Medicine & Health

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Now showing 1 - 10 of 101
  • (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) 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.

  • (2021) Mazigi, Ohannes
    Thesis
    Bacterial superantigens are a key determinant in the incessant war between man and pathogen. Several notable examples include Streptococcal pyrogenic exotoxins (SPEs), Staphylococcus aureus enterotoxin D (SED) and Peptostreptococcus magnus protein L (PpL), all of which are virulence factors that evade our adaptive immune system. However, one in particular known as Staphylococcus aureus protein A (SpA), is a classic example of a potent B cell superantigen that causes numerous pathologies in humans such as septicaemia, endocarditis and toxic shock syndrome. The highlighted feature of SpA is that it exclusively targets VH3 germline derived B cells and immunoglobulins to perturb our immune system’s natural defence mechanisms. The VH3 germline happens to be the most frequently used germline class in our naïve B cell repertoire, and this is what makes this antigen so ‘super’. Humans have exploited this feature for basic applications as its affinity for immunoglobulins provided an ideal purification reagent for recombinantly expressed antibodies. We’ve exploited it once before, but the question is can we exploit it once more? This thesis seeks to answer the question whether naturally occurring interactions between superantigens and antibodies can in fact be manipulated. Using principles of protein engineering and design, I have outlined a rational strategy to which SpA can be engineered such that its affinity and specificity can be shifted towards a non-VH3 germline class. The success of this approach was based on strategically designing a tailored library of SpA domain mutants by targeting key contact residues that govern its binding. Coupling this with phage display technology enabled high throughput selection of superior variants that not only showed exclusive affinity to recombinantly expressed VH1-69 germline antibodies but also the ability to maintain functionality in context to live B cells. Having never been attempted before, the novelty of this work engenders a myriad of potential biotech applications for engineered SpA. More importantly however, the findings from this work proves that superantigen properties can be exploited. During the course of this Ph.D., the COVID19 pandemic quickly emerged as a world health crisis. The desperate search for therapeutic intervention quickly ensued. Success from the previous work on bacterial superantigens begged the question whether the same principles of molecular engineering can be adopted in context to antibody engineering. Here, I showcase how SARS antibodies can be engineered such that their affinity and specificity is shifted towards the COVID19 virus. For this, I adopt the same rationale of targeted mutagenesis using structural insights for tailored library design and phage display technology for high throughput screening. This enabled the discovery of several high affinity antibody candidates that were not only mutationally robust against the emergent strains but also harboured potent neutralising capabilities. This work offers an excellent strategy to rapidly generate highly desirable COVID19 antibodies that have strong applications as anti-viral drug therapies and/or reagents for diagnostic tools. Furthermore, it provides a framework for general antibody discovery techniques that can be used to combat current and future infectious disease outbreaks.

  • (2022) Mitchell, Janet
    Thesis
    This doctoral research investigated the meaningful relationships of people living with dementia who experience changed behaviours in residential aged care. This is an unresearched field, and current evidence suggests that the wellbeing of these residents is not prioritised in their care. The construct meaningful relationships was a representation of the quality of interactions and relationships in which residents engaged and, hence, their wellbeing. The study contributed to a re-envisioning of dementia care and noted a connection between legislative and regulatory mechanisms and a resident’s quality of life (wellbeing). An historical and integrated review of the literature was adopted to determine the role of relationships in portrayals of dementia and dementia care and the extent to which relationships were considered. The review explored retained capabilities among people living with dementia. It laid the foundation for the study’s adoption of the expression: meaningful relationships. The study’s design is multiple methods with data triangulation. The research included observation of study residents’ interactions during mornings, afternoons, and evenings. It selected social network methods, using structured interviews with study participants. A person-centred environment and care assessment of each of the five care homes was conducted. The home’s quality of care was investigated via participant interviews. Resident interactions were observed to be few and of short duration, although mostly affirming. In some care homes, most resident-affirming interactions were with their family or close friends and other residents; in others, they were between staff and residents. Social network analysis showed good interaction between staff, but interactions varied between visiting personnel and between each of the three study groups—staff, residents’ families and friends, and visiting personnel. Levels of relational person-centred care varied across the five homes. Comparison of these data sources suggested an association between the adoption of relational person-centred care and the quality and extent of interactions and relationships that occurred. Analysis of quality of care and person-centred care interview responses and observation field notes provided insights into the meaningful relationships that occurred for residents. The results indicated that the provision of relational person-centred dementia care is associated with meaningful relationships for residents in residential care homes.

  • (2022) Chander, Russell
    Thesis
    Social cognition refers to the range of skills and abilities that enable humans to detect and process information from one’s social environment, formulate a mental understanding of one’s social situation, and behave in socially appropriate ways. These include abilities such as theory of mind (ToM; also referred to as cognitive empathy), affective empathy, and social perception, as well as social behaviour. A growing body of research has sought to gain an understanding of how these phenomena manifest in the ageing process, as opposed to younger adults. The general aim of this thesis was to study the changes in social cognition with ageing, examine its relationship with other cognitive functions, and determine its association with genetic, neuroanatomical, and socioenvironmental factors. The first study explored the effect of polymorphisms of the oxytocin receptor gene on empathy using meta-analysis of existing studies including novel data from the Sydney Memory and Ageing Study (Sydney MAS). The second study developed a short-form version of the Reading the Mind in the Eyes Test (RMET), an assessment for theory of mind, via machine learning algorithms using Sydney MAS data. The third study explored social cognitive performance in Sydney MAS participants with subjective cognitive decline, mild cognitive impairment, and dementia. The fourth study identified key neuroimaging regions associated with empathy using volumetric analysis. The fifth study comprehensively indexed social cognition in nondemented community-dwelling older adults, and identified which subdomains were related to the ageing process and to other factors. This thesis found that normal ageing saw mild changes in ToM and social perception, and executive function somewhat compensated for this performance. Neurocognitive disorders were associated with far-reaching changes in these subdomains and some changes in social behavior. Empathy was related to volumes of the insula, supramarginal gyrus, and frontal lobe small vessel disease, and was not related to genetic sensitivity to oxytocin. A short-form version of the RMET was also developed. These findings improve on the understanding of social cognitive abilities in older adults, and facilitate the adoption of social cognition measures in clinical settings involving older adults.