Medicine (St Vincent's) - Theses
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ItemAdipose-derived mesenchymal cell derivation, characterization and differentiation for potential use in cell replacement therapy for diabetes( 2013)Type 1 diabetes (T1D) is characterized by the loss of insulin-producing β-cells in the pancreas. T1D can be treated using cadaveric islet transplantation, but this therapy is severely limited by a lack of donor pancreas. To develop an alternative cell therapy, candidate populations were identified through epigenetic characterization of multiple tissues. Histone modification status at the promoter region of key endocrine pancreatic genes was assessed using chromatin immunoprecipitation sequencing (ChIP-seq) and validated using promoter-specific TaqMan-based quantitative PCR (qPCR). Visceral fat was identified as a tissue retaining epigenetic signatures similar to those observed in the pancreas. Human adipose-derived mesenchymal cells (AMCs) were characterized using flowcytometry, confocal microscopy, qPCR, in situ PCR and next generation sequencing technologies. Multiple transcription factor-encoding adenoviruses (e.g. Pdx1, MafA, Ngn3) were employed to determine the differentiation potential of these cells. Analysis of multiple pancreatic hormones and transcription factors in these samples demonstrated consistent differentiation. The differentiation potential was further explored using AMCs isolated from transgenic mice that express GFP under the regulation of Pdx1 (pancreatic and duodenal homeobox 1) or insulin-1 gene promoters. GFP expression was quantitated as an index of gene promoter activity during differentiation to insulin-producing cells, in the presence of various pro-differentiation small molecules. Human AMCs were exposed to a standard differentiation protocol and seen to migrate to form islet-like cell aggregates (ICAs), showing significant increases in islet hormone transcripts in vitro. These adipose-derived ICAs were transplanted into immunocompromised animals using two models of transplantation. Cells were transplanted in a Theracyte immunoisolation device into the peritoneum, and within a blood clot under the kidney capsule. Transplanted cells maintained expression of endocrine pancreatic transcription factors and did not undergo a regressive mesenchymal transition following surgery. Circulating blood samples collected from peripheral circulation of these mice, following a glucose injection, showed that differentiated and engrafted human AMCs could sense, transcribe, translate, package and secrete insulin in response to a glucose stimulus. These studies indicate that human AMCs can differentiate into insulin-producing cells in vitro and have potential for cell replacement therapy in diabetes.
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ItemDiabetes telephone coaching study: a randomised controlled trial and economic analysis( 2013)Aims: The randomised controlled trial (RCT) aimed to assess the efficacy of telephone coaching on glycaemic control, risk factor status and adherence to monitoring requirements in patients with poorly controlled type 2 diabetes (T2DM), both at the intervention’s conclusion (six months) and in the post-intervention period (12 months). The study also involved a cost-effectiveness analysis of the intervention, both in a within-trial setting and in a 10 year modelled scenario. Finally, this study sought to estimate the annual cost of treating Australians with poorly controlled T2DM. Method:Participants with T2DM, HbA1C >7% (n=94) were randomised to receive usual care plus six months of telephone coaching, or usual care only. Coaching involved assessment, education and goal setting regarding diet, exercise, medications and adherence to diabetes monitoring requirements. The primary outcome was HbA1C at six months. Secondary outcomes included HbA1C at 12 months and other physiological and monitoring measures. The within-trial economic analysis used cost and efficacy data collected between baseline and six months of the RCT to estimate the cost-effectiveness of the telephone coaching intervention, compared to usual diabetes care. The primary outcome was an incremental cost effectiveness ratio, expressed as cost per quality adjusted life year (QALY) saved. Items costed included those attributable to medication use, general practitioner presentations, outpatient appointments, emergency department presentations, inpatient admissions and delivery of the intervention. To estimate the annual cost of treating a person with T2DM, six-monthly costs of all participants were doubled to reflect the annual cost. The modelled economic analysis used the UKPDS Outcomes Model to extrapolate outcomes collected at six months in the RCT over 10 years, assuming the ongoing delivery of the telephone coaching intervention. Outcomes included life expectancy, quality-adjusted life expectancy (QALE) and costs. A 5% discount rate was applied to all future costs and benefits. Sensitivity analyses were conducted to reflect uncertainty surrounding key input parameters. Results: The six month intervention contributed to significant improvements in HbA1C (p=0.03), fasting glucose (p=0.02), diastolic blood pressure (BP) (p=0.03) and physical activity (p=0.02). At six months, adjusted mean HbA1C in the intervention group was 7.7% (7.4 to 8.1) compared to 8.5% (8.1 to 8.8) in controls. Intervention group participants also improved their compliance with routine foot checks and pneumococcal vaccination by six months and retinal screening by 12 months. However, the intervention’s effects on glycaemic control had disappeared by 12 months. For the within-trial economic analysis, the intervention was dominated by the control condition. This is because six monthly diabetes-related costs in the intervention group were significantly higher than the control group, $5403 versus $2260, p=0.009. Owing to one death, the intervention group also experienced a non-significant decline in health utility, -0.01 (-0.03-0.01), equating to a reduction in QALE of 0.005. The estimated mean annual cost of treating a person with poorly controlled T2DM was $7020. The intervention dominated the control condition in the modelled economic analysis, contributing to cost savings of $3327 and non-significant improvements in QALE (0.2 QALE) and life expectancy (0.3 years). The intervention also dominated the control condition in most sensitivity analyses. When the baseline imbalance in terms past history of stroke was controlled, the intervention remained highly cost-effective at a cost of $4365 per QALY saved. Conclusions: Telephone coaching improves glycaemic control and adherence to complication screening in patients with poorly controlled T2DM. The effects were not sustained in the post-intervention period, therefore strategies that facilitate the maintenance of intervention gains are required to improve long term outcomes. The intervention was not cost effective during the within-trial period, but over 10 years, the intervention’s cost was predicted to be fully recovered through cost savings from the prevention of downstream morbidity. The estimated annual cost of treating a person with T2DM updates former cost estimates that were based on data collected over 10 years ago. Collectively, these results are of major relevance to clinical practice, public health practice and health policy. Findings from this study support the need for a larger, prospective multi-centre trial of telephone coaching to confirm both the clinical and economic benefits prior to their implementation in routine clinical practice.