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(2022) Sandery, BlakeThesisAcute 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.
A Biomarker-Driven Approach to Identify Pathogenic Mechanisms and Novel Therapeutic Targets in Pyoderma Gangrenosum(2023) Flora, AkshayThesisPyoderma 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.
(2023) Hallam, LauraThesisThere has been significant work in recent decades to address gender bias, exclusion and lack of sex and gender consideration in health and medical research, including identification of gender data gaps and implementation of policies to improve sex and gender consideration in research design and reporting. This thesis aimed to understand the impact of this context on current research practice and identify ways to further support meaningful change that can lead to improved health outcomes. These aims were addressed through three original research studies employing either quantitative or qualitative methods and a perspective on the field written in collaboration with other early- and mid-career researchers. Two quantitative analyses of published research were conducted to identify if the policy landscape had impacted research practice. In the field of women’s health, publications still largely focused on reproductive health issues for women in their reproductive years, and few papers aimed to conduct sex and gender analyses. In Australian health and medical research publications, sex and gender reporting were not significantly influenced by established guidelines. There was a lack of clarity around terminology, data collection and reporting of sex and gender data. A perspective on the field was written, highlighting the need to contextualise sex and gender research to improve women’s health. A Theory of Change was developed to map ways to further support changes in research practice and facilitate potential improvement in health outcomes. These pieces of work collectively identified a broad range of activities that are needed across the health and medical research sector, and along the evidence, translation and implementation pipeline. These include improving understanding of sex and gender, providing education, guidelines, policies and standards to support key actors and implementing continuous monitoring and feedback to maintain best practice and achieve a positive impact on health. In conclusion, greater discourse and policy implementation promoting consideration of sex and gender in health and medical research has not had a large impact on research practice, either in the field of women’s health, or in Australian health and medical research. Sector-wide, coordinated activities are needed to support changes in research practice to better consider sex and gender and to effectively translate and implement research findings to improve health outcomes.
Effects of deprivation and average ambient solar irradiation on bone health and osteoporosis using the UK biobank cohort study.(2023) Mahmud, MafruhaThesisOsteoporosis is a progressive bone disease characterised by low bone density and micro-architectural deterioration of bone tissue. Socioeconomic deprivation is associated with increased fracture risk. There is, however, a scarcity of, or inconclusive, research on deprivation and total bone health. Thus, in my first study, the role of deprivation on bone health, including low bone density, falls, and fractures was examined. Vitamin D is important for bone health, and humans synthesise it through exposure to solar radiation. Nowadays, although vitamin D supplementation is considered a standard way to effectively treat osteoporosis, it remains unclear whether vitamin D from sunshine has health advantages over supplements. In my second study, the relationship between exposure to average annual ambient ultraviolet B (UVB) radiation across the lifetime, measured by satellite observation, and osteoporosis was investigated. The two studies applied cross-sectional methods to baseline measures from the United Kingdom (UK) Biobank cohort, which includes 502,682 participants aged 40-69 years at recruitment from 2006 through 2010. Univariate and multivariable logistic regression models were built to estimate odds ratios for the associations between exposure and outcome while adjusting for possible confounders. Deprivation was associated with falls (odds ratio for the most deprived quintile compared to the least deprived was 1.46; 95% CI 1.42-1.49), fracture from simple fall (odds ratio for the most deprived category compared to least deprived was 1.16; 95% CI 1.13-1.19), and low bone mineral density (odds ratio for the most deprived quintile compared to least deprived was 1.31; 95% CI 1.26-1.36). The presence of a positive trend towards increasing bone health with declining deprivation suggests a dose-response relationship. No association was found between average lifetime ambient solar UVB radiation and osteoporosis. For osteopenia, only a weak protective association was found between the lowest quantile of UVB and osteopenia. In conclusion, from this large cohort, we found that material deprivation was associated with poor bone health. Using satellite observations of UVB exposure, we did not find evidence of an association between lifetime UVB exposure and the presence of osteoporosis in the UK.
Proteomic study of small extracellular vesicle protein biomarker profiles for breast cancer liquid biopsy(2023) Lee, Yu JinThesisBreast cancer (BC) is the leading cause of cancer-related death among women worldwide. Currently, the conventional method for diagnosing BC such as mammogram, is not reliable for detecting small lesions or dense breast tissue. Surgical biopsies cannot provide accurate and real-time information due to the complexity of the tumour. Small extracellular vesicles (sEVs) are one of EV subpopulations and secreted by all cell types, containing various biological cargoes that reflect their cellular origin. sEVs are an important intercellular communicator, participating in all stages of cancer metastasis, immunity, and therapeutic resistance. Studying sEVs in liquid biopsy for BC diagnosis is a new developing research area. Therefore, disease specific proteins contained in sEVs are considered as a superior choice for non-invasive liquid biopsy biomarker source in BC. In this thesis, I specifically aim to 1) Establish and optimise a method for isolating sEVs from BC cell lines and human BC plasma samples; 2) Find the most effective approach for proteomic analysis; 3) Identify potential sEV protein biomarkers using BC cells and plasma samples by LC-MS/MS proteomics for BC diagnosis and prognosis. sEVs derived from three BC cell lines (MDA-MB-231, MCF-7, and SK-BR-3), one normal breast cell line (MCF-10A), three BC patients' plasma, and three non-cancer controls were isolated using ultracentrifugation (UC), Total Exosome Isolation kits (TEI), and a combined approach of UC and TEI (UCT). In BC cell lines, the UC isolates showed a higher sEV purity and sEV marker expression, as well as a significantly higher number of sEV proteins. UC isolation identified 10 potential sEV protein biomarkers in BC cell lines. In BC plasma samples, the UCT isolates showed the highest proportion of sEV- related proteins and the lowest percentage of lipoprotein-related proteins. UCT isolates demonstrated 9 potential sEV protein biomarkers in BC plasma. In summary, I have demonstrated that the assessment of both quantity and quality of sEV isolation methods is important in selecting the optimal approach for the specific sEV research purpose depending on the sample types and downstream analysis. In addition, future validation of distinct sEV proteins identified in my study holds potential, for developing new diagnostic approaches in BC liquid biopsy and promoting the application of personalised medicine.