Expanding our horizons: an exploration of hominin landscape use in the Lower Palaeolithic of Britain and the question of upland home bases or lowland living sites.

The majority of Lower Palaeolithic assemblages are recovered from lowland fluvial locations, and hence most interpretation is based around these. It is clear, however, that these represent only a small fraction of the hominin landscape and this bias is potentially limiting our understanding of hominin organisation to only a single facet of behaviour. While recent authors have recognised the importance of upland sites, and other non-fluvial contexts, research is currently limited to highly specific studies (such as Boxgrove), and often fail to extend the purview to incorporate the wider landscape. Consequently we are still a long way from answering basic questions such as: how and why were hominids utilising particular locations? How, if at all, does behaviour respond to landscape context? Is the same pattern seen in continental Europe? This research applies a landscape approach to the British Palaeolithic, combining a technological, typological and chaîne opératoire methodology to determine assemblage signatures for a variety of landscape types (lowland riverine, lacustrine, grassland plains and uplands). An exploratory Geographical Information Systems (GIS)approach is applied to the upland study areas to gain a better understanding of settlement structuring and how behaviour responds to landscape context. The results are then considered in terms of behavioural variation, site choice, specialisation and provisioning across the landscape

To what extent can the internationalization of non-governamental organizations (NGOS) improve their effectiveness when acheving their missions?

This dissertation investigates how the strategic tool of internationalization can be used by International Non-Governmental Organizations (INGOs) in the advancement of their missions. The purpose of this study is to analyse if this strategy has helped these organizations achieve their long-term missions of eradicating poverty. The literature discusses the changing roles of NGOs in a globalized world alongside the increasing pressures for the Third Sector in terms of competition, accountability and transparency. A case study methodology is adopted referencing Yin (2009) and the advantages that this research method can have for management studies. A case study comparison is utilised when comparing ActionAid International who began its internationalization process at the end of 2003 when moving their headquarters (HQ) to Johannesburg, South Africa. In contrast, Oxfam International plans to relocate HQ to Nairobi, Kenya in 2017. The results of the study illustrate that internationalization is a complex phenomenon and both case studies had different reasons for adopting the strategic tool. This research paper hopes to provide value research for NGO managers who may decide to internationalize in the future. Limitations of the study are due to the results being from the perspective of both the organizations under investigation. Further research is recommended to analyse the effectiveness of Oxfam International after its internationalization has been completed. Alongside the task of developing a universal measure for measuring the effectiveness of INGOs

Spatio-temporal distribution and persistence of Mycobacterium Bovis in a badger population

PhD thesis Clare Benton July 2017Studying the dynamics of pathogen transmission within wildlife populations presents an array of challenges. Where populations are socially structured, this can influence parasite transmission, impacting on the effectiveness of disease management strategies. In this thesis, I focus on a well-studied social mammal, the European badger (Meles meles) which is a key wildlife reservoir of a disease of economic importance; bovine TB (caused by infection with Mycobacterium bovis). The social structuring, characteristic of high density badger populations, is of well-established importance in the transmission of bovine TB and has resulted in unexpected management outcomes. However, little is known about the role of kin structure or host genotype on transmission dynamics. In this thesis, I combine traditional spatial epidemiology and ecological analysis of a well-studied badger population with more novel genetic and genomic approaches. Firstly, I investigate the role of kin structure within badger social groups in determining early life infection risk (Chapter 3). Using host genotype data, I demonstrate that cubs who are related to infected adults experience enhanced infection risks. I then explore the role of badger genotype on outcomes of M. bovis exposure and demonstrate that inbred badgers are more likely to show evidence of progressive infection (Chapter 4). Where the social structure of badgers is stable and unmanaged, this is predicted to result in a stable spatial distribution of M. bovis infection. Motivated by an observation of change in the spatial distribution of M. bovis infection in the study population, in the absence of management, I characterise the attrition of a spatially stable infection distribution (Chapter 5). To explore the drivers of this, I detect changes in the genetic population structure (Chapter 6) and present evidence that the population has experienced a period of demographic flux. Finally, I use a novel dataset generated by whole genome sequencing of M. bovis isolates and present evidence of spatial spread of M. bovis infection across the study population (Chapter 7). To conclude, I discuss how my findings demonstrate how genetic and genomic approaches can complement traditional wildlife epidemiology approaches, how they contribute to our understanding of heterogeneity in transmission dynamics and discuss their implications for wildlife disease management.This PhD studentship was funded by the Animal and Plant Health Agency (APHA) and The University of Exeter. Data from the Woodchester Park study is used in chapters 3 – 7 of this thesis, and is funded by Defra

Preliminary Analysis of Vital Proteins of the Human Respiratory Syncytial Virus

Human Respiratory Syncytial Virus infects the vast majority of children under the age of two and reoccurs in adulthood. It is a serious global problem as severe infection and death can result in the very young or very old and in immunocompromised people. The related bovine Respiratory Syncytial Virus is a serious problem for the farming community. To date, there is no effective treatment for Respiratory Syncytial Virus infection, with drugs only available to reduce symptoms in the most severe cases. Human Respiratory Syncytial Virus produces 10 proteins carrying out a diverse array of roles for the infectivity of the virus. Despite this there is still a poor understanding of the three dimensional structure. Only two proteins have been resolved to atomic resolution, the Nucleocapsid protein and the Matrix protein. The objective of this thesis is to initiate work on a further two proteins, with the long term aim of crystallisation studies that may lead to high resolution structures. The Fusion transmembrane glycoprotein is responsible for the fusion of the virion membrane to the host cell membrane for viral entry and for the fusion of an infected cell membrane to membranes of healthy cells, spreading infectivity. Without the Fusion protein there is no infectivity and it is therefore a therapeutic target. Structural information such as a high resolution X-ray crystal structure is required to facilitate the design of inhibitors that could be future therapeutic agents. The second protein studied here is the M2-1 protein, which is a transcriptional elongation factor, involved in replication of the viral genome. Deletion of M2-1 has adverse affects on the replication of the virus. Therefore M2-1 could also make a strong target for drug design. This thesis explores what is currently known about each of these vital proteins, the advantages in inhibiting their respective activities and the possible routes to effective inhibitor design. Procedures for expression and purification of the M2-1 protein are detailed here, as are preliminary experiments into the cloning and expression of the Fusion protein in insect cells. Immunofluorescence experiments into the localisation of the Fusion protein within mammalian cells and the possible interaction of the Fusion protein with the Matrix protein are thoroughly described.

Evaluation of diagnostic tests for Trypanosoma evansi and their application in epidemiological studies in Indonesia

The diagnosis of Trypanosoma evansi infections is problematic because low, fluctuating parasitaemias are typical of sub-acute and chronic infections. Antigen-detection ELlSAs (Ag-ELISAs) that have been developed to detect trypanosomal antigens in serum are reported to be better indicators of current T. evansi infections than either parasitological or antibody-detection tests. Two T. evansi Ag-ELISAs based on different monoclonal antibodies (2G6 Ag-ELISA and Tr7 Ag-ELISA) were evaluated using buffaloes in Southeast Asia, where T. evansi is endemic and livestock are important for draught power, meat and investment. The two Ag-ELISAs were standardised in the UK, following international guidelines on data expression and quality assurance. Diagnostic sensitivities were estimated using buffaloes either experimentally infected (n=35) or naturally infected (n=l 39) with T. evansi and compared with estimates obtained for the microhaematocrit test (MHCT), mouse inoculation (MI), three antibody-detection tests (IgM ELISA, IgG ELISA and card agglutination test {CATT}). Diagnostic specificities were estimated with nonexposed British cattle (n=249) and Australian buffaloes (n=263), and positive and negative predictive values were calculated. Field studies were conducted in Central Java to estimate prevalence and true incidence rates of T. evansi infections in buffaloes. No previous studies have compared two T. evansi Ag-ELISAs, estimated the prevalence of T. evansi infections in multiple villages within a district or true incidence rates.The repeatability and robustness of the two Ag-ELISAs were shown to be high. Profiles of antigenaemia varied between individual buffaloes and between the two Ag-ELISAs. Antigen and antibody responses were first detected 7 to 42 days after infection, but in some buffaloes responses fluctuated below cut-off values during infection, whilst in other buffaloes antigen and antibody responses persisted after trypanocidal drug treatment. With the naturally-infected buffaloes, the diagnostic sensitivity estimate of the Tr7 Ag-ELISA (81%) was significantly higher than that of the 2G6 Ag-ELISA (71%), and the IgG ELISA sensitivity (89%) was significantly higher than either the IgM ELISA or CATT sensitivities (78%). The diagnostic specificity estimates obtained with the British cattle were 83% for the 2G6 Ag-ELISA and 78% for the Tr7 Ag-ELISA, and with the Australian buffaloes were 75% for the 2G6 Ag-ELISA, 78% for the Tr7 Ag-ELISA, 100% for the CATT, 89% for the IgM ELISA and 92% for the IgG ELISA. Only slight agreement was found between the two Ag-ELISAs (kappa = 0.20), but moderate agreement between the IgG ELISA and CATT (kappa = 0.58). Positive and negative predictive values ranged from 24% to 99% for prevalence values from 10% to 90%, and true prevalence was underestimated at higher test prevalence values and overestimated at lower test prevalence valuesIn Central Java, 2387 buffaloes were blood sampled in 59 villages, and estimates of test prevalence were 4% with the MHCT, 9% with MI, 58% with the 2G6 Ag-ELISA and 70% with the Tr7 Ag-ELISA, but prevalence values differed between districts and between villages. True incidence rates per animal-year at risk were 0.44 with the Tr7 Ag-ELISA and 0.22 with the 2G6 Ag-ELISA. Of 239 market buffaloes sampled, 10% were parasitaemic, 39% antigenaemic, 56% positive by IgG ELISA and 47% positive by CATT, representing an important source of T. evansi.The T. evansi Ag-ELISAs and antibody-detection tests used in this study have many advantages as screening tests over commonly used parasitological tests, in terms of their diagnostic sensitivity and ability to rapidly test large numbers of samples. The two T. evansi Ag-ELISAs could be applied in high prevalence areas, whilst antibody-detection tests (in particular, the IgG ELISA or CATT) would be more appropriate to test buffaloes in low prevalence areas or to confirm the negative-status of buffaloes prior to movement within Indonesia or export. Future work should aim to improve the specificities of the Ag-ELISAs, which were low in this study in contrast to previous reports. The CATT had a high positive predictive value even with low prevalence and could be adapted more readily to test individual buffaloes in the field. The selection of diagnostic tests for T. evansi depends not only on test validity parameters, but also on the prevalence of T. evansi in the test population, the principal testing objectives and practical consideration

THE TRANSPORT AND FATE OF FLUOXETINE HYDROCHLORIDE, DIAZEPAM AND THEIR HUMAN METABOLITES IN SEWAGE SLUDGE-AMENDED SOIL

The European Union (EU) banned disposal of sewage sludge (SS) at sea in 1998. Since that time the application rate of SS to land has risen significantly and is set to rise further. Fifty-two percent of SS was disposed to land in the UK in 2000. Land application is thus possibly an important transport route for SS-associated organic chemicals into the environment. There are now over 3000 different pharmaceutical ingredients in use in the EU and the last decade has also seen an increase in reports of pharmacologically active compounds in the environment (e.g. in watercourses, open ocean, soil). Regardless of this there is still a significant lack of knowledge as regards the transport and fate of pharmaceuticals in the environment, particularly in soils. The present project therefore investigated the biotic fate of the selective serotonin re-uptake inhibitor (SSRI), Prozac® (Fluoxetine HCI), and the 1,4-benzodiazepine, Valium® (Diazepam) and their major human metabolites Norfluoxetine HCI, Temazepam, Oxazepam and Nordiazepam in a UK SS-amended soil. Extraction techniques, such as solid phase extraction, for the analytes from a range of matrices (water, soil and plant material) were developed, which allowed subsequent analysis using developed high performance liquid chromatography - electrospray ionization - multistage mass spectrometry (HPLC-ESI-MS") techniques. Ratio calibration using deuterated internal standards allowed the generation of quantitative data. The pharmaceuticals were found to be resistant to biodegradation in both liquid culture studies (60 days), and even after prolonged exposure in SS-amended soil (>200 days; Fluoxetine HCI only). Oxazepam was the only 1,4- benzodiazepine studied which underwent biotic transformation(- 80%) in liquid culture studies. Evidence to support the theory that the transformation product seen was a 1,4- benzodiazepine tautomer, is presented. Results of what is believed to be one of the first examples of research into pharmaceutical uptake by plants are presented. In a preliminary tissue culture study the translocation of Fluoxetine HCI into Brassica stems (5% uptake) and leaves (3% uptake) confirmed that plant uptake of some pharmaceuticals may be a potential transport route in the environment. The stability of the pharmaceuticals under environmentally relevant conditions has implications for the consequent accumulation in SS-amended soils and possible subsequent uptake into plants grown on the soils.The Biotechnology and Biological Sciences Research Council and AstraZeneca, Brixham Environmental Laborator

What influences adherence to treatment in people with multiple sclerosis?

BackgroundCurrently, there are a number of disease modifying therapies (DMTs) available that can help to reduce the number of attacks experienced in relapsing remitting multiple sclerosis (RRMS). However, optimal outcomes are not always achieved due to early treatment discontinuation and low levels of overall adherence. This study sought to understand the drivers of non-adherence from a patient perspective and their potential to be modified through behaviour change interventions. MethodsA two-part scoping review was carried out to determine the drivers of adherence in people with MS and to explore how these drivers are currently being addressed through adherence interventions. The COM-B framework for adherence and BCT Taxonomy were used to operationalize these findings. Following this review, it was evident that there was a lack of qualitative research exploring drivers of adherence from the perspective of the patient themselves. Therefore a multi-country, qualitative study was conducted. Semi-structured interviews were conducted with 24 (n=12 females) people with RRMS from Germany, Spain and the United Kingdom. Insights were extracted using Framework Analysis. Findings The review identified over sixty discrete factors, across thirty-three studies, which had been found to potentially influence adherence behaviours in MS. Twenty-nine of these were identified more than once and 48% could be mapped to the COM-B model of adherence. The review also identified four successful behaviour change interventions that targeted eight of these factors. The qualitative research determined that control and conflict were the overarching themes related to adherence, whereby an increased sense of control over MS and limited conflicts with self-management behaviours and ‘day to day’ life could enhance likelihood and ability to adhere to treatment and other self-management tasks, thereby leading to potentially better outcomes. Conclusion Overall, this research found a disconnect between the majority of studies exploring drivers of adherence in MS, and the interventions which have successfully impacted adherence behaviours in the same population. A focus on ‘convenience’ data, in particular clinical and demographic factors, has done little to further our understanding in terms of how best to support this population and there is an apparent need for research exploring drivers of adherence to align more closely with intervention research. This is further supported by the qualitative research that showed the often complex interplay between multiple factors and adherence outcomes in people with MS

Courage and the soul in Plato

In the Introduction I briefly lay out the history of the value terms that I will be considering in my thesis and consider the philosophical relevance of the development of such values in the 5th century. The infiltration of modern ideas of morality into what was considered to be good to the Greeks has a great influence on the literature and philosophy of this period. Plato prioritises these quiet moral virtues, but also tries to hang on to some of what had come before, and thus faces difficulties with his moral theory. I will show that courage presents Plato with an acute difficulty when attempting to develop a consistent ethical theory. In Chapter 2 I look at the Protagoras where the main issues about courage that Plato will continue to discuss throughout his life are introduced. The questions of the extent to which the virtues can be taught and the unity of the virtues are introduced early on. What follows is an attempt to explain and justify the Socratic idea that the virtues are co-dependent and that they all in some way boil down to knowledge. In Chapter 3 on the Laches I will show that the discussion focuses more particularly on the virtue of courage and is mostly a more sophisticated attempt to understand courage than the one presented in the Protagoras. In the following three chapters (4-6) I examine the position taken in the Republic in detail, which I take to be more representative of the Platonic rather than Socratic position. Plato’s psychological model – which includes direct influence from the lower soul – is a more reasonable interpretation of the internal workings of the agent than the simpler model in the early dialogues of the only direct motivator being beliefs or knowledge. The chapter on the Laws considers the idea that some of the apparent differences between the Republic and the Laws are due to Plato’s growing realisation that courage will not be assimilated into a unified ethical theory of the type that he wishes to propose

Effects of strategies to promote children\u27s physical activity on potential mediators

The aim of this paper is to review evidence of the effectiveness of interventions that present physical activity outcomes and potential mediators of behavioural change among 4&ndash;12-year-old children. A systematic search of electronic databases for original research articles published in peer-review journals between January 1985 and the end of June 2006 was carried out. A total of 19 studies that reported intervention effects on physical activity and mediators of behavioural change were identified. The most common mediators reported included physical activity knowledge or beliefs (11 studies); self-efficacy (8 studies); and enjoyment or preference for physical activity (6 studies). Less frequently reported mediators included attitudes, behavioural capability, intentions, outcome expectancies, social norms, social support and self-concept. Seven of the 11 interventions that reported intervention effects on knowledge/beliefs stated positive changes in this mediator. Four of the eight studies that reported intervention effects on self-efficacy had significant improvements; however, only two out of six interventions reported significant improvements in physical activity enjoyment or preference. None of the studies reviewed reported whether changes in these constructs mediated changes in children\u27s physical activity behaviours. Although more than half of the studies reviewed reported a positive intervention effect on children\u27s physical activity, no study carried out a mediating analysis to attempt to identify the mechanisms of change. Future research should more clearly identify the mediators of behavioural change that are being targeted and whether this explains intervention effects.<br /