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(2022) Sandery, BlakeThesisAcute kidney injury (AKI) occurs commonly in hospitalised children and carries an increased risk of morbidity and mortality. This thesis investigates the relationship between AKI and baseline kidney function, as this has not been well explored. We studied children exposed to acyclovir, and children with cancer, as these groups both have an increased risk of AKI. Children with cancer have been shown to have high baseline kidney function, known as glomerular hyperfiltration (GH), which is poorly understood. GH is a glomerular filtration rate above normal, which we define as a measured glomerular filtration rate (NMGFR) ³160mL/min/1.73m2. In a retrospective review of 150 children treated with acyclovir, 27 (18%) developed AKI. The only factor associated with AKI on multivariable analysis in this cohort was higher baseline estimated GFR (p=0.013). We reviewed the records of 202 children who underwent allogeneic haematopoietic stem cell transplant (HSCT) for haematological malignancy. In the first 100 days post-HSCT, 173 (85.6%) children developed AKI and stage 3 AKI occurred in 58 (28.7%). Factors significantly associated with stage 3 AKI on multivariable analysis were use of ciclosporin (vs. tacrolimus) (p=0.02), total body irradiation (p=0.01), early AKI on or before day 10 post-HSCT (p=0.001), ³10% creatinine increase 24 hours after AKI onset (p=0.001), and higher pre-HSCT NMGFR (p=0.03). At 1-year, patients with stage 3 AKI had greater reduction in estimated GFR than other children (-53.9 vs -18.8mL/min/1.73m2; p=0.0002). Analysis of the above cohort combined with the records of 91 children who underwent NMGFR at time of solid organ cancer diagnosis revealed that 16% had GH. GH was more common in young children (p=0.0055) and those with acute myeloid leukaemia (p=0.02), and was associated with higher weight gain (a surrogate for fluid accumulation) post-HSCT (p=0.02). Most children with GH pre-HSCT returned to a normal GFR. Development of GH at 1-year post-HSCT was associated with prior acute GVHD. This research is among the first to demonstrate that GH is associated with an increased risk of AKI. Our results suggest that GH occurring before HSCT may have a different underlying cause to hyperfiltration occurring post-HSCT and warrants further investigation.
(2022) Overton, KristenThesisAddressing antimicrobial resistance (AMR) as a purely medical problem fails to recognise the sociological factors that drive the misuse of antimicrobials. Antimicrobial use is shaped by the local social, cultural, political and economic context. There is now widespread recognition that addressing AMR requires an understanding of the social factors that underpin our use and prescription of antimicrobials. Sociological and anthropological explorations of the global antimicrobial crisis have thus far disproportionately focused on economically wealthier nations. This is despite the recognition of economically poorer nations as sites of considerable, escalating, and often unregulated, antimicrobial use. This thesis examines the social dynamics of antimicrobial use in the Indian context through ethnographic observations and 100 qualitative interviews with doctors, community health practitioners, pharmacists, pharmacy employees and community members in Hyderabad, India. Using a constructivist grounded theory approach to data collection and analysis, the focus is on gaining an understanding of how enduring and emerging inequalities, infective risk and uncertainty, labour risks and precarious work, improvisation and self-medication, and informal and formal pharmaceutical economies shape antimicrobial use in India. Using a critical sociological lens, I explore: the dynamics of biopolitics and risk; the pharmaceuticalisation of everyday life and the vested interests therein; the economies of healthcare and antimicrobial use, including commodification and privatisation; and the vulnerability and structural violence associated with the use of antimicrobials. Knowledge of the social dynamics driving antimicrobial use can then in the future be used to inform policies and programs aimed at optimising antimicrobial use in India, appropriately tailoring them to context, rather than continuing with pan-national approaches that do little to accommodate considerations of the Global South.
Genetics, genomics and precision medicine: Innovations in childhood cancer care through the eyes of families and oncology professionals(2021) McGill, BrittanyThesisThe successful implementation of precision medicine in childhood cancer care, including genomic testing for cancer predisposition syndromes, requires close examination of the experiences of key stakeholders. Taking a multi-perspective, mixed-methods approach, I conducted an in-depth investigation of the experiences of young patients, parents, and oncology professionals in the Australian healthcare context. After presenting a summary of the relevant literature in Chapter 1, I then conducted a systematic review (n=20 studies) of children and young adults’ understanding of, and attitudes towards, clinical genetic testing for hereditary diseases, and highlighted the unique information and support needs of young patients affected by/at risk of genetic conditions (Chapter 2). In Chapter 3, I examined families’ (n=26 parents, n=9 young adults) experiences of cancer-related genetic testing in childhood and identified their unique psychosocial challenges and information needs. In Chapter 4, I documented the challenges experienced by oncology professionals (n=39 clinicians, n=15 scientists) delivering precision medicine for poor prognosis childhood cancer. Finally, in Chapter 5, I examined parents’ (n=177) preferences, expectations and recall regarding clinically relevant germline findings in the context of a precision medicine trial for poor prognosis childhood cancer. The findings of this program of work affirm the need for specialised paediatric precision medicine informational resources and supportive practices, to educate and empower families, including young patients, so that they can experience the benefits of advancing technologies without risk of deleterious psychosocial consequences. The thesis also addresses the potential for the development and evaluation of professional development initiatives to support paediatric oncology professionals in navigating the unique challenges of genomic precision medicine.