D’un point de vue historique, nous avons constaté que le parler oranais n’appartient ni aux parlers pré-hilaliens ni aux parlers hilaliens, il est issu d’un amalgame de parlers ouest-algériens introduits tardivement dans la ville après le départ des Espagnols en 1791. Notre thèse est basée sur un corpus oral constitué auprès de deux groupes de locuteurs d’âges différents. Notre travail de recherche s’articule autour de deux axes. Le premier a été motivé par la nécessité de valider la nature verbale de “ra-” à travers l’analyse du type de négation qui lui est appliqué. Le second axe concerne l’étude du fonctionnement morphosyntaxique de “ra-”. Concernant la négation nos résultats ont montré que tous les prédicats verbaux, y compris “ra-”, sont niés avec la négation discontinue “ma š”. La négation des prédicats non-verbaux est de type continu et basée sur l’utilisation de l’adverbe de négation “mešši”. Nous avons démontré dans le quatrième chapitre que “ra-” est né de la grammaticalisation de la forme inaccomplie de “ra>a/yara” (voir). “ra-” possède deux fonctions grammaticales principales, combiné aux verbes à l’inaccompli, à l’accompli ou au participe actif, il est en position d‘auxiliaire verbal. Utilisé dans des constructions à prédicat non-verbal, il prend une fonction de copule verbale. Dans ces deux emplois, il est la marque du présent. Dans certaines utilisations “ra-” fonctionne comme un verbe distributionnel à sens plein. En conclusion nous proposons de considérer “ra-” et “kān” comme les deux formes d’un même verbe irrégulier dans la mesure où nous avons deux signifiants pour un même signifié. / From a historical point of view, we found that the Oranian speaking does not belong to pre-Hilalian or Hilalian dialects; it comes from an amalgam of Western Algerian dialects introduced late in the city after the departure of Spanish in 1791. Our thesis is based on an oral corpus formed by two groups of speakers of different ages. Our research focuses on two axes. The first was motivated by the need to validate the verbal nature of "ra-" through the analysis of the type of negation applied to it. The second axis concerns the study of the morphosyntactic operation of "-ra". Regarding the negation, our results showed that all verbal predicates, including "ra-" are denied with the negation system "ma š". The negation of non-verbal predicate type is continuous and based on the use of the adverb of negation "mešši". We have shown in the fourth chapter that "ra-" was born from the grammaticalization of the unaccomplished form of "ra>a/yara" (see). "ra-" has two main grammatical functions, combined with verbs in the unaccomplished, accomplished and the active participle, it is in a position of verbal auxiliary. When used in constructions with non-verbal predicate, it takes a verbal copula function. In both jobs, it is the mark of the present. In some uses "ra-" functions as a distributional verb in full sense. In conclusion we propose to consider "-ra" and "kan" as the two forms of the same irregular verb to the extent that we have two signifiers for the same signified.

Tuberculosis (TB) remains one of the most devastating diseases in humans. Nowadays, tuberculosis therapy is not sufficient to control the TB epidemic and only lasts for 6 months to cure patients and prevent relapse; therefore, the treatment of Mycobacterium tuberculosis (Mtb) is particularly challenging (1). New antibiotics, mainly those that are derived from new chemical classes, are more likely to be more effective against resistant strains. Moreover, expanding the knowledge of the mode of action of drugs has important implications in tackling TB. Only empirical approaches can be adopted in the journey of discovering new anti-tubercular drugs until a clear picture of latency and persister cells’ physiology is achieved. Mtb has the extraordinary ability to survive under hypoxia, suggesting a high degree of metabolic plasticity. The flexibility conferred by a modular respiratory system is critical to the survival of Mtb, thereby also making it a promising area of research for new drug targets. This thesis aimed towards the characterisation of cytochrome bd-I quinol oxidase (bd-I), a respiratory component that is believed to operate during both the replicative and “dormant” Mtb phenotypes. The essential nature of Mtb bd-I, which has no human homologue, has been confirmed in a recent deep sequencing study of genes required for Mtb growth by Griffin et al. (2), further confirming its potential as a novel target. Recombinant Mtb bd-I was successfully expressed under the control of the pUC19 lac promoter in the Escherichia coli ML16 bo3/bd-I and MB44 bo3/bd-I/bd-II knockout strains, allowing “noise-free” measurement of the enzyme. Initial steady-state kinetics of the enzyme was presented using a range of quinol substrates, revealing a substrate preference for dQH2 over Q1H2 and Q2H2. A number of bd-I inhibitors were identified and their pharmacodynamic profiles against Mtb H37Rv were determined. In addition, a pharmaco-metabolomics platform was initiated to explore the cellular response of Mtb to current first-line TB drugs as well as in house bd-I and type II NADH inhibitors. The initial findings are discussed in the context of the known mode of action of the drugs and future research needs in drug discovery of this devastating disease.

My original contribution to the body of knowledge is a portfolio of evidence which includes: • An evaluation of Reache (Refugee and Asylum seekers Centre for Healthcare professionals Education) North West using a PEST (Political, Economic, Social and Technological) analysis and Thematic Content Analysis of semi-structured interviews which led to the development of the Reache North West model of education and training for refugee healthcare professionals. • The development of a course entitled Safe and Effective Clinical Communication Skills and the dissemination of this course via conference posters, oral presentations and a published journal article. In the case of the conference posters, the course was identified as good practice on two occasions. • A business case which led to the development of the Salford Communication and Language Assessment Resource (SCoLAR). This thesis analyses and critically appraises the action research, ideas, reports and publications, from 10 years of organizational experience. This also includes over ten years of personal experience teaching and managing education programmes for international students, and over four years of working with refugee healthcare professionals, assisting them in returning to their professional role in the UK. The evaluation of Reache North West sought to answer the research question ‘Are we effectively preparing refugee doctors for work in the NHS?’ Although there were only 5 respondents the evaluation answered this question positively. Also discussed is the process for the development of the safe and effective clinical communication course and the difficulty in this course to other groups of internationally trained doctors. My observations and experience of working with International Medical Graduates who have encountered language and communication difficulties are also discussed with the acknowledgement that more robust research processes are needed for future research.

Research Question: What are patients’ experiences of technology in adult intensive care? Research Objectives: -To explore patients’ perceptions of receiving care in a technological environment -To explore patients’ perceptions of how technology has influenced their experience of care Background: Technology is fundamental to the physical recovery of critically ill patients in intensive care (ICU), however, there is a suggestion in the literature that its presence may dehumanise patient care and distract the nurse from attending to patients’ psychosocial needs. Little attention has been paid to patients’ perceptions of receiving care in a technological environment. The purpose of this research, therefore, was to explore patients’ experiences of technology and care within ICU. Methods: This study was informed by Heideggerian phenomenology. The research took place in a university hospital in England. Nineteen participants who had been a patient in ICU were interviewed using a semi-structured approach. Interviews were transcribed verbatim and analysed utilising Van Manen’s framework. Findings: Resulting themes were ‘My Useless Body’ which describes how participants experienced their body as dysfunctional, disconnected and invaded by technology, ‘Making Sense of It’, which describes how participants rationalised their experiences by constructing a story, and ‘Technology and Care’, which describes how and why participants endured technologies in ICU. Conclusions: The disintegrated body is central to the critically ill’s experiences in ICU. Families play an important role in helping patients make sense of their experiences by filling in gaps in memory and helping them to sort the real from unreal memories. Families therefore require support and information resources in fulfilling this role. Patients experience technology and care as a series of paradoxical relationships: alienating yet reassuring, uncomfortable yet comforting, impersonal yet personal. Nurses maintaining a close and supportive presence and providing personal comfort and care may minimise the invasive and isolating potential of technology

This research study evaluated the use of Personal Development Planning (PDP) as a strategy to help a group of ten doctoral and fourteen postdoctoral research scientists, based in eight developing countries in Africa, enhance and progress their career development. To achieve this, a PDP system, with built-in tools and support systems was developed specifically for this purpose. Using an Action Research approach, within a framework adapted from Kirkpatrick’s “Four Levels of Evaluation” the research study evaluated the PDP system, tools and processes; and from lessons learned developed a transferable system and tools for future use with research scientists based in these and other developing countries in Africa. The study explored the following questions: (1) How do these research scientists feel about using PDP, the system and tools? (2) What is being done differently as a result of engaging with PDP – are there any learning gains, and are they applied in practice? (3) To what extent has PDP helped these research scientists feel confident about planning and managing their career development? (4) How far is it feasible to implement PDP more widely with other research scientists in Africa? Using both quantitative and qualitative data from the Group’s PDP documentation, questionnaires, nominal group technique, an online focus group discussion, and semi-structured interviews, the main study findings showed that overall the majority of the group felt that PDP made a positive contribution to helping them enhance and progress their career development; and was successful in helping them to feel confident about planning and managing their career development and progression. Given the focus and limited time, the study does not evaluate the broader impact that engagement with PDP might have on career progression. A longitudinal, follow up study would be needed to evaluate this aspect of PDP in relation to career development in Africa. The data showed that PDP is a concept that can be transferred successfully to developing country settings in Africa. It also indicated that, with the essential support elements of personal support, financial support, time and institutional support built into a PDP programme, it would be feasible to implement PDP with a similar group of research scientists in Africa. Further studies are needed to evaluate feasibility of implementing this strategy more widely in countries in Sub-Saharan Africa.

Complex social problems (the continued rise in chronic disease; resource depletion, inequality etc.) call for new social marketing frameworks to accommodate midstream and upstream action which requires collaborations with multiple actors (government, public and private sector). Service-dominant logic (SDL) (Vargo and Lusch, 2004) theoretical developments (systems thinking, value creation, networks etc.) suggest a good compatibility with the collaborative approaches required by midstream and upstream social change (Russell-Bennett, Wood and Previte, 2013). This thesis interrogates the applicability of SDL concepts (value creation and actor engagement) to social marketing. This study focuses on examining the factors influencing engagement, actor motivation and perceived value in a health social marketing context. The study adopts a case study approach and draws upon interviews, observation and document analysis to examine a Smokefree homes and cars programme (‘Smokefree’) in a city in England. Key findings of this research indicate that adopting a service orientation facilitates contextualising social marketing programmes, building capacity at the community level and adopting a long-term approach which suits better the realities of individuals. However, it also reflects that understanding and addressing contextual factors means considering the fluidity of individuals’ goals and the subjective dimension of value which might challenge pre-set programme objectives. The study indicates that a collaborative approach to value creation poses challenges in addition to the benefits. This study is one of the few (Domegan et al., 2013; Lefebvre, 2012; Russell-Bennett, Wood and Previte, 2013) to contribute to the efforts to examine the implications of a service perspective for extending social marketing theory. One of the main contributions of this study is illustrated by the articulation of service dominant benchmarks for social change programmes. A key implication for policy is that building collaborations with community services is essential to understanding individuals in context, customising offerings and supporting skill development.

Due to increasing awareness of potential Cr toxicity, there is a pressing need to establish sensitive and robust Cr fractionation and speciation methodologies that will be enable separation of the two redox Cr species (CrIII and CrVI) from different environmental phases and their quantification. The intention of this work was to assess the behaviour of Cr species, especially CrVI, in soils and the factors controlling Cr solubility, fractionation, redox transformation rates and uptake by plants. The analysis methods relied on alkaline extraction in TMAH, liquid chromatography (LC) to separate the chromium species and inductively couple plasma mass spectrometry (ICP-MS) for quantification of chromium. The interference of 40Ar12C+ background peak at mass 52 was reduced by using the CCT-KED facility of the ICP-MS. A solution of 50 mM TRIS buffer, 40 mM NH4NO3, 10-5 M ammonium-EDTA at pH 7.0 was used as the chromatographic eluent. The method developed is suitable for determining CrVI in soil, following alkaline extraction in TMAH, but not for CrIII due to poor recovery, redox transformation and strong binding of CrIII with humic acid despite attempts to preserve the trivalent species using EDTA and heating. The extraction method was applied to assessing Cr speciation and fractionation in a wide range of soil ecosystems collected from urban sites in Wolverhampton, Nottingham, London and a historical sewage sludge disposal farm in Nottinghamshire. To predict soil CrVI content the use of TMAH-extractable Cr (CrTMAH) was better (R=0.911) compared to total soil Cr content (Crtotal; R=0.554). The same analytical approaches were also applied to the development of a method to determine isotopically exchangeable CrVI in soils. This employed isotopically enriched 50CrVI as a ‘spike’ isotope added to soils suspended in varying concentrations of TMAH in an attempt to resolve a consistent fraction of isotopically exchangeable, or ‘labile’, CrVIO42- in soil. It was apparent that, because of the slow exchange kinetics of CrVI in soils, it was difficult to determine a consistent isotopically exchangeable fraction. Nevertheless, the investigation did suggest a refinement of the simple TMAH extraction protocol could enable direct determination of labile soil CrVI. The kinetics of CrVI interaction with a geocolloid (humic acid) was assessed and humic acid was found capable of both reducing CrVI and binding with the resulting CrIII species. Finally, Cr uptake by maize grown on a historical sewage sludge disposal farm was assessed with several approaches to finding a correlation between Cr in soil and Cr uptake by plants. The concentration of CrVI in soil, and its solubility, could be reasonably well predicted from Crtotal or CrTMAH and soil properties. However, restricted uptake of CrVI by the maize plants, and probably reduction of CrVI to CrIII in the root system, made it impossible to predict Cr transfer to shoots or the speciation of the Cr in maize shoots. Overall, due mainly to the apparent ability of the maize plants to control uptake and speciation of CrVI, the produce was considered safe to be consumed by ruminants as regards CrVI content.

Objectives To develop an alcohol intervention model that predicts life years (LYs), quality adjusted life years (QALYs), and healthcare costs classified by the Alcohol Use Disorder Identification Test (AUDIT) screening tool and other various risk factors related to alcohol consumption. Furthermore, the developed model was transferred to the Thai setting. Methods Eight Scottish Health Surveys from 1995-2012 were linked to Scottish morbidity records and death records for the period 1981 to the end of 2013. Parametric survival analysis was used to estimate the hazard risks of first alcohol-related and non-alcohol related hospitalisations and deaths. For men and women, multivariate data analyses were applied separately for each gender in modelling the utility score, risks of subsequent hospitalisation and annual healthcare costs within the follow-up period. Risk profiles were used for the covariates of the models as follows: age, socio-economic status, health condition, alcohol drinking (i.e. AUDIT and binge drinking), smoking, body mass index, and physical activity. According to the under-reporting bias of alcohol consumption among the survey population, this study adjusted the reported alcohol consumption using alcohol sales data. Multiple imputation approach was applied to deal with missing data. A health-state transition model with annual cycle length was developed to predict LYs, QALYs, lifetime costs, and cost-effectiveness. Probabilistic sensitivity analysis was also performed to deal with parameter uncertainty. Moreover, a methodological transferability protocol of the Thai study was detailed. Results The sample size of the cohort was 46,230. The developed model showed the association between drinking and alcohol-related and non-alcohol related hospitalisations and deaths which were calculated as LYs and QALYs. Other risk factors were also taken into account that would likely affect the outcomes of interest. The modelling showed that an increasing AUDIT score and the number of cigarettes per day were associated with an increased risk of first alcohol-attributable hospitalisation. Predicted outcomes for a male aged 30 year with high-risk drinking levels (AUDIT >7) were worse than males with low risk drinking (AUDIT ≤7), with approximately 5 LY gained and 7 QALY gained. The same results for females were obtained for high-risk drinking (AUDIT >4) compared to low-risk drinking (AUDIT ≤4), with approximately 10 LY gained and 12 QALY gained. Furthermore, an economic evaluation was performed to compare the no-intervention situation with a hypothetical health promotion intervention - which aimed to stop drinking (measured by the AUDIT) and smoking (measured by the number of cigarettes per day) behaviours. To compare the costs and benefits of the hypothetical intervention and no intervention over the lifetime period, a within-trial analysis combined with the developed model was able to capture both short- and longer-term consequences (i.e. LYs, QALYs, and healthcare costs) of the intervention. Finally, the model was able to compare cost-effectiveness ratio between risk behaviours without the new intervention and the modified risk behaviours when the new intervention is implemented. Conclusions The study highlights the potential and importance of developing health economic models utilising data from routine national health surveys linked to national hospitalisation and death records. The developed framework can be used for further economic evaluation of alcohol interventions and other health behaviour change interventions. The framework can further be transferred to other country settings.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammatory polyarthritis, typically of the small joints. Obesity, a serious global epidemic, has been shown to increase systemic inflammatory biomarkers, several of which are related to RA pathophysiology. Associations have been observed between obesity and worsened RA disease activity outcomes in crosssectional studies. Limited longitudinal studies investigated the effects of weight change on RA disease activity measures. Surgical interventions for weight loss in RA patients showed marked improvement in RA disease activity measures and outcomes but typical weight change in a clinical setting has not been investigated. OBJECTIVE: To investigate the impact of typical weight change on RA disease activity measures. METHODS: We conducted a retrospective cohort study on 178 RA patients seen in typical clinical practice that met the inclusion criteria for the study, which included patients with a minimum of two clinical disease activity assessments (CDAI) with corresponding body mass index (BMI) measures. Medical record review was conducted for each clinic visit where CDAI and BMI were measured, and at each of these visits, sociodemographic, lifestyle, medication usage, questionnaire data, RA characteristics, laboratory values, and comorbidities were collected. Linear regression was used to analyze the association between ΔBMI and ΔCDAI, defined at the dates of minimum and maximum BMI for each subject, adjusting for confounders including sex, age, disease duration, smoking status, serologic status, and steroid usage. Logistic regression was performed to evaluate whether ΔBMI was associated with low/remission RA disease activity according to accepted CDAI cutoffs. RESULTS: Unadjusted linear regression was performed on all 178 subjects to analyze the overall trend within the sample population. For every 1 kg/m2 increase in BMI, CDAI increased by 0.49 points, but these results were not statistically significant (p=0.155, 95%CI -0.176, 1.097). Subjects were stratified into BMI gain, stable, and loss groups. Within the BMI loss group (defined as those whose BMI decreased by more than 1 kg/m2), a significant association was found with ΔCDAI (β= -2.61 [p=0.028, 95%CI -4.91, -0.298]). Unadjusted linear regression on the BMI gain and stable groups was found to be not statistically significant. This association remained significant after adjusting for sex, age, disease duration, smoking status, serologic status, and steroid usage (β=-2.499 [p=0.044, 95%CI -4.94, -0.061]). There was no association between ΔBMI and low/remission RA disease activity (OR 0.990, (95%CI 0.855, 1.146). When stratified by BMI gain, stable, and loss groups there was no significant association with low/remission RA disease activity. CONCLUSION: These results suggest that weight loss may be associated with improved disease activity among patients with RA seen in a typical clinical setting. Weight loss has the potential to be a non-pharmacologic intervention to improve RA disease activity. Prospective studies of weight loss and RA disease activity are necessary to replicate these results.

For the most part, diagnostic clinical microbiology still relies on 19th century ideas and techniques, particularly microscopy and laboratory culture. In this thesis I investigate the utility of a new approach, whole-genome sequencing (WGS), to tackle current issues in infectious disease. I present four studies. The first demonstrates the utility of WGS in a hospital outbreak of Acinetobacter baumannii. The second study uses WGS to examine the evolution of drug resistance following antibiotic treatment. I then explore the use of WGS prospectively during an international outbreak of food-borne Escherichia coli infection, which caused over 50 deaths. The final study compares the performance of benchtop sequencers applied to the genome of this outbreak strain and touches on the issue of whether WGS is ready for routine use by clinical and public health laboratories. In conclusion, through this programme of work, I provide ample evidence that whole-genome sequencing of bacterial pathogens has great potential in clinical and public health microbiology. However, a number of technical and logistical challenges have yet to be addressed before such approaches can become routine.