Magister Public Health - MPH / Background: The goal of ART therapy is sustained viral load suppression with good immunological and clinical response. This optimal response to therapy results in the prevention of emergent ART drug-resistant mutations, decrease morbidity, and AIDS-related mortality and sustained retention on ART. Kenya, like most countries in Sub-Saharan Africa, has scaled-up the use of ART and is currently implementing a “Test and Treat” strategy in which any client identified and confirmed with an HIV diagnosis is initiated ART. Few studies have been carried out to ascertain the response of HIV patients initiating treatment in resource-limited settings. Moreover, it has been demonstrated that a certain proportion of patients fail to adequately respond to therapy and therefore require therapy modification. Aim: To assess treatment outcomes and calculate retention of HIV infected adult patients’ (15 years and above) initiating ART at Kakamega County General Hospital. The primary study outcome was the treatment outcome of patients-initiated ART two to three years prior to the study; while, the role of WHO criteria for screening treatment failure was assessed as a secondary outcome. Methods: This was a retrospective cohort study in which patients initiating ART between June 2014 and March 2015 were followed up until they were censored or study closed in August 2017. 284 patients were enrolled in the study after accurately matching information in their clinic files and the electronic medical record. Data were collected from patient records using a chart abstraction tool and transferred to an Access database from where the cleaning and validation of entries were done. Data from Access was transferred to STATA 15.1 for analysis. Descriptive statistics and inferential statistics were then performed to answer the research questions.

Bien que le mélanome malin cutané (MMC) ne représente que 10% des cancers cutanés, il en est la forme la plus agressive et est responsable de 90% des décès dus aux cancers de la peau. Son incidence ne cesse d'augmenter ces dernières années et atteint 10.8 cas pour 100 000 habitants chez les hommes et 11 chez les femmes. La survie médiane des patients atteint de mélanome à un stade avancé est de 6.2 mois et seulement 1 patient sur 4 est encore en vie à 1an. Le diagnostic du mélanome est uniquement histopathologique et seul l'examen de la biopsie permet de le poser définitivement. De la même façon, il n'existe pas de marqueurs pronostiques associés au mélanome malin cutané. Seuls des facteurs histologiques tels que l'épaisseur de la tumeur, le degré d'invasion ou encore l'envahissement ganglionnaire ont été validés par l'American Joint Committee on Cancer et servent de facteurs pronostiques. Cependant, bien qu'ils permettent d'évaluer le risque métastatique, leur valeur pronostique est encore très insuffisante. L'objectif de ma thèse est d'identifier et de caractériser les protéines associées à la progression tumorale du MMC. Grâce à une approche protéomique quantitative de type iTRAQ par nanoLC MS/MS, j'ai pu identifier et caractériser 2242 protéines dans un modèle cellulaire de progression tumorale du mélanome. La surexpression de huit de ces protéines dans les lignées tumorales par rapport à la lignée normale a été validée par western blot. Deux d'entre elles, TRAP1 et PDIA4 ont ensuite été validées en immunohistochimie comme marqueurs associés à la progression tumorale dans le MMC. Dans un second temps, l'implication de ces deux protéines dans les mécanismes de carcinogénèse du mélanome a été étudiée. L'inhibition de TRAP1 et de PDIA4 induit une diminution de la migration et de la viabilité de la lignée cellulaire métastatique de mélanome 1676. Enfin, la sous-expression dePDIA4 induit une inhibition du complexe Cycline D/CDK4 provoquant un blocage des cellules en phase G0/G1. Ce blocage passerait par la voie PERK liées au stress du réticulum endoplasmique. / Although cutaneous malignant melanoma (CMM) represents only 10% of skin cancers, it is the most aggressive form with 90% of deaths from skin cancer. The Incidence rate is increasing in recent years to 10.8 cases and 11 cases per 100000, in men and women respectively. The prognosis of metastatic melanoma is poor, with a median survival of only 6.2 months. Histopathologic examination remains the gold standard for melanoma diagnosis. There are no prognostic markers associated with CMM. Only histological factors such as tumor thickness, level of invasion, or lymph node involvement have been validated by the American Joint Committee on Cancer and are currently used as prognostic factors. However, although these histological factors are used to assess the risk of metastasis development, their prognostic value is still very low. The aim of my PhD work is to identify and characterize biomarkers associated with tumor progression of CMM. Using a quantitative proteomics approach (iTRAQ and nanoLCMS/MS), I was able to identify and characterize 2242 proteins in a cellular model of melanoma tumor progression. The overexpression of eight proteins in tumor cell lines compared to the normal cell line was validated by immunoblotting. Among these proteins, TRAP1 and PDIA4 were then validated by immunohistochemistry as markers associated with tumor progression in the CMM. Secondly, the involvement of these two proteins in the mechanisms of melanoma carcinogenesis has been studied. The inhibition of TRAP1 and PDIA4 induces a decrease in migration and viability of the metastatic melanoma cell line. Finally, PDIA4 under expression induce an inhibition of cyclin D/Cdk4 complex leading to G0/G1 cell-cycle arrest dependant of endoplasmic reticulum stress by the PERK pathway.

The detection of subtypes of complex diseases has important implications for diagnosis and treatment. Numerous prior studies have used data-driven approaches to identify clusters of similar patients, but it is not yet clear how to best specify what constitutes a clinically meaningful phenotype. This study explored disease subtyping on the basis of temporal development patterns. In particular, we attempted to differentiate infants with autism spectrum disorder into more fine-grained classes with distinctive patterns of early skill development. We modeled the progression of autism explicitly using a continuous-time hidden Markov model. Subsequently, we compared subjects on the basis of their trajectories through the model state space. Two approaches to subtyping were utilized, one based on time-series clustering with a custom distance function and one based on tensor factorization. A web application was also developed to facilitate the visual exploration of our results. Results suggested the presence of 3 developmental subgroups in the ASD outcome group. The two subtyping approaches are contrasted and possible future directions for research are discussed.

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Introduktion: Karies är en vanlig sjukdom som drabbar stor del av befolkningen. För att karies ska uppstå behövs tand, bakterier och frekvent intag av fermenterbara kolhydrater. En skyddande faktor mot karies är fluor vilket hämmar demineralisering samt gynnar remineralisering. Det har visats att fluorlack kan förebygga karies men även hämma kariesprogression på viss befintlig karies. Syfte: Att beskriva olika fluorlackers progressionshämmande effekt på karies. Frågeställning: Vilket fluorlack fungerar bäst i progressionshämmande syfte? Metod: En litteraturstudie Resultat: Resultatet visade progressionshämmande effekt av fluorlacker på emalj-, dentin- och rotkaries. Skillnaden mellan flera lackers effekt var på grund av olika lackningsintervall, utvärderingstid och liknande resultat svår att skilja åt. Konklusion: Alla fluorlacker, förutom Prevident (5 % NaF), involverade i denna studie sågs ha progressionshämmande effekt på karies.  Detta tyder på att fluorlackning är bättre än ingen fluorlackning oavsett fluorlack. Duraphat (5 % NaF) sågs i vissa studier ha något bättre effekt än andra fluorlacker.

Background: To describe the scoring methodology and MRI assessments used to evaluate the cross-sectional features observed in cases and controls, to define change over time for different MRI features, and to report the extent of changes over a 24-month period in the Foundation for National Institutes of Health Osteoarthritis Biomarkers Consortium study nested within the larger Osteoarthritis Initiative (OAI) Study. Methods: We conducted a nested case-control study. Cases (n = 406) were knees having both radiographic and pain progression. Controls (n = 194) were knee osteoarthritis subjects who did not meet the case definition. Groups were matched for Kellgren-Lawrence grade and body mass index. MRIs were acquired using 3 T MRI systems and assessed using the semi-quantitative MOAKS system. MRIs were read at baseline and 24 months for cartilage damage, bone marrow lesions (BML), osteophytes, meniscal damage and extrusion, and Hoffa- and effusion-synovitis. We provide the definition and distribution of change in these biomarkers over time. Results: Seventy-three percent of the cases had subregions with BML worsening (vs. 66 % in controls) (p = 0.102). Little change in osteophytes was seen over 24 months. Twenty-eight percent of cases and 10 % of controls had worsening in meniscal scores in at least one subregion (p < 0.001). Seventy-three percent of cases and 53 % of controls had at least one area with worsening in cartilage surface area (p < 0.001). More cases experienced worsening in Hoffa- and effusion synovitis than controls (17 % vs. 6 % (p < 0.001); 41 % vs. 18 % (p < 0.001), respectively). Conclusions: A wide range of MRI-detected structural pathologies was present in the FNIH cohort. More severe changes, especially for BMLs, cartilage and meniscal damage, were detected primarily among the case group suggesting that early changes in multiple structural domains are associated with radiographic worsening and symptomatic progression.

Pancreatic ductal adenocarcinoma is a highly desmoplastic tumour, and non-malignant stromal cells contribute to progression and treatment resistance. Inflammatory cells in particular are known drivers of carcinogenesis, and macrophages are one of the most abundant inflammatory leucocytes. Therefore, exploring how macrophages drive tumour progression in pancreatic cancer would not only aid in understanding disease biology but could also offer insight to novel treatment strategies. Results presented in this thesis show macrophages secrete factors that drive epithelial-to-mesenchymal transition, promote invasion and lead to expression of checkpoint inhibitors. To determine what factors were driving this phenotype, the serine protease inhibitor SerpinB3 was initially explored, as it was highly upregulated in cancer cells cultured with conditioned media from macrophages. However, SerpinB3 gene overexpression and knockdown did not confirm a direct role for this gene in mediating migration and invasion. Further investigation revealed macrophages were secreting the cytokine oncostatin M, which was driving a metastatic phenotype through activation of the STAT3 pathway. Expression of oncostatin M receptor was upregulated in cancer cells following culture with macrophage conditioned media and conferred a worse prognosis in patient samples. STAT3 pathway activation by oncostatin M led to increased invasion in vitro, particularly of the highly tumourigenic cancer stem cell population, and increased metastasis in vivo. Moreover, oncostatin M mediated expression of the immune 'checkpoint' inhibitors on the surface of pancreatic cancer cells. Using antibody and small molecule inhibitors, reversion of these signalling pathway effects were seen and preliminary data from in vivo assays showed decreased metastasis formation with cytokine receptor antibody inhibition. Overall, the findings in this thesis contribute to emerging knowledge of how tumour associated macrophages drive tumour progression in pancreatic adenocarcinoma. Not only do they promote invasion and metastatic potential through oncostatin M secretion, but also potentiate inherent biological properties of cancer stem cells and assist in immune tolerance. In addition, results provide preliminary data to support a rationale for clinical targeting of macrophage-derived oncostatin M in pancreatic cancer.

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