Birth registration data forms part of vital statistics. It is the right of the child to be registered immediately after birth and to acquire an identity and a nationality as stipulated by the Convention on the Rights of the Child (UNICEF 1989). The assessment of birth registration is important to help authorities in the processes of planning and decision making. This study investigates birth registration data at a district level with the aim to establish the data's usefulness in determining reliable completeness of births and estimating total fertility rate (TFR). The study further analyses the spatial relationships between respective districts to each other based on levels of birth completeness and total fertility rate. The Geographical Information Systems (GIS) technique of the Global Moran's Index spatial autocorrelation is used to examine the spatial distribution of completeness and TFR. The Indirect method of relational Gompertz model is used to calculate robust estimates of actual births that occurred in the twelve-month period before 2011 Census and 2016 Community Survey, respectively. Then, the Hauer and Schmertmann (2020) method of determining fertility was used to validate results from the Gompertz model. The study establishes that there was an improvement in the promptness of birth registration between 2011 and 2016, highlighted by an 82% completeness in 2011 that increased to 85% in 2016 for births that were registered within the same year of occurrence. This is evidence that mothers are registering births at younger ages than before. The TFR decreased from 2.55 in 2011 to 2.28 in 2016. Apart from that, the study illustrated that districts with higher completeness levels tend to be in major urban agglomerations. However, no spatial relationship could be established meaning that the neighbouring districts do not follow any pattern when compared to each other. It was also noted that districts with low fertility are clustered near major cities. Although there are issues with data at lower levels of disaggregation such as districts, it has been shown that the use of robust methods produces results that help to give meaningful insights of birth registration data.

Type 2 diabetes (T2D) is currently one of the major health challenges across the globe. Lifestyle changes are a key component of T2D management and there is growing interest in low carbohydrate high fat (LCHF) diets as a potential dietary strategy to improve glycaemic control, reduce T2D medication requirements, and improve body weight and lipid profiles. However, carbohydrate restriction is controversial. Results from observational studies generally do not support the food choices associated with carbohydrate restriction while results from short-term randomised controlled trials (RCTs) are more likely to show significant benefits of LCHF diets. Additionally, both study designs have limitations and opinion on LCHF diets is polarised due to ambiguities in how to interpret the available data. Chapter 1 of this thesis reviews the impact of prospective cohort studies, randomised controlled trials, and dietary policies on current opinions towards LCHF diets for the management of T2D. Uncertainty over the safety of LCHF diets remains a concern and additional observational studies and short-term RCTs of the same quality as existing research are unlikely to add any further clarity. For this reason, research focused on understanding the underlying mechanisms of carbohydrate restricted diets may be an alternative approach to alleviate or validate some of the concerns being expressed about LCHF diets. One such mechanism is the dysregulation of glucose production via gluconeogenesis, which is a key pathology of T2D but which has been incompletely studied. Indeed, the effects of LCHF eating on gluconeogenesis in T2D patients has not yet been studied, nor has gluconeogenesis been investigated in the context of T2D remission. This is an area of interest for future research and the aim of this thesis was to conduct preliminary studies to prepare the groundwork for such studies. There is large heterogeneity in the low carbohydrate diets that have been prescribed in controlled trials and the composition and characteristics of the LCHF diets that patients are finding effective in the real world is unknown. Study 1 (Chapter 2 of this thesis) aimed to better understand the LCHF diet by investigating the diet, diabetes status, and personal experiences of T2D patients who had self-selected and followed an LCHF diet of their own accord. This study was a multi-method investigation which consisted of quantitative assessments of diet and diabetes status, as well as in-depth interviews which were analysed using qualitative methods. Results from this study will be used to inform design and protocol decisions in future controlled trial studies. Study 2 (Chapter 3 of this thesis) piloted the use of stable isotope tracers for the quantification of endogenous glucose production and gluconeogenesis in the early postabsorptive state (5 hours after a meal). For methodological reasons, prior investigations have usually measured gluconeogenesis after an overnight fast and therefore, little is known about the effects of dietary composition on gluconeogenesis within the early post-absorptive state. Study 2 quantifies gluconeogenesis 5 hours after a meal and the validity of the data is discussed. Finally, Chapter 4 outlines future perspectives for research based on findings from Chapter 2 and Chapter 3.

Ngoepe and Ventikos have developed one of a growing number of computational models of thrombosis of cerebral aneurysms designed with consideration towards clinical use and research. Their model, amongst many others, utilizes computationally inexpensive steady flow conditions. However, pulsatile flow better characterizes blood flow in-vivo. Steady flow is an acceptable approximation of pulsatile flow from a fluid dynamics perspective, but there is no prior evidence suggesting whether it is an acceptable approximation when considering clot formation within a flowing environment. To this end a pulsatile flow model has been created in ANSYS® Fluent, and a function from Ngoepe and Ventikos’s computational model that simulates the release of thrombin, a chemical responsible for clotting activation, has been implemented. The output of this simulation is compared to the output of an otherwise identical simulation utilizing Particle-Image-Velocimetry (PIV) validated steady flow conditions, to determine whether clotting outcome of Ngoepe and Ventikos’s model, amongst others, differs with pulsatile flow This experiment revealed that the concentration of thrombin required for clotting activation is generated in nearly half the time when utilizing pulsatile flow over steady flow. Pulsatile flow creates unsteady flow patterns within the aneurysm, which create an environment where less thrombin is carried out of the aneurysm and into the regular bloodstream. This indicates that steady flow approximations for realistic clotting in computational models of thrombosis of cerebral aneurysms without strong consideration for the effects of pulsatile flow are inaccurate.

Bibliography: p. 400-445. / The aim of this thesis was to investigate the relationship between chronic exercise activity, aging, the neuromuscular system and the symptom of fatigue in a series of studies. The hypothesis of the thesis was that in contrast to the accepted dogma that exercise is beneficial to an individual, increasing longevity and improving quality of life, excessive or chronic exercise activity may accelerate the aging process, lead to neuromuscular damage, and cause the development of pathological symptoms or levels of fatigue.

Includes bibliographical references.

Includes bibliographical references (leaves 126-144).

Includes bibliographical references.

Small-animal imaging has been widely implemented to study succession of disease, therapeutic treatments and the effects of environmental insults. The gold standard noninvasive technique for following progression of heart failure in small-animal models is magnetic resonance imaging (MRI). The aim of this project was to adapt a clinical MRI system to perform small-animal cardiac MRI. The first part of the thesis describes the adaptations required, which included design and construction of a small-animal radiofrequency (RF) coil, physical support (cradle), a core body temperature regulation system, and optimization of pulse sequences. The system was validated using a phantom and in-vivo in 5 healthy rats. The signal-to-noise ratio (SNR) in the phantom was 91% higher using the small-animal coil compared to the standard head coil. SNRs of 7 ± 2 and 18.9 ± 0.6 were achieved in myocardium and blood, respectively, in healthy rats and MR left ventricular mass (LVM) was highly correlated with (r=0.87) with post-mortem mass. In the second part of the study, left ventricular remodeling (LVR) was investigated in a nonreperfused model of myocardial infarction (MI) in 5 sham and 7 infarcted rats. Rats were scanned at 2 and 4 weeks post surgery to allow for global and regional functional and structural analyses of the heart. Images were of sufficient quality to enable semi-automatic segmentation using Segment. Significant increase in end-systolic volume (ESV) was observed in MI rats at 2 weeks post surgery. At 4 weeks post surgery, end-diastolic volume (EDV) and ESV of MI rats were significantly higher than in sham rats. Ejection fraction (EF) of MI rats dropped significantly at 2 weeks and a further significant drop was observed at 4 weeks indicating contractile dysfunction. Wall thickness (WTh) analyses in MI rats at 4 weeks revealed significant reduction in end-diastolic (ED) wall thickness in the anterior region due to necrosis of myocytes. In the posterior region, WTh was significantly higher due to LV hypertrophy. At end-systole (ES), the MI rats revealed significant decrease in WTh in the anterior and lateral regions. MI rats suffered reduction in systolic wall thickening in all regions of the heart, indicating global contractile dysfunction.

Imaging the fetal brain in utero is challenging due to the unpredictable motion of the fetus. Although ultra-fast MRI sequences are able to image a 2D slice in under a second, thus limiting the time in which fetal motion can corrupt images, Cartesian sampling makes these sequences sensitive to signal misregistration and motion-corruption. Corruption of a single 2D slice renders it impossible to reconstruct 3D volumes from these slices without complex slice-to-volume registration. There is a need for motion-robust sequences that can produce high-resolution 3D volumes of the fetal brain. The Siemens Cardiovascular sequence was edited to produce a new radial readout that sampled a 3D spherical volume of k-space with successive diametric spokes. The diameter end points map a spiral trajectory on the surface of a sphere. The trajectory was modified so that multiple sub-volumes of data are sampled during a single acquisition where M is the number of sub-spirals and N is the number of diametric spokes per sub-spiral. This allows reconstruction of individual sub-volumes of data to produce a series of low-resolution navigator images that can be co-registered to provide information on motion during the acquisition. In this way, a segmented sequence suited to self-navigation was developed. Imaging parameters for the 3D radial sequence were optimised based on theoretical calculations and scans performed in adult brains and abdomens. Optimum values for M and N needed to be determined. Increasing M for a constant total number of projections improves the temporal accuracy of motion tracking at the expense of decreased signal to noise ratio in the navigator images. The effects of breathing and rigid body motion on image quality were also compared between 3D radial and equivalent 3D Cartesian acquisitions. Custom reconstruction code was written to separate the incoming scan data according to the sub-spiral trajectories described within the sequence such that individual navigator images could be reconstructed. Successive sub-spiral images were co-registered to the first navigator image to quantify motion during the acquisition. The resulting transformation matrices were then applied to each sub-spiral image after reconstruction and co-registered sub-spiral images combined in image space to generate the final 3D volume. To improve the quality of navigator images, a method is presented to perform navigator image reconstruction at a lower base resolution, thus reducing streaking artifacts and improving the accuracy of image co-registrations. Finally, the methods developed were applied to two fetal scans. The radial sequence was shown to be more motion-robust than an equivalent Cartesian sequence. The minimum number of diametric spokes that provided navigator images that could be accurately co-registered when scanning an adult brain was N=256, which could be acquired in 1.25 s. For abdominal scans, the minimum number of spokes was N=1024, which could be acquired in about 6 s when water excitation is applied. However, the latter could potentially be reduced by reconstructing navigator images at a lower base resolution. Although fetal scans demonstrated poor image contrast, navigator images were able to track motion during the acquisition demonstrating the potential use of this method for self-navigation. In conclusion, a motion-robust radial sequence is presented with potential applications for prospective navigation during fetal MRI.

Breast cancer remains the leading cause of cancer death among women worldwide. This is in part due to late diagnosis, high recurrence rate and the development of drug resistance. Indeed, even though oestrogen receptor-positive breast cancers are known to respond to hormonal therapy, drug resistance is a common occurrence. Furthermore, triple negative breast cancers lack a specific therapeutic target, which has led to poor treatment outcomes. Hence, there is a critical need for new therapeutic approaches. Our laboratory previously identified a novel palladium-based compound, AJ-5, that exhibit potent anti-cancer activity in triple negative and oestrogen receptor-positive breast cancer cells. However, AJ-5 is poorly soluble, therefore, a series of water soluble AJ-5-based compounds were synthesized. The aim of this study was to test and characterise the anti-cancer activity of one of these AJ-5 analogues, BTC2, in triple negative (MDA-MB-231) and oestrogen receptor-positive (MCF7) breast cancer cell lines. Cytotoxicity assays were performed and BTC2 was shown to inhibit the proliferative rates of breast cancer cells with calculated IC50 values of 0.49μM in MCF7 cells and 0.58μM in MDA-MB-231 cells. BTC2 did not display considerable selectivity to breast cancer cells as the calculated IC50 value for the normal fibroblast cell line (FG0) was found to be 0.85μM and thus the selectivity index was less than 2 in both cell lines. Clonogenic assays were performed and BTC2 was shown to inhibit the long term (10 to 21 days) survival of MCF7 and MDA-MB-231 cells as it reduced their colony forming ability. Western blot analyses and immunofluorescence with an antibody to ƴH2AX, a robust marker of DNA double strand breaks, indicated that BTC2 acts by inducing DNA damage as the levels of this protein increased in drug treated cells. Light microscopy revealed that BTC2 induced morphological features of apoptosis (membrane blebbing and cell shrinkage) and autophagy (vacuoles reminiscent of autophagosomes). To further characterise the molecular mechanism underpinning the cytotoxic effects of BTC2, western blotting was performed with antibodies against key protein markers of stress signalling, cell cycle, apoptosis and autophagy. The results indicated that BTC2 activated the p38 MAP kinase signalling pathway and the p53 response in MCF7 cells. It is worth noting that MDA-MB-231 cells have a mutant p53 but that the p53 target protein, p21, was upregulated in both MCF7 and MDA-MB-231 cells. This suggests that p21 is regulated by a p53-independent mechanism in the MDA-MB-231 cells. BTC2 was shown to induce apoptosis and autophagy in both breast cancer cell lines as demonstrated by increased levels of cleaved PARP and LC3-II respectively. Apoptosis was confirmed by Annexin V-FITC/ propidium iodide double staining using flow cytometry. Taken together, data from this study suggest that BTC2 represents a promising anti-cancer drug for the treatment of triple negative and oestrogen receptor-positive breast cancer cells.