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(2023)ThesisAims: The first study investigated the agreement between embryologists when assessing cytoplasmic strings (CS) in human blastocysts. The second study investigated the idea that embryos originating from fresh ejaculate sperm is comparable to those originating from frozen-thawed ejaculate sperm. The third study investigated and expanded on the association between the presence of CS, blastocyst quality and live birth rate. The fourth study used timelapse technology to investigate whether the presence of CS in human blastocysts was associated with a clinical pregnancy. Methods: In the first study, CS activity in one hundred blastocysts was assessed to measure inter- & intra-observer agreement. In the second study, timelapse was used to observe embryo development in those originating from fresh ejaculate sperm compared to those originating from frozen-thawed ejaculate sperm. In the third study, timelapse was used to investigate the association between the presence of CS and their characteristics, with blastocyst quality, development and live birth in one thousand day 5 human blastocysts. In the fourth study, timelapse was used to assess CS presence in blastocysts to investigate the link between those blastocysts that formed a fetal heart after transfer. Results: From the first study, a moderate level of inter and intra observer agreement was observed when five embryologist assessed day 5/6 blastocysts for the presence of CS and their vesicles. From the second study, it was found that no differences were detected in key developmental events between embryos originating from fresh ejaculate sperm compared to their frozen-thawed counterparts. The third study confirmed that CS presence in human blastocysts is associated with blastocyst quality. The fourth study, the presence of CS in human blastocysts was found to be associated with a fetal heart. Conclusions: The first study showed a moderate level of inter- and intra-observer agreement when the presence of CS and their vesicles was assessed. The second study found that there are no differences in the morphokinetic parameters of early embryo development when either fresh or frozen ejaculate sperm was used for ICSI insemination. The third study confirmed that CS presence in human blastocysts is associated with blastocyst quality. The fourth study found that the presence of cytoplasmic strings in human blastocysts is associated with the probability of clinical pregnancy with fetal heart.
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(2023)ThesisFollicular lymphoma (FL) accounts for one-third of incident non-Hodgkin lymphomas in Western countries, but its etiology is largely unexplained. I performed systematic reviews and meta-analyses, and used a population-based family case-control study to investigate the relationship between lifestyle, environmental and occupational risk factors of FL. Meta-estimates from my random-effect models showed a non-significant association with smoking, heterogeneous results for alcohol, modest increased risk with obesity, and positive associations with exposure to polychlorinated biphenyls (PCBs), chlorinated solvents and dichlorodiphenyldichloroethylene (DDT, a pesticide). The population-based case-control study included 770 FL cases and 490 family controls (siblings, partners). Participants completed a lifetime residential and work calendar and health, lifestyle, and diet questionnaires. I used unconditional logistic regression to examine associations with FL risk, including group-based trajectory modeling to examine associations with body shape and outdoor hours over the life course. I identified deaths using record linkage and applied Cox proportional regression to estimate hazard ratios for all-cause and FL-specific mortality. I observed a positive association between smoking and FL risk and mortality. Associations with recent alcohol intake and FL were null. Being obese 5 years prior to enrolment and higher body mass index 5 years prior to enrolment was associated with a modest increased FL risk, but there was no association with body shape trajectory. Body size was not associated with mortality. I observed an elevated FL risk with consumption of oily fish, but no association with mortality. I found no significant association between occupational exposure to pesticides, or extremely-low frequency magnetic fields, and FL risk. For sun exposure, I observed an inverse association with high cumulative outdoor hours and high outdoor hour maintainers over the life course, and FL risk. Policies on tobacco control, maintaining body weight within normal range, and safe use of solvents and pesticides are crucial in reducing the burden from FL. Sun exposure is not recommended as a cancer control policy, but the association may inform research on targeted therapies for this malignancy. My key findings have advanced our understanding of FL etiology and help guide risk reduction strategies and future research.
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(2023)ThesisChronic kidney disease (CKD) affects more than 1/10 people worldwide with a disproportionately high burden in disadvantaged communities. As CKD severity increases, the associated morbidity, mortality and treatment costs also increase. In the case of kidney failure, the most severe form of CKD, the costs of treatment, including life prolonging treatment with dialysis or kidney transplant, are often unaffordable in under-resourced healthcare settings. Data has been central to improving the outcomes of patients with CKD, but there continue to be important data gaps, especially in low- and lower-middle-income countries (LLMICs). In order to more comprehensively understand the burden of kidney disease, it is necessary to overcome the many challenges to data collection which exist globally. To explore how this could be achieved, this thesis examines how four different data sources can contribute to addressing gaps in understanding CKD. Firstly, the role of kidney replacement therapy (KRT) registries in LLMICs were assessed through a review of the literature and explored further by implementing a dialysis registry in Fiji. Secondly, extending data collection of a randomised controlled trial to examine how differing practice patterns across regions might impact outcomes was assessed through analysis of the extended follow-up of the Study of Heart and Renal Protection (SHARP). Thirdly, the role of administrative data was explored through a literature review and through two novel data linkage analyses. Lastly, semi-structured interviews were conducted with patients and clinicians to understand their perspectives on remote patient monitoring (RPM), a novel approach to patient data collection for dialysis treatment. The analyses examining the role of focused KRT registries in LLMICs and the utility of long-term follow-up of clinical trials to compare outcomes between regions suggest that whilst useful at describing the burden of disease and treatment, these data sources are unlikely to be central to solving major knowledge gaps due to their cost and complexity. The use of administrative data and data linkage offer an opportunity for efficient data collection in CKD and may represent a cost-effective investment for developing healthcare systems in the future. Novel data capture techniques, such as RPM, may improve CKD data collection, but a thorough understanding of the perspectives of user populations should be considered before their wider implementation.
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(2024)ThesisSuicide is a leading cause of death among young people, both globally and within Australia. Digital mental health interventions (DMHIs) have emerged as a potential solution that may curb suicide rates through mitigating suicidal ideation. However, poor engagement has hindered the adoption of DMHIs in healthcare settings due to concerns that suboptimal use may undermine their efficacy. The chief objective of this thesis was to develop and pilot a digital strategy for supporting engagement with LifeBuoy – a smartphone application (app) that helps young people with suicidal ideation. In the process, it (i) examined the link between engagement with DMHIs and clinical outcomes, (ii) synthesised existing literature on strategies for promoting engagement with DMHIs, (iii) explored user perceptions of engagement with DMHIs, (iv) designed a strategy to support engagement with LifeBuoy, and (v) examined implementation outcomes of the developed strategy. A robust positive association between engagement and post-intervention outcomes was found (Chapter 2). However, evidence on the efficacy of existing technology-supported strategies for promoting engagement with DMHIs was inconclusive (Chapter 3). According to users of mental health apps, strategies should provide digestible and practical content, be visually attractive, and leverage on platforms familiar to app users (Chapter 4). Specific ways in which principles of participatory design were applied to integrate lived experience and research to design a digital engagement strategy for LifeBuoy were described (Chapter 5). Finally, implementation data revealed moderate levels of support for the acceptability and appropriateness of the strategy (Chapter 6). This thesis has advanced the literature in several important ways. It established the relationship between engagement and outcomes in DMHIs. It extended existing evidence on the efficacy of technology-supported engagement strategies, noting that the lack of user involvement in the design process may be linked to the observed lack of efficacy. It was the first to explore users’ perceptions of the acceptability of various characteristics of engagement strategies and describe how participatory design principles could be applied in the design of a bespoke digital engagement strategy. Finally, it was the first study to examine implementation-related outcomes for an engagement strategy for a DMHI targeting suicidal ideation. Implications and future directions are discussed.