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(2022)ThesisThe aim of this study was to estimate the prevalence and identify potential determinants of cardiometabolic disease (CMD) in people with psychotic disorders in secure settings and compare these to people with psychotic disorders in the community. A systematic review of the literature was undertaken to determine existing rates of CMD indicators in people with psychotic disorders in secure settings. Data from a comprehensive health and wellbeing survey, the Forensic Mental Health Patient Survey (FMHPS), were obtained to determine the prevalence and determinants of CMD indicators in a sample of forensic patients. Findings were directly compared to a sample of people with psychotic disorders living in the community using data from the second Australian National Survey of High Impact Psychosis (SHIP). The weighted pooled prevalence rates from the reviewed studies were hypertension 25.0% (N=857, 95% CI 22.1-27.9), dyslipidaemia 29.2% (N=1,135, 95% CI 26.6-31.9), diabetes 11.2% (N=2,582, 95% CI 9.9-12.4), being overweight or obese 72.4% (N=840, 95% CI 69.4-75.5), cardiovascular disease 15.6% (N=1,047, 95% CI 13.4-17.8) and metabolic syndrome 23.5% (N=1,390, 95% CI 21.3-25.7). The prevalence of CMD indicators in the reviewed studies were predominantly higher compared to the general population. When directly compared, the forensic patient sample were older, more likely to be male, and more likely to be of Aboriginal and/or Torres Strait Islander background, than the community-based psychosis sample. The former also had higher rates of polypharmacy, clozapine prescribing, physical activity, and food consumption. However, on multivariate analysis, the forensic patients had a lower prevalence of hypertension (OR 0.36, 95% CI 0.23-0.57) and metabolic syndrome (OR 0.41, 95% CI 0.25-0.67) compared to the community-based psychosis sample. There are clearly important differences in the sociodemographic characteristics, treatment needs and lifestyle practices of forensic patients in secure settings and there may be aspects of secure care that actually reduce CMD risk, however the resultant impact on CMD prevalence is complex. Forensic patients in secure settings require early detection and assertive treatment of CMD indicators and further research to assess the feasibility and effectiveness of these interventions in secure settings is required.
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(2022)Thesis3D computer generated biomedical animations can help audiences understand and contextualise scientific information that can be challenging to communicate due to resolution and complexity. Biomedical animators bring together multiple sources of authentic scientific data, to translate abstract information into a visual form through storytelling and visualisation. The field of biomedical animation has emerged from a long history of science visualisation and science-art endeavours, and despite there being rich discourse in the fields of data visualisation and science communication, the academic literature in the field of biomedical animation is limited, and focussed on the technical methods for visualisation, or the role these animations play in scientific research, rather than the processes through which they are created. However, as the field matures, there is a need for a deeper understanding of the creative process, and the field is now poised to expose and characterise these aspects, particularly from the perspective of the practitioner. This practice-based research project aims to expose and characterise both the visible and invisible factors that influence my personal process of creating a biomedical animation, and the tacit dimensions that influence orchestrated design choices. This research project employs a multi-method and reflective practice approach with disciplined capture and documentation of critical moments of self-reflection, that ultimately comprise the data for analysis. Thematic analysis was then used to analyse the data, and to identify themes that could contribute to frameworks that represent my personal process(es) in creating 3D biomedical animations. This has allowed me to identify and contextualise my creative process both in terms of my personal and professional position as well as within the field more broadly. I am now able to better advocate for the intangible and often undervalued aspects of my creative practice, and can articulate how a hierarchical decision matrix that considers multiple inputs contributes to my creative process. These insights will also be relevant to others in the field of biomedical animation and in the field of design more broadly, who may gain a deeper insight into their own processes of working and ways of exploring creative practice.
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(2022)ThesisBackground: Anterior lumbar interbody fusion (ALIF) remains one of the mainstay surgical approaches in treating painful degenerative disc disease with or without segmental instability in the lower spine. The risk factors and complication profile for ALIF differs significantly from other established fusion techniques. Objectives: The goal of the first part of this thesis is to establish the factors associated with long-term clinical outcome (Chapter 2) and short-term perioperative outcomes (Chapter 3) following ALIF. Chapter 4 focuses on the long-term radiographic evidence for biomaterial alternatives for ALIF implants, namely titanium (Ti)-coated PEEK integrated cages. Methods and Results: From a prospective cohort analysis of 147 patients undergoing ALIF, elderly age (≥64 years old) was associated with an increased rate of subsidence but does not affect clinical outcomes. Obesity was not associated with postoperative complications or follow-up patient-reported outcomes. Failed fusion was significantly higher for smokers, and they were significantly more likely than non-smokers to experience postoperative complications such as pseudoarthrosis. To assess risk factors for perioperative complications and readmissions after ALIF, the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was analysed. ALIF was associated with prolonged length of stay and higher rate of return to operating theatre compared to posterior lumbar fusion. Obesity and alcohol intake increased the risk of 30-day readmissions. Discharge to non-home destination following ALIF was independently associated with wound complications and venous thromboembolism. Finally, a prospective follow-up study was performed to determine the long-term radiographic outcome following ALIF using Ti-coated PEEK cages with allograft and INFUSE. Effective fusion was achieved at up to 24-month follow-up for various indications including degenerative spine/disc disease, low grade lumbar isthmic spondylolisthesis, spondylotic radiculopathy and discogenic low back pain. Conclusions: Collectively, this thesis highlights the importance of personalising the care of an ALIF surgery patient, through identification and optimization of individual risk factors for short-term and long-term outcomes, as well as through choice of implant biomaterial and design.
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(2022)ThesisBreast cancer is the most common malignancy in Australian women. Despite the likelihood of survival exceeding 90%, survivorship quality of life (QOL) may be undermined by persisting treatment effects, impaired psychosocial wellbeing, and elevated risk of comorbid health conditions. Strategies for mitigating these to maintain QOL are warranted. The aim of this thesis was to investigate the feasibility and acceptability of a novel 16-week classical ballet intervention for breast cancer survivors. The thesis aimed to evaluate the effect of treatment related upper-body morbidity (UBM) on QOL after breast cancer. In the literature review (Chapter 1), QOL after breast cancer is investigated. UBM and low physical activity levels are identified as contributors to impaired health and wellbeing and proposed as targets for improving QOL. The role of dance for health and wellbeing after cancer is reviewed. Classical ballet is identified as an understudied activity after breast cancer, poised to offer benefits superior to other dance styles. The unique use of the upper body in ballet may benefit survivors with UBM. In the systematic review and meta-analysis (Chapter 2), the relationship between UBM and QOL after breast cancer treatment is evaluated. Results show individuals with UBM have significantly poorer QOL than those without across key physical, psychological, and social domains. Multi-dimensional QOL assessment tools reveal the differential effects of UBM on each area of wellbeing. Efforts to minimise UBM in order to mitigate QOL impairment are warranted. The "Ballet after breast cancer" study (Chapter 3) aimed to investigate the feasibility and acceptability of a novel 16-week classical ballet intervention for breast cancer survivors. Twenty-four women completed two ballet classes per week for the study duration. The program was deemed feasible based on recruitment (62%) and attendance (77.55%) rates and acceptable based on participant-reported outcomes including enjoyment, benefit, and likelihood of continuation and recommendation to others. Chapter 4 presents a qualitative evaluation of participant experiences in the ballet program. Perceptions of the classes gleaned from focus groups, were subject to thematic analysis. Practical recommendations for future implementation are proposed. In the discussion (Chapter 5), the results of the thesis are summarised. The implications of these findings for survivorship care and avenues for future research are presented.
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(2022)ThesisHBsAg quantification may be a potential surrogate marker for hepatitis B (HBV) DNA load in mothers with chronic hepatitis B (CHB) given the higher availability and cheaper cost. Although genotype is not routinely tested in clinical practice, there are no studies looking at whether a correlation between quantitative HBsAg (qHBsAg) and viral load is affected by genotype. HBeAg seroconversion is important as it is associated with reduced liver injury time and earlier HBeAg seroconversion confers better prognosis. There are currently no definitive predictors of HBeAg seroconversion postpartum. A retrospective cohort analysis of mothers with CHB was performed across two major liver tertiary centres in Sydney, Australian between the years 2006 to 2019. Baseline (second trimester) and post-partum variables were collected including qHBsAg, viral load, genotype and evidence of seroconversion. We found qHBsAg level > 4 log 10 IU/mL to have a weak positive correlation with high viral load >6 log 10 IU/mL. The sensitivity was 70.5%, specificity 91.0%, negative predictive value (NOV) 91.0% and positive predictive value 70.5%. HBeAg was a better test to predict high viral load with NPV 97.9%. However, quantitative HBV DNA still remains the gold standard. Genotype did not affect the correlation between quantitative HBsAg and viral load. We identified three positive predictors for HBeAg seroconversion post-partum. This was age <35 years, baseline ALT ≥50 U/L and baseline HBV DNA <8 log10IU/ml. Our SydPredScore, based on these three variables, estimates the probability of seroconversion at 2000 days as approximately 10%, 30%, 70% and 80% for 0, 1, 2, and 3 predictors respectively. For mothers with 0 predictors, the chance of HBeAg seroconversion is extremely low and consideration could be given to treat these women with antiviral therapy to prevent further liver injury.
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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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Antimicrobial Polymers as Adjuvants/Synergists of Antibiotics to Combat Multidrug-Resistant Bacteria(2022)ThesisThe emergence of multidrug-resistant (MDR) bacteria due to the overuse and misuse of antibiotics in the medical and agricultural sectors has now become a critical global healthcare issue. Antimicrobial peptides (AMPs) and synthetic mimics thereof have shown promise in combating MDR bacteria effectively, mainly because of their mechanism of action that disrupts bacteria cell membrane, consequently hindering resistance development in bacteria. However, these antimicrobials also exhibit toxicity to healthy mammalian cells at high dosage. To overcome this toxicity issue, the application of combination therapy alongside traditional antibiotics could enable the administration of these membrane-disrupting antimicrobials at lower dosage. Herein, this thesis investigates the synergetic effects of new tri-systems for combination therapy against Gram-negative bacteria which contain: i) an AMP (colistin methanesulfonate); ii) an antimicrobial polymer as AMP mimic and; iii) commercial antibiotics. It was found that colistin and the antimicrobial polymer could combine synergistically with any of the three antibiotics, doxycycline, rifampicin, and azithromycin, against wild type and MDR strains of Pseudomonas aeruginosa. Crucially, given the lower dosage of antimicrobial polymer used in these combination systems, the therapeutic index (also known as selectivity index), which is an indicator of an antimicrobial system to preferentially target bacteria over mammalian cells, is higher than the standalone agents. Furthermore, in this thesis, other selected antimicrobial polymers that are active toward mycobacteria instead of Gram-negative were also investigated as potential adjuvants or synergists to potentiate the antimicrobial activity of antibiotics against Mycobacterium smegmatis via a two-component system. Among the different families of antibiotics screened, it was found that these polymers only act as adjuvants of aminoglycosides. Overall, this thesis yields valuable new insights on combination therapy that will be useful toward combating MDR bacteria in clinical settings.
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(2022)ThesisAcute kidney injury (AKI) occurs commonly in hospitalised children and carries an increased risk of morbidity and mortality. This thesis investigates the relationship between AKI and baseline kidney function, as this has not been well explored. We studied children exposed to acyclovir, and children with cancer, as these groups both have an increased risk of AKI. Children with cancer have been shown to have high baseline kidney function, known as glomerular hyperfiltration (GH), which is poorly understood. GH is a glomerular filtration rate above normal, which we define as a measured glomerular filtration rate (NMGFR) ³160mL/min/1.73m2. In a retrospective review of 150 children treated with acyclovir, 27 (18%) developed AKI. The only factor associated with AKI on multivariable analysis in this cohort was higher baseline estimated GFR (p=0.013). We reviewed the records of 202 children who underwent allogeneic haematopoietic stem cell transplant (HSCT) for haematological malignancy. In the first 100 days post-HSCT, 173 (85.6%) children developed AKI and stage 3 AKI occurred in 58 (28.7%). Factors significantly associated with stage 3 AKI on multivariable analysis were use of ciclosporin (vs. tacrolimus) (p=0.02), total body irradiation (p=0.01), early AKI on or before day 10 post-HSCT (p=0.001), ³10% creatinine increase 24 hours after AKI onset (p=0.001), and higher pre-HSCT NMGFR (p=0.03). At 1-year, patients with stage 3 AKI had greater reduction in estimated GFR than other children (-53.9 vs -18.8mL/min/1.73m2; p=0.0002). Analysis of the above cohort combined with the records of 91 children who underwent NMGFR at time of solid organ cancer diagnosis revealed that 16% had GH. GH was more common in young children (p=0.0055) and those with acute myeloid leukaemia (p=0.02), and was associated with higher weight gain (a surrogate for fluid accumulation) post-HSCT (p=0.02). Most children with GH pre-HSCT returned to a normal GFR. Development of GH at 1-year post-HSCT was associated with prior acute GVHD. This research is among the first to demonstrate that GH is associated with an increased risk of AKI. Our results suggest that GH occurring before HSCT may have a different underlying cause to hyperfiltration occurring post-HSCT and warrants further investigation.
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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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(2022)ThesisThis thesis explores novel aspects of the neuroradiological features of tuberous sclerosis complex (TSC), including the relationship between these features and subsequent epilepsy and developmental outcome in later childhood. The neuroradiological features of TSC include cortical tubers, subependymal nodules and subependymal giant cell astrocytoma (SEGA). Patients with TSC have high rates of refractory epilepsy, developmental delay and Autism Spectrum Disorder (ASD), but are affected to varying degrees leading to a wide phenotypic spectrum. Prior studies focussing on TSC neuroradiological markers have found some associations between lesion burden and severity of neurological dysfunction, but the literature remains inconclusive. Literature regarding congenital SEGA is limited but suggested they grew more aggressively than other SEGA. The first study in this thesis addresses this literature gap through a case series of ten congenital SEGA at a single TSC referral centre. Using serial MRI, our study found median congenital SEGA growth rate of 1.1mm/yr in diameter or 150mm3/yr volumetrically, which is lower than previous reports. Congenital SEGA with volume >500mm3 had significantly higher growth rates compared with smaller SEGA. Children with congenital SEGA tended to have more severe epilepsy, developmental disability and ASD compared to genotype-matched controls, suggesting that congenital SEGA may be a biomarker for poor neurological outcome, which is a novel finding. The second study explores whether neuroradiological features of TSC on early MRI are biomarkers for neurological and developmental outcomes. Thirty-nine MRIs acquired between 18-36 months from children with TSC were scored blindly. We found children with drug resistant epilepsy (DRE) had more tubers and subependymal nodules (SEN) compared to children without DRE. More frontal tubers were found in children with impaired adaptive function and children with ASD. Therefore, tuber count and frontal tuber location on early MRI may contribute to predicting DRE, adaptive function and ASD at 5 years of age. In conclusion, this thesis determines that neuroradiological markers have an important role in understanding TSC patients’ neurological and developmental outcome at 5 years of age. Early identification of patients at risk for poor outcomes would open opportunities for early intervention and more aggressive epilepsy treatment with the aim of optimising neurological and developmental outcome.