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(2021)ThesisMultidrug resistance is a leading contributor to treatment failure in cancer patients. As elevated levels of the antioxidant glutathione (GSH) and increased expression of drug efflux pumps may both contribute to chemotherapy resistance, depleting GSH and blocking drug efflux in cancer cells may improve response to treatment. Multidrug resistance protein 1 (MRP1) is a membrane transporter that is frequently overexpressed in cancer cells. By actively effluxing a wide range of chemotherapeutic agents, MRP1 can protect the cancer cell from chemotherapy. GSH is also transported by MRP1 as a low-affinity endogenous substrate. Some small molecules (MRP1 'modulators'), upon binding to MRP1, greatly enhance this innate GSH transport whilst simultaneously blocking the efflux of chemotherapeutics. As this stimulated GSH efflux can deprive the cell of GSH, in parallel with the blocked chemotherapy efflux enhancing intracellular chemotherapy concentrations, MRP1 modulators might be used to exploit the high expression of MRP1 in cancer cells to improve treatment response. MRP1 was found to be frequently expressed in patient tumours of two difficult to treat cancer types: non-small cell lung (NSCLC) and ovarian cancer. As this MRP1 expression might be leveraged with an MRP1 modulator, two modulators were tested on high MRP1-expressing NSCLC and ovarian cancer cell lines. As single agents, the modulators reduced MRP1 drug transport by >85% and improved the efficacy of MRP1-substrate chemotherapeutics (2 5-fold). In combination with the GSH synthesis inhibitor buthionine sulfoximine, complete GSH depletion, diminished clonogenic capacity, enhanced radiosensitivity, and extended chemosensitivity were achievable selectively in high MRP1-expressing cancer cells. As MRP1 expression in NSCLC was also associated with NRF2 activation, a key driver of treatment resistance in NSCLC, the modulator and buthionine sulfoximine combination was tested and found to be effective against cell lines representative of this highly resistant subset of NSCLC. Given the therapeutic potential for MRP1 modulators, their MRP1 binding site and mechanism of action as GSH transport modulators was investigated to provide a basis for future structure-guided design of more potent and selective modulators. Overall, these findings support that the high expression of MRP1 in cancers can be exploited with MRP1 modulators to chemosensitise and radiosensitise NSCLC and ovarian cancers.
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(2021)ThesisCouples HIV Testing and Counselling (CHTC) is recommended by the World Health Organisation to increase uptake of testing in Sub-Saharan Africa (SSA). There is limited evidence about whether people in heterosexual relationships consider CHTC to be a viable HIV testing option compared to other approaches, or the perceived risks and benefits of CHTC. This thesis examined the uptake, beliefs, intentions, and experiences associated with CHTC in SSA, and in Ethiopia specifically. The thesis includes four studies in a mixed methods design: a systematic review and meta-analysis of CHTC uptake in SSA (n=14 peer-reviewed studies); a qualitative elicitation study (n=21 people in heterosexual relationships and n=11 key informants) of beliefs and intentions; a qualitative experience study (n=19 in-depth interviews) of people who had used CHTC; and the development and pilot of a survey informed by the elicitation study (n=100 individuals). New empirical findings from this research include 1) a modest (24%) uptake of CHTC among heterosexual couples in SSA, with variability by country and population sub-groups; 2) that although CHTC was regarded as important to prevent HIV transmission, some participants stated they preferred to first ‘test alone, then together’ to avoid the perceived risks of being diagnosed with HIV in the presence of their partner — including accusations of infidelity and relationship break-up; 3) key reasons for undertaking CHTC included requests by third parties, such as religious institutions, before marriage, frequent sickness, as part of antenatal care, visa application, or mistrust between partners; 4) for some couples, consequences following an HIV-positive result included ongoing disputes, abuse, and relationship breakdown. Lastly, the elicitation study findings informed the development of a new survey tool for population-level use. Pilot psychometric testing found acceptable internal constancy, discriminant validity, and predictive ability of individuals’ behavioural intentions towards CHTC. The collective findings in this thesis provide evidence that individuals are cautious of undertaking CHTC because of fears about confidentiality and potential risks to their relationships. Testing programs should monitor and assure adherence to the principles of confidentiality and voluntary testing. For individuals who decide to undertake CHTC, individual-based pre-test counselling is important to ensure informed decisions about HIV testing options.
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(2021)ThesisGonorrhoea notifications have been increasing among young Australian heterosexuals since 2009 and the reasons for this are unclear. Gonorrhoea incidence has also increased in female sex workers (FSW) since 2009. Previous studies indicate that condom-use among FSW-clients declined from 2009-2017, mainly for oral sex and a high proportion of infections in heterosexual males arise from condomless oral sex with FSW. Thus, we hypothesise that an increase in condomless sex by FSW-clients may have contributed to the rising incidence of gonorrhoea among heterosexuals in Australia. In this thesis, mathematical modelling is used to provide insights to the role of the FSW-client interaction for heterosexual gonorrhoea transmission, to explore whether the increasing notifications can be explained, even partly, by decreasing condom-use among FSW-clients, and to evaluate the potential impact of providing gonorrhoea vaccination for FSW on gonorrhoea incidence/prevalence. A deterministic compartmental model was developed to address the stated objectives and was calibrated to reported female notifications and FSW incidence data for 2009. Using adaptations of the model that included/excluded FSW-client strata, we evaluated the role of FSW-client interactions in model dynamics and sensitivity of the reproduction number (Rt) in this population to changes in key parameters. We then estimated the annual percentage decline in condom-use between 2009 and 2017 that resulted in a model-produced notification rate that is consistent with the reported increase in heterosexual notifications using the model with FSW-client strata. Finally, the potential impact of a gonococcal vaccine for FSW on heterosexual gonorrhoea rates was assessed under different assumptions regarding the mode of vaccine conferred protection. Our results suggest that Rt and the heterosexual notification rate are highly sensitive to changes in parameters that govern transmission in the model that accommodates FSW-client interactions and infection rates are consequently highly sensitive to changes in condom-use by FSW-clients. An annual decline of only 0.26% in condom-use by FSW-clients is predicted to lead to an increase in heterosexual notifications that is consistent with the observed increase in notifications. Vaccinating FSW with a partially efficacious vaccine has the potential to substantially reduce gonorrhoea prevalence over time in the heterosexual population in Australia. These findings suggest that increasing condomless sex among FSW-clients can result in marked increases in heterosexual notifications. Therefore, promoting condom-use in commercial sex may help reduce the gonorrhoea burden in young heterosexuals. Additionally, targeted vaccination of FSW may be an effective means of controlling gonorrhoea in this population.
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(2021)ThesisDementia is a leading cause of disability affecting approximately 50 million people worldwide. Currently, in Australia, there is no optimum way of monitoring the incidence or prevalence of dementia at the population level. There are also many unanswered questions regarding crucial aspects of dementia care, such as whether the provision of home-based services can reduce the time spent in residential care. Routinely collected administrative data have the potential to fill these gaps. This thesis explores the use of linked administrative data for detecting and monitoring dementia in Australia, uses these data to understand the care pathways followed by people with dementia, and addresses policy-focused questions aimed at improving dementia care. It does so by presenting the results of four research studies using the 45 and Up Study, a cohort of 267,153, recruited in 2006-2009 in New South Wales, Australia. The 45 and Up baseline survey was linked to a range of administrative datasets including records of hospitalisations, emergency department visits, aged care assessments, and claims for pharmaceuticals, medical services, aged care services and deaths for the period 2006-2016. Key findings include: (i) measuring dementia incidence with multiple linked administrative datasets identifies almost 80% of expected dementia cases (92% for those aged 80-84 years) and produces age-specific incidence rates that mirror those based on clinical diagnosis; (ii) entering residential care is the norm among people with dementia, and home-based care may not be meeting their needs at end of life; (iii) high-level home care for people with dementia may reduce the subsequent time spent in residential care; and (iv) changing to a new general practitioner (GP) when entering residential care is related to increased polypharmacy and initiation of psychotropic medicines among people with dementia. These findings will inform on-going efforts to monitor dementia incidence and care in Australia. They also have major policy implications, including emphasising the pressing need in Australia for more high-level home care packages, and highlighting end-of-life dementia care as a priority for policy development and innovation in service delivery. The link between GP continuity and psychotropic prescribing highlights a new intervention point that could assist in the efforts to reduce psychotropic prescribing in residential aged care.
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(2021)ThesisMesenchymal cells in solid tumours have multiple roles in supporting carcinogenesis. They have emerged as important mediators of immune function and as such, are regarded as promising candidates for therapeutic targeting and immunotherapy. However, conflicting preclinical results necessitate further investigation of their phenotypic diversity, beyond that described using model experimental systems or small panels of markers. This thesis applies advanced multi-omics technologies to resolve the cellular heterogeneity of mesenchymal cells inside human breast cancers. To overcome the logistical and technical challenges of studying clinical tissues using single-cell sequencing, I first present a benchmarking of tissue cryopreservation methods. Analysis of cryopreserved cell suspensions and solid tissue fragments conserved the heterogeneity of tumours and the integrity of transcriptomes. These methods were applied to subsequent parts of this thesis and importantly, increases the opportunities for sample collection in future clinical studies. I next performed single-cell analysis on a small cohort of five patients of the aggressive triple-negative subtype (TNBC). This body of work presents the first single-cell analysis of mesenchymal cells in human TNBC. I identified functionally distinct subclasses of cancer-associated fibroblasts (CAFs) and perivascular-like cells that showed strong associations with immune evasion. In light of this, a comprehensive review of how the recent wave of single cell studies have shaped our understandings of stromal-immune interactions in cancer is presented. Lastly, to expand our findings to a larger cohort of patients from all clinical subtypes, I led a study that established a large single-cell and spatial atlas of primary breast cancers. This revealed new dynamics of mesenchymal heterogeneity, where cells fell into a spectrum of cell differentiation rather than discrete subsets, supporting future strategies to manipulate cell differentiation for therapeutic benefit. Spatial transcriptomics revealed that subsets of CAFs were spatially segregated, with unique subclasses colocalising with immune cells. Using both modalities, I identified a suite of potential signalling molecules between CAFs and T-cells that show spatial proximity, offering a list of candidates to investigate in future functional studies. I envisage the findings described here to help guide the development of effective stromal directed therapies for breast cancer.
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(2021)ThesisBACKGROUND South Africa has the highest HIV burden in the world. Clinical care guidelines for HIV testing, treatment, monitoring and infant feeding have evolved in recent years. However, there are gaps in guidelines implementation and quality of services, particularly in primary care. This thesis aims to investigate the impact and implementation of HIV care interventions on service quality. METHODS This research is based at nurse-led public sector primary care clinics in northern KwaZulu-Natal, South Africa. First, the impact of continuous quality improvement (CQI) on coverage of two key antenatal HIV care tests (VL monitoring among pregnant women living with HIV, and repeat HIV testing among pregnant women not living with HIV) at seven primary care clinics, is examined. These are the primary endpoints of the MONARCH stepped-wedge trial (www.clinicaltrials.gov NCT02626351). Second, the process by which CQI was implemented in the MONARCH trial and determinants of CQI practice and ‘normalisation’, are examined. Third, the association between maternal HIV status and infant feeding (i) knowledge and (ii) practice, among women recruited to the MONARCH trial, is examined. Finally, the impact of Universal Test and Treat (UTT) on mean CD4 count at ART initiation among men and women attending 17 primary care clinics, is examined. RESULTS CQI improved HIV VL monitoring among pregnant women living with HIV, but not repeat HIV testing among pregnant women not living with HIV, and coverage of both endpoints fell short of expected targets. Despite enthusiasm for CQI, staffing shortages, gaps in guidelines knowledge, poor data quality and poor clinical documentation hampered CQI uptake and ‘normalisation’. Although women living with HIV were more knowledgeable about correct infant feeding guidelines, they were less likely to breastfeed than women not living with HIV. Whilst CD4 count at ART initiation increased due to UTT, the long-term effect was modest and men initiated ART at lower CD4 counts than women. CONCLUSIONS Whilst CQI has potential to improve quality of care in resource-poor settings, concurrent health systems strengthening initiatives are necessary for maximum impact and sustainability. More efforts are needed to improve breastfeeding uptake, and to increase early ART initiation particularly among men.
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(2021)ThesisSepsis is life threatening organ failure due to a dysregulated host response to infection. It is a leading cause of death and disability worldwide. Priorities of management include early detection and treatment with appropriate antimicrobials, along with organ support therapies administered in the intensive care unit (ICU). Corticosteroids are an adjunctive therapy used to treat patients with septic shock. They modulate the immune and cardiovascular response to infection, reducing the duration of mechanical ventilation and ICU stay. The longer-term health and economic impacts of corticosteroid treatment are unknown. There is also a paucity of data describing the longer-term health and economic burden of sepsis for patients treated in Australian ICUs. This thesis contributes novel data to describe sepsis survivorship in Australia, including the longer-term health and economic burden of sepsis and septic shock, and the longer-term health and economic implications of adjunctive corticosteroid treatment in women and men with septic shock. The main findings are: 1. In a propensity score matched analysis of ICU patients with and without sepsis: 1. Patients with sepsis had increased healthcare resource use and costs, compared to other critically ill patients. 2. In a cost-effectiveness analysis of a clinical trial assessing the impact of hydrocortisone treatment compared to placebo on mortality due to septic shock: 1. Hydrocortisone treatment in the ICU did not significantly impact longer-term mortality, health-related quality-of-life, healthcare resource use or costs. 2. Hydrocortisone treatment was unlikely to be cost-effective overall, but more likely to be cost-effective in women, compared to men. 3. In a follow-up sex-disaggregated analysis of the trial: 1. Women treated with hydrocortisone had a higher risk of shock recurrence, compared to men. 2. Hydrocortisone treatment significantly reduced the time to ICU discharge and cessation of mechanical ventilation in men, but not in women. Sepsis survivors experience ongoing disease sequelae, resulting in increased healthcare resource use and costs. Hydrocortisone treatment, administered in the ICU, does not mitigate the longer-term sequelae of sepsis and is unlikely to be cost-effective. Strategies to reduce the sequelae of sepsis, including understanding sex differences and other health inequalities, is an important direction for future research.
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(2021)ThesisBackground: Oocyte quality is the rate-limiting factor to the success of in-vitro fertilisation (IVF). Growth differentiating factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are key oocyte-secreted growth factors that act on the surrounding cumulus cells (CC) to regulate their functions and oocyte quality. Reliable quantification of these factors and the relationship between their levels and oocyte quality have not been demonstrated to date. Measuring GDF9 and BMP15 from CC discarded during IVF treatment could be useful for studying the role of these factors in female reproductive potential. Aim: To develop specific ELISAs for GDF9 and BMP15 quantification in discarded CC from ICSI patients and correlate their levels to patient characteristics and reproductive outcomes. Method: GDF9 and BMP15 ELISAs were developed and applied to extracts from discarded CC. Optimised extraction conditions allowed for a simultaneous extraction of protein and DNA (used as a measure of cell count for protein normalisation). A pooled extract from human granulosa cells was used as a standard, as non-parallelism was observed between CC extract and recombinant GDF9 and BMP15. Results: The ELISAs developed were specific for GDF9 and BMP15. Maternal age and polycystic ovaries/polycystic ovary syndrome were factors for change in BMP15 on pooled CC from individual patients in the first study (n=120) but not in the second (n=81). Embryo developmental trajectory was not associated with their levels. GDF9 and BMP15 measured on CC from individual oocytes (n=181) varied considerably between oocytes within and between patients, and GDF9 levels were higher in older patients. GDF9 and BMP15 were not associated with embryo developmental outcomes but their ratio was associated with blastocyst quality. Correlation between GDF9 and BMP15 on individual oocytes was remarkably strong (p<0.0001). Conclusion: The current study showed that levels of CC-bound human GDF9 and BMP15 were not linked with embryo developmental outcomes using existing assays. Studying the relative dosage of these proteins may provide a useful diagnostic. Strong correlation between GDF9 and BMP15 suggested that native GDF9 and BMP15 form a heterodimer in-vivo. Further research into the native forms of human GDF9 and BMP15, and their levels is needed to gain a better understanding of their physiological roles. Development of new generation assays able to measure different forms of the two proteins will be required
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(2021)ThesisThe growing number of individuals living with multimorbidity – the presence of two or more chronic conditions – is a challenge facing many healthcare systems internationally. Multimorbidity has been hailed a priority for research and practice, but Australian studies of multimorbidity are impeded by the lack of national primary care data, data silos, researcher access to data, and limited information contained within the data that are available. This thesis demonstrates how data linkage can be used to enhance the understanding of multimorbidity and its outcomes via a series of studies using Australian linked data sources, including claims-based, cohort study and clinical registry datasets for residents of NSW, Australia's most populous state. Thesis studies found variations in the recording of common health conditions between hospitals, under ascertainment of multimorbidity in administrative data, and differences in the estimates of multimorbidity dependent on the data used. Thesis studies also showed we can enhance our understanding of multimorbidity by exploring related concepts of patient risk and complexity. Within administrative hospital inpatient data, one-third of hospitalised patients had both multimorbidity and elevated risks of frailty – and these patients had worse outcomes than those with one or neither factor. The addition of clinical registry data also improved risk adjustment for hospital readmission performance indicators for total knee and hip replacement over and above models including multimorbidity measured using administrative hospital inpatient data. The research presented here highlights the benefits of the use of linked data in Australian multimorbidity research in three ways. Firstly, it underlines the need for incorporation of chronic disease information from multiple databases, including self-reported, inpatient, and claims-based data to accurately capture the extent of chronic disease and to identify people with multimorbidity. Secondly, it emphasises the need to examine complexities in the interplay between drivers of adverse outcomes – including multimorbidity, frailty and clinical assessment of a patient's overall health – in identifying patients with increased risk of complications and informing future hospital resource planning. And thirdly, it demonstrates the value of integrating new data sources, such as clinical registries with linked administrative data for improving risk-adjustment of hospital performance measures.
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(2021)ThesisChronic kidney disease (CKD) is a major public health issue affecting 10% of the global population and resulting in 1.2 million deaths. The risk of all-cause and cardiovascular mortality is inversely proportional to declining eGFR such that individuals with CKD are more likely to die, primarily due to a cardiovascular cause, than survive to the point of requiring dialysis. These poor outcomes are related to a myriad of factors including multimorbidity, medial vascular calcification and underlying haemostatic dysfunction. Polypharmacy is a key consequence of the disease burden experienced by CKD patients. It is linked with poor adherence, adverse drug reactions, falls and increased hospitalisations. A post-hoc analysis of the CKD-FIX study was conducted to assess the prevalence and predictors of polypharmacy in CKD patients. It found that polypharmacy, defined as ≥5 medications, and hyperpolypharmacy, defined as ≥10 medications, were found in 77.5% and 34.3% of patients respectively. Age ≥65 yrs, diabetes, cardiovascular disease and hyperlipidemia were independently associated with polypharmacy. However, limiting polypharmacy via appropriate prescribing is hampered by the lack of data in patients with advanced CKD. Despite the disproportionate cardiovascular disease burden in CKD, the benefits and risks of dual antiplatelet therapy are not known. Therefore a systematic review of randomised controlled trials on the effectiveness of dual antiplatelet therapy in CKD was conducted. Nineteen trials with 27,308 participants were analysed with all but 3 trials excluding participants with dialysis-dependent kidney failure. Compared with aspirin monotherapy or no study medication, P2Y12 inhibitor-based dual antiplatelet therapy significantly reduced the risks of major adverse cardiovascular events, myocardial infarction and stroke; but increased the risk of major bleeding. There was insufficient evidence to conclude whether patients with advanced stages of CKD and dialysis-dependent kidney failure derived benefit. In conclusion, CKD patients represent an expanding population that is at high risk of adverse outcomes. Polypharmacy is common in patients with CKD and is related to age and multimorbidity. Further research on medication appropriateness and deprescribing are needed. In particular, adequately powered randomized trials are required to evaluate the effectiveness of dual antiplatelet therapy in patients with advanced stages of CKD and cardiovascular disease.