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Since discovery H. pylori has been one of the most intensively researched bacteria. Although the majority of those infected remain asymptomatic it can lead to serious diseases which carry significant morbidity and mortality. The most serious complication of H. pylori infection is gastric cancer and one of the most effective ways to reduce the associated mortality is to detect pre-malignant disease, as this develops in a step wise manner. Using advanced endoscopy is one way to detect pre-malignant conditions but due to the variety in endoscopic techniques and mucosal classifications the diagnosis is often dependent on histology. This work aimed to develop simple, accurate classification systems to detect H. pylori associated disease. The sensitivity and specificity of magnification Narrow Band Imaging for detecting H. pylori gastritis was 69% and 67%, intestinal metaplasia 87% and 97% and dysplasia 92% and 98% respectively. H. pylori is also associated with iron deficiency anaemia but the mechanisms remain unclear. In children it has been proposed that H. pylori disrupts iron regulatory mechanisms via the peptide hepcidin but this has not been extensively researched in adults. Serum hepcidin was significantly lower in H. pylori infected anaemic individuals and anaemic individuals without evidence of infection when compared to controls (9-fold, p=0.009 and 5-fold, p < 0.0001 respectively). These results are opposite to data from children, possibly explained by the presence of gastric atrophy. The cellular localisation of ferroportin was different in the H. pylori infected group which could be due to local cytokine production. Gaining a better understanding of this mechanism could aid the development of more targeted investigation and treatment. However, with regards to allergic and autoimmune conditions, there is growing evidence to suggest H. pylori is inversely associated. It is believed that any benefit associated with H. pylori is confined to childhood when the immune system is developing. A significant reduction was seen in IL10+ Tregs (p=0.0029) after successful eradication suggesting the removal of H. pylori may have systemic consequences on the immune system that are still not fully understood. This work has highlighted the use of endoscopic techniques to identify individuals at risk of disease. It has also described the effects of eradication on the immune system which potentially could have implications for individuals with allergic conditions with regards to eradication therapy.

The global disease scape is constantly shifting, influenced by demographic transitions, altering the balance of the burden of infectious and non‐communicable diseases. The epidemiological transitions can be divided into three stages: the first, an increase in infectious disease burden as populations settled, then grew into towns and cities providing conditions for infectious agents to maintain spread; the second transition follows industrialisation, changes in lifestyle, diet and improved sanitation whereby infectious diseases are reduced and non‐communicable disease (NCD) prevalence increases; the third transition describes the re‐emergence of infectious diseases as the AIDS epidemic and other emerging and re‐emerging disease outbreaks lead to an increasing burden of infectious diseases, particularly in developing countries. Analysis of the disease‐scape has been carried out using WHO Global Burden of Disease data and correlation to demographic factors calculated using World Bank Development Indicators. The balance of chronic NCDs and infectious diseases can be represented numerically as the unit rate of infectious to non‐communicable diseases. The rate, which indicates at which end the continuum lies can then be correlated to these demographic development indicators to assess the factors which are influential to the continuum. As the balance of infectious and non‐communicable diseases around the world alters, the focus of the advocacy at the global health level has been examined to assess if the trends follow that of the shifting continuum. This has been carried out through an assessment of the WHO World Health Assembly (WHA) resolutions adopted annually between 1948 and 2013 on the subject of infectious and/or non-communicable diseases. The principle of International health stemmed from the need to contain the international spread of communicable diseases, so it is not surprising that in the first decade of the WHO, 88% of the resolutions adopted for infectious and non‐communicable disease were adopted for infectious diseases. In the latest ten years of the WHO, 72% of the Assembly resolutions for infectious and non‐communicable diseases were focused on infectious diseases; this indicates that while there has been a shift in the balance, the adopted resolutions still focus heavily on infectious diseases. An example of how advocacy can elevate diseases to a higher position on the global health agenda is that of the Neglected Tropical Diseases. Following the Millennium Development Goals, this group of seventeen diseases has been highlighted as being “neglected” in terms of funding, research and political will. A review of the campaign to highlight this shows how global health advocacy can elevate diseases to a prominent position on the global health agenda. With this in mind, the advocacy for a sub‐group of Neglected Zoonotic Diseases has been examined at the WHA level. The results highlight the sporadic nature of support to control these diseases, and that activism for control of some of the major zoonotic diseases remains lacking. Rabies is explored as an example of a disease for which there are recommendations and support at the global level for the control and elimination of the disease, but for which barriers to control exist locally in endemic countries. The advocacy for diseases at the global health level has the possibility to impact the priorities of health care within individual nations. However the advocacy at this level may take time to reflect the changes within the disease‐scape. The impact of such advocacy is also limited by local political will, availability of resources and local cultural implications. Therefore there is a need to ensure that efforts to control diseases are tailored to specific populations and that resources are made available to support the advocacy.

Long-term conditions (LTCs) are a leading cause of morbidity and mortality worldwide. Health behaviours are a component of many self-management regimes. However, adoption of health behaviours for people with LTCs is relatively low. The purpose of this thesis was to explore the role of the future as it influenced the decision to invest in health for people with LTCs. Specifically, I examined the association between the time discount rate and economic insecurity to explore how the future influences health behaviours. In the first empirical chapter, I found that the time discount rate was associated with maintained physical activity participation but not healthy eating or low-risk alcohol consumption in older adults who have at least one LTC. In the second empirical chapter, I found economic insecurity, which is the anxiety produced from an unsafe financial future, was associated with smoking in older women and physical activity in older men. In the final empirical chapter, I explored how health itself may influence perceptions of the future by investigating the effect of a lagged health shock on the time discount rate in a sample of Danish adults. I found positive health shocks were associated with becoming more future-oriented in women at the 90% significance level and more present-oriented in men at the 95% significance level. The findings of this thesis may be used in the development of policy and interventions to support commencement and adherence to self-management regimes for people with LTCs.

In the human gastric mucosa, an inflammatory response stimulated by H. pylori infection can lead to gastric cancer and peptic ulcer disease. Expression of the i1 active variant of Vacuolating Cytotoxin A (VacA) by the colonising bacterial strain has been identified as an independent risk factor for disease. VacA skews the adaptive immune response towards a regulatory phenotype to promote persistent H. pylori colonisation. In H. pylori-infected individuals, regulatory T cells (Tregs), which suppress inflammation through mechanisms including interleukin-10 (IL-10) production, are thought to play a role in protection against extra-gastric diseases such as multiple sclerosis and oesophageal cancer. IL-10 is an immunomodulatory cytokine which is expressed by several immune cell types including regulatory B cells (Bregs), whose role in H. pylori infection is unclear. Blood was donated by uninfected and infected patients, and those who underwent successful eradication of their H. pylori infection. A flow cytometry antibody panel was developed to quantify the relative frequencies of peripheral blood Bregs and Tregs, and investigate differences according to H. pylori status. Mice were also infected with H. pylori to determine VacA i1 versus i2 differences in the induced regulatory B and T cell frequencies. Stool samples were collected from patients to develop a VacA i-region PCR-based diagnostic test. Results showed that compared to during H. pylori infection, the proportion of IL-10-producing Tregs in the peripheral blood of patients declined after successful eradication therapy. A pilot study in mice revealed B lymphocytes to be another important source of IL-10, and the population expanded after H. pylori infection. In a study of H. pylori-positive, H. pylori-negative and H. pylori-eradicated patients, there were no significant differences in peripheral blood Breg or IL-10+ Breg frequencies. Data from an expanded mouse study using blood and spleen showed that VacA variants in a colonising H. pylori strain did not induce differences in Breg or Treg frequencies 9 weeks after wildtype or mutant H. pylori SS1 infection. The H. pylori 16S gene was successfully detected in stool DNA samples and could be used to determine infection status, but the development of a vacA i-region PCR-based typing stool test was unsuccessful. Previous work in the research group has identified how Treg frequencies are associated with H. pylori infection and disease. While Bregs are capable of producing IL-10 after stimulation, their role in H. pylori infection in mice and humans appears to be limited. The consistency of peripheral blood Treg frequencies in patients from their infected state until two years post-eradication is a start to understanding whether H. pylori-induced extra-gastric protection may also be maintained after eradication. While stool remains a promising resource for non-invasively diagnosing H. pylori infection worldwide, there are strong concerns about contamination and reproducibility which are unlikely to be overcome for use in a clinical setting.

Background: After three decades, Human Immunodeficiency Virus (HIV) continues to pose significant threats globally. The efforts to curb the HIV epidemic have required investment in research, with clinical trials being a major focus, to develop HIV prevention, treatment, and cure interventions. A large portion of such research has been undertaken within low income settings, due to the high burden of HIV and the availability of willing volunteers within this setting. HIV research calls for the implementation of ethical research practice which is informed by policy guidelines. However, current policies are largely informed by inputs from high income countries, and lack the voices of those closely involved in research implementation. In order to contribute to ethics policy development in HIV research, it is essential to involve different stakeholders by exploring their experiences/views on the issue. Existing research in this field has mainly explored experience of recruitment and trial conduct, while very little has been done on trial closure, indicating a significant evidence gap worth exploring. This research therefore sought to illuminate, explore and understand the significant issues regarding the care of HIV positive drug trial participants during closure of HIV clinical trials, within a low income setting, specifically, Uganda. Study aim: The study aimed to explore how care is perceived and enacted in HIV drug trial closure in Uganda, by addressing the following specific objectives: 1. From the perspective of research participants and research staff, to explore the views, opinions and understandings of the ethical/legal/moral post-trial obligations in HIV drug trials. 2. From the perspective of research staff, to explore the experiences, practices and processes related to care for HIV drug post-trial participants in a low income setting. 3. From the perspective of research participants, to explore the experiences of care at trial closure. 4. From the perspective of research participants, to explore the experiences of transitioning from HIV research to care/community. Methodology: The study adopted an interpretive-constructivist approach, and employed a social constructivist grounded theory methodology. The study included a total of 21 trial participants and 22 research staff from three different HIV drug trials, in two Ugandan research institutions. In addition, relevant ethical documents were reviewed from two of the included trials. Data collection and analysis followed the principles of grounded theory, with data collection and preliminary analysis being undertaken concurrently, and earlier data informing subsequent data collection. Data collection strategies included individual interviews, focus group discussions, and key informant interviews. Data was collected over a period of 10 months, from October 2014 to August, 2015. NVivo10 software was used to manage the data. Ethical approval was received from the University of Nottingham UK and The AIDS Support Organization (TASO) Uganda, Research Ethics Committees (RECs). The study was registered with the Uganda National Council for Science and Technology (UNCST), as SS 3608. Permission to conduct the research was granted by the respective research institutions, and written informed consent was received from all respondents. Findings: The findings showed that trial closure was often stressful for HIV positive participants in Uganda, and often resulted in negative psychological, socio-economic and health impacts. The negative effects mainly resulted from being stopped from accessing research related health care, which was of a significantly higher quality, and the inability to find alternative care to match the research standards. The main concerns which arose during the transition process of participants from HIV drug trials to usual care facilities include: the loss of the quality care and valued relationships in research, the need to find and link to alternative care facilities, the need to meet the increased financial needs, and worries about the effects/outcomes of research participation. These concerns demanded a range of additional care and supportive strategies from researchers (and other stakeholders). A conceptual model, the model of ‘Facilitated Transition’ was developed, which summarises the findings of this research and provides a diagrammatic representation of the research findings, showing the links and relationships between the different elements. The research established that the transition of HIV positive trial participants from research to usual care facilities is a process, which appears to consist of three overlapping phases. These phases include: The pre-closure phase which represents events occurring before the actual trial closure but that underpin post-trial care, the trial closure phase which is the active phase of the closure, in which trial participants are prepared and exited from the trials, and the post-trial phase which represents the events occurring after trial participants have been linked to post-trial care facilities until 12 months later. These phases are demarcated by specific time points, which reflect how the transition process evolves, proceeds and concludes. At the various phases of the process, specific concerns (care needs) arise, being influenced by the participants’ previous care experiences and perceptions, plus their health and socio-economic positions. Specific actions are required to proactively facilitate trial participants during these phases. These actions are underpinned by the perceived ethical and moral responsibilities of the researchers, and are principally aimed at establishing a continuum of HIV care and treatment after trial closure, promoting positive care experiences for trial participants during the transition, and enabling the settlement and adaptation of trial participants to care in the public healthcare system. Conclusions: This is the first known study to investigate perspectives on post-trial care among HIV positive trial participants in a low income setting, from those closely engaged in the research process. This study has provided novel contributions in the area of HIV research ethics and post-trial care in general. The study has established that trial closure involving HIV positive participants raises significant ethical, moral and practical concerns in the Ugandan context. The findings further demonstrated that current post-trial care practice does not meet all the care needs of the HIV positive trial participants. Existing ethical recommendations on post-trial care place an emphasis on the need to ensure access to trial drugs and provision of trial results, where as less attention is given to other important aspects, as revealed in this research. To meet the post-trial care needs of HIV positive participants in Uganda, a comprehensive trial closure strategy is required. In addition to the already existing aspects of post-trial care, the new strategy should aim to: (i) address the financial needs of trial participants through financial assessment, support and empowerment, (ii) provide practical support during linkage to post-trial care, and (iii) offer post-trial follow-up to monitor and support the participants. Implementing these recommendations may require involvement of various stakeholders, including researchers, ethics authorities, research funders and donors, public healthcare workers, families, trial participants, and the community. Recommendations for future research: Further research is required to ascertain the rates of linkage to care, and to assess the health outcomes of post-trial participants following trial exit. In addition, a study to target the views of other stakeholders, such as the public healthcare facility workers, the family, and ethics authorities on post-trial care may be essential to understand better the ways in which to support HIV positive trial participants in Uganda. Furthermore, a longitudinal prospective study on a larger sample is required to test the model proposed in this research. And finally, there is need to deliberate more on the ethical and moral implications of financial benefits in HIV research involving HIV positive participants in a low income setting.

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The management of breast cancer has changed over the last century, with surgeries becoming less invasive and adjuvant therapies becoming indispensible. Sentinel lymph node biopsies (SLNB) have replaced axillary nodal dissections as a method of staging an axilla in early breast cancer. However, 70% of SLNBs are negative. The aim of this study was to determine if wecould decrease the rate of negative sentinel lymph node biopsies? A retrospective review over a 10 month period was undertaken. Patients undergoing a SLNB and who had a documented negative axillary ultrasound report were included. One hundred and fifty onepatients were eligible for inclusion. Patients’ ultrasound reports and initial biopsy specimen characteristics (ER/PR/Her2-neu, LVI, Grade, Location) were compared to their axillary nodal findings on histology. An ultrasound was able to predict a pathologically negative axilla in 71.6% of patients. Exclusion of micrometastasis increased the negative predictive value to82.8%. If the ultrasound was negative in a histologically positive axilla, it was likely that only 3 or less nodes were involved. Nodal metastasis could not be predicted based on the tumour characteristics that were reported on the initial tumour biopsy specimens(ER/PR/Her2- neu, LVI, Grade, Location). LVI and DCIS on the initial biopsy specimens were poorly correlated with the final histology specimen findings.. The results show that an ultrasound cannot currently replace a SLNB as an accurate means of evaluating an axilla. A clear limitation is the inability to detect micrometastasis, however the role of micrometastasis in axillary staging is diminishing. Ultrasonographic evaluation of the axilla is currently reported in a non-standardised manner. Classification systems do exist, and if applied to current reporting will increase the negative predictive value of ultrasonography. In the future, the combination of improved reporting standards of axillary ultrasounds, as well as the surgical conservatism with regard to the management of micrometastasis and small volume metastasis in the axilla will hopefully reduce the rate of negative SLNB’s.

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