Medicine (RMH) - Theses
Permanent URI for this collection
Search Results
1 - 10 of 11
-
ItemImproving clinical outcomes for patients with diabetes related foot complications( 2005)Background: Individuals with diabetes have a 15% lifetime risk of developing a foot ulcer, which are ultimately responsible for over 100,000 amputations being performed each year in the United States. Although it has been well documented that we currently have the available knowledge to successfully heal approximately 90% of such ulcers, amputation and admission rates for these conditions continue to increase. Aim: To determine if management approaches and clinical outcomes (length of stay, amputation rate), for individuals with diabetes related foot complications, can be improved with the introduction of a novel evidence-based clinical guideline by a multidisciplinary team of health professionals. Theories regarding guideline dissemination and implementation will be explored in an attempt to identify strategies that are more effective in achieving sustained clinical change. Methods: A novel evidence-based clinical guideline was created, by reviewing 266 articles specific to the area. The guideline was specifically designed to encourage a systematic and global approach to the clinical assessment, investigation and management of individuals with diabetes related foot complications. The clinical guideline was initially introduced into the pre-existing environment of the hospital, drawing upon published dissemination and implementation strategies / theories. Two-month prospective studies were undertaken both prior and post guideline implementation, evaluating the extent of guideline uptake and the corresponding changes to clinical care. In response to these findings, efforts were made to further improve guideline utilisation by specifically addressing identified barriers to implementation in a second launch of the guideline. A further two-month prospective study was undertaken, 1-year post the initial launch. As sustained changes to health care provision were not achieved at this time, a final strategy to be employed was to use a multidisciplinary team of health professionals, including representatives from endocrinology, podiatry, vascular surgery, infectious diseases, diabetes educators, dietician, clinical psychology, rehabilitation and radiology, to implement the clinical guideline as a part of a newly created, centralised Diabetic Foot Unit (DFU). Results: The evidence-based clinical guideline was insufficient, in itself; to encourage health professionals to change their clinical approach when managing someone with a diabetes related foot complication. Despite identifying many barriers preventing the more widespread uptake of the guideline and multidisciplinary team (professional autonomy, knowledge deficits, environmental and patient barriers) the only approach that achieved significant change was the creation of a centralised, multidisciplinary, diabetic foot unit. With the introduction of the DFU, a complete clinical examination of the foot was undertaken in all patients, investigations were tailored to the specific condition, mean length of stay was reduced by 5 days per admission and there was a significant reduction in the amputation rate. Conclusion: Implementation of (i) an evidence-based clinical guideline, (ii) a multidisciplinary team, and (iii) centralised DFU, can improve all aspects of health provision, with corresponding reductions in length of stay and amputation rates. The development of this complete package for health provision suggests that similar results should be achievable with the introduction of this approach to other health institutions.
-
ItemChronic pain in older people( 2001-04)Despite the expansion of research into chronic nonmalignant pain, a majority of reported studies are based on patient populations of specialised pain management clinics, which may not adequately represent older people with chronic nonmalignant pain in the general community. Therefore, the overall aim of the present thesis was to fill some gaps in this knowledge base. The findings of the present thesis support the notion that older people who attend multidisciplinary pain management centres are probably not representative of those with pain who live in the general community but do not attend specialised treatment centres. Indeed a conceptual framework developed from the findings suggest that less than 3 percent of a random community sample of older people with chronic pain share the profile of those who attend a multidisciplinary pain management centre. The majority (86 percent) of the community sample were found to have mild chronic pain that can be adequately managed in the community. However, about 11 percent of the community sample have moderate chronic pain, and it is probable that additional community-based pain management services can improve the management of pain. Development of instruments to measure the perceived helpfulness and use of pain management strategies by community-dwelling older people with chronic pain is another area that has not received adequate attention. A preliminary survey questionnaire was developed to measure the use and perceived helpfulness of pain management strategies in community dwelling older people. The findings have provided new insight from the user’s perspective regarding the relative effectiveness of different pain management strategies, and highlighted the potential clinical application of strategies that are less commonly used, such as TENS (transcutaneous electrical nerve stimulation), and relaxation techniques that are beneficial for specific subgroups of older people with chronic pain. The evaluation of the efficacy of a community-based intervention program that provides free choice of intervention for improving outcomes for older people with chronic pain showed that the program was successful in reducing pain and improving level of physical activity for those who completed the program when they were compared with matched subjects who did not participate. The findings also suggest that an educational seminar can have a positive impact that empower participants to make a more informed choice regarding interventions for managing pain. However, the long-term effect of the program has not been established. Therefore, further research will be needed to evaluate whether this approach is a viable alternative clinical option for effective, accessible, and low cost pain management for the general community of older people with chronic pain. The pain management service model was developed based on a synthesis of the findings. The model was based on a targeted approach that focuses on community-based interventions designed to improve access and outcomes for the majority of community-dwelling older people with chronic non-malignant pain who do not use specialised pain management services. Overall, the findings of the present thesis have enhanced our understanding of the management of chronic non-malignant pain in community-dwelling older people, which has important implications for the development of services, and has generated hypothesis for future research that may contribute to improve outcomes for older people with chronic non-malignant pain.
-
ItemRegulation of SNARE proteins in macrophages by colony stimulating factor-1( 2007)Macrophages serve key roles in host defence by initiating inflammatory responses to infection and/or injury. They contribute to innate immunity by secreting a range of pro-inflammatory cytokines (e.g. TNF and IL-6) upon activation as well as by phagocytosing pathogens and dead cells, which is necessary for the resolution of inflammation and effective wound repair. Macrophages also contribute to adaptive immunity by functioning as antigen presenting cells.Colony stimulating factor 1 (CSF-1) is the major growth factor governing the differentiation, proliferation and survival of macrophages. Although not as well appreciated, CSF-1 also regulates some of the immune functions of macrophages, such as cytokine secretion and phagocytosis. However, the mechanisms by which CSF-1 governs the immune functions of macrophages are poorly understood. Cytokine secretion, phagocytosis and antigen presentation involve various vesicle trafficking and membrane fusion events, processes in which SNARE proteins play vital roles. Thus, the hypothesis tested in this thesis was that CSF-1 modulates the immune functions of macrophages by regulating the expression and/or activity of SNARE proteins that regulate endocytic and exocytic processes.In this study, the endosomal SNARE protein syntaxin 7 was identified, via microarray analysis, as a CSF-1 inducible gene in primary mouse macrophages. Syntaxin 7 has previously been detected in phagosomal membranes in macrophages. Furthermore, syntaxin 7 has recently been implicated in the secretion of cytokines (e.g. TNF) from macrophages by forming a novel complex with syntaxin 6, Vti1b and VAMP3.
-
ItemSleep disordered breathing in stable methadone maintenance treatment patients( 2006-02)Methadone is a long acting mu-opioid and is the most effective treatment for heroin addiction. However, opioids depress respiration and methadone maintenance treatment (MMT) patients have a higher mortality rate than the general population. Teichtahl et al conducted a pilot study and found 6 out of 10 MMT patients had central sleep apnea (CSA). But no definite conclusions were made regarding the prevalence and possible pathogenesis of CSA in the patients due to the small sample size and lack of blood toxicology data. The present project aims to confirm the preliminary results and further quantify the sleep disordered breathing (SDB) in stable MMT patients and to delineate the pathogenesis involved. (For complete abstract open document)
-
ItemA study of the experiences of primiparous mothers who initiated breastfeeding( 2000)The aims of this study were:-identify breast feeding problems mothers have experienced-formulate theories about what could be done to improve breastfeeding outcomes-consider if it is practicable for the health care system to implement these changes-explore what strategies might be developed to improve breastfeeding outcomes beyond the health care system.
-
ItemThe HIT epitope( 2001)Heparin-induced thrombocytopenia (HIT) is a disorder found in some patients who developed thrombocytopenia after given heparin and similar glycosaminoglycans, with an incidence of 3%. There is little experimental study on the predisposition to HIT, while the pathogenesis of HIT has been investigated more widely. The currently favoured model is based on the activation of platelets FeγRII by HIT IgG, which only occur when the HIT IgG is in complex with PF4 and glycosaminoglycan. However, no study has looked into platelets activation by the HIT antibody beyond the binding to FeγRII. As the signal transduction pathways of platelets activation become increasingly understood, the activation of platelets by the HIT antibody await further in-depth studies. The involvement of endothelial cells in HIT is also an area that demands further detailed studies. Almost nothing is known about the immunogenesis of HIT, apart from isolated animal study based on idiotype. The possibility of involvement of cellular immunity in HIT is only studied very recently. HIT may be diagnosed by a functional assay based on activation of platelets or immunoasaay based on the detection of anti-PF4-hcparin antibody. A map of the HIT epitope is essential in elucidating the various aspects of HIT. It is now known that the majority, if not all HIT antibodies bind to a complex of hPF4 and heparin. Although the role of heparin or similar glycosaminoglycan is not fully understood, it is plausible that the HIT epitope is presented entirely on the PF4 tetramer. Heparin presumably serves to modify the presentation of the HIT epitope on the PF4 tetramers. One model contends that heparin alters the conformation of each PF4 tetramer, such that a neo-epitope is exposed on binding to heparin. On the other hand, when heparin is absent, the HIT epitope is hidden within the PF4 tetramer. An alternative model is based on the alignment of many PF4 tetramers by chains of heparin polysaccharides. Knowledge of the HIT epitope is crucial in unravelling the interaction between the HIT antibody and its antigen, and the subsequent platelets activation. This study uses site directed mutagenesis to create a comprehensive set of hPF4 mutant proteins. By measuring the binding avidity of these mutant PF4s with a batch of HIT sera, the contribution of the surface residues of PF4 tetramer is estimated. Subsequently, a single HIT population epitope is mapped on hPF4. Using graphical molecular modelling, several possible ways in which the HIT antibody, PF4 and heparin may interact with each other are examined. Viewing PF4 as a six faceted cuboid, the HIT epitope is found to be presented predominantly on one pair of opposite faces. The heparin binding helical pairs are located on a different pair of opposite faces. When a curve is drawn around the PF4 tetramer along the longitudinal axes of the two pairs of α-helices, the HIT epitope bearing faces are the pair that are crossed by this curve. This finding is significant because it is consistent with a model of interaction between PF4 and heparin, in which heparin chains bind to four pairs of lysine residues on each pair of α-helices in a orthogonal orientation between the longitudinal axes of the heparin chain and the helical pair. The finding is also consistent with a modified model in which heparin binds to the pair of opposite faces whose normal axes are directed perpendicular to the longitudinal axes of the paired α-helices. It is of significance to note that the pair of faces containing the HIT epitope are the only pairs which have a paucity of positively charged amino acid residues. If the HIT epitope resides on any of the other two pairs of faces, the HIT antibody will be forced to compete with heparin for binding to regions containing positively charged residues. The localisation of the HIT epitope on the pair of faces poor in positively charged residues is also significant, as PF4 tetramers are free to be aligned into arrays via cross-linking by heparin chains. These arrays of heparin cross-linked PF4 arrays have their HIT epitope bearing facets exposed. HIT IgG are facilitated to bind onto arrays of HIT epitopes aligned in optimal positions for coordinated binding of HIT IgG. The net effect of such coordinated binding is the oligomerisation of HIT IgG. When the oligomerised HIT IgG bind to Feγ receptors, the latter were forced to undergo lateral movement in the cell membrane in order to reach the binding targets. The resultant clustering of Feγ receptors on the cell membrane is expected to serve as trigger for downstream signal transduction which eventually leads to the activation of platelets. It may be some time yet before the finding of this study can be confirmed by 3D structural mapping of the HIT epitope using X-ray crystallography or NMR study. The tetrameric nature of PF4 and the tri-molecular interaction pose enormous barrier to this approach. In the meantime, the functionally determined HIT epitope will serve as a model for further experimental investigation and understanding of HIT.
-
ItemThe ErbB family of receptor tyrosine kinases in vestibular schwannoma and meningioma( 2004)Neoplastic disease whether benign or malignant, is the aberrant uncontrolled proliferation of cells within any given compartment of the human body, leading to the formation of a tumour. Such proliferation of cells, known as transformation, is due to deregulation of cellular mechanisms that control normal growth and development, so that transformed cells become independent of factors that usually provide constraints for cell growth. Intracranial tumourigenesis essentially results in tumours of the brain, the meninges, the pituitary gland and/or the cranial nerves. (From Chapter 1)
-
ItemDevelopments in the evaluation of oxygen uptake with emphasis on cardiopulmonary exercise testing, and its application to the preoperative assessment of surgical patients( 2009)The introduction of the Swan-Ganz catheter into clinical practice in 1985 facilitated a paradigm change in the management of patients undergoing major surgery. This development made it possible to measure cardiac output and calculate oxygen delivery and uptake in real time at the bedside. These advances together with the development of the portable programmable computer, meant that the attending clinician had access to more data than had ever been possible before. The modern Intensive Care Unit (ICU) evolved alongside these developments, enabling the use of a constellation of high technology equipment which was becoming available. At the same time there was considerable controversy around what was the most appropriate use of the ICU. This controversy was not resolved by the introduction of APACHE II in 1985 which allowed intensivists to correlate severity of illness with survival more reliably than previously. Our group published a paper in 1988, which showed that it was possible to identify high-risk surgical patients pre-operatively with the use of the Swan-Ganz catheter and schedule them for ICU admission post-operatively. In the late 1980s the metabolic cart became available clinically. Using this machine it was possible to measure oxygen uptake and calculate cardiac output non-invasively during exercise. The physiological data that became available with the use of this technology made possible reliable risk assessment of patients scheduled for major surgery. In 1989 a unique opportunity became available to the author to compare data from exercising patients obtained with a metabolic cart with data obtained synchronously with a Swan-Ganz catheter. Comparing this data enabled the investigation of the physiology of exercise in patients with cardiac failure in a way that would not have been possible by use of either a Swan-Ganz catheter or a metabolic cart alone. In 1993 our group published a paper from our laboratory about risk evaluation in surgical patients using Cardiopulmonary Exercise Testing (CPET). The data in this paper was pivotal to the belief that post-operative mortality was a function of cardiac failure and not myocardial ischaemia. In 1999 we published a prospective study involving 548 patients scheduled for major surgery. The results in this paper showed that mortality was inexorably linked to ventricular function. The data suggested that myocardial ischaemia per se was not the cause of post-operatively mortality, unless it was associated with cardiac failure. Other methods of pre-operative evaluation are discussed and it is argued that some of the common methods in use are flawed e.g. the use of metabolic equivalents and the use of stair climbing. The American College of Cardiology and American Heart Association (ACC/AHA) guidelines on pre-operative evaluation of non-cardiac surgical patients, place considerable emphasis on both these methods. This thesis contains a critique of some of the key aspects of these guidelines. An increasing numbers of patients presenting for surgery are taking beta-adrenergic blocking drugs. The use of these drugs has received close examination both from the ACC/AHA guidelines and a contemporary major multicentre trial. It is argued that the use of CPET in evaluating the use of these drugs is very important as management protocols for these patients can be generated from CPET data.
-
ItemConceptualising and measuring health literacy from the patient perspective( 2009)The current patient-centred healthcare approach encourages individuals to assume greater roles in decisions about their health. The premise is that patients who are well informed about healthcare options are more likely to adhere to prescribed treatments and achieve better health outcomes. This approach assumes that patients have an adequate level of health literacy. While a range of definitions exist, health literacy is commonly defined as an individual’s ability to seek, understand and utilise health information to make appropriate health decisions. Health literacy is increasingly recognised as a complex multi-dimensional concept which involves interactions between individual abilities and broader environmental factors. However across definitions, there has been little consultation with patients to understand what is important to effectively seek, understand and utilise health information. The lack of a consensual understanding has led to debate as to what health literacy represents and how it should be measured. A range of measures exist with the predominant approach being the testing of individual literacy abilities. However measures do not assess the range of attributes described in definitions. Thus a considerable gap exists between how health literacy is defined and how it is measured. This thesis focused on addressing this gap. The objectives were to: (i) critically appraise existing health literacy measures (ii) develop a conceptual framework from the patient perspective and (iii) use this framework to develop a comprehensive measure of health literacy. A multi-method qualitative and quantitative approach was used: (1) Systematic review and appraisal of the content, development and psychometric properties of health literacy measures. (2) In-depth consultations with patients across healthcare and disease continuums to develop a conceptual framework. (3) Development of a new health literacy measure based on the conceptual framework using a classical test theory approach. A critical appraisal of the literature revealed that the majority of health literacy measures are not based on a conceptual framework and none appeared to adequately measure a person’s ability to seek, understand and utilise health information. Content focussed primarily on reading, comprehension and numeracy skills and scoring was poorly defined. Only five of the 19 measures had evidence of acceptable reliability. The conceptual framework of health literacy from the patient perspective identified 17 key elements: six individual abilities and 11 broader contextual factors that are important to seek, understand and utilise health information and expanded previous conceptualisations of health literacy. This informed the development of the Health Literacy Management Scale (HeLMS) which measures six generic and potentially modifiable abilities and three specific broader social factors. Overall the HeLMS measures an individual’s ability to seek, understand and utilise health information within the healthcare setting. The HeLMS consists of 29 items across eight domains. Rigorous psychometric testing demonstrates that it possesses strong construct validity and high reliability (coefficient α >0.80 for all eight domains). This research provides unique contributions to the conceptualisation and measurement of health literacy. Limitations in the content and psychometric properties of previously developed measures have been identified through a systematic process. A conceptual framework derived from the patient perspective identifies a range of components that provide new insight into: (i) constructs that should be incorporated to measure health literacy and (ii) areas that need to be addressed to improve health literacy. The development of the HeLMS now allows for a more comprehensive assessment of health literacy. Information from the conceptual framework and the HeLMS are likely to be useful tools to inform the development of public health initiatives to enhance patient participation in the management of their health.
-
ItemMechanisms and mapping of ventricular arrhythmias in cardiomyopathy( 2009)Heart failure due to ischemic and dilated cardiomyopathy is a large and expanding public health problem, and ventricular arrhythmias are a common and potentially fatal complication of this condition. Despite extensive investigation, the mechanisms of ventricular arrhythmias in cardiomyopathy remain incompletely understood. This thesis examines these mechanisms, particularly with reference to the potential role of the underlying electrophysiologic substrate. It also evaluates the validity and utility of some of the tools commonly used to assist in the mapping and catheter ablation of ventricular arrhythmias. The central rationale of this thesis is that the mechanisms of ventricular arrhythmogenesis in cardiomyopathy are optimally studied by comparing ischemic and dilated cardiomyopathy patients with spontaneous (rather than inducible) ventricular tachycardia to otherwise similar heart failure patients who have never developed clinical arrhythmias. This has been done in the two largest projects herein. In the setting of ischemic cardiomyopathy, it is demonstrated that there are large differences in the electrophysiologic substrate between the groups such that patients with clinical ventricular tachycardia have substantially greater endocardial scarring as inferred by the presence of low-voltage zones and scar-related electrograms compared to control cardiomyopathy patients with no spontaneous arrhythmias. Furthermore, there appear to be fundamental differences in the nature of the scarring process with ventricular tachycardia patients having more abnormal electrograms per unit area of low-voltage and more scar-related putative conducting channels (which may form critical diastolic isthmuses in tachycardia). This was accompanied by a lower rate of ventricular tachycardia inducibility in the control patients. Taken together these findings point to a major role for the electrophysiologic substrate in ventricular arrhythmogenesis in the setting of ischemic cardiomyopathy. The situation in dilated cardiomyopathy is more complicated and although significant endocardial substrate differences were again seen in this context, there was marked heterogeneity in the group with ventricular tachycardia with some patients having extensive low-voltage zones and others having normal endocardial voltage. As the pericardium could not be accessed for ethical reasons in control patients with no clinical arrhythmia, the precise role of an abnormal epicardial substrate was not able to be defined in this study. Another project in this thesis examines potential improvements (in the form of a multielectrode mapping catheter) to a widely used electroanatomic mapping system that can assist in mapping ventricular tachycardia circuits and the substrates underlying them. A further project compares magnetic resonance imaging and electroanatomic substrate mapping in defining ventricular scarring in the context of cardiomyopathy. And finally, electroanatomic mapping is used to look at endocardial activation patterns and electrical dyssynchrony in cardiomyopathy patients with and without left bundle branch block. The demonstrated variability in these factors may underlie the significant non-response rates to cardiac resynchronization therapy. In summary, it is apparent from this work that the electrophysiologic substrate plays a crucial role in mechanism of the ventricular arrhythmias seen in heart failure patients with ischemic and dilated cardiomyopathy. An improved understanding of these mechanisms may in turn lead to better diagnosis, risk stratification and ultimately management of heart failure patients suffering from, or at risk of developing these potentially lethal arrhythmias.