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Title page, contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / The development of gene therapy for clinical use continues to face many hurdles. A major issue is the limitation of gene delivery technology. This body of work describes strategies for improving the selectivity and efficacy of gene delivery to vascular endothelium, with emphasis on delivery to pulmonary vasculature in vivo. Several important principles were established which continue to be of relevance to the field. The work progresses from vector development through to the use of new vector strategies in the application of novel gene delivery approaches in disease models. Work in gene therapy and vector development began in the Division of Human Gene Therapy, University of Alabama at Birmingham, under the mentorship of Prof David T Curiel and has continued through international collaborations and the establishment of my own laboratory in the Hanson Institute with affiliate links to the University of Adelaide. The work presented in this thesis consists entirely of published material, either as book chapters (three) or peer reviewed journal articles (twelve). The sequence of material progresses from a broad introduction to the field on Gene Therapy, more specific chapters dealing with pulmonary gene delivery including a detailed methodology chapter. The peer reviewed works contain an evolution of work dealing with the development of strategies to target adenoviral gene delivery vectors to the pulmonary vascular endothelium. This work encompasses the use of bi-specific conjugates, genetic modification of viral capsid (outer coat) proteins and the use of cell-specific promoters. The work progresses to a demonstration of the therapeutic gains achieved with the use of targeted over non-targeted vectors in animal models and culminates with a highly novel application of modulation of the bone morphogenetic protein pathway in pulmonary hypertension. A component of the work focuses on enhanced gene delivery to vein grafts exVIVO. There are many key original contributions encompassed within the work, including 1) first use of conjugate-based retargeting to vascular cells, 2) first demonstration that tropism modification could alter in vivo biodistribution of virus, 3) first demonstration of cell-specific retargeting of adenoviral vector after systemic vascular injection in vivo (a technique still unsurpassed in the field), 4) first demonstration of the in vivo selectivity gains achieved by combined cell-specific promoters with viral retargeting, 5) first demonstration of therapeutic gains achieved by targeting in a vascular context and 6) first demonstration that modulation of the BMPR2 pathway can have a therapeutic impact in pulmonary hypertension. Importantly, the targeting work I have developed has been adapted and used by others and laid a foundation for further vector improvements. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1349837 / Thesis (M.D.) -- University of Adelaide, School of Medicine, 2009

Title page, contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / The development of gene therapy for clinical use continues to face many hurdles. A major issue is the limitation of gene delivery technology. This body of work describes strategies for improving the selectivity and efficacy of gene delivery to vascular endothelium, with emphasis on delivery to pulmonary vasculature in vivo. Several important principles were established which continue to be of relevance to the field. The work progresses from vector development through to the use of new vector strategies in the application of novel gene delivery approaches in disease models. Work in gene therapy and vector development began in the Division of Human Gene Therapy, University of Alabama at Birmingham, under the mentorship of Prof David T Curiel and has continued through international collaborations and the establishment of my own laboratory in the Hanson Institute with affiliate links to the University of Adelaide. The work presented in this thesis consists entirely of published material, either as book chapters (three) or peer reviewed journal articles (twelve). The sequence of material progresses from a broad introduction to the field on Gene Therapy, more specific chapters dealing with pulmonary gene delivery including a detailed methodology chapter. The peer reviewed works contain an evolution of work dealing with the development of strategies to target adenoviral gene delivery vectors to the pulmonary vascular endothelium. This work encompasses the use of bi-specific conjugates, genetic modification of viral capsid (outer coat) proteins and the use of cell-specific promoters. The work progresses to a demonstration of the therapeutic gains achieved with the use of targeted over non-targeted vectors in animal models and culminates with a highly novel application of modulation of the bone morphogenetic protein pathway in pulmonary hypertension. A component of the work focuses on enhanced gene delivery to vein grafts exVIVO. There are many key original contributions encompassed within the work, including 1) first use of conjugate-based retargeting to vascular cells, 2) first demonstration that tropism modification could alter in vivo biodistribution of virus, 3) first demonstration of cell-specific retargeting of adenoviral vector after systemic vascular injection in vivo (a technique still unsurpassed in the field), 4) first demonstration of the in vivo selectivity gains achieved by combined cell-specific promoters with viral retargeting, 5) first demonstration of therapeutic gains achieved by targeting in a vascular context and 6) first demonstration that modulation of the BMPR2 pathway can have a therapeutic impact in pulmonary hypertension. Importantly, the targeting work I have developed has been adapted and used by others and laid a foundation for further vector improvements. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1349837 / Thesis (M.D.) -- University of Adelaide, School of Medicine, 2009

Background: Patients with pre-existing vascular disease are known to have worse outcomes after acute myocardial infarction (AMI). However, there is limited data for outcomes stratified by type and number of vascular territories involved. Methods: Using the Nationwide Inpatient Sample (2015–2017), we examined outcomes of AMI in patients with pre-existent vascular disease stratified by number as well as types of diseased beds including all five major vascular sites: cardiac, cerebrovascular, renal, aortic and peripheral vascular disease (PVD). Multivariable logistic regression was used to determine the adjusted odds ratios (aOR) of adverse outcomes and invasive procedure utilization. Results: Out of 2,184,614 AMI admissions, 49.7% had pre-existent vascular disease. The odds of major adverse cardiovascular and cerebrovascular events (MACCE), mortality, ischemic stroke and major bleeding incrementally increased and was highest in those with ≥3 vascular sites involved (aOR for MACCE 1.16, CI 1.13–1.19; mortality 1.3, CI 1.26–1.34; stroke 1.15, CI 1.1–1.2; major bleeding 1.21, CI 1.16–1.25). Amongst those with a single pre-existent diseased vascular bed, the adjusted odds of MACCE appeared to be higher in those with PVD (1.28, CI 1.26–1.31), aortic disease (1.24, CI 1.19–1.29), and cerebrovascular disease (1.22, CI 1.2–1.25). Patients with pre-existent vascular disease had a lower overall likelihood of undergoing invasive revascularization procedures. Conclusions: Approximately half of the population presenting with AMI have pre-existent vascular disease. There is an incremental increase in adverse outcomes with increasing number of diseased vascular beds, with further differences in outcomes and utilization of invasive procedures based on sub-types of sites involved.

Background: Patients with pre-existing vascular disease are known to have worse outcomes after acute myocardial infarction (AMI). However, there is limited data for outcomes stratified by type and number of vascular territories involved. Methods: Using the Nationwide Inpatient Sample (2015–2017), we examined outcomes of AMI in patients with pre-existent vascular disease stratified by number as well as types of diseased beds including all five major vascular sites: cardiac, cerebrovascular, renal, aortic and peripheral vascular disease (PVD). Multivariable logistic regression was used to determine the adjusted odds ratios (aOR) of adverse outcomes and invasive procedure utilization. Results: Out of 2,184,614 AMI admissions, 49.7% had pre-existent vascular disease. The odds of major adverse cardiovascular and cerebrovascular events (MACCE), mortality, ischemic stroke and major bleeding incrementally increased and was highest in those with ≥3 vascular sites involved (aOR for MACCE 1.16, CI 1.13–1.19; mortality 1.3, CI 1.26–1.34; stroke 1.15, CI 1.1–1.2; major bleeding 1.21, CI 1.16–1.25). Amongst those with a single pre-existent diseased vascular bed, the adjusted odds of MACCE appeared to be higher in those with PVD (1.28, CI 1.26–1.31), aortic disease (1.24, CI 1.19–1.29), and cerebrovascular disease (1.22, CI 1.2–1.25). Patients with pre-existent vascular disease had a lower overall likelihood of undergoing invasive revascularization procedures. Conclusions: Approximately half of the population presenting with AMI have pre-existent vascular disease. There is an incremental increase in adverse outcomes with increasing number of diseased vascular beds, with further differences in outcomes and utilization of invasive procedures based on sub-types of sites involved.

During a surveillance programme all the known diabetics (1150) were identified from a general population of 97,034 representing all patients registered with 10 general practices. A control group of 751 non-diabetic subjects were also drawn from the same general population. A single observer reviewed 1077 (93.6%) of the diabetics and 480 (69%) of the controls. Peripheral vascular disease was detected using doppler ankle/brachial pressure index in 20.6% (95% CI 18.2-23.0) of diabetics and 9.6% (95% CI 7.0-11.2) of controls. There was no significant difference between the prevalence in non-insulin dependent and insulin dependent diabetics after adjusting for age. The prevalence in either type of diabetes was however significantly greater than in controls. Multiple logistic regression analysis revealed that age, cerebrovascular disease, coronary artery disease, mean systolic blood pressure, blood glucose, proteinuria and serum cholesterol were significantly and independently associated with the presence of peripheral vascular disease in diabetics. Body mass index was inversely associated. For controls only age and smoking were found to be significant variables. Neuropathy determined by clinical evaluation and sensory vibration thresholds was found in 16.8% (95% CI 14.6-19.0) of diabetics and 2.9% (95% CI 1.4-4.3) of controls (p<O.001). There was however no significant difference between insulin dependent and non-insulin dependent diabetics after accounting for age. Alcohol intake, age, height, HbAl, foot deformity and the presence of any retinopathy were significantly associated with neuropathy in diabetics and only male sex, age and foot deformity in controls. Past or present foot ulceration occurred in 7.4% (95% CI 5.8-9.0) of diabetics and 2.5% (95% CI 1.1-3.9) of controls (p<O.00l). Amputation was found in 1.4% (95% CI 0.7-2.1) of diabetics but in no controls. Using logistic regression analysis ulceration was significantly associated with duration of diabetes, foot deformity, absent light touch, impaired pain perception, an absent dorsalis pedis pulse and the presence of any retinopathy. For controls only absent light touch was significant. Using a stepwise multiple regression only age and duration of diabetes were significantly associated with the presence of amputation.

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