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(2021)ThesisOocyte-secreted growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are critical paracrine regulators of female fertility. Recent studies demonstrated that serum concentrations are associated with the number of oocytes retrieved during IVF, and therefore potential clinical use as biomarkers. However, it is unknown if serum GDF9 or BMP15 is affected by the presence of endometriosis. An exploratory case-control study was prospectively performed on 60 women who underwent planned laparoscopy between April 2017 and August 2018 at two hospitals. GDF9 and BMP15 were measured by validated immunoassays in pre-operative serum samples. Data were analysed relative to laparoscopic assessment of endometriosis and staging. There were 35 women with confirmed laparoscopic diagnosis of endometriosis and 25 controls with no evidence of endometriosis at laparoscopy. GDF9 was detectable in 40% of controls and 48% of cases. There was no difference in median GDF9 concentrations between controls (20.0 pg/ml, range 20.0-2504 pg/ml) and cases (20.0 pg/ml, range 20.0-2963 pg/ml). BMP15 was detectable in 48% of controls and 58% of cases, with no difference in median concentrations between controls (26.5 pg/ml, range 24.0-1499 pg/ml) and cases (24.0 pg/ml, range 24.0-796 pg/ml). Furthermore, there were no significant differences in the proportion of detectable samples or concentrations of GDF9 or BMP15 with differing severities of endometriosis. In conclusion, serum concentrations of oocyte-secreted factors, GDF9 and BMP15 did not differ between control patients and patients with endometriosis. For clinical application of GDF9 and BMP15 serum biomarkers in reproductive medicine, quantitation in serum is unlikely to be aberrant due to the presence of endometriosis.
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(2022)ThesisTuberous sclerosis complex (TSC) is an autosomal dominant condition caused by pathogenic variants in the TSC1 or TSC2 gene with a prevalence of 8.8 per 100 000. TSC is associated with variable neurodevelopmental outcomes, seizures and benign tumours in various organs. Around 10-15% have no pathogenic variants identified – the “no mutations identified” (NMI) cohort. Previously, this cohort were reported to be phenotypically milder and have mosaic/intronic variants. Many have reproductive concerns, but options are not open to them without a molecular diagnosis. This study aims to determine the phenotype of an Australian NMI cohort, and if testing multiple samples of an individual would allow for an improved diagnostic yield using a testing strategy that may be viable in a diagnostic laboratory. The first study discussed the phenotype of the NMI cohort in the Sydney Children’s Hospital TSC management clinic, a tertiary referral centre. A medical records review was used to compare the clinical picture of those in the NMI, heterozygous, and mosaic cohorts. This showed that although those in the NMI cohort likely have a milder neurodevelopmental outcome, they are no different to the heterozygous cohort when considering the number of organ systems involved. This differs from the previous literature. The second study explored the use of multiple samples in deep sequencing of the NMI cohort. Massively parallel sequencing (MPS) using a custom target capture panel consisting of the whole genomic region of TSC1 and TSC2 was performed. A minimum of 2 samples was tested for each participant, including affected tissue where possible. Sequencing occurred with a target read depth of 500x initially and proceeded to 4000x for those who remained persistently NMI. A diagnostic yield of 72% was achieved in the probands tested, with the majority being mosaic variants and the remainder missed heterozygous variants. The use of multiple samples allowed for validation of otherwise discarded low-level mosaic variants. In conclusion, this thesis explored the phenotype and genotype of the NMI cohort. It showed that those in this cohort may not be as mild as previously suggested. Testing multiple samples allows for detection of germline mosaic variants on MPS without excessive cost and the need for specialised techniques. Scaling this up to diagnostic testing is likely viable, which would ultimately be critical for optimal clinical care of the NMI cohort.
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(2021)ThesisA growing body of research has documented adverse mental health outcomes for adult asylum seekers and unaccompanied children exposed to prolonged resettlement stress and residential insecurity. There is little information however on the wellbeing of children who seek asylum as part of intact family units. This research examined the mental health and psychosocial functioning of a cohort of asylum-seeking children and their primary caregiver affected by insecure residency while living in the community, compared to refugee and immigrant children and families. The project investigated the prevalence of psychosocial problems among Iranian and Afghani asylum seeker, refugee and immigrant children and adolescents, and their caregivers who arrived in Australia from 2010. In total, n=196 asylum seeker, immigrant and refugee children aged between 5-18 years old, and their primary caregiver were asked about family visa status, country of origin, level of education, parent symptoms of posttraumatic stress disorder (Harvard Trauma Questionnaire) and child wellbeing (Strengths and Difficulties Questionnaire). An additional n=362 Farsi and Dari speaking children, recruited through the Building a New Life in Australia (BNLA) study, a national representative sample of families with permanent refugee visas, was also included. Findings revealed that asylum seeker children display significantly more psychosocial problems compared to children from families with full refugee protection and immigrant background within the current sample and when benchmarked against a national sample of Farsi-Dari speaking refugee children. Higher parental posttraumatic stress disorder symptoms were found to be a significant predictor of poorer child psychosocial functioning. This effect was more marked for children in families with insecure residency. At a policy level the findings raise important questions in relation to the Australian Government’s harsh immigration regime which has heartless disregard for the people and specific children who are harmed. It is important that future research examine further the prospective impact of harsh immigration policies and possible protective factors that can be used to promote better outcomes.
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(2023)ThesisIntroduction: The benefits of physical activity for reducing falls risk and improving mood and mental functioning have been well documented. However, programs targeting both falls risk and mental health are lacking. The COVID-19 pandemic also highlighted that older adults are at an increased risk of social isolation and physical inactivity. The aim of this trial was to investigate the effect of a Facebook-delivered, combined health promotion, balance training, exercise program, and support group (MovingTogether) on mental and physical health for community dwelling older adults. Methods: Adults aged 60+ years were recruited via social and print media to a randomised controlled trial with a waitlist control. Participants were required to have access to Facebook and a computer or tablet and be inactive as per WHO guidelines. The intervention group joined a private Facebook group where allied health facilitators provided targeted healthy lifestyle education throughout a 10-week program with weekly telehealth group calls. Intervention participants also had access to an evidence-based eHealth balance exercise program, StandingTall and tailored strength and aerobic exercise guidance. Outcomes included psychological distress (primary outcome), physical activity, social capital, concern about falling, loneliness, physical functioning, quality of life and physical activity enjoyment (secondary outcomes). These were assessed at baseline, post-program (week 10) and 1-month follow-up. Linear mixed models were applied for each outcome measure excluding physical activity evaluated by a generalised linear mixed model, as per an intention-to-treat approach to determine between group differences. Results: Participants (N = 80) were 89% female, with a mean age of 66.3 years (SD = 4.92). Participants were randomised to intervention (n = 37) and waitlist control (n = 43) groups. The intervention group had a program completion rate of 59% (22 out of 37) and 64% of all participants (51 out of 80) completed post-program questionnaires. At week 10, there was a significant difference between groups in psychological distress (P=0.04), but no significant difference in physical activity, social capital, concern about falling, loneliness, physical functioning, quality of life or physical activity enjoyment. No significant changes were found at the 1-month follow-up point. Discussion: A 10-week Facebook-delivered health promotion program significantly improved levels of psychological distress but did not change secondary outcomes in older adults. The high dropout rate (36%) is important to note. High Facebook engagement warrants further investigation of Facebook delivery. Future research should consider strategies to account for high dropout rates. Conclusion: MovingTogether significantly improved psychological distress in older adults, although results may have been affected by dropout rate. This trial has implications for the recruitment, engagement, and delivery of physical activity programs for older adults, and offers directions for future research in these areas.
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(2024)ThesisOne-third of women globally will experience Gender Based Violence (GBV) in their lifetime. GBV is a risk factor for noncommunicable diseases including post-traumatic stress disorder, depression, anxiety, chronic pain and cardiovascular disease. Noncommunicable diseases are associated with physical inactivity, which can further exacerbate mental health symptoms and cardiometabolic risk. Physical activity may therefore be an important target for intervention to improve health outcomes among people who experience GBV. Health professionals, including exercise professionals, are likely to encounter people who experience GBV as part of routine practice, yet their readiness to respond appropriately is unknown. This thesis aimed to i) determine whether individuals who have experienced GBV engage in different levels of physical activity and/or sedentary behaviour compared to individuals who have not been exposed to GBV; and ii) determine preparedness of exercise physiologists, physiotherapists and other allied health professionals (AHPs) to respond to and support a person who has experienced GBV. Chapter Two was a systematic review to explore aim (i). Electronic databases were searched from inception until May 2023. Eligible studies were original research publications that reported a quantitative measure on physical activity and/or sedentary behaviour in a group of people who have experienced any form of GBV as well as a comparator group with people who had not experienced GBV. A total of 856 studies were identified in database searches of PubMed, Embase, PSYCinfo, SPORTDiscus and CINAHL. From screening, 11 eligible studies were identified. Most studies were conducted in the United States (n=9, 82%) and most participant groups were exclusively female (n=9, 82%). The most common form of GBV measured in studies was Intimate Partner violence (n=5, 45%). Five studies reported that individuals who had experienced GBV engaged in lower levels of physical activity compared to those without a history of GBV. However, results were mixed, and the overall evidence did not support our hypothesis, that people who have experienced GBV engage in less physical activity compared to people who have not been exposed to GBV. No studies examined levels of sedentary behaviour. The overall quality of studies was poor, indicated by risk of bias and study quality scores, with 55% (n=6) of studies rated as fair and 45% (n=5) rated as poor quality based on the Newcastle Ottawa Scale. No studies used validated tools to measure levels of physical activity and inconsistent across studies precluding pooling and statistical analysis. Chapter Three was a mixed-methods study to explore aim (ii). Study advertisement was posted to social media with a link to an online survey, as well as researchers’ contact details for participants to volunteer to participate in an interview. The modified Physician Readiness to Manage Intimate Partner Violence Survey (PREMIS) survey was used to assess AHPs perceived preparation, knowledge, opinions and practice issues. Qualitative interviews with AHPs were also conducted to explore understanding of participants’ readiness to identify and respond to GBV. In total, n=105 participants completed the modified PREMIS. Most participants were female (n=78, 74%), from Australia (n=95, 90%) and exercise physiologists (n=43, 41%). Most (80%) of the sample had received one hour or less of GBV training. Mean preparedness scores were low among respondents for perceived preparation (2.79 out of 7) and perceived knowledge (2.68 out of 7). Qualitative interviews were subsequently conducted with n=10 AHPs. Thematic analysis identified four themes: knowledge, lack of confidence, seeking GBV training and clarification of AHPs role. Individuals who experience GBV may have lower physical activity levels compared to individuals not exposed to GBV, however more research with validated tools to accurately determine physical activity and sedentary behaviour levels of people who have experienced GBV is needed. Despite recognition of the importance and agreement of the relevance to AHPs practice, this workforce felt underprepared, had low perceived knowledge and lacked confidence to respond to and support people who have experienced GBV. More research is needed to understand the complex bidirectional relationship between experiencing GBV and physical activity and to further clarify the role of exercise and other allied health professionals’ in supporting people who experience GBV.
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(2022)ThesisBackground The shared decision making (SDM) process when deciding the appropriateness of dialysis for an older individual with advanced CKD can be complex and challenging. There is a paucity of data on the survival, symptoms and quality of life of patients on a conservative non-dialytic kidney management (CKM) pathway. Furthermore, prognostication in these patients is difficult as existing predictive tools for mortality have not been extensively validated in the elderly CKD population. Chapter 1 provides a detailed literature review. Aims and Methods This aims of this research was to assist clinicians in the shared decision-making process by: Providing data that clinicians and patients desire to know when making treatment decisions about the appropriateness of dialysis for an older individual: exploring survival, symptom burden and hospitalisation rates (Chapter 2). Assessing the utility and applicability of existing prognostication tools in the older CKD population (Chapter 3). We conducted a single-centre observational study on patients aged ≥65 years at St George Hospital, Sydney. Survival was analysed with Kaplan Meier Survival curves and Cox proportional hazard models. Symptom burden and hospitalisation rates were evaluated using linear mixed modelling. Validation of existing predictive tools for mortality were performed using logistic regression and calculation of the Hosmer-Lemeshow statistic. Results and Conclusion Older patients with advanced CKD have high mortality, comorbidity and symptom burden. In CKM patients, median survival was 15 and 8 months from the time their estimated glomerular filtration rate (eGFR) fell to 15 and 10ml/min/1.73m2 respectively. Survival from the time of modality choice or dialysis initiation was 14 months in the CKM and 53 months in the dialysis group. Survival was longer for dialysis cohort from all time points (p<0.001). Factors that reduced survival included higher comorbidities, poor nutritional status and heart failure. The symptom burden of most CKM patients improved by their 3rd clinic visit when managed by a multidisciplinary Renal Supportive Care program and unplanned hospitalisation rates were 2-fold lower compared to the dialysis cohort. Existing prognostication tools performed poorly in our study cohort. More studies are needed in this area. These data should assist clinicians in the shared decision-making process.
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(2023)ThesisThe ability to examine eyes and identify pathology in Ophthalmology is dependent on the availability and capability of optical instrument technologies. For many clinicians, teachers and medical students who cannot access appropriate optical instruments, these users have been blinded to seeing inside eyes. In comparison, the optical technology in iPhones and other smartphones is widely available. Their extraordinary inbuilt cameras and photo processing software makes smartphones an ideal readymade platform to develop new optical instruments to examine eyes. This thesis developed five inexpensive optical instrument prototypes and showed proofs of concepts for an iPhone Direct Ophthalmoscope, Near Infrared Non-Mydriatic iPhone Ophthalmoscope, iPhone Exophthalmometer, Operating Microscope Recording System and a ‘Heads up’ repurposed Slit Lamp. The prototypes were substantially lower in cost when compared with existing devices on the market, offering viable alternative optical instruments in clinical practice. A working prototype of the Near Infrared Non-Mydriatic Ophthalmoscope can be developed in future research, which would eliminate the need for using mydriatic eye drops to dilate pupils before retinal examinations. This research can be used to develop affordable and widely available precision optical instruments based on smartphones for eye examinations in clinics, classrooms and throughout developing countries.
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(2023)ThesisBackground Patients with end-stage kidney disease require functioning vascular access to support haemodialysis. Of the main three types, the central venous catheter (CVC) is used in approximately 60% and 80% of incident haemodialysis (HD) patients in Australia and New Zealand dialysis units, respectively. A significant concern with the use of CVC in nephrology practice is the burden of HD catheter-related bloodstream infection (HD CRBSI). HD CRBSI is a major yet preventable complication of HD CVC and is associated with increased patient morbidity and mortality, prolonged hospitalisation, and high healthcare costs. Reduction of HD CRBSI rates is an important priority for HD facilities to minimise patient harms attributed to the use of CVC. While evidence-based strategies to address HD CRBSI are available, an important challenge lies in defining HD CRBSI consistently and accurately measuring the burden of HD CVC utilisation and related-infectious complications. There is marked heterogeneity in the measurement and reporting of HD CRBSI across Australia and New Zealand. The lack of systematic approach in HD CRBSI surveillance has led to limited reliability of infection-related catheter outcomes and comparability of HD CRBSI rates with other dialysis facilities for benchmarking. Methods This thesis used descriptive and analytical approaches comprising three interdependent chapters: (1) a comprehensive review of the existing literature to explore the current utilisation of HD CVC and to describe the challenges in HD CRBSI measurement and reporting. The next two chapters were secondary analyses of the REDUcing the burden of dialysis Catheter ComplicaTIOns—a National approach (REDUCCTION) trial: (2) analysis of catheter exposure and HD CRBSI burden in the participating New Zealand dialysis units, and (3) level of agreement in the reporting of HD CRBSI between the participating Australian and New Zealand renal services and the REDUCCTION trial adjudicators. Results In Chapter 1, the difficulties in measuring and reporting rates of HD CVC infections were addressed. The absence of a standard definition for categorising true HD CRBSIs events results in varying reports of infection rates. In light of the increased morbidity and mortality associated with HD CRBSIs, many countries have made reporting of HD CVC infection outcomes mandatory. Efforts to prevent HD CRBSIs have been focused on utilising care bundles to improve patient outcomes. However, there is a need to enhance the methods used to collect and report HD CRBSIs by implementing comprehensive facility-wide systems. While outcome adjudication has the potential to add reliability in site-reported events, its practicality at the health service level remains in doubt. The use of cost-effective and resource-efficient tools, e.g., administrative and clinical registry data, to validate HD CRBSI reporting could be a useful method to address the resource issues posed by independent outcome adjudication. Chapter 2 presented the routinely collected data on HD CVC from the REDUCCTION trial in New Zealand, which enrolled 894 patients and involved the insertion of 1,337 HD CVC, resulting in 157,142 catheter days of exposure. The patient demographics and catheter utilisation patterns in New Zealand were comparable to those in the Australian cohort. The analysis of catheter-related infection outcomes indicated that New Zealand has a lower rate of confirmed HD CRBSIs recorded, as determined by the same definition, collection, and reporting methods used in the REDUCCTION trial. The results show that Australian and New Zealand dialysis services have HD CRBSI rates that are relatively lower than other countries. The subgroup analysis revealed a degree of variability in HD CRBSI rates at the service level. However, we have yet to explore specific service-level factors in this analysis. We will explore this relationship when the national administrative data becomes available. Chapter 3 revealed a high level of agreement between the site-reported HD CRBSI and the adjudicated outcomes. The substantial concordance in HD CRBSI reporting between kidney services and adjudicators suggests that site-reported events could be reliable and utilised without the need for adjudication. The systematic data collection and standardised definition of HD CRBSI implemented during the REDUCCTION trial allowed for comparability of HD CVC infection outcomes between Australia and New Zealand. Although outcome adjudication is a robust approach for validating study outcomes, it is costly and resource-intensive; hence, a more cost-effective and practical alternative should be considered. Conclusion The thesis contributes to a new understanding of the HD CVC utilisation patterns and the burden of HD CRBSI in New Zealand. A deeper insight into the true burden of HD CVC exposure and the impact of HD CRBSI among the HD population in Australia and New Zealand has the potential to inform clinical decision-making and guide the development of evidence-based recommendations aimed at improving patient outcomes. The implementation of a standardised outcome definition and systematic data reporting system during the REDUCCTION trial provided reliability in HD CVC data, making it a valuable resource for benchmarking. Future work is required to ascertain the feasibility of using administrative data as an alternative approach to traditional independent outcome adjudication. With the consistent application of the systematic methods established in the REDUCCTION trial, the reporting of HD CRBSI could be integrated into the national clinical registry, and HD CVC-related infections could be considered a performance indicator across dialysis services.
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(2023)ThesisPyoderma Gangrenosum (PG) is an inflammatory cutaneous disease with no standard highly effective treatment. Novel therapeutics with a predictable treatment response are desperately needed, although a major barrier for this is the incomplete understanding of the molecular mechanisms that underpin this disease. Traditionally, PG was thought to be driven by a local dysregulated neutrophilic response. Recent investigations however have identified elevated levels of interleukin (IL) -23 and IL-17 in the serum and tissue of PG patients, suggesting that the Th17 axis may play a role within this disease. This thesis characterises the molecular mechanisms underlying PG and assesses whether the Th17 axis and related cytokines are major drivers of this disease. A systematic review was performed to collate biomarkers that have been associated with PG. Following this, an exploratory analysis of existing and other possible biomarkers of disease activity associated with active and resolving PG was conducted through an open label, single arm clinical trial. Participants diagnosed with active PG underwent lesional and non-lesional biopsies at baseline, with subsequent systemic administration of subcutaneous tildrakizumab (IL-23 antagonist) 200 mg, at dosing intervals of week 0, week 4, and week 8, with repeat lesional and non-lesional biopsies performed at week 12 (trial completion). Clinical markers of disease activity such as ulcer size, physicians’ global assessment, visual analogue scale scores, and quality of life scores were measured throughout the trial. An a priori analysis of biomarkers gathered from the systematic review conducted was performed on biopsied whole skin samples either through RNA sequencing by a nanostring multiple gene expression assay, or through immunohistochemistry, with comparisons made between healthy control (HC), baseline lesional, non-lesional and lesional tissue at week 12 of the trial. Various biomarkers associated with PG including IL-23, IL-17A and IL-17F cytokines were elevated in baseline lesional tissue, and to a lesser extent non-lesional tissue, when compared to HC. These inflammatory mediators had a reduced expression within PG tissue in response to IL-23 antagonism. A statistically significant improvement in quality-of-life scores and VAS scores was identified in participants. A reduction in ulcer size was also noted in ulcerative PG but not peristomal PG. The results of this thesis give valuable insights into the role of the Th17 axis in the development of ulcerative PG, and identifies the IL-23 antagonist tildrakizumab as an effective treatment for ulcerative PG.
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(2023)ThesisIn Australia, approximately 19,000 hip fractures occur annually with a mortality of 8.2% at 30-days and 22.1% at 1-year following presentation. Many factors contribute to mortality including variation in the processes and systems of care. This thesis investigates how variation in surgical procedures undertaken for hip fracture impacts mortality and whether one approach to surgery is better than another in relation to mortality. Linked data from the Australian Hip Fracture Registry and National Death Index was used to evaluate the impact of two approaches to surgical intervention: 1) use of cement fixation during arthroplasty for intracapsular fractures (Study 1, n=15,405), and 2) type of fixation for intertrochanteric fractures (Study 2, n=16,667) on mortality at 30-days and 1-year. Analytic tests were utilised including descriptive analysis (chi-squared, t-test and ANOVA test), Kaplan-Meier survival curves, adjusted multilevel logistic regression, adjusted instrumental variable analysis, and adjusted Cox modelling to test the association of mortality between groups and minimising confounding. Significant findings included: 1. In the adjusted analysis, compared to uncemented, there was no significant increase in 30-day nor 1-year mortality with cement use in arthroplasty. 2. Despite a significant increase in 30-day mortality for long compared to short IM nail fixation in the adjusted multilevel regression, this was not shown in the Cox modelling and IV analysis suggesting residual confounding was responsible for the regression result. 3. There was no significant increase in 30-day mortality for SHS compared to short IM nail fixation. 4. There was no significant increase in 1-year mortality between long IM nail or SHS compared to short IM nail fixation. This thesis demonstrates that cement use in arthroplasty and IM nail fixation for intertrochanteric fractures are not associated with excess mortality. Choice of procedure should be informed by postoperative functional outcomes including measures important to older people as well as cost. Further prospective research with large datasets could explore the economic impact, functional outcomes, and quality of life impact of such surgical variation to better guide future practice.