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Medicine & Health
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(2018) Rasoli Pirozyan, MehdiThesisThe CD8+ T cell responses play a pivotal role in controlling viral replication during HCV infection. HCV evades the immune system by rapid viral evolution affording escape from immune selection pressure including at MHC-I restricted epitopes. However, some CTL epitopes remain conserved well past the time of establishment of chronic infection, implying additional mechanisms immune failure exists. CD8+ T cells exhibiting an exhausted phenotype have been extensively reported during the chronic stage of illness for chronic viral infections, such as HCV and HIV. Additionally, impaired differentiation and trafficking of CD8+ T cells is known to be associated with immune escape and exhaustion of CTLs, but the timing and mechanisms and expression patterns of inhibitory receptors as wells as impairments in differentiation during primary HCV infection remains unclear. HCV-specific CD8+ T cell responses against the transmitted founder virus identified via ELISpot. Immune escape was observed in the NGS data set in ~33% of all ELISpot identified epitopes. The majority of HCV-specific CD8+ responses identified via IFN- ELSPOT in chronic progressors were also characterised by a dominant population of terminally differentiated effector memory cells (CCR7lowCD45ROhighKLRG1highCD127low), and elevated expression of co-inhibitory markers (PD-1 and 2B4) targeting both conserved as well as escaped HCV variants at the peak of immune response (as early as 70-90 days post infection). However, evidence of long-term central memory subpopulations with moderate IFN-γ production was identified in a subset of responses. There was an association of viral escape with the magnitude (IFN- production) of the response, suggesting ongoing evolution of CTLs in response to prolonged viral exposure. Analysis of T-bet expression revealed that T-bet expression on HCV-specific CD8+ T cell was not associated with clearance. Immuno-phenotyping of liver showed that, liver was enriched with T cells expressing the chemokine receptors CCR2, CCR5, CXCR3, and CXCR6. Additionally, the studies revealed preferential expression of CXCR3 on HCV-specific CD8+ T cells in both chronic and acute HCV infection suggesting a key role for CXCR3 in regulation of HCV-specific CD8+ T cell trafficking to the site of infection in the liver. Taken together the studies in this thesis provide both consistent findings with more limited studies in HCV and comparable contexts in HIV, and clear contrasts with previous reports in murine LCMV models. The findings offer novel insights into our understanding of the immunopathgenesis of primary HCV and into HCV vaccine design.
(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.
Using machine learning to understand and improve care and outcomes for patients with head and neck cancer(2023) Kotevski, DamianThesisHead and neck cancer (HNC) is a complex disease with diversity in treatment modality and survival by anatomical site of origin. There is limited knowledge of the utility of oncology information systems (OIS) for the collection and reporting of HNC data during routine clinical practice to investigate prognostic factors and predict head and neck cancer-specific survival (HNCSS). Routinely collected structured data was extracted from an OIS from seven major hospitals in Australia for patients diagnosed with HNC between 2000 and 2017 and treated with definitive radiotherapy. Deaths were obtained from the National Death Index via record linkage, and HNCSS was measured from the date of diagnosis until death from HNC. Open-source machine learning and nomogram models were used to predict HNCSS and perform multivariable analysis to identify prognostic factors. Descriptive and survival analysis was used to identify inter-hospital variation in data collection, primary radiotherapy treatment, and survival. A random sample of clinical radiation oncology documents from an OIS were anonymised using a customised open-source tool (Microsoft Presidio) to evaluate the use of unstructured information for medical research. Not all user-defined fields were routinely completed and not all hospitals relied solely on the OIS, with one hospital collecting disease information in a parallel database. However, structured information collected in a standardised way with minimal missing data during routine clinical practice in an OIS can be used to predict two-year HNCSS with high performance. Evidence of inter-hospital variation in data completeness, primary radiotherapy dose, and five-year HNCSS was detected. The presence of missing data in the OIS reduced the number of predictors for prognostic analysis and prevented exploratory analysis to explain differences in survival by hospital. Lastly, the application of the anonymisation tool on unstructured clinical information sourced from an OIS demonstrated safe and secure use for some fields and a need to improve the detection and removal of person names. Data mining techniques for unstructured data or strategies to improve structured data collection should be explored to enable the development of prediction models using more complete data, patients, and variables, followed by external validation to confirm model performance.