Advances in our understanding of the pathophysiology of atrial fibrillation (AF) and atrial macro-reentry through improvements in technology has led to the development of treatment approaches involving catheter ablation. However, outcomes have been suboptimal possibly due to an incomplete understanding of the underlying mechanisms of these arrhythmias. Using novel three-dimensional (3D) mapping techniques, this thesis aims to answer unresolved questions in our understanding of the mechanisms of human persistent AF and atrial macro-reentry. Recent work using phase mapping has suggested that rotors may act as drivers for persistent AF with studies from different centers reporting promising findings of acute termination and long term freedom from AF with ablation at the rotor center. However, these encouraging results have not been observed consistently possibly due to the two-dimensional (2D) representation of the left atrium (LA) in this mapping technique. In Chapter 2, we used a novel 3D phase mapping technology that takes into account patient-specific left atrial geometry to display phase to determine the dominant propagation patterns in patients with persistent AF. We observed transient rotors in the majority of patients, however, they were present for only a small fraction of the total recording time with the dominant propagation pattern overall being single broad wavefronts. An additional assumption of the abovementioned 2D phase mapping system is that the 64 electrodes of the Constellation basket catheter are arranged in a uniform 8x8 grid in a fixed position within the 2D representation of the LA. These spatial assumptions may lead to errors in phase animation as the actual 3D locations of the basket catheter are not taken into consideration. In Chapter 3, we therefore determined whether rotational activity detected in 2D phase maps were observed in corresponding 3D phase maps. We found that none of the rotors observed in 2D phase maps were seen in the same time segments and anatomical locations in 3D phase maps. The 2D phase detected rotors either corresponded in 3D phase maps to wavefronts (single or multiple), disorganized activity or an absence of basket coverage at the corresponding 3D anatomical site. With the increasing clinical use of the Constellation basket catheter in currently available mapping systems, Chapter 4 evaluated the efficacy of this catheter. We found that there were significant limitations of the basket catheter in terms of electrode contact and coverage of the LA. In addition, there was regional variation of coverage with preferential coverage of the lateral wall and absence of contact with the septum. These findings suggest that there is a need for the development of high density basket catheters which provide uniform LA coverage. Prior to the current focus on AF, atrial macro-reentry was the subject of extensive research. The recent development of high-density high-resolution 3D mapping provides an opportunity to study atrial macro-reentry to a level of detail not previously attainable. In Chapter 5, we sought to determine the location of the posterior line of block and characterize the relationship between substrate and conduction in patients with right atrial macro-reentry. We found that in the majority of patients with cavotricuspid-isthmus (CTI) dependent atrial macro-reentry, the posterior line of block was located at the posteromedial right atrium (RA). In addition, we observed the presence of highly variable and localized zones of slow conduction which were associated with abnormal atrial substrate resulting in individual variation of propagation patterns. In Chapter 6, using high-density high-resolution 3D mapping, we evaluated the concept of epicardial-endocardial breakthrough (EEB) that has been postulated as a mechanism for persistent AF. We hypothesized that if EEB is present during AF, and dependent on anatomically located muscle bundles, then evidence for this may be present during stable atrial macro-reentry. We observed that EEB sites were predominantly located at the posterior RA. Activation maps during tachycardia and stable CS pacing demonstrated EEB at the same anatomical location. Systematic entrainment confirmed that these EEB sites were part of the active circuit. The ongoing utility of entrainment has been questioned in the current era of high-density high-resolution 3D mapping. Entrainment has many pitfalls such as an unexpectedly long post-pacing interval (PPI) despite proximity to the active circuit. However, the limitations of visual representation of high-density 3D maps are unclear. In Chapter 7, using both 3D mapping and systematic entrainment in atrial macro-reentry, we observed that entrainment was critical in distinguishing between active and passive circuits. High-density 3D mapping alone may create the appearance of a complete circuit which is actually passive. On other hand, high-density 3D mapping provided new insights by identifying highly localized zones of slow conduction that when located proximal to an entrainment pacing site resulted in long PPI despite proximity to the active circuit. These findings suggest that high-density 3D mapping and entrainment are complementary techniques in atrial macro-reentry.

The acquired immunodeficiency syndrome caused by the human immunodeficiency virus is an important issue for Australia’s African communities. As in other industrialised countries, African immigrants are over-represented in Australia’s HIV epidemic, diagnosed late and endure social isolation after diagnosis, but focused responses, applied without understanding local HIV epidemiology and social context, risk intensifying stigma against African communities and African Australian people living with HIV in Australia. This study explored the social epidemiology and clinical features of HIV in Victoria’s African communities, collecting data from national and Victorian HIV surveillance databases, a clinical case series of African-born HIV patients and a qualitative inquiry with several African communities. Diverse geographical, biological, psychosocial and structural factors influenced exposure, diagnosis, clinical features and experience of living with HIV. Most exposure occurred in Africa, prior to migration, through heterosexual sex. Some occurred after migration, in Australia and abroad, through heterosexual sex and sex between men. Low self-perceived risk and lack of awareness of HIV in Australia contributed to exposure and delayed diagnosis. HIV was understood as a deadly, highly contagious “African” disease, posing little threat in Australia, being one of several intersecting challenges to the wellbeing and cohesion of African communities during resettlement. Understanding of HIV was based largely on experience in Africa and the process of HIV screening during immigration. HIV-related stigma, based on risk stereotypes of sexual immorality and fear of contagion and death, was the major barrier to social support and information. Key clinical issues for African-born PLHIV included high prevalence of TB and viral hepatitis. HIV treatment uptake was high and response was good. HIV exposure via sex between men led to HIV-1 subtype B infection; those with heterosexual or other exposure carried various non-B subtypes. African communities actively participated in the study leading to greater engagement in Victorian and national HIV responses. Study results provided insights into HIV epidemiology and clinical features in Victoria’s African communities and informed a conceptual framework that should further the understanding of HIV epidemiology in mobile and marginalised populations.

It is well established that pathogens target host cholesterol metabolism in order to survive and replicate. The perturbation of host cellular cholesterol metabolism caused by pathogens can lead to metabolic complications, such as atherosclerosis and neurodegenerative diseases. The aim of this study was to elucidate the mechanisms responsible for perturbation of intracellular cholesterol metabolism caused by pathogens. The mechanistic understanding of this process is essential as it may provide new insight into pathogenesis of infections and their metabolic complications and new approaches for targeting cholesterol metabolism as a new treatment for both infection and their associated metabolic disorders. In this study we investigated the effects of two dissimilar pathogens, HIV and prion, on the cholesterol removal process, known as the Reverse Cholesterol Transport (RCT) pathway. It has been shown that both HIV and prion rely heavily on host cholesterol during the replication cycle. Although they are two very dissimilar pathogens, both utilise lipid rafts in the host cell in order to successfully replicate. It was hypothesised that both HIV and prion pathogens target the RCT pathway in order to acquire sufficient cholesterol to successfully replicate. In this thesis, it was shown that both HIV and the prion pathogen targets the ATP binding cassette transporter A1 (ABCA1) dependent cholesterol trafficking pathway; by diverting intracellular cholesterol to lipid raft domains, thereby stabilising the lipid raft platform for further pathogen propagation. It was shown that both HIV and prion infection inhibits ABCA1 dependent cholesterol efflux. The mechanism behind this functional impairment is the displacement of ABCA1 from the cell surface into the intracellular compartments, which significantly reduces the abundance of ABCA1 on the cell surface that is available to participate in cholesterol efflux. HIV infection significantly increased the risk of atherosclerosis by impairing the cholesterol efflux pathway. The viral protein responsible for the deregulation of cholesterol metabolism is Nef. RAW264.7 murine macrophages and RAW264.7 cells stably transfected with Nef were used to investigate the mechanism responsible for perturbation of cholesterol metabolism. Transfection of macrophages with Nef led to an enhanced movement of cellular cholesterol to lipid rafts and an increased abundance of rafts as validated by using three independent techniques. The knockdown of ABCA1 expression by siRNA or inhibition ABCA1 function by chemical compounds further promotes cholesterol trafficking towards lipid rafts, suggesting Nef does not use ABCA1 for transporting cholesterol to rafts, but rather competes with ABCA1 for cholesterol. Furthermore, it has been shown that Nef affects functionality of ABCA1 by mislocalisation of ABCA1. Nef caused the redistribution of ABCA1 between raft and non-raft fractions of the plasma membrane, and decreased the surface exposure of ABCA1. Furthermore, Nef increased colocalisation of ABCA1 with the lysosome marker LAMP-1, suggesting that Nef interacts with ABCA1 by redirecting it into lysosomes for degradation, resulting in an accumulation of cholesterol. Moreover, two mouse models of atherosclerosis (C57/BL6 and apoE-/-) were used to further investigate the effects of Nef on the development of atherosclerosis. Both in-vivo mouse models further support the notion that Nef significantly increased the risk of atherosclerosis by increasing cholesterol accumulation in macrophages, while having limited effects on inflammation at both systemic (in the plasma) and local (within atherosclerotic lesions) levels. Systemically, Nef also caused a sharp elevation of triglyceride level. Taken these results together, the combination of dyslipidemia and hypertriglyceridemia further support that Nef may also be a contributor to HIV induced atherosclerosis. During prion infection, conversion of prion protein (PrPC) into a pathological isoform (PrPSc) occurs in lipid rafts and is dependent on cholesterol. Here, it was shown that prion infection promotes an increased abundance of ABCA1. Despite this, cholesterol efflux in both prion infected mouse neuronal and fibroblast cells was reduced, consequently leading to an accumulation of cellular cholesterol. Increased abundance of ABCA1 in prion disease was also confirmed in prion-infected mice. Mechanistically, conversion of PrPC to the pathological isoform led to PrPSc accumulation in rafts and a displacement of ABCA1 from rafts and the cell surface toward intracellular compartments. These effects were abolished with reversal of prion infection or by loading cells with cholesterol. Stimulation of ABCA1 expression reduced the conversion of prion protein into the pathological form upon infection. These findings demonstrate a reciprocal connection between prion infection and cellular cholesterol metabolism, where cholesterol plays an important role in the pathogenesis of the infection and its effect on neuronal cells. Given the importance of ABCA1 in the pathogenesis of HIV and prion infection, treatment with LXR agonist or overexpression of ABCA1 may significantly reduce the rate of HIV and/or prion infection. It appears that, in addition to maintaining cellular cholesterol content and restricting raft formation, the ABCA1 transporter also plays a role of an innate immune factor against HIV and prions. Given that many intracellular pathogens critically depend on rafts in their pathogenesis, increasing ABCA1 expression can be potentially used as an anti-infection therapeutic strategy.

Background: Research has consistently shown that obesity negatively impacts on pregnancy, birth and the newborn but the extent of the problem in rural women has been largely unstudied. Objectives: The principal aims of this research were to describe the prevalence and impact of obesity on maternal and perinatal outcomes in a rural cohort; examine the relationships between maternal characteristics, health behaviours and obesity on interventions and outcomes; and compare the effect of obesity across three cohorts of rural women. The project also involved the examination of the definitional and measurement variations of maternal obesity and the development of an alternative method of classifying maternal and perinatal outcomes that focuses on the overall condition of mother and baby following pregnancy and birth. Methods: Analysis of body mass index (BMI) as a measure of obesity was conducted and comparisons of models of measurement, particularly the gestation when weight was recorded, was undertaken to clarify the definition and measurement of maternal BMI. The use of BMI as a continuous, ordinal and dichotomised variable was also assessed. An expert panel was used to develop a new tool for the classification of maternal and perinatal outcomes that was then compared with traditional measures and tools. Retrospective analyses of the obstetric records of rural cohorts from 1 January 2005 to 31 December 2010 were undertaken to determine the prevalence and impact of maternal obesity on the course of pregnancy and birth and outcomes. Results: A very high prevalence of maternal obesity was identified in the preliminary study of more than 6500 singleton deliveries over six years in a rural setting. BMI was shown to be a satisfactory measure of maternal obesity, irrespective of the gestation at time of measurement. Maternal obesity was found to impact on outcomes (classified by the new tool developed to identify women and babies in healthy condition, the Maternal and Perinatal Outcome Measure: MPOM)). Women with a BMI of 35 – 40 kg/m2 had the highest risk of adverse outcomes. The likelihood of adverse outcomes in obese women was compounded by the presence of additional risk factors. Comparison of risk across the cohorts suggested continuity of care may have a moderating effect on the impact of obesity. Implications for policy, delivery or practice: The results of this study suggest that it is appropriate to use weight recorded at booking, irrespective of gestation, in studies of maternal obesity. This is important as it avoids the exclusion of women from studies based on gestation at booking, thus limiting potential selection bias. The use of MPOM as a quality measure (through the classification and review of outcomes) could significantly improve the understanding of obstetric services and the risk factors involved. In research contexts, the MPOM can be used in the development of predictive models, aimed at better understanding the factors that impact upon maternal and perinatal outcomes. This thesis contributes to clinicians’ understanding of the impact of obesity on maternal and perinatal outcomes in rural women. The findings that additional risk factors have a greater impact on outcomes in obese women, particularly in the absence of continuity of care service models, also has implications for maternity service providers. Further research is required to prospectively assess the moderating effect of continuity of care on adverse outcome rates in obese women. In conclusion, this thesis represents a thorough investigation of the impact of obesity on maternal and perinatal outcomes in rural women. It demonstrates that obesity is a significant predictor of adverse outcomes, as measured by a newly developed tool that classifies on the basis of the overall condition of both mother and baby. These results have important implications for both clinical practice, and future research in this topic area.

Background: Nosocomial infections cause significant morbidity and mortality in developed and developing countries. Prevention of nosocomial infection is central to providing high quality, safe healthcare. Transmission of microorganisms between patients by healthcare workers and irrational antibiotic use have been identified as preventable etiological factors for nosocomial infections. Aims: To develop multifaceted infection control and antibiotic stewardship programs and evaluate the effectiveness of these measures on nosocomial infection, antibiotic use, hand hygiene compliance, and mortality. Methods: An uncontrolled before-and-after study was conducted over 27 months involving around 2600 patients at the Dr Sardjito teaching hospital in Yogyakarta, Indonesia. Patients who were admitted to the PICU and general paediatric wards for more than 48 hours were included. All eligible children were observed daily to see whether they fulfilled criteria for nosocomial infections. The assessment of nosocomial infections was made based on the United States Centers for Disease Control and Prevention (CDC) criteria. Irrational antibiotic use was assessed when patients presented with community-acquired infection or were treated with antibiotics. The standard for empirical antibiotic prescribing was on the recommendations contained in the WHO Pocketbook of Hospital Care for Children. Hand hygiene compliance was observed directly among the healthcare workers using the “Five moments for hand hygiene” observation form. In the pre-intervention period, the proportion of nosocomial infection, irrational antibiotic use and hand hygiene compliance were prospectively collected over 12 months. The multifaceted intervention, including hand hygiene campaigns, antibiotic guidelines based on the WHO Pocketbook of Hospital Care for Children, and other elementary infection control practices, was implemented over 3 months. The means of intervention included lectures, trainings, outreach visit, reminders, audit and performance feedback. In the post-intervention period, identical data collection was prospectively collected over 12 months as outlined in the pre-intervention period. The outcome measures in the pre-and-post intervention periods were compared. The 2 statistics or Fisher Exact Test were used to analyze the various proportions by comparing the pre-intervention and the post-intervention period. A probability value < 0.05 was considered to denote statistical significance. The relative risk (RR) reduction and its confidence interval (CI) were also provided to compare the effect of the interventions between both periods. Results: This study found a large burden of nosocomial infection in children in Indonesia. The incidence of nosocomial infection was 22.6% (277/1227) and mortality in children with nosocomial infection was 24.5% (68/277). A multifaceted intervention on infection control and antibiotic stewardship was effective in reducing nosocomial infection and improving rational use of antibiotics. In all wards combined, compliance with the interventions lead to a reduction of nosocomial infections, from 277/1227 (22.6%) to 123/1419 (8.6%) [RR (95%CI) 0.38 (0.31-0.46)]. Irrational antibiotic use declined from 336/780 episodes of antibiotic use (43%) to 182/882 episodes of antibiotic use (20.6%) [RR (95%CI) 0.46 (0.40-0.55)]. Hand hygiene compliance increased from 319/1690 observed episodes of patient care (18.9%) to 1125/1789 observed episodes of patient care (62.9%) [RR 3.33 (95%CI) (2.99-3.70)]. Risk of in-hospital mortality decreased from 127/1227 (10.4%) to 114/1419 (8%) [RR (95%CI) 0.78 (0.61-0.97)]. Conclusions: Multifaceted interventions, including hand hygiene campaigns and antibiotic stewardship, are effective in reducing nosocomial infections, improving rational use of antibiotics, improving hand hygiene compliance, and reducing mortality in children in Yogyakarta, Indonesia.

Undernutrition in prevalent in Aboriginal communities, in utero, infancy and childhood. It influences childhood morbidity and mortality and growth patterns. Undernutrition and poor socio-economic status also contribute to endemic and epidemic infectious disease, including scabies and streptococcal infection. It has been suggested that early undernutrition, and streptococcal and scabies infection are risk factors for renal disease, which is at epidemic levels and increasing. This thesis examines the prevalence of undernutrition in newborns and infants in an Aboriginal community over time, and its impact on childhood growth and child and adult renal markers. The association between skin lesions, streptococcal serology, post-streptococcal glomerulonephritis (PSGN) and renal markers as evaluated through a community wide screening program in 1992-1995 is also examined. Birthweights have increased since the 1960s, but they are still much lower than the non-Aboriginal values. Weights in infancy have decreased since the 1960s. At screening in childhood stunting was common, reflecting the presence of long-term poor nutrition in infancy. In both adults and children, birth weight and infant weights were negatively associated with albuminuria measured by the albumin to creatine ratio (ACR).

The monitoring of fetal lambs in-vivo, has been previously carried out by using hard-wires. This work presents an alternative method for monitoring, by use of radiofrequency biotelemetry, with which there are no hard wires. With biotelemetry, a more "natural" recording may take place from the fetus. Long term, natural monitoring of fetal development has not been possible in the past.The design and implementation of a system capable of providing continuous, isolated monitoring is presented. The problems associated with the development and subsequent use of this system will be presented, especially the problem of noise.Data acquisition and analysis methods are also introduced and developed to suit the large amounts of information produced by the biotelemetry system.Analysed data from two fetal animals are presented and the significance of the reduced information is discussed.

This study concerned a primary health care approach to trachoma control in two Central Australian Aboriginal communities. The World Health Organization (WHO) has advocated that the best method to control trachoma is the SAFE strategy (Surgery, Antibiotics, Facial hygiene, and Environmental improvements), and this approach was adopted. The communities, Pipalyatjara and Mimili, with populations slightly less than 300 each, are located in the Anangu Pitjantjatjara (AP) lands of Central Australia, in the northwest corner of the South Australia territory. At Pipalyatjara, a full SAFE-type intervention was undertaken, with the ‘E’ component designed and implemented by the NHC (Nganampa Health Council Inc.). At Mimili, only a SAF-type of intervention was implemented. Baseline data was gathered for 18 months from March 1999 through September 2000 (five visits to Pipalyatjara and four at Mimili), and included determining trachoma prevalence levels using the WHO system, facial cleanliness, and nasal discharge parameters. A trachoma health program was implemented at the end of this period and a one-time dose of azithromycin was given in September of 2000. The chief focus of the study was children under 15 years of age. Improvements in road sealing, landscaping, and the creation of mounds were started to improve dust control. Concurrently, efforts were made in the houses of the residents to improve the nine healthy living practices, which were scored in two surveys, in March 1999 and August 2001. Trachoma prevalence, and levels of facial cleanliness and nasal discharge were determined at 3, 6, and 12 months following antibiotic administration. In children less than 15 years of age, the pre-intervention prevalence level of TF (Trachoma Follicular) was 42% at Pipalyatjara, and 44% at Mimili. For the 1-9 year age group, the TF prevalence was 47% and 54% respectively. For TI (Trachoma Intense), the pre-intervention prevalence was 8% for Pipalyatjara, and 9% for Mimili. The TF prevalence, adjusted for clustering, and using only individuals present at baseline and follow-up (3, 6, and 12 months post-intervention), was 41.5%, 21.2%, 20.0%, and 20.0% at Pipalyatjara respectively. For Mimili, the corresponding prevalence figures were 43.5%, 18.2%, 18.2%, and 30%. In the 1-9 year age group, a lower TF prevalence existed between the pre-intervention and 12-month post-intervention points at Pipalyatjara compared to Mimili. The TF prevalence after the intervention was also lower for males compared to females, when the cohorts were grouped by gender, rather than community. It is posited that reinfection was much higher at Mimili within this age group, however, in both communities, there appeared to be a core of females whose trachoma status did not change. This is speculated as mainly being caused by prolonged inflammation, though persistent infection C. Trachomatis cannot be ruled out. Facial cleanliness and nasal discharge continued to improve throughout the intervention at both communities, but at the 3-month post-intervention point no longer became a good predictor of trachoma. It is not known whether the improvements in the environment at Pipalyatjara were responsible for the reduction in trachoma prevalence 12 months after the intervention, relative to Mimili.

Influenza A virus is a major human pathogen that is caused by RNA viruses of the Orthomyxoviridae family. It causes respiratory tract infections with a range of clinical outcomes and are a considerable threat to human health. Understanding the mechanisms and the signalling pathways underlying viral infection has become an important goal in respiratory research. During an inflammatory response, immune cells must be able to communicate with one another and such communication mechanisms depend heavily on activating a series of intracellular signalling pathways necessary for removing the pathogen. The majority of intracellular signaling pathways are highly regulated by protein kinases, a family in which the Lyn tyrosine kinase belongs in. Lyn is expressed in most immune cells, except T cells and are key initiators of signal transduction. The studies in this thesis have established a role for the Lyn tyrosine kinase is regulating inflammatory cell recruitment and activation in anti-viral immune responses. Mice deficient in Lyn experienced less weight loss upon infection and show both enhanced innate and adaptive immune responses to influenza (using the influenza A viruses, Mem71 and A/PR8 virus). In addition, Lyn-/- mice also display increased cytokine gene expression. In contrast, influenza infection of mice constitutively expressing Lyn recovered less quickly, show increased morbidity and also displayed delayed immune cell kinetics and T cell responses after infection. The results in this thesis suggest that the Lyn plays an important regulatory role during anti-viral responses. Understanding the Lyn signaling pathway may allow for better understanding of the biological mechanisms controlling the pathogenesis and host immune responses to influenza and may be a target for therapeutic intervention.

Background: Circadian blood pressure (BP) variation patterns have been defined by day and night BP changes measured by 24-hour ambulatory BP monitoring. Abnormal circadian BP patterns include non-dipper, reverse dipper, and extreme dipper patterns due to their association with cardiovascular/cerebrovascular risk and worse prognosis. Impaired autonomic nervous system function has been considered to be related to abnormal BP dipping profiles. People with abnormal circadian BP variation have a high risk of developing stroke and patients with stroke tend to have more prevalent abnormal circadian BP patterns. However, there are no data concerning circadian BP patterns in patients with transient ischaemic attack (TIA) or minor stroke. Aims: The aims of the present study were to demonstrate the distribution of circadian BP patterns in patients with TIA or minor stroke in comparison to controls, and to investigate their association with autonomic nervous system function. Methods: This was a cross-sectional comparison study, with a prospective, observational sub-study following up patients with TIA or minor stroke for three months after the initial event. Patients with TIA or minor stroke and no previous stroke history were approached and recruited within seven days after their initial event at the Austin Hospital or the Northern Hospital TIA Clinic, both located in Melbourne, Australia. Control participants were age and gender group-matched, and recruited from among family members, friends of recruited patients, patients from the Austin Hospital Stroke Prevention Clinic, or the Hypertension Clinic. Volunteers from the local community were also recruited as control participants via newspaper advertisement. A face-to-face interview, clinic BP measurement, 24-hour ambulatory BP monitoring, and a 15 minute electrocardiogram-based heart rate variability (HRV) for autonomic nervous system function assessment were conducted for all participants. These tests were repeated at a three-month follow-up assessment for the TIA/minor stroke participants. The primary outcome of the study was recurrent stroke/TIA during the follow-up period. Blood pressure patterns were classified into dipper, non-dipper, reverse dipper, and extreme dipper based on published criteria. Statistical analyses were performed using Stata version 10 software. Results: There were 158 participants, including 76 patients (mean age 67.2 years, male 58%) and 82 controls (mean age 65.6 years, male 55%). There were 47 patients with TIA and 29 patients with minor stroke. There were no significant differences for age, gender and most risk factors between patients and controls. Patients had a higher mean body mass index (28.7 kg/ m2 versus 26.9 kg/ m2), greater prevalence of hypertension (72% versus 49%) and atrial fibrillation (17% versus 1%) than controls. Fifty-eight patients (76.3%) returned to the clinic for a face-to-face follow-up interview, and had a second 24-hour period of ambulatory BP monitoring. Blood pressure measured by ambulatory BP monitoring was shown to be well controlled (24-hour ambulatory BP < 130/80 mm Hg) in patients within seven days, and at three-months after the initial TIA/minor stroke event. Although not significant, the average clinic BP was higher than the average daytime BP (net difference in systolic BP: 13 mm Hg for patients, 8 mm Hg for controls; net difference in diastolic BP: 5 mm Hg for patients, 2 mm Hg for controls) and 24-hour ambulatory BP (net difference in systolic BP: 16 mm Hg for patients, 10 mm Hg for controls; net difference in diastolic BP: 7 mm Hg for patients, 4 mm Hg for controls) for both patients and controls. There was poor agreement between ambulatory BP and clinic BP measurements, for example, concordance correlation coefficient, r = 0.5 (95% CI: 0.4 to 0.6) for agreement between the average clinic systolic BP, and the average 24-hour systolic BP. A systolic dipper pattern was found in 31.6% of patients with TIA or minor stroke. However, the prevalence of abnormal circadian BP patterns in patients was not significantly different to that among controls. Heart rate variability did not differ significantly between patients and controls, for example, the standard deviation of the average normal-to-normal QRS intervals (Standard Deviation of Normal to Normal [SDNN], one of the parameters in the HRV analysis) was 43.1 ms (95% CI: 37.0 to 49.2) for patients, and 42.2 ms (95% CI: 37.6 to 46.8) for controls (p = 0.8). During the three-month follow-up period, there were 26 recurrent TIA events identified in 15 patients (TIA risk 19.7%), and four stroke events occurred in four patients (stroke risk 5.3%). There was no association between circadian BP patterns and risk of recurrent stroke/TIA. Conclusion: Patients with TIA or minor stroke had no more prevalent abnormal circadian BP patterns and no greater impairment of autonomic nervous system function when compared to controls. These findings differ from the existing evidence for patients with stroke.

Crohn’s disease (CD) is an inflammatory bowel disease (IBD) of unknown aetiology. It affects up to 0.2% of the population and causes significant morbidity and increased mortality. Medical and surgical treatments are available but neither are curative. Functional and genome-wide association studies suggest that defective luminal bacterial handling by the gut innate immune system contributes to pathogenesis. Pathogenic bacteria may also play a role and there has been particular focus on gastrointestinal (GI) mucosal adherent-invasive E.coli (AIEC) which are prevalent in CD. The purpose of this thesis was to characterise GI mucosal E.coli strains and examine the interaction of E.coli and other bacteria with macrophages in CD. A case-control study of cultured GI mucosal biopsies from patients with CD, ulcerative colitis (UC) and healthy controls illustrated that mucosal E.coli were most prevalent in CD and were cultured from both inflamed and uninflamed CD mucosa. There was substantial variety of E.coli genotype and phenotype in IBD patients and healthy controls. AIEC were identified only in mucosa from CD patients and adherent CD strains shared characteristics with extraintestinal pathogenic E.coli. A subsequent study demonstrated that E.coli could be identified in lamina propria macrophages commonly in CD, rarely in UC and not in healthy controls. There was a clear pattern of macrophage cytokine polarisation in relation to the presence or absence of intracellular E.coli. The CD autophagy risk allele ATG16L1 was associated with higher macrophage cytokine mRNA expression in CD. In vitro studies demonstrated prolonged survival of E.coli but not S.aureus in monocytes from patients with CD. This possible bacterial killing defect did not appear to relate to respiratory burst dysfunction as this was normal in CD monocytes. Finally, a rapid in vitro monocyte intracellular survival assay for a luminescent Mycobacterium avium ssp paratuberculosis (MAP) strain was developed and validated. MAP survived in monocytes from both patients with CD and healthy controls for at least 2 weeks. In conclusion, this thesis provides evidence for a potential role of an abnormal interaction between lamina propria macrophages and E.coli in CD pathogenesis.

This study examines the translation of Clinical Governance (CG) policy into risk practices into Aged Persons Mental Health (APMH). CG is the system in which clinicians and governing bodies share responsibility and are held accountable for the delivery of safe quality health care. Policy indicates that it is the health care organisation's responsibility to embed CG as 'everyday business', ensuring that this is not just an optional 'add-on' for care provision. However, since its inception, CG has received mixed reviews both in Australia, and internationally. It is emphasised that CG must be driven through all levels of an organisation, not just emerge as a whole new bureaucracy of its own. The relationship between effective CG and positive consumer outcomes make this especially pertinent in Aged Persons Mental Health. In Australia, Aged care services collectively assist over one million older adults. Although there have been improvements in the range and quality of aged care services over time, several key weaknesses remain. For example, workforce shortages (including the higher than average age of the workforce), uncompetitive wages and over-regulation, and the variable quality in terms of service provision, all hinder improvement initiatives in some way. Additionally, APMH (as in other areas of health) also experience the need for a larger workforce in the context of an ever shrinking pool of recruits. The retirement of the 'Baby Boomers', with their higher expectations of health care, will also place additional pressure on aged care services in the future. More importantly for CG however, is that the system will be challenged by a substantial population increase overall; one that is expected to bring with it increasing diagnostic complexity for the older adult. Consequently, the broad aim of this research is to understand if, and how, clinical governance policies influence risk management practices in APMH. More specifically, this thesis explores the: degree of understanding of CG between the various participant groups; range of facilitators and inhibitors to CG implementation; and possible improvement strategies for embedding CG into practice. A qualitative design was considered appropriate in order to fulfil these aims, which resulted in the development of a three-staged approach. This ensured that data was triangulated from multiple perspectives, with the study strengthened further by using a variety of data collection techniques (including individual and group interviews, and document analysis). Information from three distinct participant groups was obtained across the three stages. Specifically, interviews were carried out with Policy-makers and Organisational Implementers. In addition, the views of clinicians in APMH residential care facilities were sought via case studies. A comprehensive document review of Australian CG policy was also conducted. Collectively, the qualitative approaches of Miles and Huberman, Scott, and Kurland, then provide a framework from which to understand and present the findings. As a result, perceived deficits in knowledge, communication and leadership were identified as barriers to the effective translation of CG policy into practice. Furthermore, the heavy managerial reliance on the risk component of the model (including documentation and reporting) to the perceived detriment of other aspects, was also considered to be problematic. In summary, these findings suggest that the true value of CG may be lost if restricted to mandated ‘tick-box’ reporting, rather than being strengthened by an approach that conceptualises and promotes CG in a way that clinicians understand. Ultimately, if change fails to occur, attention may be diverted away from the quality of care that CG was originally intended to support. Finally, this research provides a new perspective from which to consider the facilitators, limitations, and strategies for improving the translation of CG into risk practices in APMH. A new model for reframing the existing CG approach, and addressing these issues in APMH, is put forward.