Medicine & Health

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  • (2022) Sandaradura, Indy
    Thesis
    Despite advances in critical care medicine, severe infections and sepsis-related mortality remain a pressing problem. There is considerable evidence of under- and overexposure from standard dosing regimens across numerous antimicrobial classes in critically ill patients, a result of pharmacokinetic alterations arising from unique pathophysiologic changes. Timely initiation of adequately dosed antimicrobial therapy is recognised to be paramount in improving clinical outcomes in sepsis. Therapeutic drug monitoring (TDM), a tool traditionally used to minimise toxicity of glycopeptides and aminoglycosides, is increasingly being used to increase the precision of antimicrobial dose regimens in critical illness. ‘Emerging’ candidates for which TDM is recommended include β-lactam antibiotics, linezolid, ciprofloxacin, and antifungal, antiviral and antimycobacterial drugs. Little is known about the current uptake of TDM for these agents in Australian hospitals and the barriers to TDM implementation. Performing TDM also presents a learning opportunity whereby the probability of attaining therapeutic targets using empiric dosing strategies may be (re)evaluated. Chapter 1 presents an overview of the challenges facing clinicians prescribing antimicrobials for critically ill patients and potential ways TDM data can be used to overcome these challenges. Chapter 2 explores performance, clinician attitudes and barriers to implementation of TDM for emerging antimicrobial candidates, mapping out current unmet clinical need and providing a framework for TDM data driven precision antimicrobial dosing in subsequent chapters. Chapter 3 examines concentration–toxicity relationships in critically ill patients treated with β-lactam antibiotics and defines threshold concentrations associated with neuro- and nephrotoxicity. Chapter 3 also identifies factors that contribute to underexposure of antibiotics in critically ill patients. Chapter 4 investigates the pharmacokinetics and current dosing regimens of the antifungal drug fluconazole, another emerging TDM candidate. These findings are extended in Chapter 5 with an evaluation of a novel model-based dosing strategy for fluconazole. The findings from Chapters 3 and 4 leverage TDM data to provide insights into critically ill patients at risk of under- and overexposure of antimicrobials, and the use of novel antimicrobial dosing strategies. Chapter 6 discusses the clinical implications of this work and recommendations for future research.

  • (2022) Sloane, Jennifer
    Thesis
    From a child interrupting a conversation between her parents to ask "What's for dinner?" to a nurse interrupting a physician in the middle of a complex procedure with an urgent message, interruptions are an inevitable part of our daily lives no matter who we are, where we live, or what we do. Interruptions can have a variety of affects on people's performance and behavior. While interruptions may sometimes facilitate performance, often interruptions have negative consequences. For example, interruptions may result in people making more errors or forgetting to complete a prior task altogether. This thesis examines existing strategies to help mitigate interruption costs and explores the effects of interruptions within different decision environments. Chapter I introduces the topic by discussing a few theoretical frameworks of interruptions and reviewing prior research on what makes interruptions disruptive. One strategy to minimize interruption costs is to use what is called an interruption lag, which can be thought of as taking time to prepare for a pending interruption. Chapter II presents a novel experiment to systematically explore the potential benefits of interruptions lags and an alternative intervention (i.e. providing feedback) when interruption lags are not possible. Chapters III and IV discuss the results from three experiments and a final replication study that all focus on how interruptions affect people's decision making in unique environments. The environments consist of easy problems (i.e. basic arithmetic problems) and trick problems, designed in such a way to lead the reader down an incorrect path. Results from these studies were mixed. While there was some evidence that interruptions may make people more susceptible to falling for the trick answer, this finding was inconsistent across all the experiments. Chapter V applies the findings from the previous chapters to a medical context. This chapter presents novel medical cases that were developed with the help of a medical expert. These cases consisted of easy, hard, and trick cases designed for medical students. The goals of this chapter were to validate the cases and to investigate the effects of interruptions within the different case types. The final chapter (Chapter VI) concludes with a general discussion of the experimental findings, the theoretical implications of the results, and the broader implications of this research for the field of medicine.

  • (2022) Liao, Peiwen
    Thesis
    Background People with intellectual disability are at high risk of developing several health conditions, including epilepsy. Research on the clinical characteristics of people with intellectual disability and epilepsy is abundant. However, their health needs and health service use, which can reflect how they fare in the current health system, remain insufficiently examined. Methods The thesis comprises four studies. The first is a systematic literature review to quantify physical health conditions in people with intellectual disability and derive a detailed understanding of their health status. The remaining retrospective cohort studies were based on linked administrative datasets from health and disability services in the jurisdiction of New South Wales (NSW), Australia. Individuals aged 5-64 years with a diagnosis of epilepsy were identified from NSW hospital admission data, and diagnoses of intellectual disability were ascertained from disability and health service records. The studies examined and compared the risk of rehospitalisation and emergency department (ED) presentation after epilepsy hospitalisation and mortality in people with and without intellectual disability. Factors associated with hospital use and mortality were also investigated for those with both diagnoses. Results The systematic review added new knowledge about the risk of physical health conditions in people with intellectual disability. It identified conditions of the highest risk, including epilepsy, and conditions likely being under-detected. The linked data projects revealed that 1) intellectual disability is independently associated with a higher risk of readmission and ED presentation after epilepsy hospitalisation; 2) lower socioeconomic status and certain comorbidities are associated with an increased risk of repeat hospital use; 3) intellectual disability in people with epilepsy is associated with an increased mortality risk and a different cause of death profile. Disability and health characteristics are the main risk factors for death. Conclusions The studies generated new evidence of disparity in epilepsy-related health service use and outcomes between people with and without intellectual disability. The novel findings provide a foundation for improved clinical services provision. To better understand unmet health needs of people with intellectual disability and epilepsy, future research should investigate the use and the drivers of primary and outpatient care and antiepileptics in this population.

  • (2021) Shamsa, Aiat
    Thesis
    Oocyte-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.

  • (2022) Badge, Helen
    Thesis
    Primary total hip arthroplasty (THA) & total knee arthroplasty (TKA) are common, cost-effective surgeries that reduce the pain and disability caused by osteoarthritis. THA/TKA are associated with a small risk of complications, such as venous thromboembolism (VTE) and surgical site infection (SSI), resulting in poorer outcomes. VTE & SSI prophylaxis clinical practice guidelines exist, but it is unclear whether service providers comply, or whether this affects outcomes. Methods A prospective multi-centre cohort study was undertaken in consenting adults with OA having primary TKA/THA at one of 19 high-volume Australian public/private hospitals. Data were collected before and for one-year post-surgery. Compliance was calculated with the National Health & Medical Research Council (NHMRC) & Australian Orthopaedic Association (AOA) VTE clinical guidelines & Therapeutic Guidelines (TG) Antibiotic. Logistic and linear regression were undertaken to explore associations between clinical guideline non-compliance and complications and patient-reported outcomes (Oxford Hip/Knee Scores [OH/KS], EQ-5D), and cephalosporin prophylaxis and SSI. Results Data were analysed for 1875 participants. Clinical guideline non-compliance rates averaged 87% for TG Antibiotic, 65% for NHMRC VTE clinical guideline & 20.1% for AOA VTE clinical guideline. NHMRC VTE clinical guideline noncompliance was associated with an increased VTE risk (adjusted odds ratio [AOR]=2.83, 95%CI=1.59-5.28, p< 0.001) and with lower (worse) 1-year EQ-5D Index scores (β=-0.03, SE=0.008,p=0.002) & an inconsequential reduction in OH/KS (β=-0.76,SE=0.30,p=0.01). AOA VTE clinical guideline non-compliance reduced the risk of symptomatic 90-day VTE (AOR=0.1, 95%CI=0.0-0.4,p=0.01). TG Antibiotic noncompliance was associated with higher SSI risk (AOR=1.98, 95%CI=1.17-3.62,p=0.02) but not with PROMs. Reduced SSI risk was associated with cephalosporin dose (any SSI; AOR=0.68, 95%CI=0.47–0.99, p=0.05) and commencing antibiotics before skin incision (0-60 mins: any SSI, AOR=0.56,95%CI=0.36–0.89,p=0.01; DSSI, AOR=0.56,95%CI=0.36–0.89,p=0.01; ≥60 minutes: AOR=0.35, 95%CI=0.17-0.70,p=0.004; DSSI, AOR=0.35,95%CI=0.17-0.70,p=0.004). Changing dose (AOR=1.76, 95%CI=1.22–2.57,p=0.02) & receiving preoperative non-cephalosporin (AOR=1.35, 95%CI=1.01–1.81,p=0.04) increased SSI risk. Antibiotic prophylaxis duration was not associated with SSI. Summary Non-compliance with NHMRC VTE clinical guidelines & TG Antibiotic increased the risk of VTE & SSI. The contrary NHMRC & AOA VTE clinical guideline findings may be explained by AOA recommending aspirin. Increased compliance with high-quality VTE & antibiotic clinical guidelines may improve THA/TKA outcomes.

  • (2022) Meagher, Nicki
    Thesis
    Mucinous Ovarian Carcinoma (MOC) is a rare histological subtype, comprising 3-4% of all epithelial ovarian cancers. The majority (~80%) of patients are diagnosed at early stage, International Federation of Gynecology and Obstetrics (FIGO I/II), with a good prognosis after primary surgery. The key clinical challenges in MOC are: 1) identifying which patients with Stage I MOC are at risk of relapse and require adjuvant chemotherapy; 2) accurately diagnosing primary MOC from a cancer that has started elsewhere and spread to the ovary, most commonly from a gastrointestinal (GI) site; and 3) finding better treatment options for patients with advanced stage (III/IV) MOC. Using the international Ovarian Tumor Tissue Analysis consortium, this thesis sought to address these issues. Samples and data were pooled through the consortium for 3 projects: an immunohistochemistry (IHC) study on tissue microarrays examining the role of SATB2 in improving diagnosis of MOC (n=314) from colorectal and appendiceal tumours (n=230); a NanoString mRNA gene expression profiling study of mucinous ovarian borderline tumours (n=151), primary MOC (n=333), and upper (pancreatic/gastric, n=65)) and lower (colorectal/appendiceal, n=55) tumours to look for prognostic and diagnostic markers; thirdly a multicolour IHC and immune fluorescence project to quantify the immune infiltrate in MOC (n=124), assessing whether immune therapies are worth exploring for patients. In addition, an international commercial tumour profiling dataset was analysed with IHC and mutation data to examine profiles of MOC (n=295) and compare with publicly available GI profiles to look for shared treatment targets. I found that the addition of SATB2 in combination with CK7 was highly sensitive and specific in differentiating primary MOC from colorectal and appendiceal metastases, and made recommendations for clinical diagnostic practice. I confirmed that an infiltrative pattern of invasion in Stage I MOC is prognostic within the first two years of diagnosis and warrants consideration of adjuvant chemotherapy for those women. I identified that high expression of 2 genes, THBS2 and TAGLN were associated with poorer overall survival, suggesting a possible relationship with the infiltrative subtype and more aggressive disease. I confirmed prior suggestions that MOC are immunologically ‘cold’, with only 12 out of 66 early stage, and 1 out of 12 advanced stage tumours showing a T cell/PD-L1 phenotype potentially suitable for current immune based therapies. I confirmed the mutation profile of MOC with high rates of KRAS, TP53 mutations, and argued that clinical trial criteria for patients with advanced stage mucinous cancer involving the ovary should focus less on the site of origin, and more on molecular targets for basket trials with GI cancers sharing molecular features. This comprehensive body of work covers diagnosis through to treatment, with translational potential using SATB2, an infiltrative pattern of invasion in Stage I clinical decision making, targets such as THBS2 and TAGLN to be further explored and suggests a shift towards basket clinical trials with upper GI cancers due to phenotypic similarities with MOC.

  • (2022) Marinova, Maria
    Thesis
    Ovarian ageing is a major health concern with socioeconomic consequences, manifesting at the comparatively young age of around 35 years. In cancer patients who have undergone chemotherapy, this process is greatly accelerated and can lead to premature ovarian insufficiency, infertility and early menopause, which severely impact the quality of life of cancer survivors. Options for preserving fertility may be limited by the urgency of cancer treatment or by patient age. Recently, repletion with the nicotinamide adenine dinucleotide (NAD+ ) precursor nicotinamide mononucleotide (NMN) was shown to maintain reproductive function during ageing. Here, we sought to test whether NMN treatment might protect against chemotherapy-induced infertility and whether this could extend beyond fertility to other aspects of late-life health. We found that co-treatment of NMN with doxorubicin (Dox) maintains primordial follicle health, however, this did not reach statistical significance. This finding was in line with previous findings regarding the ability of NMN to maintain breeding performance during Dox. We also tested whether NMN could maintain the ovarian reserve when delivered following early-life cisplatin (CDDP) treatment, which modelled pediatric cancer treatment. While there was no impact of NMN on CDDP-induced follicle loss, this treatment did improve aspects of late-life health, with drastic improvements in bone function as measured by CT structural imaging, mechanical testing, and histological analysis. In line with the absence of an effect on ovarian reserve, there was no effect of NMN on estrogen (E2) levels, suggesting that the rescue in bone function was unrelated to ovarian effects. These promising effects may be important to maintaining the late-life health of female cancer survivors, but further work will be required to elucidate the mechanisms of action.

  • (2022) Poulton, Christopher
    Thesis
    The Inflammatory bowel diseases (IBD), include Crohn’s Disease (CD) and Ulcerative Colitis (UC), are characterised by chronic relapsing inflammation of the gastrointestinal tract. The accepted disease aetiology is the homeostatic relationship between intestinal bacteria and intestinal immunity breaks down, resulting in chronic relapsing inflammation that can irreversibly destroy the intestinal mucosa. Contributing factors for disease are thought to be host genetic factors, environmental factors and the host gut microbiome. However, disease heterogeneity and the complex characteristics of disease have made it difficult to precisely define disease causation. The aim of this thesis was to investigate characteristics of the gut microbiome at diagnosis of pediatric IBD in an attempt to describe features that may explain disease causation. Treatment naïve children with gastrointestinal symptoms undergoing investigation by colonoscopy were recruited. Prior to colonoscopy, faecal samples were collected. During colonoscopy, mucosal washings and biopsies were collected at multiple sites along the large intestine. Participants were characterised as IBD or with a Functional Gastrointestinal Disorder (FGID) using standard guidelines. Faecal samples were also collected from healthy children (HC) with no gastrointestinal symptoms. Microbial composition was investigated by 16S Ribosomal subunit (16S rRNA) analysis and whole genomic sequencing (WGS). Initial findings were that multiple sampling (mucosal washings, biopsies and feces) was more informative than a single sample and this approach was used in subsequent investigations. Initial comparisons of CD and UC showed greater variability in the gut community structure in CD. Although both UC and CD vary from FGID and HC, with UC microbial profiles more closely resembling FGID. Bacteria that accounted for most difference between inflamed and non-inflamed sites were Bacteroides, Akkermansia, Faecalibacterium, Eschricia, Odoribacter and Parabacteroides. Overall, the microbial gene functions and pathways between disease and non-disease groups, and between sample types, were similar. Combined analysis of 16S rRNA and WGS indicated some overall changes may be associated with inflammation, however individual patients appear to have unique microbial characteristics associated with disease. Therefore, patients with similar disease phenotypes may have different microbial drivers of disease. The outcomes of this thesis suggests that a personalised approach to investigating and treating disease may be warranted.

  • (2022) Cao, Jun
    Thesis
    This thesis focuses on the development and applications of magnetic resonance electrical properties tomography (MREPT), which is an emerging imaging modality to noninvasively obtain the electrical properties of tissues, such as conductivity and permittivity. Chapter 2 describes the general information about human research ethics, MRI scanner, MR sequence and the method of phase-based MREPT implemented in this thesis. Chapter 3 examines the repeatability of phase-based MREPT in the brain conductivity measurement using balanced fast field echo (bFFE) and turbo spin echo (TSE) sequences, and investigate the effects of compressed SENSE, whole-head B_1 shimming and video watching during scan on the measurement precision. Chapter 4 investigates the conductivity signal in response to short-duration visual stimulus, compares the signal and functional activation pathway with that of BOLD, and tests the consistency of functional conductivity imaging (funCI) with visual stimulation across participants. Chapter 5 extends the use of functional conductivity imaging to somatosensory stimulation and trigeminal nerve stimulation to evaluate the consistency of functional conductivity activation across different types of stimuli. In addition, visual adaptation experiment is performed to test if the repetition suppression effect can be observed using funCI. Chapter 6 explores if resting state conductivity networks can be reliably constructed using resting state funCI, evaluates the consistency of persistent homology architectures, and compares the links between nodes in the whole brain. Chapter 7 investigates the feasibility of prostate conductivity imaging using MREPT, and distinctive features in the conductivity distribution between healthy participants and participants with suspected abnormalities.

  • (2022) Aishah, Atqiya
    Thesis
    Obstructive sleep apnoea (OSA) pathogenesis is multifactorial with contributions from anatomical and non-anatomical endotypes. Current anatomical-orientated therapies are often inadequate or poorly tolerated with no pharmacotherapies available for OSA. Recent research shows that a combination of noradrenergic and anti-muscarinic agents increases upper-airway muscle activity (key non-anatomical endotype) and reduces OSA severity. Thus, my thesis aimed to investigate alternate therapies for OSA including novel pharmacotherapies targeted towards non-anatomical OSA endotypes as well as combining with existing anatomical approaches based on OSA endotype characterisation. Study 1 investigated the effects of the noradrenergic agent atomoxetine combined with 2 different anti-muscarinics (solifenacin or biperiden) with different receptor-selectivity profiles. Previous studies combined atomoxetine with the antimuscarinic oxybutynin which has broad receptor-selectivity. The goal was to gain mechanistic insight into specific antimuscarinic receptor subtypes for OSA pharmacotherapy which may also have a better side-effect profile versus oxybutynin. The different anti-muscarinics plus atomoxetine improved upper airway function and perceived next-day sleepiness in people with OSA albeit to a lesser extent compared to oxybutynin. This suggests broad or at least M2 muscarinic receptor selectivity may be important in mediating the efficacy of this drug combination for OSA pharmacotherapy. Previous studies with noradrenergic and antimuscarinic agents have been short term (≤1 week) and have not included different doses. Accordingly, in study 2, I investigated longer term (1-month) safety, tolerability, and efficacy of different doses of atomoxetine plus oxybutynin (ato-oxy) versus placebo. 1-month of ato-oxy was generally well-tolerated with a side effect profile consistent with the known profile of each agent alone. An 80/5 mg dosage combination of ato-oxy reduced key OSA severity metrics by ~50%. In study 3 I aimed to investigate if OSA endotype characterisation can be used to inform targeted therapy to resolve OSA in the clinically relevant group of patients who have an incomplete therapeutic response to oral appliance alone (~50% of patients). In these individuals, I systematically added existing anatomical therapies and emerging non-anatomical therapies (i.e., ato-oxy) according to OSA endotype characterisation. OSA was controlled in 50% of participants with addition of other existing anatomical interventions. Almost all the remaining participants were fully treated with the addition of non-anatomical pharmacotherapies. These novel findings provide important insight for the development of novel pharmacotherapy and combination therapy approaches informed by underlying physiological mechanisms for future treatment and management of OSA.