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(2001)ThesisInjectable liposomes are well known in the pharmaceutical industry for drug delivery. In particular, PEG-coated liposomes have found application for reason of their increased circulation time, which is believed to be associated with their low tendency to be opsonized. However, much of the drug never reaches the intended target site. In this study, methods for binding liposomes onto surfaces ofbiomaterials and biomedical devices were developed and applied for controlled local delivery of drugs adjacent to implanted biomedical devices. In this way the aim was to reduce drug amounts and wastage, and control the local host response to the implant, a response which with most current biomaterials typically is dominated by fibrous tissue encapsulation. Liposomes with encapsulated drugs and model substances were produced and characterized in terms of size and release performance, and bound onto polymeric surfaces. PEGylated phospholipid liposomes were produced by extrusion through polycarbonate membranes of various pore sizes. The diameters (mean and distribution) of the liposomes were characterized by photon correlation spectroscopy. For binding liposomes, polymer surfaces were coated with NeutrAvidin™, which was used for affinity capture ofbiotinylated PEGylated liposomes. NeutrAvidin™ was either covalently bound onto polymer surfaces via plasma (glow discharge) polymer coating and layers of carboxylated polymers (polyacrylic acid or carboxymethyl-dextrans) or affinity "docked" onto a PEG-Biotin gel interlayer. Detailed surface analyses (mainly X-ray Photoelectron Spectroscopy (XPS) and Atomic Force Microscopy (AFM)) were used to characterize and verify each step in the fabrication of the liposome coated surfaces. To test the in vitro efficacy ofliposome coated biomaterials, a compound known to modulate angiogenesis was encapsulated in liposomes and these liposomes attached onto solid surfaces. Results obtained with two in vitro angiogenesis model assays show that effective inhibition of angiogenesis was achieved with suitably constructed surfacebound liposome implants. The results presented in this thesis show that surface attachment of liposomes to modified polymers is feasible. Moreover, surface-bound liposomes can be successfully used as a drug delivery system to inhibit angiogenesis.
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(2002)ThesisThis is a study of the social management of human finitude, through explorations of breast cancer as a life-threatening illness. Three domains of social theory and research form the basis of theoretical analysis: the sociology of dying and death, social studies of women with breast cancer, and the sociology of human mortality. The sociology of dying and death contributes to our understandings of life-threatening illness, but fails to adequately encompass the trajectories of illness and recovery. The absence of feminist perspectives and gendered theorising towards human mortality is also evident. The methodology of this study was informed by a feminist sociological imagination and had two phases. Firstly, longitudinal semi-structured interviews with women with breast cancer (n=20) were conducted over one year. Secondly, health care providers (n=25) representative of the range of services for women with breast cancer were interviewed. Popular representations of women recovering from breast cancer illness present women engaging in heroic adventures and transforming their 'ordinary' lives into the 'extraordinary'. Did confrontation with their own mortality, through life-threatening illness, transform these women's lives? No, they did not pursue new life projects or satisfy long-held aspirations. Instead they appeared to return to 'ordinary' life, but conceived it differently. The illness narratives revealed also that women with breast cancer experienced the fateful moments of human finitude, throughout their illness trajectory. These experiences were commonly suppressed in all areas of social life, not least during the active stage of breast cancer treatment. And what of the health care providers? Some demonstrated awareness in finitude, and awareness to the finitude of others. Others did not, and actively engaged in the suppression of awareness of human mortality. In this study, life-threatening illness brought to consciousness the finiteness of human life. Of most significance is the thesis that life-threatening illness experiences are powerfully shaped and disrupted through the social management of human mortality. However, we can discern also patterns of living and healing that resist these prevailing social processes, and acknowledge the limitations of our lifetimes.
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(2001)ThesisTwo approaches were evaluated for inclusion in surveillance for HIV, HBV and HCV infection and related risk behaviours among injecting drug users in Australia. The first approach analysed routinely recorded patient data at methadone clinics. The second approach generated data from clients at Needles and Syringe Programs (NSPs) using capillary blood and a self-report questionnaire. In addition, residents' attitudes to NSPs were measured in a population-based telephone survey. Both the methadone and NSP studies confirmed a sustained low prevalence of HIV among drug injectors in Australia, except among males who also reported homosexual identity. Only male patients had HIV in the methadone study. Most patients with HIV infection did not have sexual identity recorded. Recording of sexual identity is an integral part of any HIV monitoring system. In addition, only two clinics provided data for the two years. Regular reporting of methadone patient data was not incorporated into national surveillance following the two-year trial. The NSP study design, repeated cross-sectional surveys of short duration, provided information on HIV and HCV seroprevalence, patterns of drug use and injecting and sexual risk behaviours in subpopulations defined by level of risk of acquiring infection. Nationally, 1,072 (45%), 1,497 (53%), 1,978 (48%) and 2,665 (46%) clients participated from 1995 to 1998 at 20 to 32 NSPs. HCV prevalence decreased among respondents reporting one or two years of injection from 22% (1995) to 13% (1996 & 1997, p < 0.001). Increased injection of cocaine was also reported among Sydney respondents. The design was adaptable to changing needs, yet provided consistent data. The NSP study was readily incorporated into national surveillance and the design can be applied in other settings. Support for state-wide NSPs (82%, and 88%, p = 0.04) and expansion of local NSPs was high (46% vs. 48%, p = 0.6) among 305 and 315 residents in an area of high drug use randomly selected for telephone interview in 1997 and 1998. There was also strong support for medically supervised injecting rooms (68% and 76%, p = 0.06) and prescription of heroin or cocaine (69% and 76%, p = 0.07). Monitoring indices of resident's attitudes to health services for drug users provided an informed basis for decision making and augments surveillance for blood borne viral infection and related risk behaviour among injecting drug users.
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(2008)ThesisThis thesis assesses factors associated with a number of short and long-term outcomes in HIV-infected patients receiving antiretroviral treatment in Asia. Analyses in this thesis were based on two cohorts of HIV-infected patients; The Treat Asia HIV Observational Database (TAHOD), a multi-centre prospective observational cohort from countries in Asia-Pacific region, and the HIV Netherlands Australia Thailand (HIV-NAT) collaboration cohort, a cohort of patients treated with antiretroviral treatments at HIV-NAT in Bangkok, Thailand. We examined factors associated with time to immunological failure endpoints, such as CD4≤ 200 cells/µL, CD4≤ 100 cells/ µL, and CD4 return to baseline, and with the virological failure endpoint, detectable viral load defined as a value greater than 500 copies/mL. Multivariate Cox proportional hazard models were used. Results showed that CD4 count at baseline and changes in CD4 strongly predicted immunological failure. For virological failure, detectable viral load at baseline was the strongest predictor. As a step to developing simplified monitoring strategies, in which patients with a low risk of failure could have their monitoring CD4 count and viral load tests deferred, we developed predictive models for each immunological and virological failure endpoint. Models were developed on the HIV-NAT cohort, and validated on the independent TAHOD cohort. For predictive models, the complementary log-log transformation for each endpoint was fitted appropriate to the interval censored nature of the data. To assess goodness-of-fit, cut-offs were defined for the predicted risks that separated patients from low risk to high risk. Overall, the observed versus expected failures from HIV-NAT data agreed quite well across all endpoints, probably reflecting that the HIV-NAT database was the data we built the models upon. Not only did these models fit the HIV-NAT database well, they also discriminated patients from low to high risk groups. When we validated models with TAHOD data, the observed and expected failures agreed well only in the model for CD4 count return to baseline. For most of the endpoints, the predictive models overestimated the number of failures, with predicted values larger than observed. However, the proportions of failures were lowest in the low risk group and highest in the high risk group, indicating that our models did discriminate between patients at high and low risk, and that the predictive models might still be of use for the purpose of simplified monitoring strategies. With CD4 count and viral load monitoring tests now comprising a large component of the cost of HIV treatment in resource limited settings, we developed and assessed a simplified monitoring strategy that aimed to reduce the numbers of monitoring tests performed. The predictive models developed earlier were used to calculate the probabilities of failure in TAHOD patients. We assumed that patients would have their CD4 and viral load assessments annually, at baseline and at one year, predicted risk of failure at ensuing clinical visits, week 12, 24 and 36. For patients at low predicted risk of failure at ensuing clinical visits, we assessed the effect of deferring monitoring tests, both in terms of blood tests avoided, and in terms of delaying detection of failure in some patients. A number of levels for the predicted risk of failure that lead to deferral of testing were evaluated. The results suggested that predicted probabilities of failure of 10% - 20% gave the best results across all failure endpoints. These cut-offs could save a median of 598 (51.6%) (range 37 (2.6%)_-1,218 (81.9%) ) blood tests over the first year of treatment, but would fail to detect 29 (18%) (range 10 (7.4%) - 128 (39.3%) ) failures. The median time from failure to detection in those patients who did fail and had deferred monitoring tests was 28 weeks. Rates of antiretroviral treatment change in TAHOD were examined. We identified patterns and factors associated with the rate of treatment change. Median time to the first treatment change was 3.2 years. Factors predicting rate of treatment change in TAHOD were treatment combination, being on second or third combination, number of drugs available in each site and being an injecting drug user. The overall rate of treatment change in TAHOD was 29 per 1OO-person-year. Around 30% of patients stopped their treatment due to adverse events. These rates of treatment change are lower than have been seen in patients in western countries. This may be due to patients in developing countries having access to fewer antiretroviral drugs than patients in developed countries.
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