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(2021) Oh, LawrenceThesisBackground: Cervical spine degenerative conditions effect up to two-thirds of the population and are the most common cause of acquired disability in patients over the age of 50. These disorders commonly present with axial pain, myelopathy, radiculopathy or a combination of these symptoms. Surgical intervention is generally indicated in with failure of conservative management or with evidence of cord compression or myelopathy. Anterior cervical discectomy and fusion (ACDF) is an effective option. It is not well established what factors contribute to dysphagia and recurrent laryngeal nerve palsy complications following ACDF surgery. Objective: 1. To determine the rates of dysphagia and recurrent laryngeal nerve complications following ACDF reported in the literature and potential associated factors. 2. To determine rates of dysphagia and recurrent laryngeal nerve injuries in a large Australian series of ACDF by a single surgeon. Methods: For the systematic reviews, electronic searches were performed using electronic databases. Relevant studies reporting the rate of dysphagia or recurrent laryngeal nerve injury as an endpoint for patients undergoing ACDF for degenerative disease, myelopathy, cervical canal stenosis or ossification of the posterior longitudinal ligament were identified according to prior inclusion and exclusion criteria. Statistical analysis was performed using odds ratio (OR) as the effective size. I2 was used to explore heterogeneity. For the retrospective chart review, consecutive patients undergoing ACDF from 2015 to 2019 for cervical radiculopathy and/or myelopathy were included. Univariate logistic regression analysis was performed to identify risk factors of RLN palsy, swallowing problems and adjacent-level ossification disease (ALOD). Results and conclusions: We found that based on pooled analysis that there was a higher rate of dysphagia for multiple-level ACDF (6.6%) compared with single-level ACDF (4%). The pooled incidence of recurrent laryngeal nerve palsy from the literature was 1.2%, with no difference between multiple- and single-level ACDF. These rates were similar to analysis of our retrospective series, with 1.8% patients having recurrent laryngeal nerve palsy and 4.0% with clinical dysphagia. We confirm based on our series that multi-level operation was associated with higher rate of RLN palsy, but this was not affected by other factors including age, gender, and the use of plate, internal fixation or number of screws.
Flucloxacillin concentrations and clinical outcomes in Staphylococcus aureus bacteraemia, and the impact of renal impairment on flucloxacillin pharmacokinetics(2021) Duckworth, AndrewThesisBackground: Methicillin sensitive staphylococcus aureus bacteraemia (SAB) is a common cause of bacteraemia with substantial associated mortality. Flucloxacillin is one of the first line antibiotics used in the treatment of this condition. The relationship between serum flucloxacillin concentrations below the minimum inhibitory concentration (MIC) of the pathogen and clearance of bacteraemia based on blood cultures remains uncertain. In addition, flucloxacillin is renally cleared by active tubular secretion, however the current Australian dosing guidelines do not recommend dose adjustment until the eGFR is <10 ml/min/1.73m2. We investigated the impact of estimated glomerular filtration rate (eGFR) on the serum flucloxacillin concentration. Methods: Two retrospective observational studies are presented. In the first study, 138 episodes of SAB between January 2015 and December 2018 were analysed. Inclusion criteria were age > 16 years and a positive blood culture for methicillin sensitive staphylococcus aureus. Of these, there were 30 and 41 episodes in which appropriately timed trough and mid-dosage estimated free flucloxacillin concentrations [FLX]efree, respectively, were obtained within 7 days of the initial MSSA blood culture. Differences between the persistent (blood cultures positive >72 hours) and non-persistent (<72 hours) bacteraemia groups in age, sex, focus of infection and risk factors for complicated clinical course were determined. In the second study, we analysed 396 serum flucloxacillin concentrations [FLX]total, restricted to the first per hospital admission or outpatient encounter and those simultaneously co-measured with creatinine. Inclusion criteria were age > 16 years and a serum flucloxacillin concentration measured at the study institution between May 2015 and June 2020. Free flucloxacillin concentrations [FLX]efree were estimated from total concentrations using a Michaelis-Menten model for serum albumin binding. We analysed the proportion of episodes with [FLX]efree below the upper limit oxacillin MIC for methicillin-susceptible Staphylococcus aureus (1mg/L) in this cohort, and [FLX]total>125.1mg/L - a previously identified neurotoxicity threshold, respectively, by GFR quintile. Results: In the first study, the persistent and non-persistent bacteraemia groups were found to be similar in age, sex and types of infection. Sub-MIC trough concentrations were identified in 3/17 cases of persistent bacteraemia, as compared with 0/13 cases of non-persistent bacteraemia (OR 0.0; 95% CI 0.0 to 1.4; p=0.24). Sub-MIC mid-dosage concentrations were identified in 3/22 cases of persistent bacteraemia, as compared with 0/19 cases of non-persistent bacteraemia (OR 0.0; 95% CI 0.0 to 1.28; p=0.24). In the second study, of the 396 [FLX]total samples, 242 [64.7%]) were from hospital ward inpatients, 70 (18.7%) samples were obtained from patients in ICU or HDU care, while 62 (16.6%) were from outpatients. In a multivariable regression analysis, [FLXfree] negatively correlated with eGFR. Flucloxacillin concentrations stratified by GFR quintiles were determined. The proportion of episodes with [FLXfree]<1 mg/L was significantly lower in the lower GFR quintiles when compared with the higher GFR quintile (p<0.001 for trend). Conversely, [FLX] above a previously identified neurotoxicity threshold was found to be significantly more common in lower GFR quintiles as compared with higher GFR quintiles (p<0.001 for trend). Conclusions: Sub-MIC trough or mid-dosage estimated free flucloxacillin concentrations were not associated with a lower rate of persistent bacteraemia, however the wide confidence intervals include a clinically important effect, and larger studies are warranted. Flucloxacillin concentrations were significantly negatively correlated with eGFR. Potentially subtherapeutic concentrations were more common in patients in higher eGFR quintiles, while potentially neurotoxic concentrations were more common in patients in lower eGFR quintiles but above the current threshold for dose adjustment.
(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.