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Mitochondria: An Emerging Therapeutic Target for Neurodegeneration
No full textNeurodegenerative diseases (NDs) constitute an escalating global health crisis characterised by irreversible neuronal deterioration, resulting in progressive decline of cognitive abilities, motor functions, and ultimately, quality of life. Despite extensive research efforts, current therapeutic approaches remain largely focused on symptom management rather than disease modification. A common feature across various NDs is mitochondrial dysfunction, particularly impaired mitophagy - the selective degradation of damaged mitochondria through autophagy pathways. This quality control mechanism is crucial for maintaining cellular health, especially in post-mitotic neurons where dysfunction can lead to cellular death. Despite the clear link between impaired mitophagy and neurodegeneration, there are currently no clinically approved mitophagy activators, targeting the central nervous system (CNS). This significant therapeutic gap, combined with the rising prevalence of NDs in ageing populations, underscores the urgent need for developing CNS-active mitophagy modulators.
This thesis explores the development of novel small molecule mitophagy activators for treating NDs through three main approaches: optimisation of the p62-mediated mitophagy inducer (PMI) scaffold through hybridisation, structure-activity relationship studies of Urolithin A (UroA), and computational scaffold hopping to identify new chemical entities
Thinking and Talking about Prognosis in Advanced Cancer
No full textThis thesis aimed to improve how oncologists think and talk about prognosis in advanced cancer by evaluating the usefulness of oncologists’ estimates of expected survival time, studying recommendations about the timing of discussions of prognosis, and evaluating a method for formulating and explaining prognosis.
Data was collected from 8 clinical trials where oncologists' estimates of participant's expected survival times were compared with observed survival times. Oncologists’ estimates were well-calibrated, imprecise, and independently associated with observed survival times. Simple multiples (1/4, 1/2, 2, and 3) of each estimate provided well-calibrated ranges to describe worst-case, typical, and best-case scenarios for survival.
A systematic review summarised research on timepoints when discussions about prognosis should occur. These included: at first consultation; upon disease progression; and, when there were no further anti-cancer treatments. It is important for doctors to identify appropriate timepoints to elicit patients' preferences for the timing and content of discussions about prognosis.
A web-based tool was developed to help oncologists estimate and explain worst-case, typical, and best-case scenarios for survival time. The attitudes of patients, family members, and healthcare professionals to this information, were evaluated in a single-arm clinical trial. Over 84% found it useful to receive information about prognosis formulated as 3 scenarios for survival time. This trial introduced a simple, freely accessible, web-based tool that oncologists could use routinely in their clinical practice.
This thesis provides new information about the: usefulness of oncologists’ estimates of expected survival time; recommended timing of discussions about prognosis; and methods for communicating prognosis. Improving the way oncologists think and talk about prognosis should help people affected by advanced cancer and lead to better informed decision making
Healthy ageing and active travel: Identifying age-related barriers to walking and cycling
No full textIn a period of increasing mobility technologies, sustainable transport options, and healthy ageing concerns it is timely to better understand the barriers to active travel, particularly for older adults. Drawing from a survey of 1,522 Sydney residents, we compare travel patterns and perceived barriers to walking and cycling for older adults (60+) and younger adults (18-59). Car/motorbike/Uber use and walking have frequent and consistent use across both age groups. In contrast, public transport and bicycle/e-bicycle use both decline with age. Perceived barriers to walking and cycling are analysed across age groups using logistic regression. Relative to younger adults, older adults are more likely to identify an injury or disability (OR 1.45, 95% CI 1.02 to 2.04) and the convenience of driving (OR 1.35, 95% CI 1.05 to 1.73) as barriers to walking/walking more. Conversely, older adults are less likely to identify no-one to walk with (OR 0.47, 95% CI 0.33 to 0.68), personal safety (OR, 0.28, 95% 0.17 to 0.45), traffic (OR 0.26, 95% CI 0.17 to 0.41), inadequate street lighting (OR 0.50, 95%
CI 0.27 to 0.90), no footpaths (OR 0.41, 95% CI 0.24 to 0.70), and distance (OR 0.74, 95% CI 0.58 to 0.96) as barriers to
walking/walking more. For cycling, lack of access to a bicycle (OR 2.74, 95% CI 2.15 to 3.48), and insufficient skills (OR 2.9,
95% CI 2.1 to 3.99) are key issues for older adults, while sociocultural and built environment barriers are again perceived as less of a barrier. Practical issues (distance, transport availability, skills development), personal limitations, and potentially the nature/purpose of travel are key factors associated with active travel among older adults in Sydney. Policymakers need to ensure sociocultural and built environment barriers are lowered to ensure those already walking and cycling maintain this into old age
Misinformation and Digital Policy in Australia
No full textThe circulation of misinformation and disinformation online during election campaigns has been identified as a major problem in Australia. This article was prepared for the Safer Internet Lab Snapshot series
Report on the Development of Alternative Formats and Support Options for the Disability Wellbeing Index (DWI): Promoting Accessibility, Safety, and Self-Reporting for Survey Respondents
No full textThe Centre for Disability Research and Policy (CDRP), University of Sydney, was contracted to contribute to a three-year research project, 2022-2024, funded by the National Disability Insurance Agency (NDIA) and lead by Associate Professor Gang Chen, Monash University. The overarching aim of this research project was to design and test a preference-based wellbeing instrument that captures factors impacting on the wellbeing of people with disability in Australia, now known as the Disability Wellbeing Index (DWI). The role of the team based at the CDRP was to facilitate people with disabilities being involved in each stage of the research, including accessibility, safe environment, and self-reporting considerations for survey respondents.
This is the third of four reports documenting the contribution of the team at the CDRP. In this report, we describe the process undertaken by the CDRP team from July-September 2023 to develop a suite of alternative formats and support options designed to address accessibility for self-report and safety considerations for completing the DWI. The final versions of the DWI preference weighting survey and support options offered to survey respondents are also presented
Does a successor trustee owe a fiduciary obligation to the former trustee not to frustrate their indemnity?
No full textThe nature of a trustee's indemnity has been the subject of recent appellate judicial treatment in the United Kingdom and in Australia. Owing to the prevalence of the trading trust in Australia, the High Court of Australia has recently had occasion to consider whether a successor trustee owes a fiduciary duty to not frustrate a former trustee's indemnity over trust assets. That decision has addressed divergences between Australia and the United Kingdom on the nature of the indemnity and reminds us of fundamental starting points about the law of trusts that are often forgotten
Overflowing the frame: an autoethnographic study of creative self-efficacy using painting as a parallel mode of inquiry.
No full textThis transdisciplinary inquiry examines creative self-efficacy through an autoethnographic lens, using painting as a parallel mode of research. Engaging with Karwowski and Beghetto’s (2019) Creative Behaviour as Agentic Action (CBAA) model, this study explores the intersection of agency, creative self-efficacy, and creativity in teaching and artistic practices. As both an artist and educator, I explore the liminal space between pedagogy and learning, using this to interrogate how arts-based pedagogy builds equity and agency in learners and learning settings. This inquiry asserts that creative self-efficacy is an essential, evolving construct shaped by agency, experience, and reflection. By spilling out of conventional frames—both literal and conceptual—I invite new understandings of creativity as an act of survival, resistance, and transformation
Seeing one another as equals: which disparities of regard are incompatible with egalitarian social relations?
No full textWhich disparities of regard are objectionable from the point of view of equality, and why? I argue that
many disparities of regard are objectionable not because they constitute objectionable treatment per
se, but because of the way of seeing one another that they reflect. After outlining the idea of a
disparity of regard (§1.1), I argue that contemporary relational egalitarian accounts are generally
grounded in the idea of respect for persons, developed in terms of a (comprehensive or political)
liberal conception of the person (§1.2). This underpins the idea that disparities of regard are
objectionable because they undermine self-respect and self-esteem (§2.1),
or because they are incompatible with civic friendship (§2.2). I introduce a range of intuitively
objectionable cases which cannot be captured by the foregoing approaches (§3.1). I then consider
the idea that disparities of regard are objectionable insofar as they constitute hierarchies of status
(§3.2). The most influential version of this approach fails, centrally because it relies on an unspecified
idea of merit. In the fourth chapter I defend my own substantive account of seeing one another as
equals (§4.1) and the valuable egalitarian social relation this constitutes (§4.2)
Novel Lessons: Reading the Governess in the English Novel of the Long Nineteenth Century
No full textGovernesses abound in the English novel of the long nineteenth century, representing the challenges faced by unmarried middle-class women who sought to retain their respectability while earning a wage, and an educational system that primarily aimed to prepare young women for the marriage market. This thesis considers the governess as a teacher, and in relation to the Bildungsroman and the marriage plot, illustrating how the governess is formed in and by the novel, and what the governess can teach us about the novel form. In striving to address the governess as an educator, rather than primarily or exclusively as a woman or an instance of class precarity, the thesis frequently encounters the novel’s tendency to obfuscate the governess’s work. However, through its argument that the governess’s significance for the novel is often predicated on the apparent insignificance of her labour, the thesis allows the governess to be understood both within particular educational, social and cultural institutions and frameworks, and in relation to the novel, which is theorised as an important repository, exemplar and instrument of pedagogy.
By tracing governess characters in a series of novels written by women, this thesis illuminates complex workings of character and plot, and the capacity of the governess to comment upon, question, augment and destablilise stories of education and development. Chapter 1 focuses on the minor governess characters in Burney’s Camilla (1796) and Austen’s Emma (1815), chapter 2 on the governess as heroine in Anne Brontë’s Agnes Grey (1847) and Charlotte Brontë’s Jane Eyre (1847), chapter 3 on the governesses in disguise in Gaskell’s Ruth (1853) and Wood’s East Lynne (1861), and chapter 4 on the governess’s moves abroad in Charlotte Brontë’s Villette (1853) and Richardson’s Pointed Roofs (1915). Reading these pairs of novels side-by-side facilitates interrogations of the shape and direction of the English novel’s plots and pedagogies
How do different approaches to the economic modelling of genetic and genomic tests drive differences in results?
No full textIn many countries, including Australia, health technologies undergo evaluation by a Health Technology Assessment body to inform decisions around public funding. These evaluations include an assessment of the cost-effectiveness (value for money) of a health intervention. Traditionally, economic evaluations were designed to assess a test or treatment for a single condition and an ‘average person’, where the costs and outcomes followed straightforward trajectories. Genetic and genomic tests, however, can assess multiple genes and produce results for multiple conditions, including variants of unknown significance and secondary findings, with dynamic impacts on costs and outcomes. Current economic evaluation methods struggle to deal with this complexity.
The overarching objective of the current research was to examine the impact of different approaches to economic modelling of genetic and genomic tests and the potential for these to lead to different public funding decisions for these tests. The focus was on two key challenges of economic methods: (1) Model Structure and (2) Selection of Outcomes. This thesis begins with a comprehensive review of economic models for genetic and genomic testing, which identified non-invasive prenatal testing (NIPT) as a case study. The subsequent stages were: (a) developing multiple model structures of NIPT for the detection of Down syndrome, and populating these models with consistent parameters to allow the impact of selected structural variations to be assessed; (b) conducting three focus group discussions with the Australian public to inform the development of a discrete choice experiment (DCE); (c) the DCE, which valued intermediate outcomes through willingness to pay estimates (WTP); and (d) extending two models developed in stage (a) by incorporating the WTP estimates derived from the DCE within both net marginal benefit and cost-utility analyses