Mathematical models are a fundamental component of many epidemiological studies. While models of infectious disease are well established, there are evident methodological gaps when attempting to provide realistic descriptions of particular biological systems. In this thesis we probe questions related to two global public health problems, zoonotic influenza and depression, requiring innovative modelling approaches to be developed, analysed and fitted to data. We give particular consideration to parameter inference schemes to gain insights into the dynamics of these illnesses, and model simulation for validation and prediction purposes, including assessing intervention impact. First, we investigate zoonotic influenza transmission at a local scale, our example being H5N1 in Bangladesh. It is vital to devise new models incorporating zoonotic transmission, and establish the factors enabling both continued transmission within poultry and spillover across the poultry-human divide. We outline a set of candidate transmission models, with a zoonotic transmission component, parameterised with a Bayesian inference scheme using data from two H5N1 outbreaks in the Dhaka region. Applied at two distinct spatial scales, we elucidate the model considerations that best capture the size and spatial distribution of reported cases. Simulations then illustrate the predicted impact of interventions designed to reduce H5N1 transmission. Second, the emergence of influenza strains with pandemic potential is considered from a global viewpoint. Using a Bayesian model selection approach we compare plausible model hypotheses regarding the mechanisms driving influenza pandemic occurrences. Analysing the time periods between putative influenza pandemics since 1700, it is shown the weight of evidence favours influenza pandemic emergence being history-dependent, rather than a memoryless process. Predictive distributions are then presented for the expected number of pandemic events from 2010 to 2110. Third, spread of behaviour-linked health problems are amenable to being represented with methodological approaches typically used to model infectious diseases. We explore this with regards to depression, using a longitudinal dataset comprising information on both the in-school friendships and mood status of US adolescents. A novel model is described that exploits the dynamical behaviour of mood over time to ascertain which mood states spread on social networks, via a contagion-like mechanism, and which do not.

Clinical practice guidelines are developed worldwide, at an ever increasing rate (Sandström et al., 2015) and accessed internationally without a full understanding as to whether they are applicable in cross cultural settings. Informed by a review of the literature which identified a range of theories, frameworks and models to guide knowledge translation, the Promoting Action on Research Implementation in Health Services (PARIHS) framework (Kitson et al., 1998b), was selected as a suitable framework to explore evidence based clinical guideline development work in a cross cultural context. This research study was an exploration of the appropriateness and utility of the PARIHS framework, in the cultural translation and adaptation of an evidence based clinical practice guideline into clinical practice in the healthcare system in Malta. It also aimed to identify challenges and barriers to successful cultural translation and implementation to inform future cross cultural knowledge translation programs. A case study using an embedded single case was used. Data collection consisted of two focus groups with multidisciplinary healthcare professionals (n=11 and n=5), eighteen semi structured interviews (n=9 pre and n=9 post) and non-participant observation of two guideline development groups. Data was analysed both inductively and deductively using Framework Analysis. Findings of the study indicate that the components of the PARIHS framework of evidence, context and facilitation are useful to guide the cultural translation and adaptation of an evidence based clinical practice guideline. In addition, a number of challenges and barriers to successful translation and potential implementation were identified; the influence of politics, culture and context, stakeholder involvement including patient involvement, and resources, both human and financial. Overall the PARIHS framework is a useful tool to guide the cultural translation and adaptation of an evidence based clinical practice guideline. The study identified important additions to the PARIHS framework to improve its utility: expanding the use of culture in the PARIHS framework to include macro, meso and micro dimensions; the need for a definition of what context means within the PARIHS framework; the inclusion of politics as a sub element of context; the importance of resources, and acknowledging the role of the patient within the framework.

This thesis presents work from six papers written by the late Dr Carl McQueen during his time as a National Institute for Health Research Doctoral Research Fellow working at the University of Warwick. It explores how best to improve the outcomes of patients who sustain major trauma in the UK – something McQueen was passionate about. Mobile enhanced care teams can bring the specialist skills usually limited to a hospital to the patient’s side at the point of injury. One of the key specialist interventions such teams can provide is prehospital anaesthesia. In a retrospective observational study from a regional enhanced care team, McQueen showed that prehospital anaesthesia was delivered with a high success rate to patient who sustained major trauma and were unconscious, with or without airway compromise. The decision about when to send an enhanced care team to the scene of an emergency is challenging. Often insufficient information is available about the nature of the victim’s injury or illness to make an informed decision. McQueen showed that it was relatively rare for patients with medical problems or those linked to equestrian incidents to require specialist intervention. McQueen also showed the location of patients requiring enhanced care skills varies by time of day with most incidents at night occurring around cities / large towns. A systematic review of the literature found little evidence to guide decision making for primary dispatch of the enhanced care teams. Despite the paucity of evidence for triage systems to inform dispatch of enhanced care teams, reorganisation of regional trauma services in the West Midlands appears to have improved targeted dispatch of enhanced care teams. Together these papers show the potential for benefit from better co-ordination of enhanced care teams.

Introduction: Despite considerable efforts directed at developing international evidence based guidelines to improve clinical management, adoption of evidence based practices can be poor in low-income settings including Kenya. Studies in Africa rarely consider the implementation and change processes as influenced by the structural and organizational context in which clinicians are embedded nor how these can influence performance. This thesis builds on existing literature and theory on behavioural change, clinician-managers’ identity construction processes and contextualized leadership processes by examining these and their effect on guideline adoption in the complex contexts of Kenyan county hospitals. Methods: Methodologically I explored these issues through qualitative ethnographic approaches using in-depth interviews, focus group discussions and non-participant observations. I analyzed data inductively and deductively borrowing from the grounded theory approach to develop plausible explanations of collated data and observations. Results: Early work indicated limited attention to local dissemination of the new guidelines and poor leadership in implementing Evidence Based Medicine (EBM) as key barriers. However, specially introduced ‘study facilitators’ as part of an intervention study emerged as leaders of change often acting as role models, friendly supervisors and peer educators to facilitate EBM implementation. Further work reviewing literature on the roles of clinical mid-level managers (MLMs; department leaders) in improving service delivery emphasized the importance of ‘soft skills’ e.g. building interpersonal relationships, mentoring, coaching and effective communication skills. Subsequent in-depth empiric work on identity transitions of these clinical MLMs indicated that ‘identity work’, drawing on competing professional and managerial institutional logics resulted into ‘willing’, ‘ambivalent’ and ‘reluctant’ hybrids. Distributed leadership by hybrids was undermined by existing hierarchical professional autonomy and cadre delineations between nurses and doctors in the public county hospitals we studied. Discussion: The thesis describes both a set of work and a research journey. My initial work was predominantly based on applying the Theory of Planned Behaviour to explain behaviour of front-line health workers. However, it quickly became clear that this provided only a partial understanding of guideline adoption within a hospital overlooking the pivotal role of clinical team leaders / in influencing change. There emerged valuable lessons for current Kenyan leadership and management development programmes which are likely to be transferable to other African health systems. Particular recommendations from this work are the importance of a focus on the soft-skills of those stepping into clinical hybrid manager roles and considering the ‘practical norms’ of Kenyan public hospitals in understanding the gap between desired official institutional norms and health workers actual behavioural practices.

Bacterial infection is a major cause of morbidity and mortality in sub-Saharan Africa especially among young children. Despite the high burden of disease caused by bacterial infection in Africa, there remains a significant paucity of data on the molecular epidemiology of most pathogens in the sub-region. Healthcare facilities are generally underfunded in West Africa and most facilities lack the basic capacity to perform standard microbiological identification of bacterial pathogens. Understanding the biology and epidemiology of pathogens is fundamental to a successful intervention strategy. Genomics offers unprecedented insights into the epidemiology and biology of infectious diseases, which dominate the public health agenda in West Africa. Here, I introduce a case study of three important pathogens in West Africa. I describe a unique scenario associated with each pathogen and present WGS as a solution to the problem. Firstly, whole genome sequencing has provided insights into the evolutionary origin of Staphylococcus aureus in monkeys from The Gambia and established that monkeys in The Gambia do not pose a threat of serving as reservoirs of highly virulent S. aureus that can infect humans. Secondly, genomics has unravelled the evolutionary mechanisms that led to the emergence of a novel clone of serotype 1 Streptococcus pneumoniae, which caused an outbreak of meningitis in Ghana following the introduction of the 13-valent pneumococcal vaccine, PCV-13. Thirdly, through genomics we are beginning to build a deeper understanding of the epidemiology of Mycobacterium tuberculosis complex in West Africa. Genomics is unravelling the evolutionary mechanisms that are driving the emergence of multidrug resistant tuberculosis. Importantly, genomics has shown that lineages of MTBC that are endemic to West Africa are the principal proponents of multidrug resistance in this sub-region. The time has come for West Africa to embrace the genomics era and exploit the full potential of microbial genomics. I hope that my work will inspire West African scientists to embrace whole genome sequencing in the fight against infectious bacterial disease.

This PhD submission presents a case study of an academic group working as infomediaries at the interface between research and global policy, and at the interface between global policy and national decisions: advising on methodological issues, conducting systematic evidence reviews in response to information needs, and developing approaches for reinterpreting global guidance for national decision-making. The included systematic reviews were among the first to adopt innovative elements such as: summary of findings tables, standardized language reflecting the level of certainty in effect estimates, logic frameworks, and brief economic summaries; and have contributed to the further development of these methods. This work has helped to establish formal and transparent methods within global malaria guidance, and contributed to improved standards in global guidance more broadly.

Background: Rheumatoid Arthritis (RA) is associated with increased risk of cardiovascular disease (CVD). Physical inactivity is a modifiable risk factors of CVD and frequently associated with impaired functional status and health related quality of life. Objectives: This single blind randomised controlled trial investigated the impact of a pedometer-supported walking and education programme (Walk for RA-WARA) on PA, sedentary time, PA self-efficacy, disease activity, functional capacity, quality of life and cardiovascular (CV) risk in people with RA. Methods: Seventy-six individuals, aged 56 (±15) years and within 5 years from RA diagnosis were randomly assigned to either the WARA intervention group (six weekly group education sessions and two booster sessions at 3 and 6 months) or the control group (single session). Demographic data were recorded and Body Mass Index (BMI), Waist-Hip ratio (WHR), Waist-Height ratio (WHtR), and blood pressure were measured. The primary outcomes were objectively measured PA profiles, daily step counts and time spent sedentary, using an activPALTM and self-reported using international physical activity questionnaire (IPAQ). Functional status was assessed with six-minute walk test (6MWT), health assessment questionnaire (HAQ), and hand grip strength. Rheumatoid arthritis quality of life (RAQoL) and PA Self-efficacy were evaluated. Blood samples were taken and the 10-year risk of CVD scores were calculated, using the Scottish Intercollegiate Guidelines Network (ASSIGN). Data were analysed descriptively and mixed generalised linear models (GLM) were used incorporating restricted maximum likelihood (REML) and post-hoc analyses. Interviews were undertaken with 10 people from the intervention and data were analysed thematically using the framework approach and NVivo 11 software. Results: The intervention group showed a significantly greater increase than the control group in steps/day at 3 months (by 3413 (1835-4990) steps/day, mean (95%CI)) (P < 0.001), and 6 months (3599 (2135-5062) steps/day) (P < 0.001) and a significant reduction in IPAQ weekday (P=0.014) and weekend sitting time (P=0.046). There were significant improvements in 6MWT (P < 0.001), PA self-efficacy (P=0.008), systolic blood pressure (P=0.002) and ASSIGN scores (P < 0.001) in the intervention group. Participants found education sessions, booster sessions, hand-outs, pedometer, PA diaries were important factors in increasing their step counts. In addition, they stated that WARA programme was enjoyable and helpful in terms of raising their knowledge regarding their condition. They also reported they felt much healthier and their mood had improved. Conclusions: The 6-month WARA intervention was effective in promoting PA, PA self-efficacy, physical function, and reducing the 10-year risk of CVD. The WARA programme may be a useful adjunct to current clinical practice in rheumatology.

Os radionuclídeos naturais das séries radioativas do 238U, 235U e 232Th são frequentemente utilizados como traçadores em estudos ambientais para a compreensão da dinâmica que ocorre no ambiente marinho e terrestre, como por exemplo, em pesquisas de processos oceânicos e gerenciamento da região costeira. No ambiente marinho, estes radionuclídeos podem ser empregados para estimar fluxos biogeoquímicos de partículas e de nutrientes que ocorrem tanto na coluna dágua, quanto nos sedimentos. Várias pesquisas aplicam a distribuição e o respectivo desequilíbrio dos radionuclídeos naturais no meio ambiente, inclusive em modelos geocronológicos para se obter informações históricas em testemunhos sedimentares. Nesse estudo, realizou-se a caracterização radioquímica das distribuições de 226Ra, 228Ra e 210Pb de uma coluna sedimentar denominada 1B (248 cm de comprimento), coletada na Baía do Almirantado, Antártica. A metodologia utilizada incluiu a lixiviação ácida de amostras de sedimentos, seguida de separação radioquímica sequencial de 226Ra e de 228Ra pela co-precipitação com Ba(Ra)SO4 e de 210Pb pela co-precipitação com PbCrO4. Todas as medidas foram realizadas pela contagem alfa e beta total dos precipitados obtidos, em um detector proporcional de fluxo gasoso de baixa radiação de fundo. As concentrações de atividade de 226Ra e 210Pb foram empregadas para se estimar a atividade de 210Pbnão-suportado presentes no perfil sedimentar 1B. Considerando-se as concentrações de atividade de 210Pbnão-suportado obtidas e a aplicação do modelo CIC(Constant Initial Concentration), foi possível determinar a taxa de sedimentação de 0,59±0,05 cm/ ano. / The natural radionuclides from radioactive series of 238U, 235U and 232Th have been applied as tracers in environmental studies for understanding the dynamics that occur in both marine and terrestrial environment, as for example, in research of oceanic processes and management of the coastal region. In the marine environment, these radionuclides can be used to estimate biogeochemical fluxes of marine particles and nutrients that occur in the water column as well as in the sediment. Several research works applied the distribution and the respective disequilibrium degree of natural radionuclides in the environment, including geochronological models for obtaining historical information on samples of certain sediment profile. In this study we performed a radiochemical characterization of the distribution of 226Ra, 228Ra and 210Pb from a sedimentary column called 1B (248 cm long) collected in the Admiralty Bay, Antarctic Peninsula region. The methodology used included the acid leaching of sediment samples followed by the radiochemical sequential separation of 226Ra and 228Ra by co-precipitation with Ba(Ra)SO4 and 210Pb by co-precipitation with PbCrO4. All measurements were carried out by counting of gross alpha and gross beta measures in a low background gas flow proportional detector. The activity concentrations of 226Ra and 210Pb were used to estimate the unsupported 210Pb activities present in sediment profile 1 B. Based on unsupported 210Pb data and the application of the CIC model (Constant Initial Concentration), it was possible to determine the sedimentation rate of 0.59 ± 0.05 cm /year.

The aim of this study was to determine the extent of dissemination of pCT, a blaCTX-M-14 carrying plasmid, and to investigate the factors which allow pCT to stably persist within bacterial populations. DNA sequencing of pCT allowed the design of a PCR assay for rapid detection of pCT, which showed pCT has disseminated worldwide in bacteria from humans, animals and the environment. pCT was stably maintained in the absence of β-lactam antibiotic pressure in four different bacterial host strains over ~70 generations, and conferred neither a fitness advantage nor disadvantage to two host E. coli strains. Seven pCT genes of interest in relation to plasmid success were identified and insertionally inactivated to investigate their role in the ‘success’ of this plasmid. Inactivation the conjugation pilus reduced the frequency of pCT transfer however inactivation of the five other pCT genes had no consistent effect on the host bacterial strain persistence or dissemination. In conclusion, pCT was shown to be a globally successful plasmid. The persistence and spread of pCT is postulated to be due to a combination of stability, a lack of a fitness burden and proficient conjugation, rather than any one particular gene or phenotypic benefit conferred to the host.

This body of work sought to explore kinematic impairments which may underlie falls incidences during turning following stroke and review the evidence for the effectiveness of interventions aimed at improving aspects of locomotor coordination which are key to controlling turning. A systematic review of the literature identified insufficient homogeneity of high quality evidence to determine if task specific locomotor practice interventions are effective in improving aspects of gait coordination which are key to the controlling turning. The review highlighted a need for a better understanding of the nature of coordination deficits in functional walking tasks, such as turning, after stroke. In order to provide a base of knowledge regarding abnormalities in the coordination of locomotor patterns during turning while walking, two experimental studies were undertaken. The studies employed analysis of full-body kinematics during turns made under pre-planned and reactive conditions as well as turns of different magnitudes and those made by participants with and without a falls history. Findings from Study 1 showed a strong trend for participants with stroke (in particular those with lesions involving the basal ganglia) to initiate pre-planned turns later than their age-match counterpart. Turns made in response to an external cue were made in a similar manner to healthy controls. Results from study 2 indicate that while participants with stroke and falls history took significantly longer to turn, all other aspects of the movement pattern were similar to healthy controls and non-fallers. Therefore, incidences of falls during turning following stroke may not be due to impaired movement patterns alone. On this basis, we suggest that rehabilitation efforts and further studies should address the interplay of impaired movement production with other factors such as attention.