The Development of Health System Resiliency: How Kenya\u27s Experience with Malaria Impacted Its Reaction to the COVID-19 Pandemic

Public health scholars have recently focused on health system resiliency to explain how previous experiences dealing with public health crises impact the healthcare sector, public behavior, and policy response to novel crises. However, it is unclear how resiliency develops. This study contributes by testing whether a health system’s experience with a health emergency and significant interventions impacts the response to a novel crisis. This research asks, “How has Kenya’s experience with malaria impacted its response to COVID-19?” Using the United States Agency for International Development (USAID) Malaria Indicator Survey (MIS), I develop a malaria adherence score to measure county-level compliance with standard malaria prevention protocols. I use publicly available data from the Kenyan Ministry of Health\u27s (MOH) situation reports and the Bureau of Statistics to create cumulative COVID-19 prevalence and vaccination rates for each county. I test the hypothesis that higher malaria adherence scores are associated with higher COVID-19 vaccination uptake in a given community. Controlling for a host of other factors that could explain COVID-19 outcomes, I find mixed evidence in support of the hypothesis. Counties with higher rates of malaria protocol adherence are associated with higher COVID-19 vaccination rates. However, rates of malaria protocol adherence were also associated with higher COVID-19 rates, which challenges the expectation that previous compliance with interventions leads to more resilient health systems. Issues of reverse causality, ecological inference, and incomplete data limit the scope of the findings and are addressed in the discussion

Exploring the impact of heterogeneities on HIV dynamics within host

This thesis is concerned with exploring how cell heterogeneity and drug resistance can cause long term persistence of HIV. We examine models of multiple viral strains to assess the impact of drug resistance on viral persistence and extend our cell heterogeneity models to include multiple strains. Chapter 1 summarises the nature of HIV infection within host. The key barriers to HIV eradication within host and the role of mathematical models to help understand these issues are discussed. In Chapter 2 we analyse models that include cell heterogeneity. We find robust long term viral persistence is possible on therapy and differences in viral load between body compartments explained by cell heterogeneity. The inclusion of a drug sanctuary also allows low level viral load on treatment. Competition and evolutionary models of wildtype and drug resistant strains of virus are described in Chapter 3. We analyse two models containing three strains of virus with different mutation mechanisms. We find that the proportion of the minority strains of virus is determined by the number of mutations away from the dominant strain. In Chapter 4 we extend our cell heterogeneity models from Chapter 2 to include a drug resistant strain of virus. We find that when a drug sanctuary is present coexistence is possible in the absence of an evolutionary mechanism. The two compartment model also shows differential dominance whereby a different strain is dominant in each compartment. within the host. We find the latent cell reservoir acts as an archive for previously dominant viral strains when there is a mechanism for latent cell maintenance and that the balance between ongoing viral and latent cell replication determines the longevity of the archive.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

RNA sequencing of non-coding RNAs in ischaemic heart disease

Ischaemic heart disease is a major cause of death worldwide and a leading cause of mortality and morbidity in New Zealand. Older adults and those of Māori and Pacific ancestry are particularly affected. Ischaemic heart disease accounts for over half of all cardiovascular disease mortality and, again, rates are more than twice as high among Māori than non-Māori. Ischaemic heart disease can lead to myocardial infarction (heart attack) which, if not fatal, can then lead to heart failure, a complex, multifactorial disease characterised by neurohormonal signalling and remodelling of the heart. Currently the natriuretic peptides are the international gold standard for diganosing heart failure and are also excellent prognostic markers in patients with heart failure. However, there is still a clinical need for early biomarkers of myocardial ischaemia (to identify people at risk of myocardial infarction) and to identify patients at risk of developing heart failure before detrimental remodelling has occurred. As sequencing technologies have evolved there has been intense research in the fields of circulating cell free DNA and RNA, especially non-coding RNA. As RNA is actively transcribed, it has the advantage of providing a ‘real time’ insight into the disease status of an individual. Recent discoveries have highlighted the regulatory roles and diseases associated with non-coding RNAs, including long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). LncRNAs have been demonstrated to have mutliple functional roles both within the nucleus and cytoplasm such as chromatin remodelling, histone modification, transcription factor recruitment, formation of subnuclear structures and control of mRNA translation and decay. CircRNA, a relative newcomer, has also been demonstrated to have functional roles such as sequestering miRNAs, binding proteins and even coding for peptides. There is great excitment for the potential utility of circRNAs as biomarkers as, due to their circular structure, they are more resistant to degradation in the circulation than their linear RNA counterparts. The overall aim of this thesis was to identify non-coding RNAs associated with ischaemic heart disease. To address this aim, a bioinformatics pipeline was developed to identify mRNAs, lncRNAs including putative novel lncRNAs, and circRNAs using short-read RNA Sequencing (RNA-Seq) data. This pipeline was tested and validated with publicly available data and used to screen for candidate mRNA and lncRNA biomarkers associated with ischaemic heart disease in human heart tissue. A whole genome network correlation approach identified several promising candidate biomarkers for myocardial ischaemia including several novel lncRNAs, which were validated with long-read Nanopore sequencing in independent samples. The sub-cellular localisation of three promising lncRNAs candidates (two annotated lncRNAs, one novel lncRNA) was identified using the in-situ hybridisation assay, RNAscope®. Next, an RNA-Seq protocol was developed to detect mRNAs, lncRNAs and circRNAs in human plasma. This protocol was applied to plasma from patients with ischaemic heart disease and healthy controls to screen for candidate mRNA, lncRNA and circRNA biomarkers for progression from ischaemic heart disease to heart failure. Although candidate biomarkers for disease progression could not be detected in these patients several additional lncRNA candidates for the presence of ischaemic heart disease were identified. In summary, this study has established a bioinformatics pipeline and methodology for identifying and validating putative novel lncRNAs and circRNAs in human tissue and plasma. This work has identified several promising candidate lncRNA biomarkers for ischaemic heart disease, which, if validated, may provide early diagnostic information in high-risk patients. The pipeline is freely available to download at https://github.com/zoeward-nz/Ph

Health care process modelling: which method when?

Objective The role of process modelling has been widely recognized for effective quality improvement. However, application in health care is somewhat limited since the health care community lacks knowledge about a broad range of methods and their applicability to health care. Therefore, the objectives of this paper are to present a summary description of a limited number of distinct modelling methods and evaluate how health care workers perceive them. Methods Various process modelling methods from several different disciplines were reviewed and characterized. Case studies in three different health care scenarios were carried out to model those processes and evaluate how health care workers perceive the usability and utility of the process models. Results Eight distinct modelling methods were identified and characterized by what the modelling elements in each explicitly represents. Flowcharts, which had been most extensively used by the participants, were most favoured in terms of their usability and utility. However, some alternative methods, although having been used by a much smaller number of participants, were considered to be helpful, specifically in understanding certain aspects of complex processes, e.g. communication diagrams for understanding interactions, swim lane activity diagrams for roles and responsibilities and state transition diagrams for a patient-centred perspective. Discussion We believe that it is important to make the various process modelling methods more easily accessible to health care by providing clear guidelines or computer-based tool support for health care-specific process modelling. These supports can assist health care workers to apply initially unfamiliar, but eventually more effective modelling methods

Evaluating the cost-effectiveness of existing needle and syringe programmes in preventing hepatitis C transmission in people who inject drugs

AIM: To evaluate the cost-effectiveness of needle and syringe programmes (NSPs) compared with no NSPs on hepatitis C virus (HCV) transmission in the United Kingdom. DESIGN: Cost-effectiveness analysis from a National Health Service (NHS)/health-provider perspective, utilizing a dynamic transmission model of HCV infection and disease progression, calibrated using city-specific surveillance and survey data, and primary data collection on NSP costs. The effectiveness of NSPs preventing HCV acquisition was based on empirical evidence. SETTING AND PARTICIPANTS: UK settings with different chronic HCV prevalence among people who inject drugs (PWID): Dundee (26%), Walsall (18%) and Bristol (45%) INTERVENTIONS: Current NSP provision is compared with a counterfactual scenario where NSPs are removed for 10 years and then returned to existing levels with effects collected for 40 years. MEASUREMENTS: HCV infections and cost per quality-adjusted life year (QALY) gained through NSPs over 50 years. FINDINGS: Compared with a willingness-to-pay threshold of £20 000 per QALY gained, NSPs were highly cost-effective over a time-horizon of 50 years and decreased the number of HCV incident infections. The mean incremental cost-effectiveness ratio was cost-saving in Dundee and Bristol, and £596 per QALY gained in Walsall, with 78, 46 and 40% of simulations being cost-saving in each city, respectively, with differences driven by coverage of NSP and HCV prevalence (lowest in Walsall). More than 90% of simulations were cost-effective at the willingness-to-pay threshold. Results were robust to sensitivity analyses, including varying the time-horizon, HCV treatment cost and numbers of HCV treatments per year. CONCLUSIONS: Needle and syringe programmes are a highly effective low-cost intervention to reduce hepatitis C virus transmission, and in some settings they are cost-saving. Needle and syringe programmes are likely to remain cost-effective irrespective of changes in hepatitis C virus treatment cost and scale-up

Lysenin Channels as Sensors for Ions and Molecules

Lysenin is a pore-forming protein extracted from the earthworm Eisenia fetida, which inserts large conductance pores in artificial and natural lipid membranes containing sphingomyelin. Its cytolytic and hemolytic activity is rather indicative of a pore-forming toxin; however, lysenin channels present intricate regulatory features manifested as a reduction in conductance upon exposure to multivalent ions. Lysenin pores also present a large unobstructed channel, which enables the translocation of analytes, such as short DNA and peptide molecules, driven by electrochemical gradients. These important features of lysenin channels provide opportunities for using them as sensors for a large variety of applications. In this respect, this literature review is focused on investigations aimed at the potential use of lysenin channels as analytical tools. The described explorations include interactions with multivalent inorganic and organic cations, analyses on the reversibility of such interactions, insights into the regulation mechanisms of lysenin channels, interactions with purines, stochastic sensing of peptides and DNA molecules, and evidence of molecular translocation. Lysenin channels present themselves as versatile sensing platforms that exploit either intrinsic regulatory features or the changes in ionic currents elicited when molecules thread the conducting pathway, which may be further developed into analytical tools of high specificity and sensitivity or exploited for other scientific biotechnological applications