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Developing and testing a framework for using Social Enterprise, Digital Health, and Citizen Engagement to deliver Integrated People-Centered Health Services(2022) Godinho, MyronThesisTo achieve Universal Health Coverage and the United Nations’ Sustainable Development Goals’ by 2030, the World Health Organisation recommended the use of social enterprise, digital technology, and citizen engagement in the delivery of Integrated People-Centered Health Services (IPCHS). We aimed to develop and test a framework for using social enterprise, digital health, and citizen engagement to deliver IPCHS and achieve the WHO strategic vision for 21st-century primary care. We conducted a hermeneutic review of frameworks, models, and theories on social enterprise, digital health, citizen engagement, and IPCHS. This involved multiple iterative cycles of (i) searching and acquisition, followed by (ii) critical analysis and interpretation of literature to assemble arguments and evidence for conceptual relationships. This process identified a set of constructs that we synthesized into a conceptual framework to provide theoretical grounding for an empirical inquiry into how social enterprises use digital technology to engage citizens in co-creating IPCHS. We tested this preliminary framework with two community health alliances (CHAs) in South Western Sydney (SWS), namely the Wollondilly Health Alliance and the Fairfield City Health Alliance (FCHA). Each CHA comprised the local council of the local government area (LGA), the SWS Local Health District, and the SWS Primary Health Network who collaborated to address the health challenges faced by local communities. We developed comparative case studies using a combination of documentary analysis and semi-structured interviews with stakeholders from both CHAs. The reassignment of CHA staff to address the COVID-19 pandemic limited CHA operations and prevented many CHA stakeholders from participating in the case study, possibly introducing selection bias. Nonetheless, findings from the case studies yielded evidence for several of the conceptual relationships between social enterprise, digital health citizen engagement, and IPCHS identified in our initial framework; but also suggested that greater organizational maturity was required for the CHAs to operate as social enterprises. Considering these findings, we revised our initial framework, and then used it to develop a maturity model to suggest how health organizations like CHAs can achieve greater organizational maturity to operate as social enterprises that use digital technology to engage citizens in co-creating IPCHS.
(2022) Okuba, TolesaThesisChild growth failure (CGF) is associated with high morbidity which can predispose children to impaired cognitive development. Despite decades of interventions, a high level of CGF has persisted in Ethiopia. A likely key reason for this situation is the undetermined role of water, sanitation, and hygiene (WASH) on child growth. The overarching aim of this thesis was to examine the effects of WASH on child growth in Ethiopia. Data were extensively analysed from the Ethiopia Demographic and Health Survey (EDHS) from 2000 to 2016, and a systematic review was conducted for the thesis. Logistic regression models were fitted to assess the association of access to household WASH facilities with child growth outcomes. We conducted a systematic review and meta-analysis of WASH interventions, separately, and when combined with nutrition. To estimate trends of CGF, we used adjusted margins of predicted probabilities. Socioeconomic inequalities in CGF were estimated using a concentration curve and indices. Children with access to improved household WASH facilities were 33% less likely to have stunting. Non-randomized controlled trial studies (non-RCTs) showed an effect of WASH interventions alone on height-for-age (HAZ) (Mean difference (MD)= 0.14; 95% CI: 0.08 to 0.21) while RCTs did not. WASH alone of non-RCTs and RCTs that were delivered over 18 to 60 months indicated an effect on HAZ (MD = 0.04; 95% CI: 0.01 to 0.08). RCTs showed an effect on children < 2 years (MD = 0.07; 95% CI: 0.01 to 0.13). WASH combined with nutrition showed an effect on HAZ compared with no intervention (MD = 0.13; 95% CI: 0.08 to 0.17) and on weight-for-age (WAZ) (MD = 0.09; 95% CI: 0.05 to 0.13). There was evidence of a decline in levels of CGF between 2000 and 2016 in Ethiopia. In particular, there was a greater steady decline between 2005 and 2011 compared with other periods. Access to improved household WASH facilities mainly contributed to the reduction of CGF. Between 2000 and 2016, the concentration index increased from -0.072 to -0.139 for stunting, -0.088 to -0.131 for underweight and -0.015 to -0.050 for wasting. Key socioeconomic predictors of these inequalities were identified through decomposition analyses. Socioeconomic status of the household, geographic region, antenatal care (ANC), parental education and access to household WASH facilities largely contributed to the inequalities. Access to improved household WASH facilities was strongly associated with reduced odds of stunting. WASH interventions alone improved HAZ when delivered over 18 to 60 months and in the first 1000 days of a child’s life. The effect was stronger when WASH was combined with nutrition interventions. Integrated WASH with nutrition interventions may be an effective way of improving child growth outcomes. Improving identified predictors of socioeconomic status would most likely reduce inequalities in CGF.
(2020) Khan, MahjabeenThesisPseudomonas aeruginosa causes both contact lens and non-contact lens-related keratitis (corneal infection). This opportunistic bacterium naturally has the ability to resist the mechanism of action of many antibiotics which are used for treatment. P. aeruginosa resistance patterns and the mechanism of resistance in isolates from keratitis are not well understood. This thesis described the phenotypic and genotypic patterns of antimicrobial resistance and compared these between ocular isolates of P. aeruginosa from Australia (contact lens) and India (non-contact lens). Changes in the antimicrobial susceptibility between isolates over time were also analysed. Susceptibility to antibiotics, multipurpose disinfecting solutions and disinfectants was analysed for twenty-seven Australian isolates from contact lens-related keratitis and forty non-contact lens-related isolated from India. The whole genomes of fourteen Australian (historical and recent) and twelve Indian isolates were sequenced using Illumina® MiSeq®. Computational analysis of the genomes was performed to analyse their core and pan genomes and these were examined for the presence of acquired resistance genes, virulence genes, gene mutations, and these compared to their phenotypic resistance to antibiotics. Indian isolates possessed large pan genomes with more acquired resistance (30) genes and larger numbers of genetic variations. The Indian isolates contained clones of three sequence types ST308, ST316 and ST491, whereas Australian isolates contained only one sequence type ST233. Isolates with larger gene variations had mutations in the DNA mismatch repair system. Most multi-drug resistant Indian (non-contact lens) isolates were exoU +. Indian isolates had large accessory genes compared to Australian isolates and this increased the pan genome size of the Indian isolates. The number of core genome mutations were larger in the Indian isolates a median of 50006 (IQR=26967-50600) compared to Australian isolates a median of 26317 (IQR=25681-33780). There were differences between isolates from Australia and India with respect to their antibiotic resistance and associated genes. Indian strains had more genetic diversity and were multi-drug resistant. However, there was no evidence of substantial genetic or phenotypic changes within isolates from their respective countries.
Sodium glucose cotransporter 2 inhibition to improve outcomes in type 2 diabetes and chronic kidney disease(2022) Neuen, BrendonThesisType 2 diabetes is a major global health issue. It is projected that by 2045, 783 million people worldwide will be living with diabetes, making it one of the leading contributors to premature death globally. Approximately 30 to 40% of individuals with diabetes develop chronic kidney disease (CKD), making diabetes the leading cause of CKD worldwide. Despite glucose, blood pressure and lipid lowering, and treatment with renin-angiotensin system (RAS) blockade, the risk of cardiovascular events, kidney failure and death remains high for millions of people with diabetes and CKD worldwide. Originally developed to lower blood glucose, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to have favourable effects on multiple metabolic risk factors including blood pressure, glucose, body weight and albuminuria. Large, randomized trials, including those reported herein, have demonstrated the capacity of these agents to reduce the risk of cardiovascular events, kidney failure and extend survival in increasingly diverse populations, including those without diabetes. This doctorate aims to evaluate the efficacy and safety of SGLT2 inhibitors in people with type 2 diabetes and CKD. Chapter 1 introduces the doctorate, summarizing the epidemiology of type 2 diabetes and CKD, as well as traditional approaches to improving outcomes in this population and the potential role for SGLT2 inhibition in people with diabetes. Chapter 2 provides an overview of SGLT2 inhibitors, practical considerations and evidence for their use in people with type 2 diabetes from cardiovascular outcome trials. Chapters 3 to 5 assess the efficacy and safety of the SGLT2 inhibitor, canagliflozin, across different levels of kidney function, defined by estimated glomerular filtration rate (eGFR) and albuminuria, using data from the CANVAS Program. Whilst the relative effects of canagliflozin on cardiovascular and kidney outcomes are consistent across different levels of eGFR and albuminuria, absolute risk reductions are largest for individuals with severely increased albuminuria. Further, the Kidney Disease Improving Global Outcomes classification of CKD, which combines eGFR and albuminuria to risk stratify individuals, can accurately identify those who are likely to derive the greatest absolute benefits with treatment. In Chapter 6, the results of a systematic review and meta-analysis are presented, which demonstrate that for people with type 2 diabetes, SGLT2 inhibitors substantially reduce the risk of the most important patient-centred kidney outcome – the need for dialysis, kidney transplantation or death due to kidney disease – and provide protection against acute kidney injury. The results of a meta-analysis are presented in Chapter 7, indicating that the benefits of SGLT2 inhibitors are similar with and without metformin, which is widely recommended as first-line glucose lowering therapy in type 2 diabetes. In Chapter 8, an individual participant data meta-analysis demonstrated that SGLT2 inhibitors reduce the risk of serious hyperkalaemia in people with type 2 diabetes at high cardiovascular risk and/or with CKD, which may enable better use of RAS blockade and mineralocorticoid receptor antagonists to improve cardiorenal outcomes. Chapter 9 explores questions about this class of agent that remain to be answered by ongoing randomized trials, and how SGLT2 inhibitors and other kidney protective therapies might be used for people with CKD in the future. Taken together, the findings of this doctorate provide compelling evidence that SGLT2 inhibitors should be routinely offered to individual with type 2 diabetes to safely reduce the risk of major kidney outcomes and cardiovascular events.
(2020) Rowlands, BenjaminThesisSirtuins (SIRTs) comprise a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, capable of affecting health-span and DNA expression. In cell-culture and peripheral-tissue models, researchers have identified that SIRT1 and SIRT2 are also capable of changing enzymatic activity in glycolysis and Krebs cycle. In brain, the impact of SIRT1 and SIRT2 deacetylase activity on metabolism is poorly understood. The aim of this project was to determine if metabolic pathways in brain could be regulated by SIRT1 and SIRT2-mediated deacetylation in mammalian systems. An established ex vivo reductionist model of brain metabolism was used to test the hypothesis that direct inhibition, activation or ablation of SIRT1 or SIRT2 deacetylase activity would result in significant changes in brain metabolism. Alterations in brain metabolism were assessed by examining changes in 13C-enriched substrates, and metabolite pools with 13C and 1H nuclear magnetic resonance spectroscopy. Chapter three provides evidence that approximately 30% of the GABA synthesized from [1,2-13C]acetate was made directly in neurons. Activation of neuronal specific SIRT1 caused an increase in the incorporation of [1,2-13C]acetate into brain, while activation of astrocytes with potassium depolarization caused a decrease in [1,2-13C]acetate incorporation. These results indicate that acetate is not a reliable marker, nor exclusively metabolised in astrocytes. Further, brain metabolism of acetate is modulated through enzyme acetylation regulated by SIRT1 deacetylase activity. Results in chapter four posit that activation of SIRT1 with SRT 1720 directly stimulated incorporation of 13C into Krebs cycle intermediates and reduced incorporation into lactate. Several off-target effects were observed for SIRT1 activator resveratrol and SIRT1 inhibitory EX-527 that questions their suitability for study of SIRT1 activity. Chapter five concludes that inhibition of SIRT deacetylase activity by AGK2 produced an effect consistent with glutamatergic AMPA receptor activation, in keeping with known SIRT2 targets. Potent SIRT2 inhibitor C64 increased 13C label incorporation into GABA from [1-13C]D-glucose in guinea pigs, and glutamine from [1,2-13C]acetate in WT mice, an effect that was also observed in SIRT2 KO mice. These results indicate that SIRT2 deacetylase activity may impact neurotransmitter systems. This thesis supports the theory that SIRT1 and SIRT2 deacetylase activity can influence brain metabolism in mammalian systems.