Background: Type 2 Diabetes is a chronic metabolic condition which occurs as a result of insufficient insulin production and insulin resistance. This results in less glucose uptake by muscle and fat cells, allowing blood glucose levels to rise in the body. Higher blood glucose levels place patients at an increased risk of diabetes-related complications. The treatment is characterised by the initiation, switching and intensification of antidiabetic medications. The goal for patients with diabetes is to maintain glycaemic control, with blood glucose levels (HbA1c) between 6.5-7.0%(48-53mmol/mol). International guidelines recommend prescribing of metformin at initiation but there is no consensus on optimal agents in a combination regimen. The aim of this thesis was to assess the drug utilisation patterns of first-line therapies and the impact of this pathway on second-line regimens. This entailed: (i.) observing the prescribing of the first-line therapy, (ii.) characterising the medication-taking process of the first-line therapy and effectiveness of the regimens, and (iii.) determining the most effective second-line regimen in delaying the onset of microvascular complications. Methods: Patients with type 2 diabetes, prescribed a first-line antidiabetic regimen, were identified from the Clinical Practice Research Datalink (a large UK anonymised primary care database) between 01/01/05 and 31/12/09, were followed-up until 31/12/12. A multinomial logistic regression model was used to assess the relationship between patient characteristics and the choice of first-line agent. Adherence to first-line therapy was estimated using the Medication Possession Ratio calculation, expressing the percentage of days covered by a drug supply. To assess the factors influencing achievement of glycaemic goals from the first-line therapy, a logistic regression analysis was performed. To investigate second-line regimens, a Marginal Structural Cox model was implemented to explore the causal relationships between the time to development of microvascular complications and the second-line regimens. Results: Of the 72,429 individuals diagnosed with type 2 diabetes, 44,838 started therapy with an antidiabetic medication regimen. Metformin and sulphonylureas were the most frequently prescribed agents at initiation (82.9% and 9.8%,respectively). Deviations from metformin were associated with patients presenting with higher HbA1c levels, lower BMI values and had concurrent prescriptions (immunosuppressants and oral corticosteroids). Achieving glycaemic control, to the target of 6.5% (48mmol/mol), was only met in 22.7% of patients. Characteristics of the patient, choice of first-line agent and medical support influenced the effectiveness of the treatments. Patients at the greatest risk of failing to achieve the target glycaemic goal from therapy had HbA1c levels>8.0% (64mmol/mol) and a BMI≥25kg/m2. Adherence was significantly associated with greater lowering of HbA1c levels but these reductions did not guarantee reaching the ideal glycaemic target. Intensification of the monotherapy to a dual therapy regimen was observed in 30.2% of patients in a mean time of 2 years. The most frequently prescribed second-line regimens consisted of metformin/sulphonylurea (SU) (74.5%), metformin/thiazolidinediones(TZD) (11.3%) and metformin/DPP-4 inhibitors (14.2%). Metformin/SU was the most effective dual therapy regimen for delaying the onset of microvascular diagnoses. The rate of development of these events was significantly higher for the DPP-4 combination in comparison to the SU combination with a hazard ratio of 1.85 (95% CI: 1.53,2.24). A TZD combination resulted in a non-significant increase of 19% in the rate of development compared to the SU combination (HR 1.19; 95% CI: 0.98,1.47). Metformin/SU resulted in the greatest lowering in HbA1c levels (-3.3%; 12mmol/mol) in comparison to the DPP-4 and TZD regimens. Conclusions: It is unlikely that patients starting first-line therapy with high HbA1c levels will be able to reduce blood glucose levels sufficiently on a monotherapy regimen. It is important for practitioners to consider a faster uptake of a dual therapy regimen (metformin/SU) to prevent sustained suboptimal glycaemic control and reduce the risk of future complications. Other important considerations in the optimal treatment pathway would be to provide more frequent support from health professionals; this may help to highlight inadequate drug regimens, offer management of risk factors and provide education. These aspects may help patients to achieve better control of their condition, with the aim of reducing the risk of diabetes-related complications; which, severely impact patient quality of life and NHS costs and resources.

In this bachelor project, Leon Falk has examined the interplay and collective improvisation in New Orleans jazz and related genres - in particular the interplay among the wind instrumentalists in New Orleans jazz and brass bands. The main goal has been to develop as a trombone player and ensemble musician.This reflective thesis includes a description of the process of the project and the exam concert, a historical reflection about the New Orleans jazz and brass band tradition and an analysis of 9 interviews with contemporary musicians playing traditional jazz: Jens "Jesse" Lindgren, Björn Ingelstam, Ulf Johansson Werre, Joakim Falk, Claes Ringqvist, Klas Lindqvist, Hans Ingelstam, Niklas Carlsson and Örjan Kjellin. The thesis ends with a conclusive reflection about the project as a whole and Leon Falk's own play style in ensemble with other wind instruments. / <p><strong>Repertoar examenskonsert: </strong>St James Infirmiry (trad), Room Rent Blues (Irving Newton), At the Georgia Camp Meeting (Kerry Mills), Should I Reveal (Nacio H Brown / Arthur Freed), Savoy Blues (Edward Kid Ory), While We Danced At the Mardi Gras (Alfred M Opler / John H Mercer), Cash is King (Leon Falk), Girl Of My Dreams (Sunny Clapp).<strong>Musiker examenskonert: </strong>Leon Falk (trombon/sång), Adam Falk (klarinett/tenorsaxofon), Erik Tengholm (trumpet/kornett), Jocke Falk (trumpet/kornett), Uno Dvärby (kontrabas/banjo), Sara Karkkonen (piano), Jonathan Leidecker (trummor).</p>

Background and Aims: Type 2 diabetes mellitus (T2DM) is a chronic progressive condition characterised by hyperglycaemia due to insulin deficiency with or without insulin resistance. The prevalence of diabetes is increasing rapidly worldwide and it has a significant burden on health care resources with estimated costs of up to 10% of health expenditure in the UK. With an ageing population, people are now living longer with diabetes which consequently leads to increased multimorbidity and polypharmacy. Some previous studies have not assessed the effect of demographic or geographic factors (such as age, gender, UK nation and social deprivation) on the incidence and prevalence of T2DM in the UK over the past decade. In addition, detailed reports on the patterns of comorbidities in T2DM patients are sparse. Patients with T2DM are at a two-fold higher risk for cardiovascular (CV) disease. Some earlier studies assessing the CV risk associated with available therapies have been inconclusive in determining the preferred regimens. This thesis aimed to: i) assess the incidence and prevalence of T2DM in the UK; ii) investigate and compare mortality risk between T2DM patients and patients without diabetes and explore if it explains the observed prevalence rates; iii) examine the patterns of comorbidities in T2DM patients and matched comparators without diabetes; and iv) assess the comparative CV risk associated with second-line diabetes therapies. Methods: All the studies in this thesis used data from the UK Clinical Practice Research Datalink. Access to linked national hospitalisation, deprivation and mortality data was obtained for the individual studies. Annual overall and gender-specific incidence and prevalence of T2DM were calculated for the study period 2004-2014. Rates were standardised by age bands, gender, neighbourhood social deprivation, and UK nation and expressed per 10,000 person-years (PYRs) with 95% confidence intervals (95% CI). For the mortality analysis, T2DM patients (cases) were matched to patients without diabetes (controls) on age, gender and general practice. Annual mortality rates for the matched T2DM and patients without diabetes were calculated and compared. Cox regression analysis was used to examine the effect of important covariates on the risk for all-cause mortality in the matched cohort and calculate hazard ratios (HR) and 95% CI. The multimorbidity profile in T2DM cases and matched controls, registered in English general practices, were also examined. Annual prevalence rates of 18 physical and mental health comorbidities were determined between 2004 and 2014 using linked primary care and hospitalisation records. For the CV risk analysis, patients prescribed a second-line medication after greater than or equal to90days of metformin monotherapy between 1998 and 2011 were identified. Using a retrospective cohort study design, inverse probability of treatment-weighted time-varying Cox regression models were used to estimate HRs and 95% CI for developing a major CV event (myocardial infarction, stroke, acute coronary syndrome, unstable angina, coronary revascularisation, or CV death) associated with second-line therapies after adjusting for clinically important CV risk factors. Results: The prevalence of T2DM nearly doubled from 320.62 (95% CI: 318.83; 322.41) in 2004 to 526.36 per 10,000 PYR (95% CI: 523.81; 528.91) in 2014, whereas the incidence was relatively stable with overall rate of 43.07 per 10,000 PYR (95% CI: 40.06; 46.09). Gender-specific incidence and prevalence rates were markedly higher in men than women. Between 2004 and 2014, the prevalence increased from 380.31 (95% CI: 377.48; 383.13) to 625.45 (95% CI: 621.37; 629.52) in men and from 268.56 (95% CI: 266.22; 270.90) to 437.28 (95% CI: 433.94; 440.62) in women. Overall, older individuals, men, and residents in the most deprived locations were more likely to have T2DM. Wales and Northern Ireland had higher prevalence rates than the other UK nations. In the all-cause mortality analysis, 20,312 (11.5%) patients with T2DM died, as compared with 79,951 (9.1%) controls. The adjusted survival model showed that patients with T2DM were at significantly greater risk for mortality in comparison with patients without diabetes (HR: 1.26, 95% CI: 1.20; 1.32). Mortality rates decreased over time in both cases and controls. The multimorbidity study showed that comorbidities were more prevalent in patients diagnosed with T2DM in comparison with patients without diabetes. The number of patients with two comorbidities increased between 2004 and 2014. The prevalence of cardiovascular disease (CVD) in T2DM patients was double that of matched control patients. DPP-4 inhibitors, thiazolidinediones and sulphonylureas add-on therapies to metformin were the most commonly-prescribed second-line therapies. The time-varying survival models showed that DPP-4 inhibitors (HR: 0.78, 95% CI: 0.55; 1.11) and thiazolidinediones (HR: 0.68, 95% CI: 0.54; 0.85) add-on therapies were associated with lower risk for major CVD compared to sulphonylurea add-on therapy when all added to initial metformin. Conclusions: The prevalence of T2DM is increasing rapidly in the UK. Patients with T2DM are at significantly greater risk for mortality than patients without diabetes. However, with the declining mortality rates over the past decade, patients are now living longer to develop comorbidities. CVD was the most prevalent comorbidity in T2DM cases in comparison with people without diabetes. This is important as CVD is the main cause of mortality in patients with T2DM. Thiazolidinedione combination with metformin was associated with significantly lower CV risk in comparison with sulphonylurea add-on therapies to metformin. Lower, but non-statistically significant, risks were also found with DPP-4 inhibitors add-on therapies. These real-world findings add to the existing knowledge on the epidemiology of T2DM, provide novel insight on the patterns of multimorbidity in these patients and clinically relevant evidence on the CV risk associated with commonly-prescribed second-line regimens. Future larger studies are needed to confirm the observed CV benefits associated with antidiabetic therapies.

La tuberculose (TB), provoquée par Mycobacterium tuberculosis, est une des trois maladies prioritaires dans le monde. Les TB multi-résistantes (MDR) et ultra-résistantes (XDR-TB) représentent des obstacles majeurs pour la lutte antituberculeuse. Dans les pays à MDR-TB élevée, comme le Vietnam, la détection insuffisante de la résistance aux antibiotiques est un des facteurs principaux qui favorisent la transmission des souches résistantes. De plus, dans ces pays, encore très peu de choses sont connues sur la résistance à la pyrazinamide et aux antibiotiques de seconde ligne et sur les déterminants génétiques liés à ces résistances. Dans ce contexte, ce travail vise donc à acquérir des connaissances sur la résistance aux antibiotiques au Vietnam et à étudier comment M. tuberculosis évolue de l’état sensible à l’état ultra-résistant.260 isolats cliniques collectés au Vietnam entre 2005 et 2009 ont été inclus. Diverses techniques et analyses ont été utilisées: tests de sensibilité aux médicaments (développement d'un test à temps réduit), spoligotypage et MIRU-VNTR (24 loci) et séquençage de gènes. Les données ont été analysées par des analyses statistiques et phylogénétiques. Ce travail s’est d’abord focalisé sur la caractérisation d’isolats hautement résistants et sur la résistance à la pyrazinamide. Une forte proportion d'isolats quadruple résistants aux antibiotiques de première ligne a été identifiée comme pré-XDR et XDR et en majorité appartenant à la famille Beijing. L'analyse moléculaire a également révélé une forte proportion d'isolats, en particulier MDR, quadruple résistants et de la famille Beijing, portant des mutations associées à la résistance à la pyrazinamide.L'analyse génétique et phylogénétique globale a ensuite montré une grande diversité de profils de mutations dans chaque famille et chaque cluster MIRU-VNTR. Ces données suggèrent que M. tuberculosis peut suivre des chemins évolutifs variés pour devenir ultra-résistant. La prédominance de mutations et de combinaisons de mutations associées à un haut niveau de résistance et à un faible coût en termes de fitness suggère un effet cumulatif des mutations et un rôle de l’épistasie dans l'acquisition de la résistance multiple. De plus, une fréquence élevée de mutations compensatoires associées à la résistance à la rifampicine a été détectée chez les isolats très résistants. Ces processus semblent donc influencer fortement l'évolution de la résistance dans notre échantillon. Il est à noter que les mutations liées à des niveaux de résistance élevée et à de faibles coûts en termes de fitness, ainsi que les mutations compensatoires étaient plus particulièrement associées à la famille Beijing.En conclusion, ce travail fournit des connaissances uniques sur la résistance aux antibiotiques chez M. tuberculosis au Vietnam. En particulier, ces données prédisent une évolution de la résistance vers une situation de plus en plus préoccupante. Premièrement, la famille Beijing, en cours d’invasion au Vietnam, apparaît associée à de hauts niveaux de résistance, de faible coût en termes de fitness et aux mutations compensatoires. Deuxièmement, le risque élevé de résistance à la pyrazinamide remet en question son efficacité et son utilisation dans les traitements contre la MDR et la XDR-TB. Troisièmement, les données suggèrent une évolution de M. tuberculosis vers un potentiel de résistance plus élevé par effet cumulatif des mutations associés à la résistance et l’existence de phénomènes d’épistasie. Comme les échantillons étudiés dans ce travail ont été collectés, l’étape suivante est de valider nos hypothèses sur des données actualisées.Enfin, ce travail avec les données déjà publiées a permis d’établir, pour la première fois, un inventaire des mutations associées à la résistance aux antibiotiques chez M. tuberculosis au Vietnam. Cette base de données sera utilisée pour le développement d'une puce à ADN pour la détection rapide de la résistance aux antibiotiques au Vietnam. / Tuberculosis (TB) is one of the deadliest infectious diseases worldwide, mainly caused by Mycobacterium tuberculosis. Multidrug resistant (MDR) and extensively drug resistant (XDR) TB are currently main challenges for TB control. In high MDR-TB burden countries like Vietnam, one of the main factors of drug resistant strain spread is the insufficient capacity of drug resistance detection. Besides, still little is known in these countries about the resistance to second line and pyrazinamide drugs (key drugs in the MDR-TB treatment) and the genetic determinants linked to these resistances. In this context, this work aimed to acquire knowledge on drug resistance in Vietnam and to understand how M. tuberculosis evolved from sensitive to highly drug resistance form by molecular analysis.260 clinical isolates collected in Vietnam between 2005 and 2009 were included. Various techniques and analyses were used: drug susceptibility testing (development of a test with a reduced turn-around time), spoligotyping and 24-MIRU-VNTR typing and gene sequencing. The data were analyzed by statistical and phylogenetic analyses.First, this work was focused on highly drug resistant M. tuberculosis clinical isolates and pyrazinamide resistance. A high proportion of quadruple first-line drug resistant isolates (resistant to isoniazid, rifampicin, streptomycin and ethambutol) have been characterized as pre-XDR and XDR isolates, belonging especially to Beijing family. The molecular analysis revealed also high proportion of drug resistant isolates carrying highly confident pyrazinamide resistance-associated mutations, particularly in MDR and quadruple resistant isolates and in Beijing family.Second, the genetic and phylogenetic analyses showed high diversity of mutation patterns within each family and each MIRU-VNTR cluster suggesting various evolutionary trajectories towards first and second-line drug resistance. The predominance of specific mutations and combinations of mutations associated with high level of resistance and low fitness cost suggests a cumulative effect of mutations and a role for epistasis in multiple-drug resistance acquisition. In addition, high frequency of fitness-compensatory mutations associated with rifampicin resistant mutations was detected in highly drug resistant isolates. These processes may drive the evolution of drug resistance in this sample and lead to a successful spread of highly drug resistant strains. It is worth noting that Beijing family was specifically linked to high-level drug resistance and low fitness cost mutations and to compensatory mutations.In conclusion, this work provides knowledge on the resistance to the first and second-line anti-TB drugs in clinical M. tuberculosis samples collected in Vietnam between 2005 and 2009. These data predict an evolution towards a more problematic situation in terms of drug resistance. First, because the Beijing family, which is currently invading Vietnam, is associated with highly drug resistance, mutations linked to high-level drug resistance and low fitness cost and compensatory mutations. Second, the high risk of pyrazinamide resistance in our sample challenges the efficacy and the use of this drug in MDR-TB treatment. Third, our data suggest an evolution of M. tuberculosis towards a higher potential of drug resistance because of a probable cumulative effect of drug resistant mutations and epistatic interactions. Since the samples under study were collected between 2005-2009, the next step is to test our hypotheses on a recent sampling. Finally, this study together with published data allowed making, for the first time, an inventory of the drug resistance associated mutations in M. tuberculosis isolates from Vietnam.

Poor decision making among clinicians to transferring human immune deficiency virus (HIV) patients into second-line antiretroviral therapy (ART) has led to an increase in morbidity and mortality to people living with HIV (PLHIV). No clear barriers are known for clinicians not switching their patients. This is a descriptive qualitative research aimed to discover obstacles that influence clinicians' decision making to transferring patients into second-line ART despite higher level resistance to first-line ART. The researcher applied a participatory action research framework to solve the identified barriers with clinicians. Using the research questions the researcher explored reasons, perceived barriers and enabling factors for clinicians delay in making decision to transferring HIV patients into second-line ART. In-depth semistructured interviews were conducted with 30 participants. Six thematic areas (a) clinicians' capacity to diagnose treatment failure, (b) laboratory investigations, (c) availability, access, and tolerability to second-line ART, (d) clinicians' perceptions on ARV medicines, (e) clients' readiness for ARV medicines, and (f) adherence and retention to ARV medicines were analysed using STATA. Readiness, adherence and retention to ART, knowledge, competence and experience on ART , lack of viral load testing, and shortage of second-line ART were the common major barriers for clinicians in determining transferring patients into second-line ART. The government of Tanzania should acknowledge and create participation, responsibility, and commitment strategies to reduce the observed barriers. Findings of this study generates knowledge and provide actionable plans to help clinicians easily identify HIV patients who are in need of second-line ART.