Medicine (RMH) - Theses
Permanent URI for this collection
Search Results
1 - 10 of 36
-
ItemDevelopment of Biosensor and Lab-on-a-chip Device for Molecular Diagnostics( 2021)Medical diagnostic testing at or near the patient is called point-of-care testing (POCT), which can potentially play a vital role in clinical decision making. The desired characteristics of POCT include rapid turnaround, cost-effectiveness, and high sensitivity and specificity. However, few POCT devices are available in routine practice. The overarching aim of this thesis was to develop a versatile POCT device for immunodiagnostic and precision medicine. Three sub-studies were undertaken under these two themes towards this goal. The first theme focused on immunodiagnostics applications utilizing magnetic biosensors. The POC device development using the existing immunosensors is limited due to the uneven distribution of tagged particles, inability to measure the three-dimensional region, reduced sensitivity due to background interference from the biological sample, nonlinear characteristic, non-specific detection, complexity on integration, and performance limitation due to detection circuitry. The magnetic biosensor was hypothesized to have the potential to overcome these limitations. Under this theme, the first objective was to develop a novel magnetic biosensor platform. While magnetic field detection technologies are well established for applications in the military, geology, archaeology, mining, spacecraft, and mobile phone, adaptation to POCT devices is yet to be explored. The magnetic field biosensors under development tend to be multilayered and require an expensive fabrication process. A low-cost and affordable biosensing platform is required for an effective point-of-care diagnosis in a resource-limited environment. Hence, an elliptical-shaped planar hall effect (EPHE) sensor was designed, fabricated, characterized, and optimized to quantitate magnetic beads. The developed sensor demonstrated the ability to detect 4.5 um magnetic beads, which had the limit of detection of 200 beads/uL. The second objective of the first theme was to demonstrate the potential clinical utility of the EPHE sensor. Glial fibrillary acidic protein (GFAP) was targeted for this purpose because it is a promising blood biomarker for diagnosing a range of serious neurological disorders, including traumatic brain injury and acute stroke. Early detection of GFAP in blood or plasma would enable more timely administration of appropriate intervention to improve treatment outcomes. However, the unavailability of a point-of-care device for GFAP detection has hampered the clinical utility of GFAP as a diagnostic biomarker in the clinical setting. This sub-study aimed to develop a novel GFAP quantification technique using magnetic bead-based functionalization of EPHE sensor. The sensor demonstrated a limit of detection of 120 ng/mL, with a linear correlation between sensor measurement and GFAP concentration (R2=0.9857) over the range of 100 - 180 ng/mL. Furthermore, the developed sensor can be utilized to detect other clinically relevant biomarkers with modified functionalization. The objective of the second theme was to develop a lab-on-a-chip device for genetic testing, specifically the HLA-B*15:02 allele. Screening of this human leukocyte antigen (HLA) allele before administering carbamazepine is recommended to prevent life-threatening hypersensitivity. However, the unavailability of a point-of-care device impedes this screening process. Our research group previously developed a two-step HLA-B*15:02 detection technique utilizing loop-mediated isothermal amplification (LAMP) on the tube, which requires device development to translate into a portable platform. Here, we report a heater-integrated lab-on-a-chip device for the LAMP amplification, rapidly detecting HLA-B alleles colorimetrically. Collectively, the studies of the first theme demonstrated proof of principle that the magnetic biosensor may be able to overcome the limitation of the existing immunosensors relating to the background interference. The developed low-cost biosensing platform is adaptable for multiple biomarker detection. The study of the second theme demonstrated the low-cost and portable lab-on-a-chip device for DNA amplification-based detection technique.
-
ItemPredicting poor clinical outcomes among older inpatients( 2021)Predicting poor clinical outcomes among inpatients has significant impacts on clinical decision making and treatment plan. A valid prognostic tool allows early interventions and patient-specific therapies by identifying patients who are at a higher risk of poor clinical outcomes. The Comprehensive Geriatric Assessment (CGA), a multidisciplinary diagnostic and treatment process, is implemented in geriatric rehabilitation inpatients and it includes multiple validated clinical assessment tools to evaluate older patients’ medical, psychosocial and functional limitations. The primary objective of this PhD thesis is to evaluate the performance of morbidity measures and frailty assessment tools in predicting poor clinical outcomes among geriatric rehabilitation inpatients. The systematic review included in this thesis shows that morbidity measures, predominantly the Charlson Comorbidity Index (CCI) and the Cumulative Illness Rating Scale (CIRS) and Geriatric Index of Comorbidity (GIC), are predictive for post-discharge mortality among older inpatients and the predictive performances are better in longer follow-up period. However, they are not predictive for functional decline among older inpatients. A total of 1890 geriatric rehabilitation inpatients (median age 83.4 [IQR 77.6-88.4] years, 56% female) were included in this thesis. They were mostly independent two-week prior to hospitalization (median Activities of Daily Living (ADL) score: 6 [IQR 4-6]; median Instrumental (I)ADL score: 5 [IQR 2-7] respectively). At admission to the geriatric rehabilitation wards, they had a median CCI score of 2 [IQR 1-4] and were mostly frail (median Clinical Frailty Scale (CFS) score: 6 [IQR 5-7]). Among these geriatric rehabilitation inpatients, three distinct functional trajectories were identified from two-week prior to hospitalization to three-month post-discharge: remained poor, deteriorated and recovered. Cognitive impairment and greater frailty status, assessed using the CFS, were each associated with deterioration and remaining poor in patients’ functional performance. Greater frailty status, assessed using the CFS, was also shown to be associated with in-hospital, three-month and one-year post-discharge mortality. An increased frailty severity from admission to discharge from geriatric rehabilitation was also associated with three-month post-discharge mortality. This thesis shows that frailty assessment tools, based on either clinical judgment (CFS) or laboratory tests (frailty index-laboratory test (FI-lab)), were poor predictors for one-year mortality among geriatric rehabilitation inpatients. Nonetheless, the clinical judgement-based frailty assessment tool (CFS) was slightly better than the laboratory test-based assessment tools (FI-lab and modified FI-lab) in predicting mortality and that they were all significantly associated with one-year mortality. Furthermore, this thesis includes a study applying the machine learning approach and the characteristics included in the CGA were shown to be poor predictors for geriatric rehabilitation length of stay. Lastly, greater frailty status, assessed using the CFS, was associated with the transitions from premorbid functional performance to institutionalisation and mortality from two-week preadmission to three-month post-discharge. This thesis emphasises the importance of assessing patients’ frailty status at geriatric rehabilitation admission as it reflects those with a higher risk of poor clinical outcomes. Future studies should focus on evaluating the treatment and intervention for frailty and investigate the importance of other CGA components.
-
ItemPost-reperfusion pathophysiology and secondary injury in ischemic stroke( 2021)Stroke is the second most common cause of death and third leading cause of long-term disability worldwide. The majority of strokes are due to arterial occlusions causing cerebral ischemia, where urgent restoration of blood flow is the primary goal of acute treatment. However, nearly 40% of patients nevertheless develop significant disability, even when occluded vessels are rapidly recanalized. This failure to improve from seemingly successful intervention is not well understood. In addition to injury already established pre-treatment, other subsequent pathological mechanisms may compromise the benefit of reperfusion. Adverse events after reperfusion causing additional cerebral injury may be an important but underappreciated factor contributing to poor outcome. Overt clinical manifestations of secondary injury include malignant cerebral edema and symptomatic intracerebral hemorrhage. Experimental studies suggest post-stroke inflammation and microvascular dysfunction are involved in perpetuating injury even after blood flow is restored to ischemic tissue. This thesis uses neuroimaging to explore pathophysiological processes after reperfusion that may contribute to unfavorable outcomes in patients with acute ischemic stroke. The first component of the thesis studies the effect of ischemia and reperfusion on cerebral tissue, re-examining the conventional approach of dichotomizing tissue fate as either infarcted or salvaged. Using cerebral edema as a clinical example of secondary injury, the thesis then explores factors involved in the development of post-stroke cerebral edema. How tissue may respond differently to reperfusion, and whether reperfusion may be paradoxically detrimental in humans is studied. Comparison of imaging markers currently used to measure cerebral edema is performed. Finally, the thesis investigates persistent tissue perfusion abnormalities in patients with apparently successful intervention. Better understanding of pathophysiological processes contributing to adverse outcomes after reperfusion may offer potential avenues to improve the efficacy of current reperfusion treatments. Identifying imaging correlates of these processes may help prognostication in clinical practice and improve patient selection for future trials targeting secondary injury.
-
ItemIMproving Palliative care Education and Training Using Simulation in Dementia (IMPETUS-D)( 2021)This thesis is about providing quality palliative and end-of-life care to people with dementia who live in residential aged care homes. Dementia is a progressive and life-limiting neurological condition that mainly affects older people. In Australia, there are currently over 450,000 people living with dementia where it is the second leading cause of death and third leading cause of disability burden. Most people who live in residential aged care homes have a diagnosis of dementia, and this is where they will spend the last months or years of life. However, there have been several reports including the recent Royal Commission into Aged Care Quality and Safety, to show the quality of palliative dementia care provided in residential aged care is often suboptimal and inadequate levels of staff knowledge and skills to deliver high quality palliative dementia care has been identified as a key contributing factor. The main objective of this thesis was to evaluate the effectiveness of a simulation training intervention on dementia-specific palliative and end-of-life care aimed at staff who work in residential aged care homes. To achieve this objective, three separate but related research studies were conducted. The first study was a systematic review that builds on the background literature review that found there was a paucity of studies assessing the effectiveness of staff training programs in dementia palliative care; and most previous studies used didactic lecture presentations. Alternatively, simulation is an immersive education method that offers unique educational opportunities for experiential learning with no risk to patients. There is a growing evidence-base to support use of simulation in health care, but it has not been well researched in dementia care or aged care. The systematic review presented in this thesis aimed to synthesise the evidence-base for use of health care worker simulation training in palliative care for non-cancer life-limiting conditions, including dementia. Five articles met the inclusion criteria and were summarised and critically appraised. None of the identified studies were about dementia care, and none were aimed at people who work in aged care – highlighting a gap in the evidence base. All studies aimed to improve clinician communication skills, and only one study included education and training on symptom management. The findings supported the need for more rigorously designed, randomised and multi-site trials, and confirmed the need for trials that assess simulation training interventions about the specific palliative care needs of people with dementia and their families. The second study was the main PhD project - the IMproving Palliative care Education and Training Using Simulation in Dementia (IMPETUS-D) cluster randomised controlled trial with process evaluation. The primary aim of the study was to assess the effectiveness of the IMPETUS-D training program on reducing transfers to and/or deaths in hospital. Secondary aims were to improve staff knowledge and attitudes towards palliative dementia care, improve bereaved carer satisfaction with end-of-life care, and to assess fidelity and participant acceptability of the training program. IMPETUS-D was a simulation-based training intervention on dementia-specific palliative and end-of-life care, developed for nurses and personal carers who work in residential care. The training was developed as part of a nationally funded project by experts in simulation and health care professional education and comprised of 11 modules that all participants could access and complete. There were three core modules for nursing staff and five core modules for personal carers, and remaining modules were recommended. Twenty-four residential aged care facilities (clusters) were randomised into the control or intervention group. Staff from the 12-intervention facilities had access to the IMPETUS-D training, and staff from the 12-control facilities had access to usual training opportunities. At 6-months follow-up, there were no statistically significant differences in the composite primary outcome of proportion of unplanned hospital transfers and/or deaths in hospital (odds ratio of 1.14, p=0.44), or in secondary outcomes of change in staff knowledge and attitudes towards palliative care in dementia (mean qPAD scores 60.1 intervention vs 59.5 control, p=0.77), and bereaved carer satisfaction with care (mean SWC-EOLD scores 26.6 intervention vs 27.3 control, p=0.80). Staff who participated in the training intervention reported the modules were relevant to their work and would recommend the modules to colleagues. However, the main challenge was the suboptimal levels of staff participation, with only 26% of staff completing at least one module (reach) and under 5% completing all their core modules (dose). Further, these suboptimal levels of reach and dose likely inhibited adequate assessment of program effectiveness. The process evaluation explored barriers to staff participation using the Consolidated Framework of Implementation Research (CFIR). The introduction of the new aged care standards occurred at the same time as implementation of IMPETUS-D training, and this impacted on IMPETUS-D participation as the administrative tasks and additional training requirements were far greater than anticipated and took priority and time away from IMPETUS-D (CFIR-construct Relative Priority). Leaders played an important role in implementation of the training intervention, and in keeping with results from other studies facilities with managers who actively supported the project and encouraged staff involvement had greater success (CFIR-construct Leadership Engagement). Not having adequate time to do the training was a main barrier reported by staff (CFIR-construct Available Resources). Many felt overworked and had other duties outside of work; these issues are not unique to this study. The complexity and design quality of the intervention also affected participation (CFIR-construct Intervention Characteristics). The training intervention was complex in terms of the number of modules, its location on a separate e-learning platform, and the multiple disciplines it targeted. IMPETUS-D was an online program which staff could access via the internet. However, staff preferred to learn in small groups, face-to-face and at work. In response, facilitated sessions were held at each of the care homes. This flexible approach enabled more staff to participate. Other strategies were used to increase likelihood of implementation success. This included paying staff if they completed the training outside of work time and formally appointing three Project Coordinators (PCs) as Internal Implementation Leaders (CFIR construct). The PCs worked for the organisation and had nursing experience in residential aged care. They were supported by the PhD researcher but had variable research and implementation experience and there was turnover in one position. Staff participation may have been improved if local barriers were identified and addressed earlier, and a more customised approach used. The third study was conducted in response to the background literature review which found few studies used validated and reliable instruments to measure participants’ learning. It explored the psychometric properties of the Questionnaire on Palliative care for Advanced Dementia (qPAD), an instrument used to assess residential aged care staff knowledge of, and attitudes towards palliative care in dementia. This study built on the exploratory factor analysis (EFA) previously reported by the qPAD developers. Data from over 700 staff surveys collected as part of the IMPETUS-D study were used to conduct the exploratory and confirmatory factor analyses of the qPAD knowledge test and attitude scale. This study showed some differences and similarities to the original USA EFA study. The EFA of the knowledge test produced a four-factor solution, but factor labels were difficult to define, and one item loaded weakly; compared to the previous EFA that produced a three-factor solution in which six items loaded weakly. In both studies, the EFA of the attitude scale yielded a three-factor solution, and the same three items of the attitude scale loaded onto the factor labelled “Perceptions and beliefs”. However, two items (items 6 and 12) loaded onto different factors across the two studies. Overall, the attitude scale performed well with good content validity and internal consistency, whereas the knowledge test did not perform well. These findings highlighted the need to further develop robust tools to measure staff knowledge of palliative care in dementia validated for Australian residential aged care. In summary, while the IMPETUS-D study was unable to show changes in staff or resident outcomes, it confirmed staff wanted more training in dementia-specific palliative care. Staff who participated in IMPETUS-D found the modules relevant to their work and would recommend the training to colleagues. Despite this, overall levels of staff participation were suboptimal, but facilities with greater leadership engagement had better uptake of the training. Opportunities for further research include evaluation of a more simplified and sustainable version of the IMPETUS-D training intervention, and research to establish strategies that optimise staff participation and successfully influence implementation.
-
ItemAntibiotic Stewardship in Australian rural hospitals( 2021)Australia has a high per capita consumption of antibiotics. Much of this antibiotic use is inappropriate or unnecessary, contributing to poor patient outcomes such as unresolved infection or antibiotic-related side effects. Antibiotic stewardship (AMS) programs in hospitals are a component of a multi-faceted approach to optimise antibiotic use. Compared to AMS programs in metropolitan hospitals, significant gaps exist in our knowledge about AMS programs operating in lower resource settings, such as regional, rural and remote (rural) hospitals. While the literature describes some models to increase local capacity for AMS or access to infectious diseases advice, this wisdom is predominately derived from small studies in international hospitals. Therefore, this PhD sought to address the paucity of information on optimising AMS programs in Australian rural hospitals. First, it was necessary to establish whether there was unwanted variation in antibiotic prescribing in Australian rural hospitals. An analysis of National Antimicrobial Prescribing Survey (NAPS) data from 2014-2016 found that inappropriate antibiotic prescribing was higher in rural hospitals compared to metropolitan hospitals. A sub-analysis identified cellulitis and some high-risk infections (such as sepsis) as priority areas for action. To address this unwanted variation in antibiotic prescribing, an in-depth understanding of the barriers, enablers and potential models for AMS programs in the Australian rural setting was required. These were identified through a series of focus groups and key informant interviews with hospital staff and AMS innovators respectively. Synthesis of the findings of these studies revealed specific considerations for the delivery of AMS programs in rural hospitals that differ from metropolitan hospitals. This included a culture of independence and self-reliance by local clinicians, interconnected work-life relationships, geographical location of the hospital influencing antibiotic choice, inability to meaningfully benchmark performance and a lack of resources (leading to key person dependencies and the risk of burnout). Network arrangements were recognised as an important way to build capacity. The aforementioned work led to the conceptualisation of a multi-centre study which utilised two of the findings; a) that cellulitis was a condition where antibiotic prescribing in rural hospitals could improve and b) that AMS network approaches should be facilitated. The study co-designed, implemented and evaluated a cellulitis management plan (including a consumer leaflet) in three Victorian rural hospitals. Although unable to show a statistically significant improvement in antibiotic appropriateness after the introduction of the cellulitis management plan, patient satisfaction with the information provided about cellulitis increased when the consumer leaflet was received. The study was a compelling example of how health services and consumers can work together to create shared resources and improve the consumer experience. This PhD has identified that to optimise AMS in the rural setting, more Australian rural hospitals must share their AMS program structures and outcomes so that the organisational conditions and intensity of input required to have real impact on antibiotic prescribing practices can be established. Given the unique connectedness that exists in rural communities, there is the opportunity to adopt a true one health approach and create new partnerships across acute, primary, aged, dentistry and veterinary sectors to collectively improve antibiotic prescribing.
-
ItemMobile and non-invasive devices as a diagnostic tool for physicians in detecting and classifying different seizure types( 2021)Introduction Epilepsy is one of the most common neurological disorders, affecting approximately 1 to 2% of the population. Epileptic seizures are caused by abnormal electrophysiological changes in the brain. In contrast, psychogenic non-epileptic seizures (PNES) are a class of seizures that are involuntary events, not caused by abnormal electrical discharges, but are thought to be a manifestation of psychological distress. The similarities in the observed behaviour between convulsive epileptic and convulsive psychogenic non-epileptic seizures (PNES) pose diagnostic difficulties. 20% of convulsive epileptic seizures are still misdiagnosed as PNES, delaying appropriate treatment for psychogenic seizures by an average of 5 to 7 years. This causes a poor prognosis and quality of life, as well as significant financial and social consequences. The current gold standard method to differentiate between the two is long-term Video Electroencephalography Monitoring (VEM), which is expensive and confined to few specialist centres. Therefore, a timely and accurate method of diagnosis outside the hospital setting is needed. Non-invasive and ambulatory devices are one such option being explored in this field, to not only detect convulsive epileptic seizures and PNES accurately, but also non-convulsive epileptic seizures. These devices typically measure physiological parameters such as 3-dimensional (3D) accelerometry, surface electromyographic signals (sEMG), heart rate, either separately or together, depending on the device. This approach is being recognised as automated seizure detection. This thesis aimed to investigate one such device, using 3D accelerometry, to differentiate between convulsive epileptic seizures and PNES. A further meta-analysis was conducted to quantify the accuracy of the devices, parameters and algorithms used in published studies for detecting all seizure types, including focal, generalised and psychogenic non-epileptic seizures Method In the first study, an off-the-shelf wireless, ambulatory device (Apple iPod) measuring 3D accelerometry was tested to investigate its sensitivity and false alarm rates for generalised tonic-clonic seizures (GTCS) and PNES. For this, consenting patients in the video-EEG monitoring (VEM) unit during their admission, were recruited, with the wireless device attached to their upper limbs. The data from the accelerometers went through an automated process using a machine learning algorithm, whereby convulsive activity detected was classified as a GTCS or PNES. The automated output for each seizure detected was compared to the corresponding VEM diagnosis to determine the device’s reliability using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and Cohen’s Kappa test. In the second study, a systematic review and meta-analysis was conducted involving two independent reviewers, to identify studies reporting the performance of mobile, non-invasive devices for the automated seizure detection of various seizure types. Limitations of these studies are acknowledged, and the directions for future studies are proposed. Results The overall finding of this thesis was that most non-invasive, ambulatory devices investigated for automated seizure detection have high sensitivities and acceptable false alarm rates for GTCS and PNES. This was evident in the first study where 13 PNES from five patients and 11 motor epileptic seizures were recorded during video-EEG monitoring. The sensitivity for detecting PNES and GTCS using 3D accelerometry was found to be 100% and 72.7%, respectively, with a FAR of 2.4 per 24 hours. The systematic review found that few studies have investigated the utility of ambulatory devices in the automated detection of focal seizures or the combination of both focal and GTCS. Moreover, the use of differing algorithms for each study, was found to increase heterogeneity. This implied that results between each study could not be directly compared, even when similar parameters were being used. This may hinder the ability to investigate these devices from moving to phase 4 studies where they may be tested in an out of hospital setting, the ultimate goal of utilising automated seizure detection. Conclusion The automated wireless device accelerometer tested in this study was shown to be sensitive in detecting and classifying both GTCS and PNES. There are a limited number of studies investigating the automated detection of focal seizures that are experienced by the majority of patients with epilepsy. The inability to compare studies due to the use of varied machine learning algorithms, may limit the use of such devices in phase 4 studies. It is essential that future studies involve larger population groups and determine automated detection for focal seizures. Furthermore, using pre-defined algorithms that have already displayed high sensitivities and low false alarm rates, particularly for the automated detection of GTCS and PNES, should be a priority for future research.
-
ItemClinical Whole Genome Sequencing in Early Onset Dementia and Genomic Modifiers of APOE e4/e4 Risk( 2021)Background When a genetic cause is suspected in a person with dementia, it creates unique diagnostic and management challenges to the clinicians. Even in specialised neurogenetics clinics, these patients and their families face significant delays in diagnosis. The main cause for this delay is the incremental nature of the genetic tests performed in these clinics. This is due to the lack of a single, comprehensive genetic test that could identify the different types of genetic variants associated with dementia. Another problem in dementia genetics is the inability to predict the risk of Alzheimer disease (AD) in people with the APOE e4/e4 genotype, despite it being a well-known high-risk genotype. The diversity in cognition among APOE e4 homozygotes can range from early-onset AD to a lifetime with no symptoms. Identifying the modifiers of such variation will enable further refinement of risk prediction for people with this genotype. This thesis describes two main studies. First is a study that explores the clinical impact of whole genome sequencing (WGS) in patients with early onset dementia (EOD). The second study investigates the modifying effect of genomic factors, including a polygenic risk score (PRS), between APOE e4/e4 participants with EOD (onset <65 years) and elderly (aged >75 years) who have escaped AD despite their high-risk genotype and advanced age. Methods WGS analysis was performed in 50 patients with EOD, exploring point mutations, small insertions and deletions using a targeted panel of 117 genes, followed by a “Mendeliome” approach with a broad range of Mendelian disease genes, not included in the targeted panel. Structural variants (SV) as well as short tandem repeats (STR) were also analysed. A polygenic hazard score (PHS) was calculated in patients with AD. In order to examine the APOE e4/e4 genomic modifiers, first, a systematic review was conducted to search the literature for evidence of any genetic modifiers already published. As no clear answers could be deduced from the literature, a novel phenotypic extremes study was designed to examine the modifying effect of a PRS between cognitively healthy APOE e4 homozygotes aged >/=75 years (n=213) and early-onset APOE e4 homozygote AD cases aged 90th percentile risk. Although fifteen studies met the inclusion criteria for the systematic review of APOE e4/e4 modifiers, only two SNPs (CASP7 rs10553596 and SERPINA3 rs4934-A/A) had sufficient evidence towards risk modification/resilience in APOE e4 homozygote participants. The CASP7 rs10553596 deletion variant was not captured in the genotyping platforms used in the phenotypic extremes participants and could not be imputed reliably and therefore was not analysed. The frequency of the SERPINA3 rs4934-A/A variant was not different between the extreme phenotypic cases and controls. The phenotypic extremes PRS study demonstrated that the PRS for AD was significantly higher in APOE e4 homozygote AD cases compared with older cognitively healthy APOE e4/e4 controls (OR 8.39; CI 2.0 to 35.2; p=0.003). Conclusions The clinical whole genome study showed that WGS can act as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD. The APOE e4/e4 extremes phenotyping study has identified a risk modifying PRS, comprised of common AD associated variants, that could explain the variability in clinical presentation in people with APOE e4/e4. Larger studies are needed to further validate both the WGS and modifying PRS results. Moreover, qualitative studies and cost-effectiveness analysis are needed to understand how these results would impact patients with dementia in the “real-world” setting.
-
ItemNo Preview AvailableExpanding our understanding of the clinico-epidemiology, cellular biology and pathogenesis of human prion diseases( 2021)This thesis primarily constitutes a compendium of published manuscripts encapsulating a substantial volume of work relating to prion diseases, undertaken from 1999 to 2020 through the Australian National Creutzfeldt-Jakob Disease Registry based at the University of Melbourne, frequently in collaboration with pre-eminent domestic and international scholars in the field of prion diseases. The thesis is divided into two principal parts. The first comprises 78 peer-reviewed papers submitted in full, representing a diverse array of acclaimed, often landmark or pivotal, studies published in prestigious general medical and specialist journals where I have been either senior and corresponding author, primary author or leader of the Australian contribution in major multi-national projects. This body of work is divided into seven sections spanning: normal prion protein cellular biology; prion pathogenesis; human prion disease epidemiological studies; human prion disease bio-marker studies; clinical aspects of human prion disease; prion disease treatment studies; and studies of human prion-like diseases. A short review at the start of the thesis and a preamble before each of these sections dealing with my principal publications are offered to place these published studies in the context of extant clinical and scientific literature. The second part of the thesis is submitted for completeness, comprising four sub-sections encompassing 61 publications and reports, listed by title and publication details, dealing with human prion disease for which I was a significant contributor.
-
ItemMechanisms Driving Persistent Atrial Fibrillation: Insights from Endocardial-Epicardial Dissociation and Regional High-Density Mapping of the Human Atrium( 2020)Atrial fibrillation (AF) is an extremely common clinical problem with increasing global prevalence. Besides its frequent association with stroke, heart failure and increased mortality, recent data have shown the significant quality of life impairment and psychological distress that results from this arrhythmia. The clinical spectrum of AF can manifest as brief episodic paroxysmal AF or as a sustained arrhythmia in persistent AF in patients with progressive atrial disease. Mechanistically, paroxysmal AF is often triggered by rapidly firing impulses that originate in the pulmonary veins, allowing catheter-mediated elimination of sources, with clinical success rates of 70–85%. However, in persistent AF, the mechanism that sustains the arrhythmia remains incompletely understood and is a topic of ongoing debate. Recent advances in cardiac mapping and computational methods have suggested localised drivers and non-pulmonary vein triggers particularly from the left atrial appendage but there is also accumulating evidence that the atrium frequently functions electrically as a 3-dimensional structure and there exists endocardial-epicardial dissociation in activation during AF. The aims of this thesis are three-fold: Firstly, we review the evidence for the current and expanding indications for catheter ablation in AF and highlight some of the novel tools and technological advancements that have emerged in the recent years for achieving durable pulmonary vein isolation (PVI). Secondly, we investigate the role of some of the novel mechanisms that potentially sustain persistent AF. We addressed this first by systematically reviewing the evidence for a computational mapping technique thought to identify localised sources and then performed a series of cardiac mapping studies in humans. These high-density mapping studies characterised atrial endocardial-epicardial electrical dissociation in the presence of structural heart disease and explored the mechanistic role of localised sources in the left atrium and the left atrial appendage (LAA) in persistent AF. Finally, given the emerging evidence for the mental health effects from AF, we discuss the rationale and methodology of a randomised controlled study comparing catheter ablation with medical therapy on psychological distress and neurocognitive function in patients with AF. Chapter 1 summarizes several aspects of AF including the epidemiology, our current understanding of the classic and novel mechanisms of AF the mechanistic role of risk factors and their implications in remodelling and atrial cardiomyopathy. Chapter 2 reviews the role of catheter ablation in AF and highlights the recent technological advancements. Catheter ablation is a safe and effective rhythm control strategy for symptomatic patients who failed medical therapy or who prefer not to take medications and there is emerging evidence for its role in mortality reduction in AF patients with heart failure. Pulmonary vein isolation is the cornerstone approach and both radiofrequency and cryoablation have similar efficacy. Mounting evidence demonstrates the importance of risk factor management for improving ablation outcomes. In the era of high-density cardiac mapping, FIRM (focal impulse and rotor modulation) emerged as a novel computational mapping technique to identify rotors and focal sources that could potentially be targeted during catheter ablation. Despite early promising results, many studies that followed showed mixed outcomes and indeed, some others showed a pro-arrhythmic consequence. Chapter 3 presents a systematic review and meta-analysis of 11 observational studies and demonstrates the wide variability in the medium-term outcomes of FIRM guided ablation and explores the significant heterogeneity between published studies. Chapters 4 and 5 examine the characteristics of endocardial-epicardial dissociation (EED) in patients with structural heart disease. We performed high-density simultaneous endocardial-epicardial phase mapping of the right atrium in patients undergoing cardiac surgery to study this. In Chapter 3 we report the for the first time, functional EED based on observations of synchronous activation during sinus rhythm and EED in activation timing and wavefront propagation during pacing drive and premature extra-stimulation providing compelling evidence for the functional nature of the atrial substrate. Chapter 4 presents data of phase mapping prolonged persistent AF recordings. The results provide novel evidence for endocardial-epicardial wave front mismatch in AF along with marked EED with temporal heterogeneity. In Chapter 6 we sought to characterise the preferential 3-dimensional nature of sinoatrial conduction in humans using simultaneous endocardial-epicardial mapping of the sinus node region. In intact hearts of patients with structural heart disease, data confirmed the presence of multiple differential endocardial and epicardial sino-atrial exits and hence the redundant structure of the pacemaker complex. This is consistent with data from optical mapping of ex-vivo human hearts and demonstrates that clinical sinus node dysfunction only occurs in the setting of advanced atrial structural remodelling. Recently, data from cohort studies and a randomised controlled trial have shown that LAA isolation improves ablation outcomes in patients undergoing redo ablation for persistent AF. However, there have been concerning reports that such empirical ablation is associated with a heightened risk of LAA thrombus, even in patients who are anticoagulated. Furthermore, data from mapping studies have also shown mixed results on the potential role of LAA as a driver in persistent AF. In Chapter 7 we examine the role of localised sources in the left atrium particularly in the LAA by performing regional high-density mapping of persistent AF. In addition to finding infrequent drivers in the left atrium, this project also showed paucity of triggers from the LAA providing further evidence of its passive role rather than an active driver in persistent AF. Besides physical symptoms that patients with AF experience, recent data has shown the enormity of mental health effects that AF can have that is often underappreciated by clinicians. More importantly, preliminary data from observational studies show the benefits of catheter ablation to improve mental health. Chapters 8 and 9 present the methodology and rationale of a multicentre, randomised controlled trial that assesses the impact of catheter ablation on psychological distress and neurocognitive function in patients with AF. The study has completed recruitment and successfully enrolled 100 participants across the Royal Melbourne and Alfred Hospitals and completion of analysis is expected by March 2022. Chapters 10 and 11 conclude by summarizing the key findings of the studies and their clinical implications. Further, it paves the way for future work that might progress our understanding of AF, especially in light of novel mechanisms
-
ItemGlutamate as a biomarker of post-stroke epilepsy( 2021)Stroke is one of the most important causes of acquired epilepsy in adults. Patients with seizures after stroke have higher mortality and disability than those without seizures. There is a building body of evidence to suggest that post-stroke epilepsy may be mediated by dysregulation of glutamate homeostasis, given the central role of glutamate in the pathogenesis of both stroke and seizures. There is currently no evidence to support the use of antiseizure medications as primary prevention of epilepsy in stroke patients. Ideally, anti-epileptogenic treatment would be targeted at those stroke patients at highest risk of epilepsy according to established biomarkers – studying glutamate as one such biomarker has been limited by a reliance on invasive procedures including lumbar puncture to quantify concentrations of glutamate in the brain. This thesis focuses on the role of 7T MRI as a method of brain glutamate quantification in the setting of stroke. The research has been conducted in the Department of Neurology, Royal Melbourne Hospital, the Department of Medicine (The Royal Melbourne Hospital), University of Melbourne, and the Melbourne Node of the National Imaging Facility, Department of Radiology, University of Melbourne. 22 patients with acute ischaemic or haemorrhagic stroke were recruited from the inpatient stroke unit at Royal Melbourne Hospital, with 7T MRI scans performed at the Melbourne Brain Centre Imaging Unit, University of Melbourne. In addition, peripheral blood samples were collected and underwent metabolomics analysis for plasma glutamate quantification at the Monash Institute of Pharmaceutical Sciences, Parkville. Across the patient cohort, glutamate concentration was lower in the region of infarction than in the corresponding hemisphere, when measured by Magnetic Resonance Spectroscopy. When measured by glutamate weighted chemical exchange saturation transfer imaging (GluCEST), the results were more heterogeneous, ranging from decreased to increased, ipsilateral to infarction. One patient in the cohort developed post-stroke epilepsy, with a GluCEST profile similar to the population overall. A single haemorrhagic stroke patient suffered a seizure prior to scan acquisition, with a pattern of increased cortical GluCEST contrast consistent with a post-seizure effect. The second part of the thesis focuses on a study protocol examining the anti-epileptogenic potential of the glutamate receptor antagonist and antiseizure medication perampanel in a population at high risk of post-stroke epilepsy. This involves a collaboration of clinicians at four Melbourne Hospitals (Alfred Hospital, Royal Melbourne Hospital, Monash Medical Centre, Austin Hospital), led by the candidate. Finally, there is evidence that patients with epilepsy have an increased risk of developing cerebrovascular or cardiovascular disease, although it is unclear whether this is due primarily to the epilepsy itself, or non-epilepsy factors such as antiseizure medications. The third part of the thesis comprises a data linkage study in the Department of Neurology, Royal Melbourne Hospital, based on medical records from a database of admitted video EEG monitoring patients from 1995 to 2015. It was found that the incidence of new-onset cerebrovascular disease was higher in epilepsy patients compared with the general Victorian population, although there was no difference in the composite incidence of cerebrovascular disease, cardiovascular disease and peripheral vascular between epilepsy and non-epilepsy patients in the cohort. Furthermore, patients taking treatment with valproic acid were at lower risk than both those taking enzyme-inducing antiseizure medications and those taking neither valproic acid nor enzyme-inducing antiseizure medications. Collectively, these results emphasise the role of non-epilepsy factors such as social determinants of health, medical comorbidity, and epilepsy treatment, in influencing vascular risk.