and neuronal systems. Furthermore, our population genetic analysis revealed that the minor allele frequencies (MAF) of the SNPs residing in the identified genes are generally higher in the three malaria endemic populations compared to global populations. Overall, our results suggest that severe malaria resistance trait is attributed to multiple genes that are enriched in pathways linked to severe malaria pathogenesis. This highlights the possibility of harnessing new malaria therapeutics that can simultaneously target multiple malaria protective host molecular pathways. In conclusions, this project showed that malaria resistance trait is mainly a polygenic trait which is influenced by genes and pathways linked to blood stage lifecycle of P. falciparum. These findings constitute the foundations for future experimental studies that can potentially lead to translational medicine including development of new vaccines and therapeutics. However, ‘-omics' studies including those implemented in this study, are limited to single datatype analysis and lack adequate power to explain the complexity of molecular processes and usually lead to identification of correlations than causations. Thus, beyond singe locus analysis, the future direction of malaria resistance requires a paradigm shift from single-omics to multi-stage and multi-dimensional integrative multi-omics studies that combines multiple data types from the human host, the parasite, and the environment. The current biotechnological and statistical advances may eventually lead to the feasibility of systems biology studies and revolutionize malaria research.

Includes bibliography. / The aim of this thesis was to investigate the extent of peripheral and central components in the development of fatigue during maximal exercise. Fatigue during maximal and supramaximal excercise has traditionally been modelled from the peripheral context of an inadequate capacity to supply metabolic substrate to the contracting muscles to meet the increased energy demand.

The intraparietal sulcus (IPS) is a prominent feature in the parietal lobe and extends posteriorly from the postcentral sulcus through the parietal lobe to end in the occipital. It is involved in visuospatial functions and is known to play a critical role in number processing. Fetal alcohol spectrum disorders (FASD) result from prenatal exposure to alcohol and are particularly prevalent in the Western Cape region of South Africa. Arithmetic is a domain of cognitive function that is particularly sensitive to prenatal alcohol exposure, and effects on arithmetic remain significant after controlling for lower IQ. Magnetic resonance imaging (MRI) was used to investigate the morphology of the IPS and whether this morphology had a relation to the number processing abilities of children prenatally exposed to alcohol in a Western Cape community. Participants were 9 to 14-year-old children from the same community in Cape Town, South Africa, who formed part of a study aimed at investigating the effects of prenatal alcohol exposure (PAE) on brain structure and function particularly during number processing. Mothers were interviewed regarding alcohol consumption during pregnancy using a timeline follow-back approach. The first analysis included designing a protocol for manually parcellating the IPS into two regions of interest (ROI): the medial wall (MIPS) and the lateral wall (LIPS) respectively. The neuroimaging program MultiTracer was used for the manual tracing and to calculate the volume of the cortex of both the MIPS and LIPS. The purpose of this first analysis was to examine the effects of PAE on IPS volume and asymmetry using manual tracing, the relation between IPS volume and number processing performance, and potential moderation by PAE of the relation between IPS volume and number processing performance. Results indicated that when comparing the FAS/PFAS (Fetal Alcohol Syndrome/Partial FAS) children to the controls, PAE had an effect on the left LIPS and higher arithmetic scores were associated with larger bilateral MIPS volumes suggesting that the effect of PAE on math may not be moderated by IPS volume. The left LIPS was significantly smaller in FAS/PFAS individuals when compared by FASD diagnosis, and this remained a trend after controlling for potential confounders. In the second analysis, the automated neuroimaging software program FreeSurfer was used to parcellate the IPS. These volumes were then compared with our previously manually traced volumes. Intra-rater reliability testing was statistically significant for consistency and absolute agreement indicating good retraceability of the designed protocol for manual tracing. Both left and right IPS volumes were significantly larger with the manually traced method compared to automated tracing. The manually traced left IPS yielded stronger results when comparing volumes by diagnostic groups, conversely the automated volumes showed stronger associations with alcohol measures. A possible explanation is that FreeSurfer parcellated the IPS differently to our protocol and does not take into account the extensive variability of the morphology of the sulcus. BrainVoyager QX, another neuroimaging software program was used in the third analysis when looking at the BOLD fMRI data of the participants. For this analysis, the manually traced MIPS and LIPS were subdivided into five ROI's for the left and right hemispheres respectively: (1) the superior MIPS, (2) the medial branch of the MIPS, (3) the inferior MIPS, (4) the superior LIPS, and (5) the inferior LIPS. The percent signal change were calculated for each participant for the proximity judgement (PJ) tasks they performed inside the scanner. Associations of the percent signal change of the ROI's of the PAE children with absolute alcohol per occasion (oz) were all significant even after controlling for IQ except the left inferior LIPS, supporting what is found in the literature. The current findings, in agreement with previous studies, demonstrate that PAE is associated with both structural and functional changes in the brain. While the morphology of the IPS may not moderate the effects of PAE on arithmetic function, some cortical volumes within the IPS were sensitive to PAE. Moreover, altered activation of the IPS in the performance of magnitude comparison tasks was strongly associated with PAE. The IPS is an extremely variable structure whose anatomy is often misunderstood, which emphasises the importance of anatomical knowledge for imaging studies. Future research will refine the protocol for manual tracing of the IPS, which may lead to greater understanding of the functions of the different areas. It is to be hoped that these findings will give more insight into understanding the functioning of children and adults with FASDs and contribute to more effective therapeutic interventions for these individuals.

Rob Henricus Petrus Henst was born on the 12th of March in Schaijk, the Netherlands. He graduated from pre-vocational secondary education (VMBO) in 2005 and continued to study process and laboratory technology at an intermediate vocational educational (MBO) institution. In 2009, Rob started with a Bachelor of Science degree, majoring in Life Science with a minor in Exercise Science. For his undergraduate thesis in 2012, he moved to South Africa where he was introduced to chronobiology in exercise science. In 2013, Rob continued to study in South Africa for his Master of Science (Exercise Science) degree and published his first peer-reviewed article in the Journal of Biological Rhythms. He then developed an interest in sleep and cardiometabolic health, specifically in the context of public health. In 2015, these interests were combined and lead to his current PhD thesis on a sleep behaviour intervention for the betterment of cardiometabolic health. In this year, he also co-founded the business unit Sleep Science within the Sports Science Institute of South Africa to help individuals sleep better. In 2019, Rob moved back to the Netherlands to write the final pages of his PhD thesis.