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Background: Colorectal, lung, breast, and prostate cancers are the most common cancers in England. Cancer prognosis and cancer survival are widely used performance measures of cancer care. Patient experience is a key aspect of healthcare quality and widely considered as the third pillar of healthcare quality alongside patient safety and clinical effectiveness. Improving cancer patients' experiences and their subsequent survival were emphasised in the recent cancer care strategies in England. Previous research has identified sociodemographic variation in cancer patients' experiences in England. An important but as yet unanswered question is whether the variation seen in cancer patients' experiences is also associated with their subsequent survival. Aims: This PhD thesis consists of five projects: Project 1: A systematic review to examine how patients' experiences have been linked to survival. Project 2: A population-based case control study to assess the representativeness of Cancer Patient Experience Survey (CPES) responders. Project 3: A cross sectional study to assess how Clinical Nurse Specialists (CNS) influence patients' experiences with cancer care. Project 4: A systematic review to assess what factors influence cancer patients' experiences. Project 5: A population-based cohort study to assess the association between patients' experiences with CNS care and their subsequent survival. Methods : I used a mixture of different analyses to carry out the five projects in this thesis. Two systematic reviews were carried out for projects 1 and 5. The rest of the thesis analyses focused on colorectal, lung, breast and prostate cancer patients responding to CPES during 2010-2014 using the linked NCRAS-CPES at Public Health England. I assessed the representativeness of CPES using a population-based case-control design and assessed the role of CNS in cancer care using a population-based cross-sectional study. In the final project, I conducted a population-based cohort study to assess the association between cancer patients' experiences with CNS and their subsequent survival. Results : Project 1: systematic review. This review included 16 studies and showed that satisfaction with care and psychosocial support were the aspects of experience associated with survival. Positive, negative or no association between experience and survival were reported across the studies included in the review. Project 2: representativeness of CPES responders. Compared with controls, CPES responders across all cancers were found to be younger, more likely to have a White ethnic background, to be resident in less deprived areas and diagnosed with earlier stage disease. Median survival for responders was also higher for the CPES responders than the general cancer population across all cancers. Project 3: role of CNS in patients' experiences. Across all cancer types, patients who reported being given the name of a CNS reported better experiences across several aspects of care. Experiences of being involved in treatment decisions was most strongly associated with reporting being given a CNS name across all cancers. Project 4: factors influencing patients' experiences. This review included 38 studies from several countries and showed that there are several factors affecting cancer patients' experiences at patient, disease, and healthcare system levels. Cancer type, prognosis, and patients' demographic characteristics were consistently linked with variation in patients' experiences across many countries. Project 5: patients' experiences with CNS and their subsequent survival. Overall, there was variation in cancer patients' survival in relation to their reported communication experiences with CNS. Among the three compared groups (excellent experience, non-excellent experience, and no CNS name given), patients who reported not being given a CNS name had the worst survival. In the adjusted Cox regression analysis, the results show that among those who reported not being given a CNS name, the highest risk of death was in those with colorectal, breast and prostate cancers only (colorectal HR: 1.40; 95% CI: 1.32-1.84; breast HR: 1.34; 95% CI: 1.25-1.44; prostate HR: 1.09; 95% CI: 0.99-1.13). However, this association seemed to disappear among lung cancer patients when accounting for cofounders. The possibility that reverse causation might have explained this finding was considered where possible. Conclusion: This thesis has established new knowledge by assessing the literature that has explored the associations between cancer patients' experiences and their subsequent survival. It has also highlighted the complexity of such a relationship and discussed the appropriate theoretical and methodological approach to assess it. Findings from this thesis on the importance of CNS in improving cancer patients' experiences and the factors affecting these are important for cancer charities, patient representatives and health professionals and managers using CPES findings to assess and improve care, as well policy makers. This thesis also established methodological approaches that might be useful for future research on patient experience in cancer care settings.

Timely diagnosis of a brain tumour is an important aspect of health care provision. There are no known risk factors for brain tumours in the majority of patients and most brain tumours are diagnosed following symptomatic presentation. The nature of presenting symptoms is critical to the speed of diagnosis. Understanding how symptoms are associated with the length of diagnostic time and its prognostic effect is a priority for early diagnosis research which could inform strategies to achieve an earlier detection of brain cancer. This thesis focuses on four key aspects in the diagnosis, namely 1) assessing the usefulness of existing primary care referral guidelines for an urgent brain imaging; 2) describing clinical and diagnostic pathway of adult patients with any type of brain tumour prior to a diagnosis; 3) assessing the association between presenting symptoms and diagnostic intervals and their impact on clinical care and survival in patients with the most malignant brain tumour, and lastly 4) assessing the value of a brief cognitive assessment in identifying which symptomatic patients are most likely to have a brain tumour. In the first study, a total of 3257 referrals for direct-access CT (DACT) head imaging were retrospectively identified. Diagnostic yield for a brain tumour was 1.8% (N=53 scans). There were no false negative scans. Referral symptoms were categorised based on Kernick's symptom classification and NICE 2005 referral guidelines. Only referrals for "symptoms related to the CNS" achieved positive predictive value (PPV) of 3%. Nearly 80% of patients whose CT revealed a brain tumour had symptoms grouped under the "symptom related to the CNS" category. A large proportion of referrals were for a 'simple' headache (27%) but few of these patients had a tumour. Improving guidelines to better identify patients at risk of a brain tumour should be a priority, to improve speed of diagnosis and reduce unnecessary imaging and costs. However, as I explore, this will not be not straight forward, in particular because of the lack of specificity of symptoms associated with a brain tumour. The second prospective study included 180 patients with a heterogenous range of brain tumour types where I describe the clinical and diagnostic pathway to diagnosis. Patients symptoms were grouped as episodic attacks of consciousness (seizure), alarm or vague symptoms, and were recorded temporally along the patient's diagnostic journey, occurring as first, second or at any point before the diagnosis. Vague, non-specific symptoms, were the most common symptoms across the pathway and were associated with increased diagnostic interval compared to episodic attacks of consciousness (seizure) (median 96 days vs 22 days, respectively, adjusted odds ratio 3.0, 95%CI 1.2-7.9) and a higher likelihood of more than 3 GP visits prior to a diagnosis (aOR 5.6, 95%CI 1.2-26.1). Interestingly, over half of patients with a seizure resulting in emergency admission actually reported initial vague non-specific symptoms. In a third study, 354 patients with a high-grade glioma were retrospectively identified from local multi-disciplinary team minutes between July 2010 and March 2015. Data on primary symptoms and time to diagnosis were corroborated by contacting deceased patients' General Practitioners. Type of presenting symptoms was associated with diagnostic timeliness and overall survival. Multivariate models showed that development of cognitive symptom was an independent adverse predictor for 12-month survival (multivariate HR 1.8, 95%TCI 1.2-2.6) but was not associated with the type of surgery performed (ie biopsy versus debulking). Earlier diagnosis did not have an impact on survival. Finally, in a proof of concept study, performance on a 1-minute semantic and phonemic verbal fluency (VF) test was significantly poorer in patients with a brain tumour (n=180) compared with patients referred from primary care for brain imaging, but without a brain tumour (n=90). The biggest difference in scores between the groups was observed for semantic total VF scores compared to phonemic total VF scores (Cohen's d = -0.97 and -0.47, respectively). A score of 14 animals on SVF test was associated with an 84% sensitivity and 54% specificity for not having a brain tumour (AUC 0.75 p<0.001). Conclusion: Vague symptoms due to a brain tumour are under-recognised while existing referrals guidelines lack sensitivity. Patients with vague symptoms pose the most diagnostic challenge, particularly in primary care, but who may benefit from an earlier cancer detection most. Active screening for cognitive deficits by performing semantic verbal fluency task could potentially help a physician in risk assessment for urgent referral for head imaging/hospital assessment in suspicious cases.

India harbours the world's largest burden of tuberculosis, with approximately 27% of the estimated global burden. Although considerable measures have been taken since the roll-out of the End TB strategy, in 2015, to increase case detection and improve treatment quality, the overall quality of care remains poor and estimates on incidence remain highly uncertain, because of the poor notification rates, especially from the private healthcare sector, where nearly half of all individuals seek care. In 2017, India's National Strategic Plan for Tuberculosis Elimination brought forward extremely ambitious targets of an 80% reduction in incidence by 2025. The first step of the plan proposes a scale-up of case-detection through active case-finding, in order to increase case notification rates and reduce the diagnostic and treatment initiation delays, often associated with tuberculosis care. The evidence for the value of active case-finding interventions for tuberculosis, however, is mixed and highlights a substantial geographical imbalance of studies. A recent systematic review has encouraged the implementation of targeted active case-finding interventions, suggesting these may have an important effect on the prevalence of disease. Despite this, there remains some scepticism around these interventions, which can be costly and difficult to implement on a large scale, and because of the diverse number of factors that can affect their impact. This thesis aims to investigate the value of routine active case-finding interventions in high-burden settings, implemented using available tools for screening and diagnosis. Epidemiological data is used in the development of the mathematical models used in the analyses, and costing information is included to allow an estimation of the financial implications of this undertaking.

Background: Expressing end of life care wishes and preferences is a vital component of Advance Care Planning (ACP) which facilitates the provision of end of life care that is consistent with the patient's expressed values, beliefs and goals of care outcomes. There is an acknowledgement of the impact of contextual values on the process of expressing wishes and preferences. Aim: The aim of this study is to a gain a theoretical understanding of the process involved in expressing end of life care wishes and preferences based on the perspectives and experiences of advanced cancer patients and their family carers in Nigeria. Methods: Using a constructivist grounded theory study approach, fourteen qualitative interviews from eight patients with advanced cancer and six family members of patients with advanced cancer were analysed to construct a theoretical model that explains the process of expressing end of life care wishes and preferences in Nigeria. Results: "Rubbing minds together" explains a process by which patients with advanced cancer negotiate their way with their family members to facilitate expressing their end of life care wishes and preferences in the context of a cultural commitment to familial involvement in end of life decision making. The theory is composed of three interlinked components: controlling to seek relief, enduring and collaboration that acknowledges the ongoing overt and hidden compromises that occur in the end of life care communication in this context. Conclusion: This constructed theory emphasises the relational nature of end of life care communication in the African cancer context. This may increase healthcare professionals' understanding and be crucial to achieving an end of life care context that acknowledges and encourages family members' involvement and not only that of the patients, thereby enhancing end of life communication with Africans nearing the end of life.

Head and neck squamous cell carcinoma (HNSCC) is a significant public health problem worldwide due to its high mortality and morbidity. A notable proportion of HNSCC, particularly oral squamous cell carcinoma (OSCC), is preceded by several long-standing chronic oral mucosal diseases including oral lichen planus (OLP). However, it remains largely unknown regarding the impact of a pre-existing OLP upon the prognosis and behaviour of OSCC and its precursor, oral epithelial dysplasia (OED). Therefore, this PhD thesis has sought to determine the influence of OLP on the long-term behaviour and prognosis of oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) using data from a single UK tertiary care centre. Additionally, this thesis has made the first steps towards providing understanding of the epidemiology of HNSCC in a representative sample with common chronic oral mucosal conditions including oral lichen planus, oral submucous fibrosis, leukoplakia and periodontal diseases of the UK population. A retrospective cohort study of 299 patients with OED revealed that individuals with OED arising on a background of OLP appeared to be at higher risk of developing new primary OEDs up to 3 years (in the early years) after the first diagnosis of OED compared to those without OLP. However, the risk of malignant progression was similar between the two groups. This thesis built on these findings by investigating the impact of OLP in determining the long-term behaviour and prognosis of OSCC using a retrospective cohort study of 285 patients with OSCC. The results indicated that patients with OSCC-associated OLP were more likely to develop multiple and multifocal new primary dysplastic and OSCC events following their first oral malignancy. Despite this, there seems to be no significant association between OLP and mortality. In order to reveal more about the relationship between long-standing oral mucosal conditions and HNSCC using national-scale data, this thesis went beyond single data sources. This project provides a detailed method for appropriate data handling and curation of a linked national database of a UK population (the CALIBER platform). This allowed the development and validation of a reliable phenotype algorithm to identify patients with HNSCC from this data platform. Taken together, these findings advance understanding of the impact of OLP on the behaviour and prognosis of OED and OSCC. In addition, the HSNCC phenotype algorithm developed here represents an important step towards understanding the association between common chronic oral mucosal conditions and HNSCC in the UK.

Background: Tuberculosis is a growing public health problem and one of the major causes of death globally, killing close to 1.5 million people each year and infecting another 10.4 million, particularly in settings with weak health systems. The best way to cut TB transmission is to identify infectious TB cases early, in order to diagnose and treat them effectively. To overcome the growing TB challenge, global control efforts have shifted from disease burden reduction to eradication, with the gradual introduction of robust diagnostic technologies in high TB burden countries (HBCs), including fragile states. One such technique was the light-emitting diode fluorescence microscopy (LED). However, empirical evidence linking LED with feasibility and acceptability for regular utilization in fragile states appeared lacking. Aim: The primary aim of this study was to help improve access to good quality care (diagnosis and treatment) for TB patients in fragile states, specifically in the north-west of Somalia (Somaliland) which had introduced and implemented LED technology for regular TB testing at primary care facilities as a pilot intervention. Methods: The study utilised a theory-informed mixed method approach for data collection and analysis and included systematic literature review, analysis of routine data, key informant interviews and facility observations. Findings: The literature review revealed a weak relationship between LED technology usage and increased TB case detection in resource-poor and fragile health system settings, but otherwise little evidence of feasibility and acceptability. The analysis of routine data on LED implementation and use found no difference in the proportion of patients with negative and positive outcomes between LED and the traditional ZN technology. Iinterviews with facility staff found health workers' attitudes, perceptions and opinions on LED use generally positive. However, staff attitudes were largely negative toward the future introduction and implementation of new technologies for routine utilisation without improving the systematic and programmatic readiness of the existing health system. Interviews with policy-makers identified serious resource, structural and environmental constraints to the feasibility of LED use in fragile health systems. Conclusion: This study is the first of its kind in a fragile state to assess the feasibility and acceptability of LED, and shed light on constraints to both feasibility and acceptability of new technologies such as LED. The findings of this study add to an existing body of knowledge from other settings related to the diagnostic performance and operational feasibility of LED as a diagnostic strategy to improve patient access to quality TB diagnosis.

The aim of this PhD was to understand the long-term issues and supportive care needs experienced by teenage and young adult (TYA) childhood brain tumour survivors and their caregivers. A systematic review of the literature identified social issues (e.g. isolation) were most reported by survivors, followed by cognitive (e.g. impaired memory) and physical issues (e.g. endocrine dysfunctions). Caregivers reported uncertainty, increased responsibilities, and problems maintaining their own self-well-being and relationships. Few studies in the review addressed unmet supportive care needs. Following the review findings, a convergent mixed methods study was designed to understand the supportive care needs experienced by TYA childhood brain tumour survivors and their caregivers. A quantitative phase using a cross-sectional survey and a qualitative phase using semi-structured interviews was conducted, and the results of these two phases integrated. Participants included childhood brain tumour survivors, at least five years from diagnosis, currently aged 13-30 and their primary caregivers. 112 participants (69 survivors/43 caregivers) completed the survey and 22 face-to-face semi-structured interviews were conducted (11 survivors/11 caregivers). The integrated findings indicate that both survivors and caregivers have unmet needs many years after diagnosis. Survivors were faced with wanting to achieve key milestones as they move into young adulthood, but late effects of treatment often made this difficult. Survivors specifically had high unmet needs in relation to their psychological health, social lives (including romantic relationships), employment, and independence. Whilst caregivers had unmet needs regarding their own psychological well-being and survivor financial issues. Survivors further from diagnosis, unemployed survivors and single caregivers were more likely to report unmet needs. Currently there are barriers preventing survivors and caregivers accessing supportive services. This thesis provides leads to improving supportive care and long-term follow-up services. Understanding unmet needs and recognising what services are required is critical to improving survivor and caregiver quality of long-term survival.

Background: Cervical cancer has always been a significant public health issue, mostly in developing countries. The low attendance to screening programs has been evidenced to increase among the rural community due to lack of knowledge. Method: The research was divided into two different studies and adopted a mixed-method research approach. Study 1 assessed the awareness/knowledge and health beliefs of rural women regarding cervical cancer and its impact on screening participation using the Health Belief Model as a theoretical framework. About 436 rural women ≥18 years completed the questionnaire. Study 2 assessed the perception of relevant implementation strategy among health stakeholders, of which 22 of them were recruited and interviewed. Participants involved in both studies were recruited from Imo State, South-East Nigeria. Results: SPSS v.20 was used for study 1 analysis. Findings showed that the awareness of cervical cancer has a significant impact on screening participation. Also, >50% of the women lack knowledge of cervical cancer and believe they are less susceptible to the disease but perceive the disease outcome as highly severe. The main identified barriers to screening were, lack of money (86%), lack of information/awareness (85.8%), screening location is far (74.5%), and lack of knowledge of where screening is done (61.7%). Study 2 adopted thematic analysis using the NVivo software. Strategies to improve awareness have not been effective in reducing cervical cancer disease or increasing screening participation among rural women in Imo State, Nigeria. Conclusion: This research suggests better ways of increasing the awareness/knowledge of cervical cancer and screening among the target population. The benefits of screening ought to be routinely discussed, and policies tailored to women's needs mostly at the community level need to be drafted.

Background: People who die from cancer (cancer decedents) frequently attend unscheduled care; little is known about what factors influence these presentations. Most research focuses on Accident & Emergency (A&E) and does not consider GP Out-of-hours (GPOOH) services. Aim:  Describe demographic, clinical, temporal and prescribing factors that are associated with unscheduled care use by cancer decedents in their last year of life. Design and Setting: Retrospective cohort study of all 2,443 cancer decedents in Tayside, Scotland. Clinical, demographic, cancer registry and prescribing datasets were linked to routinely collected clinical data using the Community Health Index number. Method: Anonymised linked data were analysed in SafeHaven. Analysis was descriptive, with binary logistic regression and GEE Analysis used to examine adjusted associations for demographic and clinical factors in patient-level and attendance-level analyses respectively, and Poisson regression used to test associations between prescribing and unscheduled care use. Results: 77.9% of cancer decedents attended unscheduled care in the year before death. Most only attended GPOOH (n=1,070;56.2%), with the rest attending A&E only (n=204, 10.7%), or both (n=630, 33.1%). Age, gender, deprivation and cancer type were not significantly associated unscheduled care attendance. People living rurally were less likely to attend unscheduled care (AOR=0.64(0.50 to 0.82)). Pain was the commonest clinical reason for presenting (GPOOH:10.5%, A&E:28.8%). 21% of people dying from cancer were frequent (≥5 attendances/year) users and accounted for over half (57.7%) of unscheduled care attendances. Many attendances occurred in the last week (19.7%), four weeks (36.7%) and twelve weeks (60.3%) of life. Prescribing of palliative care medications increased towards the end of life. Eight in ten cancer decedents were prescribed opioids; however, only two-thirds were co-prescribed laxatives or anti-emetics, and only one in ten were prescribed breakthrough medication. Cancer decedents who attended unscheduled care received more prescriptions per person in all drug categories, compared to those who did not attend unscheduled care. Frequent and very frequent attenders received more than double the number of prescriptions per person for every drug category, compared to non-attenders. Multiple demographic factors, cancer type, and timing of diagnosis, influenced whether or not cancer decedents were prescribed particular drugs or drug categories in their last year of life. Conclusion: Unscheduled care attendance by cancer decedents was substantially higher than previously reported, increased dramatically towards the end of life, was largely independent of demographic factors and cancer type, and was commonly for pain and other palliative care symptoms. Most cancer decedents seen in unscheduled care were close to their date of death. Prescribing in the last year of life was associated with demographic, cancer type and temporal factors, and was associated with type and frequency of unscheduled care use.

Cancer diagnosis and treatment are a stressful experience for a patient of any age. However, compared to younger children or adults, adolescents and young adults (AYA) are a distinct group of patients with unique challenges due to their developmental period. Literature suggests that up to a third of AYA patients may be at risk for developing psychopathology. While there is an increasing interest in studying psychosocial outcomes in AYAs, little is understood about the mechanisms of psychosocial wellbeing in this population. This thesis uses a variety of research methods to examine factors associated with resilience and psychopathology in youth living with cancer and beyond cancer and aims to identify intervention targets to promote holistic recovery of young people with cancer. Because psychosocial oncology is a young and rapidly evolving field, I begin by a short overview of some of the methodological challenges I faced in my research. In particular, I wanted to address the issue of not using cancer-specific questionnaires, and lack of longitudinal and data-driven approaches. To this end, I have innovatively used a mixed-methods approach to explore how individual, as well as socio-environmental factors are associated with psychological outcomes in young patients and survivors. I begin by a systematic review of the literature, which provides an insight into the prevalence rates of psychopathology and identifies some of the risk factors for psychiatric disorders. Subsequently, I present qualitative analysis of in-depth interviews about life with and beyond cancer. For my third study, I developed an online survey to collect information about psychological wellbeing, including cancer-specific questionnaires. Using this data, I employed network analysis to explore if any symptoms of psychopathology and cancer worries are particularly salient and contribute more to the overall symptomatology than the rest. Lastly, I conclude with a longitudinal analysis of a clinical dataset in Canada, where I explored psychological wellbeing and its relationship with fatigue, a commonly endorsed symptom. Due to the global pandemic COVID-19 and its consequent disruption, I complemented my online survey with an auxiliary study that explored the impact of the pandemic on the wellbeing of young people with cancer who were considered at risk for infections. Together, the research presented in this thesis contributes evidence to support that a subset of young people with cancer report psychopathology, and those at risk may be particularly vulnerable in the times of distress, such as the global pandemic. However, psychopathology may result from vastly different, individually led modifiable pathways, which can be addressed with a more personalized approach to care in the future. Psychosocial adaptation to cancer in young people is a complex process with many factors at play. This thesis begins to uncover a few, introduces innovative methods to counteract the existing mythological pitfalls and concludes by proposing future directions for strengthening research in psychosocial oncology and reducing the inequalities of outcomes in young people with cancer.

Amongst patients with incurable cancer, many will experience unintentional weight loss, loss of appetite and a range of symptoms that adversely affect the ability to eat and drink. This thesis explores the role of diet and nutrition in the palliative phase of cancer care as perceived by patients and their carers and the healthcare professionals involved in providing support. The work sought to explore the views on the role of diet before cancer and once diagnosed, the experience and identification of diet-related issues, what mattered and why and the suitability and adoption of management strategies. To explore the issues and complexities, a qualitative approach using case study methodology was considered the most appropriate. Semi-structured interviews were the primary source of data with secondary sources including medical records, policies, training and resources. Interviews and data collected was thematically analysed. Patients with incurable cancer, deemed palliative, were purposively sampled to include a variety of cancer types likely to experience diet-related issues. Each patient was asked to nominate a family member or friend, and two healthcare professionals who had been, or were involved in their care, to participate in the study. Four patients, three carers and seven healthcare professionals participated. Patients had the following cancers: melanoma with brain secondaries; head and neck with lung secondaries; pancreatic cancer; lung cancer with liver metastases. Several overarching themes were identified which included: the complexity of diet, cancer and symptoms; disruption and distortion: the altered meaning of food and preservation of self; identification of what mattered through nutrition conversations and observations; strategies to deal with diet-related issues including adaptations, adjustment, acceptance of a new norm; facilitators of nutritional care including knowledge acquisition, culture and environment. The findings have offered new insights into the identification and management of diet-related issues, weight loss and cachexia in advanced cancer and been used to develop a framework for training and clinical practice. It is hoped dissemination of the findings will assist in shaping strategies to improve nutritional care and provide advice for the growing numbers of patients receiving palliative care.

BACKGROUND: Vascular Access Devices (VAD) are essential for the delivery of intravenous therapies. As patients often live with these devices in place for many months, it is important to understand how patients with cancer make sense of living with these devices. AIM: To explore, in-depth, the lived experience of patients with a Vascular Access Device (VAD). DESIGN/METHODS: This study followed a qualitative approach using Interpretive Phenomenological Analysis (IPA) principles. A purposive sampling technique was used to identify eleven patients with cancer who had a vascular access device in situ and were willing to share their experiences. Semi-structured interviews were the data collection tool. Interviews were digitally recorded, transcribed, and analysed using IPA principles. FINDINGS: Four superordinate themes emerged from the interview data: The self under attack; Being rescued/Being robbed; Protection of self/Protection of others; and Bewilderment and dismay at the lack of staff competence. The study discovered that the insertion of a long-term VAD changes the self and affects the psychological, social, and personal self and impacts on self-esteem and self-image. The insertion of a VAD results in restrictions and limitations to life and can lead to living with distrust and fear. Despite this, VADs are accepted and are eventually embodied. These findings add to existing knowledge by developing the meaning of living with a VAD. To illuminate this understanding and articulate the new knowledge, a conceptual framework entitled the Vicious Cycle of Vascular Access was developed. DISCUSSION: When the decision is made to insert a long-term VAD, both the body and mind should be considered. Steps should be taken to improve the lives of people living with a VAD through improved education and training for Health Care Professionals and by increasing support for people with VAD.

Background: Tuberculosis (TB), a major global public health concern, is known as a disease of the poor. However, evidence on the economic burden of TB is limited, and so is the literature on the impact of poverty alleviation strategies, such as social protection (SP), on financial protection for TB patients. This PhD aimed to contribute to the body of knowledge on the costs and affordability of TB care, and on the potential mitigation effect of SP on TB patient costs. Conceptual analyses and empirical data I collected as part of a nationally representative TB patient cost survey in Ghana were used to address these objectives: 1) Provide evidence on the level, and composition, of costs incurred by TB-affected households and affordability of TB care; 2) Investigate determinants of costs, and the impact of National Health Insurance (NHIS) on costs; 3) Explore the potential impact of costs on TB treatment outcomes. Results: This thesis showed that TB patients in Ghana face financial catastrophe and impoverishment due to the cost of TB care. The poorest and those with drug-resistant TB have increased odds of experiencing catastrophic costs. NHIS in its current form is not effective in defraying costs, and its expansion will not be effective to relieve the financial burden for TB-affected households. Further, this thesis did not find an effect of costs on treatment outcomes as, like most TB patient cost surveys, our study was not powered to detect such an association. Conclusion: SP schemes require enhancement if they are to protect TB patients from financial catastrophe. Evidence generated from this thesis provides original insights into affordability of TB care, lending weight to policy recommendations on financial protection for TB patients. This PhD also shows both the potential and limitations of TB patient cost surveys to assess the impact of social protection strategies on costs, and of TB-related costs on treatment outcomes, thus calling for further methodological developments, and outlining a clear map for future research.

Background National Institute for Health and Care Excellence (NICE) recommends all men with prostate cancer undergoing androgen deprivation therapy (ADT) should be offered a 12-week supervised resistance and aerobic exercise programme, delivered twice-weekly, to reduce fatigue and improve quality of life. Healthcare professionals (HCPs) are in a prime position to support delivery of these recommendations, yet very few do. Methods The Medical Research Council (MRC) and Behaviour Change Wheel (BCW) guidance were used to develop an intervention for HCPs to provide exercise recommendation, support, and exercise referral for men on ADT. Initially, a systematic review of interventions to promote exercise behaviour in cancer survivors and a rapid review of the cancer clinical exercise recommendations was undertaken. Target behaviours for HCPs were identified from these reviews. Interview transcripts with thirty-five HCPs were then analysed using the Theoretical Domains Framework (TDF) to understand barriers to target behaviours. Intervention functions and behaviour change techniques (BCTs) were selected and the mode of delivery determined. The intervention was refined with the input of key stakeholders in the form rehearsal deliveries, focus groups and a workshop. The training package was delivered and evaluated at two NHS sites. Results From the literature reviews, seven target behaviours were identified to support the delivery of the NICE recommendations. Key barriers to target behaviours were identified, these included a perceived lack of time, concerns about patient capabilities to exercise and lack of awareness of the recommendations. Six intervention functions and twenty-two BCTs were included in the intervention. A face-to-face, half-day, interactive and skills-based training-package, with followup at 12-weeks was developed and delivered to seventeen HCPs. Delivery of all seven target behaviours was evident, although poor adherence to ‘in clinic’ audio-recordings limited fidelity assessment. Conclusions A feasible and acceptable training package for HCPs was developed that resulted in exercise recommendation, exercise support and exercise referral to men with prostate cancer on ADT. Further evaluation is required to further assess fidelity of the delivered behaviours.

Tuberculosis (TB) in intermediate-burden settings presents an annual incidence rate between 10 and 100 per 100,000 population, with burden concentrating in older adults. Although these settings do not comprise a major part of global TB burden, understanding their epidemics can cast light on priorities for TB elimination elsewhere. In this thesis, using Taiwan as a country example, I apply mathematical models to explore the opportunities and challenges for TB control in such settings. I first evaluate a current policy question about discontinuing universal Bacillus Calmette-Guerin vaccination in Taiwan, considering the vaccine benefits and side-effects. The analysis shows that a substantial cost reduction would occur following the discontinuation, while an uncertain net health impact would result from different assumptions of vaccine protection. Next, I explore the mechanisms driving a notable feature of the TB epidemic - the concentrated burden in the elderly. A combination effect of ‘immune senescence’, ’declining transmission’, and ’age-specific assortativity’ is most likely to explain the wide age disparities, as well as the declining trend of TB burden. I also discuss further evidence for characterising these mechanisms. In collaboration with the Taiwan TB programme, I incorporate key risk structures of TB and compare the impacts of potential strategies for meeting the End TB goals. Model projections reveal a limited effect of active case-finding but great potential of preventive therapy in reducing TB burden, with incremental contribution from glycaemic control. Additionally, critical determinants of the epidemiological impacts are evaluated. Overall, in the intermediate-burden settings like Taiwan, ageing trend will present considerable challenges in achieving TB elimination. Consequently, control strategies which address remote infection in elders will be increasingly crucial. Learnings from this thesis can be useful in strategic planning for other countries approaching similar conditions of TB burden. Meanwhile, uncertainties in TB epidemiology and interventions need further assessment.

Background: Breast cancer is one of the most common cancers in the UK and incidence is increasing. Efforts to promote early diagnoses along with advances in treatments mean people are surviving for longer with breast cancer. This, coupled with the long-term treatment requirements of the condition, have created increasing demand for primary care-based services to support survivors. The current role of community pharmacists in cancer services focuses largely on prevention and early diagnosis. However, as one of the most accessible healthcare providers in primary care, community pharmacists have potential scope to take on a more significant role in supporting breast cancer survivors. The aim of this study was to identify the opportunities for community pharmacists to develop their role in providing support and improving health outcomes for people living with and after breast cancer. Methods: This mixed methods study took a sequential approach with the findings from each phase informing the design of the next. Phase 1 consisted of a retrospective cohort study. National primary care prescribing data from the Clinical Practice Research Datalink was utilised to explore prescribing patterns in current practice and identify potential healthcare needs of breast cancer survivors. Data were analysed using descriptive statistics. Phases 2 to 4 used qualitative approaches to explore the perspectives of breast cancer survivors, community pharmacists and stakeholders respectively. Phase 2 consisted of focus groups and interviews with survivors, investigating experiences of the breast cancer care received in the community and identifying areas where community pharmacists might have scope to support. In Phase 3, online focus groups were conducted with community pharmacists to explore attitudes and feasibility of new roles or interventions. Phase 4 involved interviews with a range of stakeholders to establish their perspectives on findings and gain insight into future work. Survivor and stakeholder data were digitally audio-recorded, whilst transcripts of the typed discussions from the online community pharmacist focus groups were saved. All qualitative data were analysed using iterative thematic analysis. Findings: National prescribing data revealed that 53% (n=3084) of adjuvant endocrine therapy users with sufficient follow-up did not complete the recommended five years of treatment as per the national guidance. Frequent switching between endocrine therapies was also a concern, with 32% (n=3930) of users switching up to five times. Both are associated with increased risk of recurrence and mortality. As experts in medicines optimisation, the role of the community pharmacist could be key to tackling this issue. Qualitative findings revealed further care needs of survivors, who reported initial information overload then feeling abandoned post-discharge. Additional information and support was required on a range of clinical, emotional and lifestyle-related issues. Early and regular contact with community pharmacists was seen as important in improving care experiences. Community pharmacists and stakeholders noted the importance of providing the right information at the right time. Strategies included appropriate signposting, collaborating with other healthcare providers and charities, tackling public perceptions of roles, and building pharmacist confidence. Potentially feasible interventions included incorporating breast cancer into existing advanced services and healthy living pharmacy campaigns. Conclusions and recommendations: This research has identified considerable scope for community pharmacists to take on a larger role in breast cancer survivorship services, highlighting several potential features of future interventions. Approaches to care should be holistic and person-centred. Increased awareness of survivor care needs amongst community pharmacists is required to encourage proactive conversations with survivors, networking activities and further training. Findings can inform the development of community pharmacy survivorship services and healthcare policy. A more integrated and multidisciplinary approach to care is required, and policymakers and commissioners should consider the benefits of community pharmacy involvement when designing new services and care pathways. Future research should further investigate the feasibility of proposed interventions and consider how they could be incorporated into the changing landscape of pharmacy services.

Background: People with advanced cancer are often prescribed complex medication regimens. This makes the process of medicines management (incorporating prescribing, dispensing, adherence and medication review) challenging for this patient population. The overall aim of this thesis was to determine how effectively medicines are managed in the home setting and to explore how medicines management may be optimised in this patient population, from the perspectives of healthcare professionals, patients and those involved in caring for people with advanced cancer (carers, family members and relevant others). Method: Qualitative and quantitative methodologies were used throughout the four studies described in this thesis. The first qualitative study employed face-to-face semistructured interviews with patients with advanced cancer and their carers to explore the main issues in managing medications in the home setting. A quantitative questionnaire study was undertaken to investigate medication adherence and beliefs about medication in community-dwelling patients with advanced cancer. A systematic review was undertaken to determine the effectiveness of interventions in improving medication adherence in community-dwelling patients with cancer. Finally, a mixed method study, using postal questionnaires and semi-structured interviews, was conducted with pharmacists to explore their approaches to caring for people with advanced cancer approaching the end of life. All qualitative studies were analysed using thematic analysis. Results: Patients with advanced cancer and their carers struggled with the daily task of managing medications. Analysis of textual data revealed four core themes; medication management, medication adherence, medication review and pharmacy involvement. Patients had varying opinions of how much medication-related information they needed, however carers all expressed a need for further information. Furthermore medication non-adherence appears to be an issue in this population. A more in depth look at medication adherence found that medication adherence in this population is sub-optimal, with full adherence reported by only 20% of participants. Younger adults (aged 45-54 years) exhibited the lowest rate of medication adherence (p= 0.004). The systematic review identified a lack of good-quality research to inform answers to the question of how to improve medication adherence in community-dwelling patients with cancer. None-the-less, complex interventions combining patient education and intensified patient care may be beneficial in enhancing medication adherence as all four of the studies that incorporated patient education in conjunction with intensified patient care led to significantly better medication adherence. Analysis of the interviews conducted with community pharmacists revealed three core themes; the current and future roles of community pharmacy, lack of integration and communication and beliefs about confidence, knowledge and training. This study found that pharmacists play an important role in providing care for patients with advanced cancer and their carers, particularly describing their emotional role, which often extended into providing support in a family’s bereavement. In some cases, despite feeling embedded in the community, pharmacists felt isolated from other healthcare professionals. However the emerging role of the general practice-based pharmacist appears to be improving communication between GPs and community pharmacists. Pharmacists expressed a desire for a more enhanced role in provision of care to patients. However, the absence of financial incentives and adequate training and education to support pharmacists are currently hindering this role. Conclusion: The findings demonstrate that medicines management for community-dwelling patients with advanced cancer is a complex issue. Further training, education and support for patients, carers and healthcare professionals are required to optimise the use of medications in this growing patient population.

Background: People affected by cancer have to self-manage the consequences of cancer long after primary treatment has ended. In cancer survivorship, self-management has been defined as awareness and active participation by the individual in their recovery, recuperation and rehabilitation to minimise the consequences of treatment, and promote survival, health and wellbeing (DH, Macmillan Cancer Support and NHS Improvement, 2010). Despite a significant drive towards promoting and supporting self-management with people affected by cancer there is a lack of research examining whether residence (rural-urban) has an influence on self-management following cancer treatment. The primary aim of this thesis was to investigate and compare self-management, in people affected by cancer following treatment from rural and urban areas. Methods: The study utilised a cross-sectional mixed methods design that incorporated both quantitative and qualitative methods of data collection. Firstly, this involved a self-completion postal questionnaire (N=227) that collected quantitative data on demographics, rural-urban residence, health status, health-promoting behaviours, patient activation, cancer-related self-efficacy and qualitative free-text information on self- management behaviours. This was followed by a series of in-depth qualitative interviews (N=34) that aimed to identify, and compare the barriers and facilitators to self-management in people affected by cancer from rural and urban settings in the East Midlands of England. Both datasets were integrated to further explain the quantitative differences that were identified between rural and urban participants. Results: Participants from rural areas reported higher scores across a range of quantitative variables, indicative of greater levels of engagement with health promoting behaviours and self-management compared to those from urban areas. Specifically, rural participants scored higher with regard to health responsibility (p<0.01; nutrition (p<0.001); spiritual growth (p<0.01); and interpersonal relationships (p<0.001). Rural respondents (63.31±13.66) had higher patient activation than those in urban areas (59.59±12.75) although this was not statistically significant at p<0.01. Those residing in rural areas (7.86±1.70) had significantly (p<0.01) greater cancer-related self-efficacy compared to those in urban areas (7.09±1.96). Rural respondents had significantly higher self-efficacy than urban respondents with regard to confidence to manage physical discomfort (p<0.01), emotional distress (p<0.001), and to contact their doctor about problems caused by cancer (p<0.01). The findings from the multivariate analysis highlighted that rural-urban residence was not a significant predictor of health-promoting behaviours, patient activation or cancer-related self-efficacy when adjusting for living arrangement, marital status, qualifications and self-reported health status. Self- reported health status proved to be a significant predictor on all three outcomes when controlling for confounders. Three themes were identified in the qualitative data which related to barriers that prevented participants from engaging with self-management: (1) Location (2) Relationship Based and (3) Personal. In relation to facilitators that enhanced participants’ active participation in their recovery, three subthemes were identified: (1) Effective Communication and Information; (2) Informal and Peer Support and (3) Motivation. The barriers and facilitators that were identified were prevalent in both the rural and urban setting. However, some aspects belonging to these barriers and facilitators were more explicit in the rural or urban environment. For example, there was a lack of bespoke support in rural areas and participants acknowledged how traveling long distances to urban centres for support groups was problematic. Motivation to engage with self-management was not unique and both sets of participants were motivated by a desire to be healthy and take part in group activities and sports. Although rural participants did have easier access to greenspaces and community activities, which could enhance motivation further. Conclusion: The quantitative findings highlighted that people in rural areas were more engaged with health-promoting behaviours and better at self-managing their health compared to those in urban areas. The majority of the barriers and facilitators that were identified were not necessarily unique to the urban or rural environment. Certainly, the qualitative data show that residency is not as unequivocal as the quantitative results would suggest. However, engagement with the local community was greater in rural areas which could account for the differences. Whilst the active treatment phase can present considerable challenges for people affected by cancer in rural areas the findings suggest that the rural environment has the potential to increase engagement with self-management in the transition to survivorship.

Cancer survival is a key metric for monitoring improvement in awareness, early diagnosis and access to effective treatments for cancer patients. For the majority of cancers, survival has been increasing for a number of decades, as a result of successful health policies and the availability of more effective treatment. Nevertheless, there is an unavoidable delay between policy implementation and impact. In parallel, the measure of survival requires follow-up information, adding to the delay in quantifying health benefits. Predictions of cancer survival for cohorts of patients most recently diagnosed could help fill the gap in our knowledge of the likely effects of cancer policies. In this thesis, I modelled the excess hazard of death as a function of predictors available in linked cancer registry data in the UK. These include age, stage and year of diagnosis, levels of deprivation, type of diagnosis, and access to curative treatment. In such contexts, selecting the form of the model, the predictors, the shape of their effects, and potential interactive effects is challenging. Several model selection strategies are compared and their performance assessed in simulations. I provide practical guidelines for the modelling of the excess hazard of death, in particular in relation to cancer lethality, model complexity and impact of model mis-specification. Besides, these multi-variable regression models offer opportunities for predicting cancer-related death rate, for cohorts of patients most recently diagnosed, and for whom follow-up is not yet available. Along with model selection algorithms, I explore strategies based on information criteria and model averaging. Inference is therefore conditional on a pool of models of equivalent support, rather than a uniquely selected model. Advantages include absence of multiple testing, and allowance for model selection uncertainty in inference. Finally, a measure of explained variation, RE, is extended to the relative survival data setting. It is part of the model validation toolkit, and can provide estimates of how much variation in excess mortality due to cancer is explained by the models, and the variables that compose them. There are several methodological assets from the work presented here. First, excess hazard model selection is well formalised. Furthermore, the way RE is adapted to the relative survival data setting will most certainly nurture ideas for the adaptation of other validation tools, commonly used in prognosis research. Lastly, multi-model inference using model averaging is paving the way for the utilisation of ensemble learning in the prediction of excess hazard of death due to cancer. Scenario modelling is a public health application that naturally follows the work done in this PhD thesis. With well-crafted set of predictive models, simulated scenarios can be designed to identify areas for improvement in policy, prevention or treatment. Those generating largest increase in survival can lead to actual recommendations. Methodological advances and public health go hand in hand here. This work emphasises the importance of developing, assessing, and validating excess hazard models. It offers a toolkit so that accurate survival predictions help design effective policies.

This thesis explores how 67 Irish female cancer survivors experienced positive growth from cancer. With better treatment and improvements in early detection, the cancer survivor population is growing exponentially. Survivors have unmet needs and there is a need for and a shortage of psycho social supports available. We need to understand the lived experience of cancer survivors to be able to provide supports appropriate to their needs. The literature review positions this project within the research fields of survivorship and psycho-oncology. It examines the development and debates of the Model of PostTraumatic Growth which is a key framework used in this research. There are three key research questions: What is PostTraumatic Growth (PTG) in the context of female cancer recovery? To what extent does the PostTraumatic Growth Inventory effectively capture Irish women's experience of cancer recovery? And how does the PostTraumatic Growth Inventory compare to semi-structured interviews in understanding women's experiences of cancer recovery? The research employs a mixed-methods approach. The qualitative data consists of semi structured interviews and the quantitative data is derived from the PostTraumatic Growth Inventory-42. Thematic Analysis (Braun & Clarke, 2006) was used to analyse the qualitative data and Statistical Package for Social Science (SPSS) software used to analyse the quantitative data with an emphasis on descriptive statistics, correlations and Principal Components Analysis. The findings highlight the importance of quality ‘social support' especially from close friends as a significant driver of cancer recovery. Participants experienced the greatest degree of growth in the Relate to Others Factor. The findings suggest two new areas of positive growth: Proactive Mindset and Self Worth. Participants with children experienced greater positive growth compared to those who did not have children. Age, marital status and cancer stage were not predictors of growth. This research recommends maximising social support as a key recovery driver and highlights the need to develop a new PostTraumatic Growth Inventory to ensure its validity as a measurement tool of positive growth for the cancer survivor population.

Background: An advance care plan (ACP) is widely accepted as a component of palliative care. ACP is intended to facilitate a patient’s autonomy and enable the provision of care aligned to an individual’s preferences as far as is possible. Evidence shows that it can improve outcomes of care, including increasing the use of hospice and palliative care and decreasing life-sustaining treatments and hospitalisation. This is relevant to Taiwan, where the number of cancer patients with palliative care needs is increasing. However, most of the research on ACP has been developed in Western cultures, with little evidence from Asian countries. This limits the transferability of the Western-oriented ACP interventions to Taiwan. Aim To develop a culturally-adapted ACP intervention to improve outcomes for people living with advanced cancer and their family members, and to preliminarily explore its feasibility and acceptability in Taiwan. Methods: Design: A sequential qualitative mixed-methods study was employed comprising a primarily qualitative component followed by supplementary qualitative and quantitative components. Medical Research Council guidance on developing and evaluating complex interventions and the Theory of Change guided the development, refinement, and preliminary feasibility phases of the study. Setting and participants: Two inpatient hospitals (one for intervention development; one for preliminary feasibility exploration) in Taiwan. Participants were adults with advanced cancer, their family members, and healthcare professionals. Development phase: A systematic review using narrative synthesis was conducted to develop the initial logic model of ACP intervention, which was used to inform the subsequent qualitative study using semi-structured interviews with advanced cancer patients, family members and healthcare professionals in Taiwan. The qualitative study aimed at exploring their perspectives on ACP and the contextual factors to inform the culturally-adapted ACP intervention. Thematic analysis was employed for data analysis in the qualitative study. Refinement phase: A transparent expert consultation, using modified nominal group techniques, and an online consensus survey were conducted to generate recommendations for refining the culturally-adapted ACP intervention based on the clinical environment. Preliminary feasibility phase: A single group, non-controlled, mixed-methods feasibility study guided by the previous phases was conducted to explore the feasibility and acceptability of the culturally-adapted ACP intervention. The ACP intervention incorporated a one-time intervention, comprising pre-ACP preparation and follow-up consultation. Qualitative interviews explored participants’ views on their involvement in the study participation. Patients’ medical records were examined to assess intervention fidelity. Findings from both data sets were integrated following analysis. Results: Development phase: Systematic review: Nine randomised controlled trials were included, with only four articulated conceptual models. All included papers were from Western countries (the majority were from the United States of America, n=5/9) and samples were largely highly educated Caucasians. An initial ACP logic model was developed. Mechanisms through which ACP improved outcomes were identified: 1) increasing patients’ knowledge of end-of-life (EOL) care and ACP; 2) strengthening patients’ autonomous motivation; 3) building patients’ competence to undertake EOL discussions; and 4) enhancing shared decision-making in a trusting clinician-patient relationship. Qualitative study: Forty-five participants (n=15 advanced cancer patients, n=15 family members and n=15 healthcare professionals) were interviewed. Three patterns of palliative care decision-making with relevant drivers were identified: 1) choosing palliative care; 2) declining palliative care and 3) having no opportunity to choose palliative care. Key contextual factors were: 1) family-led ACP discussions; 2) respect for ‘filial responsibility’; 3) misunderstanding of the terms palliative care and 4) high-quality EOL care communication. These data were used to adapt the initial ACP logic model. Refinement phase: Transparent expert consultation: Seventeen clinical staff attended the modified nominal group and 37 multidisciplinary experts rated the online survey, which generated 44 recommendations. ACP was suggested to encompass multi-professional care to meet the individual’s preferences with family members support. Key requirements to implement ACP were: raising public awareness; staff training on enhanced communication skills and institutional and policy support for changes in practice. Preliminary feasibility phase: Preliminary feasibility study: Overall, 145 potential patients were screened for eligibility and 123 were excluded. Twenty-two patients were approached and referred for study participation, and 11 were recruited. A total of 10 ACP interventions involving 10 patients, 10 family members, and nine healthcare professionals were undertaken. The majority of the intervention components (n =10/13) were successfully implemented. Implementing the culturally-adapted ACP intervention for advanced cancer patients and their family in an inpatient hospital in Taiwan is possible. The participants reported the intervention to be acceptable. However, recruitment of patients with advanced cancer is challenging with both nearness to EOL and uncertainty about the value and benefit of palliative care and ACP in Taiwan. Four themes illustrating key contextual moderators influencing intervention feasibility were: 1) resource constraints resulting in increased clinical workload; 2) care decisions informed by previous care experience of supporting relatives of patients; 3) the requirement for financial and policy support, and 4) a presumption for EOL care provision and surrogate decision-making. Six areas for further intervention refinement were: 1) early initiative of EOL care discussions; 2) enabling patients to make informed decisions; 3) documentation to guide future care to reduce distress for patients/families; 4) simplifying the intervention to make it less abstract and more acceptable; 5) managing conflict between patients and family members around ACP, and 6) concordance with preferred care provision. Data were integrated to develop a conceptual model of ACP. Conclusion: This novel study developed a culturally-adapted ACP intervention for advanced cancer patients and their family members in Taiwan. Implementing the ACP intervention in clinical practice is possible and acceptable. Careful use of local primary data to develop a conceptual underpinning and recruitment strategies were key to achieving these goals. This study provides valuable contributions to inform future ACP intervention development in the wider Asia-Pacific region. However, testing this conceptual model in a feasibility trial collaborated with implementation science is required.

Background: Breast cancer is the most common cancer for women, globally. Social, religious and healthcare contexts have been shown to influence women’s experiences of advanced breast cancer; however, research has tended to focus on resource-rich nations. There is limited research from low-resource contexts, and little is known on the experiences of Arab, Muslim and African women with advanced breast cancer. Aim: To explore and understand the experiences of advanced breast cancer in the Islamic Republic of Mauritania, West Africa. Methods: Using a constructivist Stakian multi-case study approach, eight cases were constructed around women (n=8) with advanced breast cancer, family members (n=10) and health professionals (n=9). Data were collected longitudinally (up to nine months per case) and consisted of interviews, audio-journals, a patient reported outcome measurement scale and a performance status scale. Withincase and cross-case analysis was undertaken, with thematic analysis of qualitative data. Findings: Three key themes were identified: 1. Destiny, 2. Patience & Acceptance and 3. Journeying in search of a cure. Mauritanian women appreciate that Allah is all powerful and maintains control over their destinies and their breast cancer. A fear of causing offence to Allah influences how they express negative experiences of breast cancer and its treatments. The women’s access to information and treatment is controlled by health professionals and families. Women are, therefore, required to use their own observations and interpretations to understand their breast cancer and empower their pursuit of treatment and a cure. Conclusion: Maure women’s experiences of advanced breast cancer in Mauritania are influenced by power imbalances. Allah is all-powerful. Families and health professionals exert power over Maure women’s access to information, healthcare decisions and how they express negative experiences. This thesis demonstrates that Maure women are cognisant of these challenges and, either, accept them as reality or attempt to work around them.

Breast cancer is the most prevalent cancer in women worldwide with incidence on the increase. Despite this, as a result of earlier detection and improvements in medical treatment outcomes, survival rates are improving. However, the longer term side effects of breast cancer can adversely affect an individual’s social, cognitive and emotional functioning, profoundly impairing quality of life. As such, the primary aim of the present PhD thesis was to better understand the mechanisms involved in cognitive and emotional vulnerability in breast cancer and to develop and assess the efficacy of interventions that could better the lives of women in survivorship post diagnosis. Findings from Experiment 1 firstly indicate that targeted neurocognitive interventions can improve cognitive control and processing efficiency in breast cancer survivors, establishing that this population is receptive to treatments that provoke brain neuroplasticity. Secondly, it demonstrates that as a result of engaging top down attentional control processes, such interventions can result in sustained reductions in emotional vulnerability. Following on, using an expressive writing intervention, Experiment 2 indicates a relationship between the use of words thought to reflect cognitive reappraisal, as well as affectively negative words, with improvements in perceived cognitive function, emotional vulnerability and quality of life. That said, refinement of expressive writing paradigms is required to optimise transfer outcomes. Experiment 3 outlines an intervention study demonstrating how both mindfulness meditation training, adaptive working memory training, and a combined course of both, can result in reductions in anxious symptomatology compared to an active control condition. As a means to further understand the neurocognitive mechanisms affected by breast cancer, Experiment 4 adopts a neural approach exploring how breast cancer survivors respond to making cognitive errors in comparison to healthy controls. Findings indicated that whilst performance effects were absent, neural differences were found between groups, indicating that compensatory processes were required in order to function efficiently. Finally, whilst a large body of research now indicates that chemotherapy affects cognitive functioning post treatment, less is known about the effects of the estrogen reducing hormone therapy Tamoxifen, which is widely administered to breast cancer survivors for five to ten years post diagnosis. Study 5 employed qualitative methods to explore the lived experience of taking Tamoxifen in the absence of chemotherapy. Findings indicate that for this subset of breast cancer survivors, cognitive deficits are also present, and can greatly diminish quality of life. Overall, findings have critical implications for informing researchers, clinicians and the breast cancer population alike on the underlying mechanisms surrounding cognitive and emotional vulnerability in breast cancer.

Tuberculosis (TB) remains a public health problem in cities in high-income, low-incidence countries, such as London, where it disproportionately affects particular population groups and, as such, more effective intervention strategies are needed. With whole genome sequencing (WGS) data being increasingly used for TB epidemiology, I investigated how WGS data alongside statistical inference and mathematical modelling can improve our understanding of transmission in these population groups. By reviewing the literature on WGS in TB epidemiology studies, I concluded that whilst genomic data can improve our understanding of TB transmission, including epidemiological data alongside is helpful for mitigating uninformative genomic data or strengthening conclusions. I then employed a statistical inference method on sequencing data from a Canadian outbreak and used the inferred transmission network to determine that the outbreak had ended, demonstrating the use of genomic epidemiology in public health. As we must analyse genomic data using bioinformatics and sometimes phylogenetic methods before we can interpret it for epidemiological purposes, I undertook bioinformatics analysis of 415 genomes from a London TB outbreak and attempted to create a timed-phylogenetic tree that could be used for genomic epidemiology inferences. However, the data proved difficult to interpret resulting in a tree with little confidence, potentially due to little variation amongst the sequences. Finally, I constructed a novel mathematical transmission model to recapitulate the London outbreak and investigate public health interventions to conclude that despite loss-to-follow-up being considered an important factor amongst the cohort anecdotally, focusing interventions on reducing loss-to-follow-up or increasing re-engagement does not significantly reduce the number of outbreak cases. Finding infectious cases early achieves the most impact. In conclusion, combining epidemiological and sequencing with novel quantitative analysis using statistical inference and transmission modelling, provides useful insight into the spread of TB in urban outbreaks and illustrates the limitations of new approaches and data.

Background: Worldwide, more people are diagnosed with and die from thoracic cancer (cancers of the respiratory tract, lung and pleura) than any other cancer. Most present with incurable disease and despite new advances in treatment, will be living with the consequences of advanced disease. Patients experience an array of symptoms, which impact on function and daily life. Rehabilitation aims to ameliorate the functional impairment and improve participation in daily life. Although guidelines recommend that patients should have access to rehabilitation, few cancer services integrate rehabilitation within the core treatment pathway. Aim: This study aims to develop and assess the feasibility of testing a brief integrated rehabilitation intervention for people newly diagnosed with thoracic cancer. Method: A sequential exploratory mixed methods approach, following Medical Council Guidance for the development and evaluation of complex interventions, was used to develop and test the new rehabilitation interventions. During the development phase, a systematic review explored the application of behaviour change theory and techniques in empirical rehabilitation studies in this population. Concurrently, focus groups, held with patients, family members and clinicians, elicited views on the aims, content and delivery of the proposed rehabilitation intervention. These data were integrated with reflection on theory to inform a conceptual model of brief integrated rehabilitation and set out key components, processes and outcomes of the new rehabilitation intervention. Guidelines were followed to produce an Intervention Manual to support fidelity during delivery and evaluation of the intervention in a randomised controlled feasibility trial. During the feasibility phase, participants with a recent diagnosis of lung cancer or pleural mesothelioma on any treatment pathway were recruited to a parallel group 1:1 randomised controlled multicentre feasibility trial of short-term integrated rehabilitation plus standard care versus standard care. Primary outcomes included recruitment and retention. Target recruitment was 30% of eligible participants and for more than 50% to be retained on study at 30 days. Secondary outcomes included intervention fidelity and performance of clinical outcome measuring symptoms, physical activity, self-confidence to manage disease, quality of life and health service use. A post-trial questionnaire elicited experiences of participation in the trial. A final analysis of data integrated from each phase of the study explores how the thesis aims and objectives were met. Results: Twenty-seven studies of exercise (n=15) and symptom self-management (n=12) interventions were identified in the systematic review. Application of behavioural change tools was found to be sub-optimal. Theories were used infrequently; four studies reported use of behavioural change theory and one used a symptom theory. Across studies, a mean (range) of 7 (1-18) behaviour change techniques (BCTs) were identified from intervention reports, representing 26 of 93 possible BCTs from the behaviour change techniques taxonomy vs. The most frequently identified BCTs to enable behaviour change were ‘instructions on how to perform behaviours’ (74%), ‘behavioural practice’ (74%) and ‘action planning’ (70%). BCTs to address barriers were identified less frequently and included ‘information about health consequences’ (22%), and ‘verbal persuasion about capability’ (7%) to change perceptions about benefits and harms. Fifteen clinicians (oncologists, nurse specialists, physiotherapists and occupational therapists), nine patients and five carers participated in the focus group study. A proposed outline rehabilitation model was perceived as highly relevant for this population. Participants recommendations refined the model. Prompt, brief, rehabilitation input, delivered whilst people attend for hospital appointments or at home should maximise accessibility and acceptability. Participants recognized variation in need and all prioritised tailored support for symptom self-management, daily activities and the involvement of carers. Clinicians also prioritised achieving fitness for oncology treatment. Patients and carers prioritised a sensitive manner of approach, positivity and giving hope for the future. Participant’s recommendations for outcome measurement related to confidence in usual daily activities, symptom control, and oncology treatment completion rates over objective measures of cardiorespiratory fitness. Subsequent integration of the systematic review and focus group findings with reflection on theory informed the development of a conceptual model, an intervention manual detailing rehabilitation processes and components, and a trial protocol for testing brief integrated rehabilitation in a multi-centre randomised controlled feasibility trial. The feasibility trial recruited 54 of 159 (34%) eligible patients and 44/54 (82%) and 39/54 (72%) participants provided data at 30 days and 60 days respectively. Intervention fidelity was high: 25/26 participants allocated to integrated rehabilitation received a median 3 (range 1-3) sessions of rehabilitation over 32 (22-45) days. Trial and intervention satisfaction were high. Five participants reported that the questionnaires were difficult or long to complete and two were unhappy with group allocation. Participants who received rehabilitation valued practical advice and face to face contact. Feasibility challenges included integration with oncology services, for example accessing clinic space. Changes in clinical outcomes were modest but most apparent for physical activity levels and health-related quality of life as measured by FACT-L. An estimated sample size for a future trial was calculated based on the observed changes in the FACT-L measure. Assuming a difference of 6 points, which is similar to the point estimate of effect observed, and allowing for 25% attrition, 336 participants would be required to reliably detect this difference (80% power, p=0.05) in a future efficacy trial. Conclusion: This thesis followed Medical Research Council Guidelines to develop and test a theoretically informed intervention. It found that it is feasible to recruit and retain people with thoracic cancer to a trial of brief integrated rehabilitation in the period following diagnosis. A larger trial to examine the efficacy of integrated rehabilitation in this population is feasible, with health-related quality of life as a candidate primary outcome. The conceptual model and intervention manual will be further refined during dissemination of thesis findings. Implications for clinical practice and future research are discussed and recommendations made.

Background: Unexpected weight loss (UWL) is a non-specific symptom posing a diagnostic challenge to general practitioners (GPs). It can be associated with several conditions including cancer. There are no international or national clinical guidelines to support GPs to select patients with UWL for cancer investigation. Aim: The overall aim is to provide the evidence necessary to allow GPs to identify which patients with UWL should undergo testing for cancer. Methods: Six studies are included in this thesis. Firstly, an evidence synthesis of studies investigating the diagnostic accuracy of UWL as a diagnostic feature of cancer in primary care patients. Following this, a series of five linked studies using electronic health records data from the UK: i) a cohort study about weight recording in NHS primary care from 2000 to 2017 to establish whether weight records could be used to define weight loss; ii) an internal validation study of weight related coding to determine which codes can be used most reliably to define UWL; iii) a time-to-event matched cohort analysis of the association between UWL and cancer to ascertain the time period of increased risk for a cancer diagnosis following a presentation with UWL, for cancer overall and by cancer site and stage; iv) a cross-sectional diagnostic accuracy study investigating the predictive value of risk factors, symptoms, signs and blood test results in patients with UWL; v) the derivation and validation of prediction models to estimate cancer risk in patients with UWL, leading to the creation of simple clinical risk scores to stratify cancer risk using gender, age, risk factors, symptoms and blood tests. Results: Weight recording is not a routine activity in UK primary care. It occurs too infrequently to define UWL in epidemiological studies. Validated UWL codes represent ≥5% weight loss over six months. Coded UWL is a strong predictor of cancer diagnosis within three months of presentation to primary care. The commonest cancers in people with UWL were pancreas, cancer of unknown primary, gastro-oesophageal, lymphoma, hepatobiliary, lung, bowel and renal tract. Men aged 50 years and older who have smoked and people with co-occurring clinical features or blood test abnormalities were at greatest risk. Clinical features typically associated with specific cancer sites are markers of several cancer types when they occur with UWL. The simple clinical risk scores showed excellent discrimination, calibration and clinical utility. A risk score that prioritised ruling-out cancer investigation (sensitivity 97.5%) corresponded to 35 people with UWL being referred for investigation for each person with cancer referred and 1,730 people spared referral for each person with cancer not referred. Conclusion: A GP’s decision to code UWL is predictive of several but not all cancers. Risk factors, co-occurring clinical features, and blood test results can be used to select patients with UWL for urgent investigation. These findings will inform future clinical guidelines.

Background: Many people are living for longer with advanced cancer because of improvements in cancer treatments. Fatigue is the most prevalent and burdensome symptom in this cohort of patients. Thus, many could benefit from any improvements in the assessment and management of fatigue in advanced cancer care. This PhD explored how fatigue was talked about in advanced cancer care, how oncologists approached it and how patients dealt with it. Methods: A mixed methods design combining video-recordings, questionnaires and interviews was used. The study was divided into three parts: Part A, video-recorded observations of palliative oncology visits; Part B, interviews with patients with fatigue; and Part C, interviews with oncologists. Data from observations were analysed using content analysis and some of the concepts and tools of conversation analysis. Data from semistructured interviews were analysed using thematic analysis. The data were integrated, with the CA findings the primary component of this study and a summary of findings was produced. Results: In Part A, 60 visits were recorded, and 37 patient participants reported clinically relevant fatigue. Talk connected with fatigue occurred in 82% of consultations and was often sequentially linked with discussions around goals of care and end of life issues. Resistance to treatment recommendations and advice giving for fatigue was recurrently observed. In Part B, 22 patients with fatigue were interviewed. The overarching theme 'interconnectedness' demonstrated how participants coped with fatigue through an array of interrelated strategies and influences. In Part C, nine oncologists were interviewed. The overarching theme 'fatigue is perceived as different' described how fatigue was challenging to assess and challenged the role of the cancer doctor. Conclusions: The findings showed how fatigue is a complex phenomenon in advanced cancer care and how it can be integral to the decision-making surrounding palliative cancer treatments. For patients, fatigue is seen as an acceptable trade-off for the prolongation of life, and this was acutely observed when resistance to proposals to reduce or withdraw cancer treatments occurred. Cancer clinicians may need to consistently reassure patients that alterations to palliative cancer treatments to lessen the burden of fatigue would not reduce survival.

Background: Cancer survival in England is poorer than in other comparable countries. Older cancer patients generally have less evidence-based treatment, and poorer survival than younger patients. This is often attributed to the increasing presence of comorbidity with age. Concerns exist, particularly in England, that age-related differences in cancer outcomes arise because of clinical decision-making based on chronological age alone. This study aims to examine the impact of age on having optimal cancer management for colorectal cancer (CRC). Methods: Using population-based cancer registration records of 139,457 CRC patients diagnosed in Denmark, England, Norway and Sweden during 2010-2012, I estimate and compare age standardised stage-specific three-year net survival, and the likelihood of receiving radical surgery by age and stage. Then, focusing on the 99,942 patients diagnosed in England, I quantify how far age-related differences in patient management are mediated by comorbidity and the diagnostic route, using causal mediation. Findings: In comparison with Denmark, Norway and Sweden, CRC patients in England had lower three year net survival. There was an age gradient in the proportion treated at each stage of disease in England, which was not as evident in the other countries. Analyses focusing on patients without evidence of comorbidity in England and Denmark showed a similar trend. In England, the proportion of patients with evidence of receiving a full investigation and surgical treatment decreased with age. The age differential was partly mediated by the diagnostic route, but not by comorbidity. Interpretation: These findings suggest that the CRC survival deficit in England can be attributed partly to under-management of older patients. Complex interactions between biological, attitudinal and contextual factors may be behind these findings. Raising the proportion of patients receiving optimal management to the levels observed in comparable countries would improve CRC outcomes, provided that adequate post-operative and long-term care are also available.

Background It has long been recognised that young people have unique needs which differ from those of children or adults. Yet within healthcare, they have spent years without being recognised as a speciality within their own right. Teenage and young adult cancer networks in the United Kingdom have however evolved over the past twenty years. Services have been shaped by national guidance, released in 2005, and with much input from the charitable sector. These services in England are structured around complex networks, with secondary and tertiary care delivered in either a specialist Principal Treatment Centre, or within an associated 'designated' or 'shared care' hospital. Aims The aim of this research was to look closely at these services, to specifically examine the culture of care for young people receiving cancer care in England. The current economic climate of the National Health Service (NHS) presents an ongoing challenge for specialist health services to demonstrate their value and cost-effectiveness: teenage and young adult cancer care being one of these specialist services. Evidence to underpin specialist health services is crucial to make a difference and sustain change. Methods Adopting a case study approach through a critical realist lens, this multiple-case study was conducted across four teenage and young adult cancer networks in England. A conceptual framework consisting of three core concepts of culture was used to guide study design, conduct and reporting. A qualitative, multi-method approach was used across 24 NHS hospitals, and included: semi-structured interviews with healthcare professionals (n=41), and young people (n=29); participant observation, walking tours and shadowing techniques. Thematic analysis was used to identify themes between, within and across the four cases; deconstructing and reconstructing the components of the culture of care that emerged thereby enabling synthesis and contextualisation of data. Findings The findings of this study are presented in three parts, framed around the three core concepts of culture: the dynamic contexts of the culture; the visible processes and less visible values which underpin the culture; and the way culture was learned and shared. In terms of the context of care, the impact of the physical environment on young people's experiences of socialising and accessing peer support were highlighted. There were key features of the culture which were clear and visible. Underpinning these features were three values at the core of delivering young person-centred care: recognising individuality, empowering and promoting normality for young people. To develop a culture which embraces and promotes these core values, it was found to be particularly important to have effective communication and leadership, healthcare professionals with the right attitude, and a sufficient number of young people using a service. Conclusion and recommendations The importance of the core values that underpin care, and the need for education, effective leadership and multi-disciplinary team working, should all be recognised and prioritised when developing and evaluating interventions that contribute to the delivery of care to this unique patient group. Care delivered in an environment which promotes normality through facilitating socialisation with peers is optimal for the creation of a culture of care which is holistic and young person-centred. The findings of this study provide qualitative evidence of care delivery. This data will be further considered alongside the quantitative data generated in other workstreams of the BRIGHTLIGHT programme of research. However, taken alone, these findings provide evidence to assist all healthcare professionals and services to grow and nurture a culture of care that meets the unique needs of young people with cancer, and to improve their experiences of care; and further progress healthcare organisations towards a future where specialist, holistic care is accessible for all young people.

Introduction: Palliative radiotherapy is a standard of care for localised pain due to bone metastases. International guidance recommends single fraction treatment in preference to multiple fractions, but variation in practice exists. The cost-effectiveness of stereotactic radiotherapy in this setting is unclear. This study aimed to assess the quality of life benefits from response to treatment, cost-effectiveness and routine use of these treatments in the context of varying survival. Methods: A mixed methods approach was used: A systematic review; secondary use of trial data to assess an alternative trial end-point and support multi-level regression modelling of treatment related quality of life benefits; a qualitative interview study to understand patients values and experiences of treatment; time-driven activity-based costing to determine radiotherapy cost; cost-utility analysis, to balance the quality of life benefits and cost of treatment in the context of varying survival and identify levels of 30-day mortality which reflect cost-effective care; and an analysis of the national radiotherapy dataset to provide insight into current practice and outcomes in the English NHS. Results: With increasing proximity to death the quality of life benefits of palliative radiotherapy diminish markedly, to the extent that in the final months of life, treatment is unlikely to be cost-effective and may be associated with a net harm to the healthcare system. For those with longer survival, stereotactic radiotherapy may offer a cost-effective means to improve the quality and durability of pain control, once treatment costs have reduced beyond an initial learning-curve. Wide variation in fractionation pattern persists, with marked variation in 30-day mortality. Conclusions: A value-based approach to the use of palliative radiotherapy for bone metastases offers an opportunity for improved decisions that avoid futile treatment and improve the cost-effectiveness of care. These analyses can form the basis of a novel approach to the commissioning of stereotactic radiotherapy.

Background: There is increasing evidence demonstrating that lifestyle interventions of exercise and diet may represent a useful supportive therapy for men with prostate cancer, improving physiological and psychosocial outcomes. There has been limited investigation of the effects of such interventions in men with castrate resistant prostate cancer (CRPC), the terminal phase of the disease. It is not clear how exercise has been implemented in the prostate cancer care pathway and what a successfully implemented exercise programme might look like. Furthermore, the specific treatment and disease related barriers men with CRPC might face engaging in exercise is not documented, particularly when considering their advanced stage of disease. This work described in this thesis covers an exploration of the feasibility and acceptability of an exercise and dietary intervention to improve outcomes in men with CRPC. Methods: A healthcare professional survey was conducted to assess the extent to which NHS trusts are meeting the NICE guidelines (CG175, 1.4.19) for exercise training for men with prostate cancer on androgen deprivation therapy (ADT). Semi-structured interviews of UK healthcare professionals, specialising in prostate cancer care and based in UK National Health service (NHS) trusts were conducted. These explored underlying reasons behind the variability in NHS trusts in delivering exercise training programmes and probed the views of the HCPs regarding exercise training, including the acceptability of concurrent use of an anabolic agent for men with CRPC. A feasibility randomised controlled trial (RCT) of an exercise and dietary intervention in CRPC patients was conducted (COMRADE). Men with CRPC recruited to the RCT were randomised on a 1:1 ratio to either the intervention or usual care for 16 weeks. Men allocated the intervention received up to 24 three sessions of supervised resistance exercise a week; supplemented with whey protein and creatine monohydrate; and given dietary advice. They were also asked to partake in at least one independent moderate intensity aerobic activity lasting at least 30 minutes a week. Following the RCT, post study participant focus groups addressed patients' views on aspects of the study, particularly with regards to acceptability of trial procedures, barriers and facilitators to exercise training and the impact of living with CRPC. Results: The healthcare professional survey demonstrated significant variability between NHS trusts in the UK in delivering the NICE guidelines and that a supervised exercise training programme is not currently embedded within "usual care" for prostate cancer. The healthcare professional interviews (n=12) demonstrated support for an individualised and adaptable exercise programme for men with CRPC which could improve fitness and mitigate some of the long term effects of their cancer/cancer therapy. Their opinions reflected that comorbidities and disease/treatment specific barriers to exercise must be taken into account to support better adherence. In the feasibility RCT, n=31 men were recruited from a total of n=3607 screened (recruitment rate=13.6%). There were eighteen in the intervention and thirteen randomised to the control group. The attrition rate was 16%, with n=4 dropping out of the intervention and n=1 death in the control. Adherence to the supervised and independent exercise sessions was 69% and 78% respectively. The adherence to the whey protein was 68% and creatine was 71%. There were 4 AEs associated with trial procedures, none of which were serious. Three primary themes were identified from the participant focus groups (n=3); these included 1) living with CRPC, 2) experience and opinions of the trial, 3) attitudes and experiences of exercise training and physical activity. The findings demonstrated that the study procedures were well received by 25 the participants, including the trial assessments and format of the intervention. Valuable insights were gained for implementing future exercise intervention studies - providing participant perspectives for the success of a lifestyle behaviour study such as COMRADE. Conclusions: The findings suggest that it is feasible to randomise and retain men with CRPC to an exercise and diet intervention, however there was a high rate of attrition in the study, due to the complex nature of the disease in these men. Further work is required to address the barriers related to implementation of exercise in the prostate cancer pathway for men with CRPC.

Tuberculosis (TB) is a global health issue with significant morbidity and mortality. The Hajj religious mass gathering represents many of the risk factors for TB transmission and the disease has been reported among hospitalised pilgrims during the event. However, little data is available on the true burden of TB in Hajj or the management of TB cases in hospitals at the event including healthcare worker’s (HCWs) knowledge, attitude and practice (KAP) regarding TB. Accordingly, the thesis consists of three separate, but integrated studies, each with own objectives, literature review, methodology, result and discussion sections. Thesis studies are as follows: 1. Active PTB among hospitalised and non-hospitalised pilgrims during the Hajj mass gathering 2. Management of hospitalised Pulmonary Tuberculosis (PTB) patients during the Hajj mass gathering 3. TB knowledge, attitude and practice among HCWs during the Hajj mass gathering Aim The overall aim of this research project is to provide evidence-base for improvement of TB prevention, management and control during the Hajj mass gathering. The outcomes could be beneficial to other mass gatherings worldwide and will enrich knowledge in the new scientific discipline of “mass gatherings medicine”. Method The study was conducted in Makkah, Kingdom of Saudi Arabia (KSA), the location of the Hajj over 2 Hajj seasons (2016-2017). Structured questionnaires and forms were used to collect information related to the study population (non-hospitalised and hospitalized pilgrims with productive cough, TB cases admitted to hospitals during Hajj and Hajj healthcare workers). Information was also collected in relation to the management of TB cases in Hajj and the knowledge attitude and practice of healthcare workers delivering services during the event regarding TB and its management. Sputum samples were also collected from the hospitalised and non-hospitalised pilgrims and tested for TB using the Xpert MTB/RIF assay. Results 1. Active PTB among hospitalised and non-hospitalised pilgrims during the Hajj mass gathering For non-hospitalised pilgrims, out of the 1,510 pilgrims tested, 10 (0.66%) had undiagnosed active PTB. Underlying health conditions and cough in the household were independent risk factors for TB among this population. For hospitalised pilgrims, among the 304 patients investigated, 9 (2.9%) had active PTB and most (77.7%) of these were missed by the hospitals including multidrug-resistant TB cases. Previous TB treatment was an independent risk factor for TB among this population after adjusting for other variables 2. Management of hospitalized PTB patients during the Hajj mass gathering The study also documented the management of 32 confirmed TB patients during Hajj and explored the compliance of healthcare providers with the KSA TB management guidelines in hospitals during the mass gathering. Out of a maximum score of 10 for the selected TB management themes, the guideline compliance score was highest for infection prevention and control and surveillance (9.6) and identifying TB suspects (7.2). The least scores were obtained for treating TB (5.0) and diagnosing TB (3.0). 3. TB knowledge, attitude and practice among HCWs during the Hajj mass gathering Finally, the study conducted a KAP survey among 540 HCWs from 13 hospitals serving pilgrims in Hajj. In general, HCWs had average knowledge (mean knowledge score of 52%), above average attitude (mean attitude score of 73%) and good practice (mean practice score of 81%) regarding TB, based on the scoring system and cut-off points developed in the current study. Conclusions The results of the current study suggest that there are a number of key challenges in relation to TB at the Hajj. These include undiagnosed and missed TB cases at the event, inadequacy of current national and international TB management guidelines in the context of Hajj and important knowledge gaps, negative attitudes and wrong practices among HCWs in relation to TB. As such, TB during the Hajj mass gathering needs more attention from the scientific community and Hajj stakeholders. A raft of recommendations are proposed to optimize awareness, screening, management and treatment, prevention, and control measures for TB during Hajj as well as other mass gatherings both within Saudi Arabia and worldwide.

Population-based cancer survival is a key measure of the effectiveness of health systems in managing cancer. Monitoring survival over time and between countries is also crucial to assess inequalities and drive policies for cancer control. In this thesis, I use data from the Kuwait Cancer Registry (KCR) to produce a comprehensive profile of population-based cancer survival in Kuwait, to enable evaluation of cancer care in the country. In order to produce robust population-based net survival estimates, it is necessary to have the full date of both the cancer diagnosis and the last known vital status for all patients. All deaths must be included, irrespective of the cause of death. A new approach to obtain followup data on the vital status of all registered Kuwaiti cancer patients was implemented. This enabled the estimation of population-based cancer survival in Kuwait for the first time, using robust and unbiased methods that allow comparisons to be made over time and between different populations. Further analyses of survival by stage at diagnosis were also performed, to provide a deeper understanding of cancer survival in Kuwait. Finally, an overall assessment of progress against cancer was performed, using the three main cancer control metrics: incidence, survival and mortality. The findings demonstrate that survival has improved for many cancers in Kuwait during 2000-2013. However, further research is required to help dissect the underlying causes of the differences in survival between Kuwait and other countries with comparable income and health systems. It also highlighted the importance of more complete collection of stage data, the necessity of improving early detection, and the need for systematic production and assessment of cancer control measures in Kuwait. The findings should assist policymakers and practitioners investing in the Kuwaiti healthcare system to achieve optimal outcomes and provide guidance towards future research in the country.

Background. Severe illness, like that caused by the infectious disease tuberculosis (TB), is associated with direct expenses accessing healthcare, and indirect costs from time away from work. Cash transfers, which provide regular income transfers to eligible vulnerable households, might improve the coping capacity of poor households. This PhD aimed to investigate whether cash transfers prevent household financial hardship from severe illness. Objectives. 1. Evaluate the effect of cash transfers on changes in household income and consumption in response to severe illness. 2. Assess uptake of social protection and financial hardship amongst drug resistant TB affected households. 3. Evaluate the most effective and affordable approach for delivering cash transfers to prevent household financial hardship related to TB. Methods. Systematic review of conditional cash transfers, income shocks, and household coping; historical cohort study of self-reported severe illness and changes in household labour income and food consumption; cross-sectional survey of notified drug resistant TB costs; economic modelling of cash transfers and catastrophic TB-related costs in seven countries. Results. Systematic review identified 5 studies, which together indicate that conditional cash transfers improve households' capacity to safeguard consumption in response to shocks. Panel data analysis found no effect of self-reported severe illness on household labour income or food consumption. Cross-sectional analysis indicated that uptake of social protection, including cash transfers, reduces the likelihood of experiencing financial hardship because of drug resistant TB. In economic modelling, providing cash transfers to defray TB-related costs was more effective and affordable for preventing catastrophic costs than providing cash transfers to reduce poverty amongst households vulnerable to TB. Conclusion. Cash transfers appear to enhance the capacity of poor households to cope with severe illness. However, it remains unclear if cash transfers as currently implemented are sufficient to ensure that every household is able to meet their basic needs.

Breast cancer is the most common female cancer worldwide. This thesis aims to evaluate the cost-effectiveness of breast cancer control across different healthcare contexts and estimate the costs of breast cancer treatment. Four case studies are presented providing detailed estimates of the cost-effectiveness of risk-based breast screening in urban China, the cost-effectiveness of population-based breast screening in rural China, the cost-effectiveness of panel genetic testing among unselected breast cancer patients in the UK and US, and cost of breast cancer treatment by stage at diagnosis in England. The economic evaluation studies on breast cancer screening show that in urban China, high-risk population-based screening for breast cancer is very likely to be cost-effective. But in rural China, breast screening among the general population reports uncertain costeffectiveness and could potentially harm women's health due to false positives with the current screening tools. In a rural setting with such low breast cancer incidence, priority should be given to ensure that symptomatic women have proper access to diagnosis and treatment at an early stage as this will lead to mortality reductions without the usual screening harms. The economic evaluation on genetic testing based on a microsimulation model showed that unselected panel genetic-testing for all breast cancer patients is extremely costeffective compared to the current practice of family-history/clinical-criteria based genetic (BRCA)-testing for both UK and US health systems. This supports changing the current policy to expand genetic-testing to all women with breast cancer. Costs of breast cancer care increased with increasing stage of the disease at diagnosis in England. Considerable cost savings could be made if breast cancer was detected and treated earlier. Variations in breast cancer costs by age and region raise questions about the efficiency and consistency of breast cancer treatment patterns. Future research could be conducted by undertaking multiple imputation for missing data and censored-adjusted analysis.

Background: The burden of cancer embodies the lived experiences and perspectives of people who have dealt with the challenges and difficulties of cancer. The landscape of cancer care in the United States has transitioned to a predominantly outpatient care system, so cancer care has become increasingly burdensome on the patient and family. Aim: The thesis describes the cancer care burden experiences of Chinese, Filipino and Indian American cancer-diagnosed immigrants and their family carers as well as explores the factors associated with their cancer care burdens. Method: Interpretivist and constructivist qualitative approaches were used to gather and analyse data from 9 cancer-diagnosed individuals and 9 family carers. Purposive and snowball sampling methods were employed. A semi-structured interview format was used for data collection. Results: The analysis generated three main themes that reflect cancer care burden experiences of the sample population: psychosocial burdens, burdens related to healthcare, and competing priorities. Several factors related to social, economic, cultural, and institutional context were found to have a relationship with the cancer care burdens. Conclusion: The findings illustrate that Asian American immigrant families deal with complex and multifaceted cancer care burdens that are connected to the social, economic and cultural conditions that shape their lives. Insight from the thesis is a critical first step for understanding the pathways of cancer care burdens amongst immigrant families.

This thesis explores the connections between leprosy and kingship in thirteenth-century England and France. The kings of England and France, through the anointment they received at their coronation ceremonies, were granted a particular connection with God, and with Jesus Christ. Lepers, because of the extremity of their suffering, which was believed to be purgatorial, were valued for their spirituality. Their intercessory prayers were sought by kings and queens throughout the Middle Ages. This thesis takes a comparative approach as far as is possible with the nature of the available source material. Beginning with the disease of leprosy, it considers the position of lepers in society, both within the religious enclosure and in secular society. The responses of both religious and lay groups towards leprosy were ambiguous, being at once inclusive and exclusive. Kings Henry III and Louis IX went beyond the contemporary expectations of kingship, which would have been sufficed by the provision of charity. They were both reported to have knelt before lepers, and kissed them as though praising and kissing Christ. In this they imitated the behaviour of some of their ancestors. There are connections also to the historic belief in the royal touch, for the cure of scrofula. The patronage of the kings to lepers and leper-houses sheds light on their piety, as well as on their sense of tradition. Leper-houses which had been the beneficiaries of royal patronage in the twelfth century continued, mostly, to receive alms in the thirteenth century. The nature of patronage is also discussed, as the concern for lepers' material and spiritual welfare is very clear, particularly in the English sources. Although it is only Louis who has traditionally received recognition for his piety, Henry's actions demonstrate that he too epitomised thirteenth-century spirituality in his reverence for lepers and their spiritual value.

Background: The incidence of haematological cancers is increasing, however developments in treatment and survival rates mean that longer-term prognosis is improving. Nonetheless, the impact of cancer and its treatments remains with both short-term and long-term effects for patients and carers, which often results in persisting unmet supportive care needs. In addition, the shift of care delivery from inpatient to ambulatory setting and earlier hospital discharge, emphasises the need for services to support patients ability to self-manage. The healthcare team in an Italian Comprehensive Cancer Centre hospital implemented an ad hoc symptom management and supportive care telephone intervention based patients expressed feelings of abandonment after discharge. The intervention was unsustainable due to personnel resources and lacked a rigorous evaluation of patient acceptability. The aim of the PhD study was to develop a telephone intervention providing support and symptom management that is acceptable to patients undergoing or having undergone treatment for a haematological malignancy, based on the best available evidence. Methods: The MRC Framework was used as the basis for the development of the intervention. The evidence base to inform development was drawn from 3 sources. Firstly a systematic review of existing literature, and secondly qualitative research with key stakeholders: in-depth interviews with 20 patients with haematological malignancies and focus group(s) with a total of 10 expert haematology nurses. Framework Analysis was used to analyse data from the qualitative research. A synthesis of these findings was presented to a consensus group of key stakeholders within the local hospital setting in the subsequent modelling phase of the intervention development. Results: The application of telephone-based interventions to address cancer patients needs was evident throughout the literature within a variety of settings. Whilst it is said to be convenient, provide accessible and timely reassurance and continuity of care, it was not necessary or desirable for everyone. Stakeholders in qualitative research confirmed these findings, emphasising the need for individuality in interventions to adequately address the uniqueness of needs at different time points in the cancer trajectory. Factors including effective training for the intervention delivery, organisational support and integration into current practice were imperative for the sustainability of an intervention. The consensus group meeting agreed the definition and outline of an intervention delivered by the Primary Nurse, to monitor patients for physical, social or psychological needs and provide support through individualised care planning that can be trialled in practice. Conclusion: Unmet needs persist in patients with haematological malignancies throughout their survival trajectory, and telephone based interventions are one means of addressing these supportive care needs. The use of the MRC Framework as a guide has resulted in the development of a detailed intervention incorporating evidence from key stakeholders in order to arrive at an intervention that is acceptable both for those receiving and those delivering the intervention. Such a model may be the basis for supportive intervention in other clinical areas.

Breast cancer is one of the leading causes of death amongst women. According to the World Health Organisation (WHO), a significant increase in the incidence of breast cancer is expected in developing countries (such as Nigeria) by 2030. Mammography screening can significantly reduce the mortality and morbidity resulting from breast cancer. In Nigeria, however, 70% of the breast cancer cases are reported at its later stages, and evidence concludes that the participation level of eligible women in the mammography-screening programme is low. This study is the first to explore the factors affecting women’s attendance in mammography screening in the Lagos state via a qualitative approach. A qualitative descriptive approach is used to explore the views of susceptible women living in Lagos state. Seven focus group discussions (n= 65) and face-to-face interviews with five mammography practitioners in Lagos state were conducted. The study was guided by the theory of care seeking behaviour, and participants were questioned through semi-structured interviews and focus group guides. A conventional content analysis method was used to analyse the information gathered from the participants. Results have shown that lack of awareness among women influences their knowledge of benefits and risks, thus exposing them to several forms of fear and cultural issues (such as, trust in wonder drugs, believe in God, and the culture of non-disclosure of problems) which may directly affect their participation in mammography screenings. In addition, professionalism of mammography staff and government’s role in providing an effective mammography screening service were external factors found to influence women’s attendance. To conclude, the need for targeted education within the society is essential, as the participants identified that education might improve awareness, reduce fear and improve women’s attendance.

The thesis provides a comprehensive overview of key issues affecting practice, policy and patients, in current efforts for colorectal cancer (CRC) disease control. The global burden of CRC is expected to increase by 60% to more than 2.2 million new cases and 1.1 million deaths by 2030. CRC incidence and mortality rates vary up to 10-fold worldwide, which is thought to reflect variation in lifestyles, especially diet. Better primary prevention, and more effective early detection, in screening and surveillance, are needed to reduce the number of patients with CRC in future1. The risk factors for CRC development include genetic, behavioural, environmental and socio-economic factors. Changes to surveillance, which offer non-invasive testing and provide primary prevention interventions represent promising opportunities to improve outcomes and personalise care in those at risk of CRC. By systematic review of the literature, I highlight the gaps in comparative effectiveness analyses of post-polypectomy surveillance. Using micro-simulation methods I assess the role of non-invasive, faecal immunochemical testing in surveillance programmes, to optimise post-polypectomy surveillance programmes, and in an accompanying sub-study, I explore the value of adding an adjunct diet and lifestyle intervention. The acceptability of such revisions is exposed to patient preference evaluation by discrete choice experiment methods. These preferences are accompanied by evidence generated from the prospective evaluation of the health literacy, numeracy, sedentary behaviour levels, body mass index (BMI) and information provision about cancer risk factors, to highlight the potential opportunities for personalisation and optimisation of surveillance. Additional analysis examines the optimisation of a screening programme facing colonoscopy constraints, highlighting the attendant potential to reduce costs and save lives within current capacity.

Allosteric regulation is an efficient way of controlling enzymatic activity. In Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, ATPphosphoribosyltransferase (ATP-PRT) catalyses the first and committed step of the biosynthesis of L-histidine (L-His). L-His biosynthetic pathway is essential for Mtb and is absent in humans, making ATP-PRT an attractive target for the development of novel antibiotics. ATP-PRT is a hexamer in solution and, like other enzymes regulated via ferrodoxin-like (FL) domains, interconverts between an open active and a closed inactive conformation. Binding of L-His, its feedback allosteric inhibitor, shifts the equilibrium towards the closed state. The exact mechanisms of allosteric control of ATP-PRT activity are currently poorly understood. Likewise, it is unknown if perturbations in the allosteric regulation of ATP-PRT would be detrimental to Mtb. In this work, I characterised the allosteric regulation of ATP-PRT by L-His employing enzymology, biophysics, native mass spectrometry and X-ray crystallography. Using analogues of L-His, I showed that the allosteric inhibition is specific for L-His. A new targeted compound screen for possible allosteric regulators was developed and led to the discovery of 3-(2-Thienyl)-L-alanine (TIH) as an allosteric activator. Kinetic and structural analyses revealed uncoupling between ATP-PRT activity and conformational changes. In order to understand the molecular basis of allosteric regulation of ATP-PRT by L-His, I generated and analysed ATP-PRT variants with point mutations in the allosteric site. These mutations had a direct effect on ATP-PRT stability, activity and allosteric regulation by L-His and TIH. Overall, the results of this work show a complex allosteric regulation of ATPPRT by L-His while revealing the possibility of allosteric activation. Results with the ATP-PRT variants will guide us towards a detailed characterization of the allosteric control of ATP-PRT and its importance for Mtb, which might have implications to other FL domain-containing enzymes and prove useful for drug discovery.

Background: Early detection strategies for oral cancer aim to decrease the mortality rates and improve outcomes of the disease through early diagnosis and treatment. Guidance and regulatory bodies have an expectation that general dental practitioners will be able to promptly detect and refer patients with suspected oral cancerous lesions. However, the opportunities for early detection of oral cancer in primary dental care settings (particularly considering the low overall volume of the disease, the potentially increasing incidence rates, and the possibility of certain communities exhibiting particularly high rates) have not yet been investigated. This thesis examines the feasibility of early detection of oral cancer in primary dental care services, and undertakes risk-stratification to identify “high-risk” communities that can be utilised to target future early detection efforts. It further explores potential or missed opportunities for early detection in dental and other healthcare settings (both primary and secondary care), and assesses the feasibility of exploring routes to diagnosis. Aim: The aim of this thesis was to investigate opportunities for the early detection of oral cancer in Scotland by measuring the current burden of the disease, examining the feasibility of early detection in a dental setting, and exploring the potential role of alternative health care settings in early detection efforts. Methods: Descriptive epidemiological and data linkage cohort studies utilising national routine administrative health datasets were undertaken. The descriptive epidemiological analysis included all cases of head and neck cancer diagnosed between 1975 and 2012 and registered on the Scottish cancer Registry and annual midterm population estimates. These data were used to examine the incidence trends between 1975 and 2012 and the projected burden up to 2025 by individual subsites (oral cavity cancer, oropharyngeal cancer, and laryngeal cancer), age, sex, health board region, and socioeconomic status. The cohort study included all patients diagnosed with oral cancer between 2010 and 2012 and registered on the Scottish Cancer Registry. The individual patient data were linked to NHS dental service activity in the two years prior to diagnosis, and this linked cohort dataset and published NHS Scotland dental workforce and registration and participation statistics were used to examine dental attendance rates and the feasibility of early detection of oral cancer in the primary dental care setting. The individual patient data from the cohort were also linked to the hospital outpatient, hospital inpatient/day case, primary dental care, and general practitioner prescription databases. These four healthcare services were selected based on data availability. The linked data were used to examine all healthcare service contacts made by the cohort in the two years prior to referral. Additionally, a preliminary exploration of the referral period (defined as the one-month period prior to diagnosis) was also undertaken. Results and conclusions: The findings of this thesis showed that the incidence rates of head and neck cancer had increased in Scotland between 1975 and 2012, and this appeared to be largely driven by a dramatic rise in the rates of oropharyngeal cancer in recent decades. This burden was predicted to continue to rise up to 2025, with the rates of oropharyngeal cancer bypassing the rates of oral cavity cancer, which were expected to exhibit only a modest increase. Males, individuals above 60 years of age, and those from the most deprived areas of Scotland consistently exhibited the highest rates of cancer, irrespective of subsite. Moreover, an almost dose-like effect was seen to exist, with the rates of cancer increasing with the level of deprivation. Therefore, contrary to previous reports that oropharyngeal cancer exhibited an inverse socioeconomic profile, Scotland country-level data showed that those from the most deprived areas consistently bore the greatest incidence burden of head and neck cancer. Despite these increasing trends, the overall burden of oral cancer in Scotland was relatively low, and just over half of the cohort examined in this thesis had not contacted a general dental practitioner in the two years prior to diagnosis, thus automatically limiting opportunities for early detection. Dentists were estimated to potentially encounter one patient with oral cancer every 10 years, one patient with oral cavity cancer every 17 years, and one patient with oropharyngeal cancer every 25 years. Therefore, strategies for early detection must consider the rarity of oral cancer incidence and the poor dental attendance patterns of patients, and the expectations of dentists in these efforts must be tempered. These results also highlight the importance of improving access and uptake of dental services among those at the highest risk of developing oral cancer (i.e. those from the most deprived communities). When examining the linked cohort data and undertaking a look-back analysis of their healthcare service contact history, just under half (45%) of the patients diagnosed with oral cancer were seen to have actually visited a primary care dental service clinic in the two years prior to the start of the referral period. However, the majority of the patients with oral cancer had contacted one of the four healthcare services examined (hospital outpatient, hospital inpatient/day-case, primary dental care, and general practitioner prescription) at least once over the same period, suggesting that there were potential or missed opportunities for the early detection of oral cancer in primary dental care and alternative healthcare settings. The proportions of patients contacting the four services increased closer to the start of the referral period, as did the mean number of contacts made with each service. Although not all of these instances would have necessarily been associated with missed opportunities for early detection, it was highly likely that there were potential or missed opportunities amongst at least some of the patients with oral cancer. The two most common services contacted most recently before the start of the referral period were general practitioner prescription and hospital outpatient, and there was a possibility that these services were the sources of referral. The hospital specialties contacted most frequently during the one-month referral period were ENT, oral surgery, oral and maxillofacial surgery, and general surgery, suggesting that these contacts were likely to have been associated with the signs and symptoms of oral cancer. While no significant opportunities for the early detection of oral cancer in hospital or secondary care settings were identified, these findings demonstrated considerable potential in other primary care settings, particularly general medical practices and community pharmacies.

Socioeconomic inequality in cancer risk and incidence burden has received limited attention compared to genetic and behavioural risk factors. Where they have been studied, the temporal relationship between socioeconomic factors and cancer risk has been under explored due to the mainly cross-sectional nature of most research. Moreover, the inter-relationships of the multiple measures of socioeconomic status and, in particular, area and individual measures and their interaction with risk behaviours have also had limited attention. The overarching aim of this thesis was to investigate socioeconomic inequalities in the risk of lung and upper aero-digestive tract cancers and the relationship between this risk and socioeconomic status, area and individual based measures of socioeconomic circumstances, and behaviours such as smoking, alcohol consumption, diet and exercise. To understand and quantify the relative contribution by age, sex and tumour subtype to the socioeconomic inequalities of all cancer risk, a descriptive epidemiological study of cancer incidence in Scotland (2000-07) was undertaken. Age standardised rates per 100,000 population were calculated by direct standardisation to the European standard. A linear regression model was used to calculate the Slope Index of Inequality (SII) and Relative Index of Inequality (RII) which were employed to rank tumour and subtype contribution to all cancer risk socioeconomic inequalities by age for each sex for lung and upper aero-digestive tract (UADT) cancers separately. There were 216,305 cases excluding nonmelanoma skin cancer (all cancer) comprising 37,274 lung, 8,216 head and neck and 6,534 oesophageal cancers classified into anatomical or morphological subtypes. Socioeconomic circumstances were measured using the Scottish Index of Multiple Deprivation (SIMD). Analyses were partitioned by five-year age group and sex. RII was adapted to rank the contribution of each tumour type to all cancer socioeconomic inequalities and to examine subtype by age and sex simultaneously. The rank was defined as the proportion of all cancer socioeconomic inequality. All cancer socioeconomic inequality was greater for males than females (RII=0.366; female RII=0.279). The combination of lung and UADT socioeconomic inequalities contributed 91% and 81% respectively to all cancer socioeconomic inequality. For both sexes lung and UADT subtypes showed significant socioeconomic inequalities (P < 0.001) except oesophageal adenocarcinoma in males (P=0.193); for females, socioeconomic inequality was borderline significant (P=0.048). Although RII rank differed by sex, all lung and larynx subtypes contributed the most to all cancer socioeconomic inequality with RII rank for oral cavity, oesophagus–squamous cell and oropharynx following. For males 40-44 years old, socioeconomic inequalities increased abruptly peaking at 55-59 years. For females, socioeconomic inequalities gradually peaked 10 years later. In both sexes, the socioeconomic inequalities peak age preceded age of peak incidence. This study showed that socioeconomic inequalities in lung and UADT cancers vary greatly by age, tumour subtype and sex; these variations were likely to largely reflect differences between the sexes in risk behaviours which vary by birth cohort and are socioeconomically patterned. Longitudinal data enabled exploration of the temporal relationship between socioeconomic status and cancer incidence. An investigation of several individual and a single area-based measure of socioeconomic circumstances was undertaken in the second study of this thesis. The effect of country of birth, marital status, one area socioeconomic circumstances measure (Carstairs) and five individual socioeconomic variables (economic activity, education, occupational social class, car ownership, household tenure) on the risk associated with lung, UADT and all cancer combined (excluding non-melanoma skin cancer) were explored. A linked dataset using the Scottish Longitudinal Study and Scottish Cancer Registry was created to follow 203,658 cohort members aged 15+ years from 1991-2006. Relative risks (RR) were calculated using Poisson regression models by sex offset for person-years of follow-up. There were 21,832 first primary tumours (including 3,505 lung and 1,206 UADT cancers). Regardless of cancer, economic inactivity (versus activity) was associated with increased risk (male: RR 1.14 95% CI 1.10, 1.18; female: RR 1.06 95% CI 1.02, 1.11). For lung cancer, area deprivation remained significant after full adjustment suggesting that the area deprivation cannot be fully explained by individual variables. Not having a qualification (versus degree) was associated with increased lung cancer risk; likewise for UADT cancer risk (females only). Occupational social class associations were most pronounced and elevated for UADT risk. No car access (versus ownership) was associated with increased risk (excluding all cancer risk for males). Renting accommodation (versus home ownership) was associated with increased lung cancer risk, UADT cancer risk for males only and all cancer risk for females only. Regardless of cancer group, elevated risk was associated with no education and living in deprived areas. This study demonstrated that different and independent socioeconomic variables were inversely associated (greater incidence with lower socioeconomic circumstances) with different cancer risks in both sexes; no one socioeconomic variable had a dominant risk association or captured all aspects of socioeconomic circumstances or the full life-course. The association of multiple socioeconomic variables was likely to reflect the complexity and multifaceted nature of low socioeconomic circumstances as well as the various roles of these dimensions over the life-course. A final study investigated the role of behaviours (smoking, alcohol, diet and exercise) on the association of low socioeconomic circumstances with all cancer risk and lung and upper aero-digestive tract cancers combined (LUADT). The Scottish Cancer Registry and Scottish Health Survey data were linked to create a population study (1995-2011). There were 42,983 adults over 16 years old who were followed for 3,750,611 person-years. There were 2,130 first primary cancers diagnosed including 453 LUADT cancers. Poisson regression models, minimally adjusted by age and sex, were developed to estimate the risk association between five individual socioeconomic variables (economic activity, highest qualification, occupational social class, car ownership and housing tenure), one area-based socioeconomic indicator (SIMD) and all cancer and LUADT cancer. A further socioeconomic indicator was developed to reflect multiple low socioeconomic circumstances. This was defined as the count, at the individual participant level, of socioeconomic variables in the highest risk category. A similar multiple high risk behaviour derived variable, defined as the count of highest risk category for the following variables: current smoking status, units of alcohol consumed in a week, daily fruit and vegetable consumption and exercise sessions per week, was also calculated at the individual participant level. The minimally adjusted Poisson models were successively adjusted for behaviours (smoking, alcohol, diet and exercise) to establish any remaining contribution to cancer risk not explained by behaviour. Multiple low socioeconomic circumstances were very strongly associated with increased risk for both cancer groups. For all cancer risk, the elevated risk was nearly fully attenuated for all categories of multiple low socioeconomic circumstances when adjusted for smoking only. For LUADT cancer and in the minimally adjusted model, the risk increased in a dose-response manner., The risk associated with LUADT cancer for study participants in the highest category of multiple low socioeconomic circumstances was more than three-times greater when compared to their affluent counterparts (RR 3.35 95% CI 2.26, 4.97); this elevated risk remained at 86% compared to those with no socioeconomic disadvantage, even after full adjustment for smoking, alcohol, diet and exercise behaviours. When looking at single socioeconomic status (SES) indicators, only those who rented accommodation from a local authority remained at a 50% increased risk of LUADT cancer even after adjustment for all the behaviours (RR 1.50 95% CI 1.05, 2.16). This study demonstrated that smoking is a major inequality issue and a significant cancer risk which is socially patterned. Further analytical research is required to fully understand the pathways and mechanisms between socioeconomic circumstance and lung and upper aerodigestive cancer risk.

Introduction: Malignant Pleural Mesothelioma (MPM) is an incurable malignancy with severe symptoms. It is challenging to diagnose and with limited treatments. The studies described here aim to determine the diagnostic accuracy of four biomarkers in MPM, identify factors to aid prognosticating, and test the efficacy of a novel intervention, early specialist palliative care (SPC). Methods: In the biomarker study ELISA evaluated SMRP, Fibulin-3, Osteopontin and HMGB-1 concentrations in MPM patients. Regression analysis assessed the ability of a series of patient factors from a retrospective MPM patient cohort to predict prognosis. The RESPECT-Meso study was a randomised controlled trial assessing early SPC versus standard care in a 1:1 ratio on quality of life (QOL) in 174 MPM patients. Key findings: The biomarker study revealed effusion SMRP levels were significantly higher in MPM patients compared to benign and other malignant effusions (3170nM/L vs 210nM/L vs 428nM/L, p < 0.001). SMRP predicted MPM with an AUC of 0.93 (0.86-0.99) giving 95% sensitivity and 86% specificity at a threshold of 1150nM/L. In the analysis of prognostic factors patient age, smoking status, chest pain, weight loss, PLT count, Urea and Adjusted Calcium were independently associated with survival. Being a current smoker carried the highest hazard ratio 3.42 (1.11, 4.2) p=0.03. The RESPECT-Meso study was unable to demonstrate a difference in QOL with early SPC compared to standard care with a 1.8 mean difference between groups (95%CI: -4.9 to 8.5; p=0.59). Conclusions: This body of work evaluating three components of MPM care concludes, SMRP as a biomarker with a significant ability to predict MPM from other causes of pleural effusion in a real world clinical setting. Seven prognostic factors identified may aid clinicians to better prognosticate when planning treatments in MPM. Finally the results of the RESPECT-Meso study are reassuring of the exiting care pathway for MPM.

Evidence suggests that 26.8% of new breast cancer cases can be attributed to extrinsic influences, such as lifestyle and environmental factors. Whilst we have increased knowledge surrounding factors like alcohol and obesity, little is known regarding environmental pollutants, such as endocrine disrupting chemicals (EDCs), which are defined by their ability to interfere with the regulation of an individual's endocrine system. Research has so far proven inconclusive, with effects only observed at concentrations considerably higher than those present in human tissues and in unrepresentative assay systems. Utilising 3D in vitro assays that recapitulate characteristics of the human mammary gland, the relationship between low-dose EDC exposures (comparable to concentrations found in human tissues) and breast carcinogenesis was investigated. This work showed, both in primary cells and in the ER-positive MCF-12A cell line, that EDCs can affect acini development, gene expression and DNA methylation. Changes were indicative of neoplastic transformations, including increases to acini size and loss of circularity. Genetic and epigenetic modifications to genes associated with breast tumourigenesis, such as cell cycle regulators and tumour suppressors, were observed at concentrations relevant to human exposures. Similar changes were seen in predisposed individuals with a BRCA1 mutation, translating into a significant impact on absolute risk of breast cancer. The ability of chemical mixtures to increase breast cancer risk was also considered. When combined at concentrations in human tissues, four EDCs (dichloro-diphenyl-trichloroethane, benzophenone 3, bisphenol A and propylparaben) acted together to produce a significant effect, by disrupting acini formation and gene expression. These findings demonstrate the capacity of EDC exposures to contribute to breast cancer risk. Increasing our understanding of chemical contributions to cancer development provides opportunities for cancer prevention and more comprehensive risk model development. Results demonstrate a need for further research in this area and act as a foundation for future studies.

Skin cancer caused by exposure to sunlight and sunburn is the second biggest killer of young men aged 18 to 24 and the most preventable cancer. Skin cancer incidence and mortality have increased steadily over recent years in the UK. This thesis presents the development of strategies to foster sun protection behaviour in young men by designing new human-centred interventions. The methodological approach taken in this research is an interpretive methodology which is used to explore the underlying meaning of young men’s actions and experiences in relation to their sun protection behaviour. An exploratory study was conducted involving observations and interviews in a beach location where sun protection behaviour could be observed. The pilot data highlighted a link between young men and their sun protection behaviour and the ways in which concepts of gender and masculinity were instrumental in influencing their sun protection behaviour. The results informed the main study of the research, which was carried out through participatory design sessions. This study engaged the participants in the HCD approach in a gender-aware context which resulted in a range of sun protection interventions. The results led to the inception of the final study, which verified the sun protection interventions and the facilitated gender-aware human-centred design approach. The results highlighted a constructive relationship between HCD principles and understanding gender impacts, thus opening new avenues and knowledge paths to bridge the gap between the world of designers and the world of users. This approach goes beyond the aim of the research and contributes towards two main directions: 1) It presents the development of novel gender-aware human-centred design theory (GAHCD), and 2) it demonstrates a range of sun protection interventions to increase sun protection behaviour in young men. On this basis, the key results are presented in the form of design recommendations and guidelines for sun protection interventions for young men aged 18 to 24.

This thesis deals with the topic of head and neck cancer (HNC) follow-up from a health economics perspective. Despite recent advances in treating primary HNC, the long-term prognosis of these patients is still poor due to a high risk of cancer recurrence. Until now, there is no agreement about the best way of monitoring patients after the end of therapies. Moreover, patients’ preferences for alternative surveillance schemes are unknown. A multicentre randomized controlled trial comparing two follow-up strategies of different intensity is currently ongoing in Italy. This thesis aims at filling some of the literature “gaps” around HNC surveillance, using Italy as a case study. The first chapter introduces the topic. The second chapter is a systematic literature review and critical appraisal of economic evaluation studies of post-treatment follow-up programs in any cancer type. The third chapter is a systematic literature review and quality appraisal of studies reporting original health state utility values in HNC, with a focus on articles addressing the post-treatment phase. The fourth chapter maps the EuroQol 5-Dimension 5-Level (EQ-5D-5L) utility values from two cancer-specific measures developed by the European Organization for Research and Treatment of Cancer (EORTC) by using a variety of regression techniques (linear, Tobit, mixture models) and several EQ-5D-5L country tariff sets; the developed functions are useful to inform future economic evaluations in HNC. The fifth chapter presents an exploratory model-based economic evaluation of the two follow-up strategies under investigation in the trial, where an intensive program of radiological assessments is compared to a symptom-driven surveillance; the cost analysis is conducted from a regional healthcare system perspective in Italy. Lastly, the sixth chapter presents a discrete choice experiment using best-worst scaling to elicit patients’ preferences during follow-up at the National Cancer Institute (Milan, Italy).

An association between diabetes mellitus and tuberculosis has been established: systematic reviews suggest that individuals with diabetes are three times more likely to develop active tuberculosis disease and have nearly a two-fold increased risk of death from tuberculosis than individuals without diabetes. The context of these associations in southern Africa may differ from the rest of the world due to the high prevalence of HIV and the high prevalence of poorly controlled diabetes mellitus in this region. Most prior studies have measured glycaemia at the time of tuberculosis diagnosis as a proxy for diabetes. Physiological stress from acute TB infection can also cause hyperglycaemia, so we use the term hyperglycaemia to encompass both diagnoses until the two can be differentiated. We conducted a case-control study in Lusaka, Zambia to determine if HIV modifies any association between hyperglycaemia and active tuberculosis. We recruited 3,843 tuberculosis cases and 6,977 controls and found no evidence of an overall association between hyperglycaemia and active tuberculosis, though there was a significant effect modification by HIV: among individuals with HIV there was a positive association. A subset of cases from the case-control study were recruited to a cohort study to determine whether a dose-response relationship exists between hyperglycaemia and tuberculosis treatment outcome. We found no evidence of a relationship. A study of diagnostic accuracy used a further subset of cases from the case-control study to determine the diagnostic accuracy for diabetes mellitus of measures of hyperglycaemia used at the time of tuberculosis diagnosis compared to a reference standard. We found a low proportion of hyperglycaemia measured at the time of tuberculosis diagnosis was due to diabetes mellitus, particularly among individuals co-infected with HIV. Glycated haemoglobin showed no greater test accuracy for diabetes diagnosis at the time of tuberculosis diagnosis than fasting or random blood glucose tests.