La violence conjugale est un problème social qui engendre des coûts sérieux (Statistique Canada, 2016). Son traitement est important. Les taux d’abandon thérapeutique observés dans les programmes de traitement en groupe pour les hommes auteurs de comportements violents en contexte conjugal se situent entre 15 et 58 % (Jewell & Wormith, 2010). Ces hauts taux d’abandon réduisent l’efficacité réelle des suivis pour violence conjugale (Bowen & Gilchrist, 2006). Des études montrent que l’âge, l’occupation, le statut conjugal, le faible revenu, l’expérience de violence physique à l’enfance, la consommation de drogue et d’alcool, ainsi que la personnalité colérique et la fréquence des comportements de violence sont des variables qui permettent de prédire l’abandon d’un programme de traitement de la violence conjugale en format de groupe et de type fermé (Jewell & Wormith, 2010). Aucune étude recensée n’a étudié les prédicteurs liés à l’abandon thérapeutique d’un traitement en format individuel de type ouvert. Cette étude visait à identifier quels sont les moments-clés où il y a cessation du suivi pour violence conjugale et à vérifier quelles variables sont associées à une cessation plus ou moins précoce du traitement individuel des hommes auteurs de violence conjugale. Une batterie de questionnaires auto-rapportés a été soumise à 206 hommes francophones qui amorcent une consultation individuelle pour un problème de violence conjugale dans un centre communautaire de la province de Québec. Parmi ceux-ci se trouvaient des questionnaires évaluant l’expérience de la colère, les comportements de violence conjugale, les insécurités d’attachement amoureux et la désirabilité sociable. Le nombre de séances complétées par chaque participant a également été obtenu par le biais de l’organisme. Une première analyse de survie a permis de produire une table de survie et d’identifier trois moments où la cessation du suivi est la plus fréquente, soient une cessation précoce (1 ou 2 séances), une cessation à court terme (3 à 5 séances) et une cessation à moyen terme (après la 11e séance). L’analyse de survie par régression de Cox a ensuite permis de montrer que l’âge, le fait d’avoir complété ou non des études post-secondaires, le fait d’avoir une occupation stable (emploi ou études à temps plein) ou non, le fait de consulter sous ordonnance légale, le niveau de violence psychologique émise, ainsi que les insécurités d’attachement (évitement de l’intimité, anxiété d’abandon) sont tous des prédicteurs significatifs du moment de cessation d’un suivi individuel de type ouvert pour violence conjugale. Plus précisément, les participants qui n’ont pas complété d’études post-secondaires, qui sont sans occupation stable, qui consultent sous ordonnance de la Cour ou de la DPJ et qui présentent peu d’évitement de l’intimité ont davantage tendance à cesser leur suivi de façon précoce; les participants qui ont complété des études post-secondaires et qui présentent peu d’anxiété d’abandon ont davantage tendance à cesser leur suivi à court terme; les clients qui posent moins d’actes de violence psychologique ont davantage tendance à mettre fin à leur suivi à moyen terme. Les implications cliniques de ces résultats sont discutées

Die Bedeutung genetischer Polymorphismen im Enzym Cytochrom P450 2C9 für Pharmakokinetik und Wirkungen von Diclofenac und Ibuprofen Es wird angenommen, dass Cytochrom-P450 2C9 die 4’-Hydroxylierung des Nichtsteroidalen Antiphlogistikums Diclofenac und die Hydroxylierung von S-Ibuprofen beim Menschen katalysiert. Es existieren zwei Varianten von Cyp2C9. Deren Auswirkungen auf die Diclofenac- bzw. Ibuprofen-Pharmakokinetik und die Hemmung von Cox-1 und -2 wurde an 21 gesunden Probanden, die sämtliche Kombination der genetischen Varianten *2 und *3 aufwiesen, untersucht. Es zeigten sich keinerlei Hinweise auf eine Einschränkung des Metabolismus von Diclofenac bei heterozygoten und homozygoten Trägern der Cyp2C9-Allele *2 und *3. Darüber hinaus lagen auch die Serumkonzentrationen des Metaboliten 4’-OH-Diclofenac bei Trägern der Allele Cyp2C9 *2 und *3 nicht niedriger. Obwohl verschiedene in vitro-Untersuchungen Cyp2C9 als metabolisierendes Enzym identifizierten, ist die Pharmakokinetik von Diclofenac ist beim Menschen entweder überhaupt nicht oder nur in geringem Ausmaß von Cyp2C9-Aminosäurenpolymorphismen abhängig. Möglicherweise sind die Auswirkungen der Cyp2C9-Aminosäurenvarianten substratabhängig, oder es ist in vivo ein anderes Enzym als Cyp2C9 verantwortlich für die Bildung von 4’-OH-Diclofenac. Im Unterschied dazu hing die Pharmakokinetik von razemischem und von S-Ibuprofen vom Cyp2C9 *3-Polymorphismus ab. Die Bildung von Tx B2 (Cox-1) hing signifikant von Cyp2C9 *3-Polymorphismus ab, derselbe Trend ließ sich auch für Pg E2 (Cox-2) beobachten. Die eingeschränkte Clearance von S-Ibuprofen, die mit einer erhöhten pharmakodynamischen Aktivität einhergeht, legt nahe, dass Träger des Allels Cyp2C9*3 ein höheres Risiko tragen, nach Einnahme einer oralen Standarddosis unerwünschte Nebenwirkungen zu erleiden. / Consequences of genetic polymorphisms in Cytochrome P450 2C9 for pharmacokinetics and effects of Diclofenac and Ibuprofen. Cytochrome-P450 2C9 is considered to catalyse the 4’-hydroxylation of the nonsteroidal analgesic drug diclofenac and the hydroxylation of S-ibuprofen in humans. There are two variants of Cyp2C9. Their impact on diclofenac/ ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2 was studied in 21 healthy volunteers with all combinations of the Cyp2C9 variants *2 and *3. Blood concentrations of diclofenac/ racemic ibuprofen (and of S-ibuprofen and R-ibuprofen) were measured by HPLC. Thromboxane B2 and prostaglandin E2 were measured with use of an enzyme immunoassay. There was no evidence of impaired metabolism of diclofenac in heterozygous and homozygous carriers of the Cyp2C9 alleles *2 and *3 compared to the wildtype. Furthermore, plasma concentrations of the metabolite 4’-OH-diclofenac were not lower in carriers of Cyp2C9*2 and *3. Marked diclofenac mediated inhibition of Cox-1- and Cox-2 activity was detected in all individuals without any Cyp2C9 genotype dependent differences. Even though several in vitro studies identified Cyp2C9 as the metabolising enzyme, Diclofenac pharmacokinetics in humans is either not or only to a minor extend dependent on the Cyp2C9 amino acid polymorphisms. It may be that the Cyp2C9 amino acid variants have differential effects depending on the substrates. Alternatively, an enzyme other than Cyp2C9 may be responsible for 4’-OH-Diclofenac formation in vivo.In contrast, the pharmacokinetics of racemic and of S-ibuprofen depended on the Cyp2C9 *3-polymorphism. The Cyp2C9 variant *2 exhibited no significant effect. Formation of Tx B2 (cox-1) depended significantly on the Cyp2C9 polymorphism, the same trend was observed for Pg E2 (cox-2). The reduced S-ibuprofen total clearance accompanied by increased pharmacodynamic activity indicates an increased risk for carriers of Cyp2C9*3 to suffer from adverse effects after intake of a standard oral dose.

Metastasis is the major cause of cancer related mortality, due to a poor understanding of the metastatic process and a subsequent lack of effective anti-metastatic therapies. Evidence from experimental studies and clinical trials has shown that aspirin reduces the incidence of distant metastases. It is well established that aspirin inhibits cyclooxygenase (COX)-1 and COX-2, triggering anti-thrombotic and anti-inflammatory effects, respectively. However, the mechanisms underlying the anti-metastatic effect of aspirin are still largely unknown. By using an experimental model of pulmonary metastasis, we have found that the anti-metastatic effect of aspirin is associated with the inhibition of COX-1. In support of this, metastasis establishment was impaired in COX-1 deficient mice, suggesting a pivotal role of this isoform in the metastatic process. Looking in more detail into the metastatic cascade, we found that COX-1 contributes to the intravascular phase of metastasis and promotes the early persistence of tumour cells in the lung vasculature. In particular, COX-1 inhibition decreased the interaction of platelets with tumour cells and was associated with the reduction of endothelial activation, of tumour cell adhesion to the endothelium, of recruitment of metastasis-promoting monocytes/macrophages and of transendothelial migration. We have identified platelet-derived thromboxane A₂ (TXA₂) as the main product of COX-1 responsible for its permissive effect on metastasis. Indeed, TXA₂ delivered to mice in combination with aspirin was able to abrogate the anti-metastatic effect of aspirin. Taken together, our data suggest that the inhibition of COX-1:TXA₂ axis by aspirin is sufficient to exert an anti-metastatic effect. In particular, the inhibition of platelet-derived TXA₂ seems to affect multiple early steps of the haematogenous transit of tumour cells. In this perspective, TXA₂ might represent a more selective therapeutic target for the prevention of metastasis.

Cancer is a stem cell disease and populations of cancer stem cells (CSCs) are evident in many cancer types. CSCs exhibit similarities to normal embryonic and adult stem cells: they are able to self-renew and have the potential to give rise to a diverse array of differentiated progeny. CSCs are responsible for driving tumourigenesis and metastasis, and are inherently resistant to chemotherapy and radiotherapy. This cell population is enriched after treatment and, as a result of their tumourigenic capability, can re-populate tumour growth resulting in patient relapse, often with increased chemotherapeutic resistance. Increasing evidence supports that only by targeting this population of cells will a cure for cancer be possible. Hence, it is essential to identify pathways within CSC populations that can be targeted therapeutically. Cyclooxygenase-2 (COX-2) is an enzyme associated with inflammation and disease, and is upregulated in many cancers types. The COX-2 / prostaglandin E2 (PGE2) signalling pathway is associated with increased tumour growth, metastasis, immune evasion and overall worse patient prognosis. Recent evidence has identified that COX-2 is further upregulated in CSC populations isolated from cancer cell lines. Previously, we have shown that inhibition of COX-2 reduces CSC sphere-forming ability, a characteristic of stem cell self-renewal, suggesting a role for COX-2 in maintaining CSC populations. This work was carried out in both human and canine osteosarcoma cell lines with similar results. Cancer in dogs is a major health concern among an aging pet population. Many cancer types exhibit similarities between these species, suggesting that naturally occurring canine cancer may be a potential model for the human disease. The aim of this PhD project was to investigate the role of COX-2 in CSCs in a comparative cancer study. CSCs that express stem cell markers have been isolated from a panel of canine and human cancer cell lines including, mammary carcinoma and transitional cell carcinoma of the urinary bladder. CSCs over-express COX-2 compared to non-CSCs, therefore to determine the role of COX-2 in CSC biology the selective COX-2 inhibitor mavacoxib, a non-steroidal anti-inflammatory drug currently licenced for treating osteoarthritis in dogs, was utilised. Our results demonstrate that inhibiting COX-2 has a multifaceted impact on CSC biology, including reducing self-renewal capacity, clonogenicity, proliferation, migration, invasion and in vivo tumourigenicity. To confirm that mavacoxib is mediating these CSC-specific effects via inhibition of COX-2 rather than through unknown off-target effects, we generated canine specific-small interfering RNA to specifically reduce gene expression of COX-2. Our results confirm that mavacoxib exerts its anti-tumour effects via inhibition of COX-2. This project has highlighted a plethora of CSC-specific COX-2 effects, and to gain further insight we compared the global gene expression profiles of CSCs compared to non- CSCs isolated from a canine bladder carcinoma cell line. This data revealed that both mavacoxib and COX-2 specific siRNA target similar pathways within the two cell populations, confirming that mavacoxib exerts its effects in a COX-2 dependent manner. Interestingly, mavacoxib reduced the expression of a number of stemness related genes in the CSC population, including NOTCH and Wnt, suggesting that mavacoxib can inhibit CSC related pathways. Our overall results are comparable between canine and human cancer cell lines supporting the concept of naturally occurring tumours in dogs as models for the human disease. In conclusion, COX-2 plays an important role not only in maintaining CSC populations but also in their function, and targeting COX-2 in CSCs may provide therapeutic benefit.

Advances in next-generation sequencing and ribosomal profiling methods highlight that the proteome is likely orders of magnitude larger than previously thought. This expansion potentially occurs through translational recoding, a process that results in the expression of multiple variations of a protein from a single messenger RNA. Our laboratory demonstrated that cyclooxygenase-3/1b (COX-3/1b), a frameshifted, intron-1-retaining, alternative splice variant from the COX-1 gene, is multiply recoded, which results in the translation of at least seven different COX-3 proteins. Two of the recoded COX-3 proteins that we identified are active prostaglandin synthases and are inhibited by non-steroidal anti-inflammatory drugs (NSAIDs). Here we show that the other non-prostaglandin-generating recoded COX-3 proteins perform new roles in innate immunity, a process in which COX are known to generally function. Our analyses determined that these recoded COX-3 proteins bind at or near the amino-terminal region of ATG9a, a critical regulator of both canonical (i.e. digestive autophagy associated with mTORc inhibition and nutrient deprivation) and non-canonical (i.e. xenophagy involved in the innate immune response to invading organisms) autophagy. We further show that this process requires mTORc signaling activity, which opposes the digestive pathway. As a final confirmation of the biological relevance of these recoded COX-3 proteins and their central role in xenophagy, we demonstrate that expression of these COX-3 proteins in an encephalomyocarditis virus infection model system differentially affects infectious virion production. These COX-3 proteins also associate with recoded cytosolic nucleobindin around large, innate immune-related, large LC3-II positive structures (LLPSs). Through mutagenizing catalytic residues of recoded COX-3 proteins and drug assays, we determine LLPS formation is dependent on oxylipin generation.

Infection with human immunodeficiency virus (HIV) and progression to acquired immune deficiency syndrome (AIDS) often result in neurologic and neuropsychiatric changes, although the prognostic information available for patients affected by HIV/AIDS-related neurologic diagnoses has been limited. The objective of the present study was to characterize the patterns and predictors of survival, including the impacts of antiretroviral therapy (ART) use and potential factors in healthcare access and disparity, among patients with one or more of the following conditions: cryptococcosis, toxoplasmosis, primary central nervous system lymphoma, progressive multifocal leukoencephalopathy, and HIV-associated dementia. To accomplish this, a cohort was drawn from the Iowa HIV/AIDS reporting system, and a non-independent, university-based cohort was then used to validate the analyses conducted for the statewide sample. Patterns of ART use were identified in each cohort using logistic regression, and survival analyses were conducted using Kaplan-Meier analysis, Cox regression, and accelerated failure time modeling. Survival was poor in both cohorts, although the university-based setting (University of Iowa Hospitals and Clinics) was associated with better overall survival. Of 230 persons in the statewide cohort, 77.0% were deceased by the end of the study period (1982-2008), and the median survival was 1.13 years (95% CI: 0.90 to 1.86 years, n=225). By contrast, 56.4% of the university-based cohort was deceased by the end of the study period (1984-2009), and the median survival in this group was 3.04 years (95% CI: 1.79 to 11.62 years, n=172). Both cohorts were predominantly male, non-Hispanic white, and residents of a small metropolitan area at the time of the AIDS diagnosis. ART use had a strong protective effect on survival in both cohorts. Use of ART among patients diagnosed during the era of highly active antiretroviral therapies (HAART) was associated with an 80% reduction in the rate of death (HR=0.20, 95% CI: 0.08 to 0.46) compared to the non-users diagnosed during the pre-HAART era (that is, prior to 1996), after adjustment for age, race, birth sex, healthcare facility type, opportunistic infection count, HIV transmission risk category, neurologic condition, years since AIDS diagnosis, and timing of neuro-AIDS in a Cox regression model. In the UIHC cohort, the adjusted expected survival time among ART/HAART users was 37.71 (95% CI: 14.44 to 99.48) times that among non-users. Women had significantly poorer outcomes than men in the statewide cohort (adjusted HR=2.31, 95% CI: 1.22 to 4.35), and a similar, non-significant trend was observed among university-based cases. Secondary analyses suggested that this difference persisted over the course of the epidemic and was not attributable to differential ART response among men and women. Evidence for a role of disease severity, psychosocial support, and/or psychiatric comorbidity in the differential survival of men and women was identified. This study provides useful prognostic data for patients and providers and may guide future research efforts aimed toward improved survival for neuro-AIDS patients. The survival disadvantage of women compared to men should be confirmed and the mechanisms underlying this disparity elucidated. Meanwhile, clinical and public health efforts might be directed towards screening, treatment, and support for women affected by neuro-AIDS, including potential assessment of comorbid psychiatric disorders.

This work aims to enhance the Ensemble Kalman Filter performance by transforming the non-Gaussian state variables into Gaussian variables to be a step closer to optimality. This is done by using univariate and multivariate Box-Cox transformation. Some History matching methods such as Kalman filter, particle filter and the ensemble Kalman filter are reviewed and applied to a test case in the reservoir application. The key idea is to apply the transformation before the update step and then transform back after applying the Kalman correction. In general, the results of the multivariate method was promising, despite the fact it over-estimated some variables.

Doctor en Ingeniería de Minas / La caracterización de fracturas es crítica en minería a cielo abierto y subterránea, así como en ingeniería geológica e ingeniería de petróleo, para comprender las propiedades mecánicas e hidráulicas del macizo rocoso. Dado que se observa una fracción muy pequeña de las fracturas en un área de estudio, no es aconsejable un modelo determinístico de la red de fracturas y, a menudo, es preferible un modelo estocástico. Esta tesis se centra en el llamado modelo Cox-Booleano de discos planos para describir redes de fracturas discretas, que se basa en la definición de un proceso puntual de Cox que representa los centros de fracturas, así como en una distribución de las orientaciones y de los diámetros de fracturas. El problema específico abordado es la inferencia de los parámetros del modelo, basada en información de muestreo 1D o 2D que se origina a partir de sondajes, observaciones en líneas o bidimensionales. Las soluciones actuales al problema de inferencia suelen ser aproximadas o incipientes, especialmente en lo que se refiere al potencial del proceso de Cox subyacente, que consiste en un campo aleatorio que modela el número promedio de centros de fracturas por unidad de volumen del macizo rocoso. Se desarrollan tres métodos para modelar los parámetros de un modelo Cox-Booleano. El primero se centra en la estimación de la distribución de diámetros de fracturas en función de la distribución de longitudes de trazas determinadas a partir de observaciones areales. El segundo método aborda el problema de predecir espacialmente la intensidad de fracturas (P32) y cuantificar la incertidumbre en los valores verdaderos de P32, utilizando la información de las discontinuidades observadas a lo largo de sondajes. El tercer método permite inferir la distribución del potencial en base a la intensidad de fracturas como una variable auxiliar y a una identidad general entre las distribuciones de diámetros de fracturas, de la intensidad de fracturas y del campo potencial sobre un soporte de bloque grande. Las herramientas y métodos propuestos se aplican a estudios de casos sintéticos y reales para demostrar su aplicabilidad. El conocimiento de los parámetros del modelo abre el camino para simular el DFN en el espacio y condicionar la simulación a datos observados.

<p><strong>Målsättning</strong><strong></strong></p><p>Att utreda skillnader i tillgänglighet till insulinpump mellan olika patientgrupper samt vad som orsakar ett byte till insulinpump.</p><p><strong>Metod</strong><strong></strong></p><p>Data från 7224 individer med typ 1 diabetes vid tio olika vårdenheter analyserades för att utreda effekterna av njurfunktion, kön, långtidsblodsocker, insulindos, diabetesduration samt ålder. Jämförelsen mellan patientgrupper utfördes med logistisk regression som en tvärsnittsstudie och Cox-regression för att utreda vad som föregått ett byte till pump.</p><p><strong>Resultat</strong><strong></strong></p><p>Genom logistisk regression erhölls en bild av hur skillnader mellan patienter som använder insulinpump och patienter som inte gör det ser ut i dagsläget. Cox-regressionen tar med ett tidsperspektiv och ger på så sätt svar på vad som föregått ett byte till insulinpump. Dessa analyser gav liknande resultat gällande variabler konstanta över tiden. Kvinnor använder pump i större utsträckning än män och andelen pumpanvändare skiljer sig åt vid olika vårdenheter. I dagsläget visar sig hög ålder sänka sannolikheten att använda insulinpump, vilket bekräftas vid den tidsberoende studien som visade hur sannolikheten att byta till pump är avsevärt lägre vid hög ålder. Långtidsblodsockret har också tydlig effekt på sannolikheten att gå över till pump där ett högt långtidsblodsocker medför hög sannolikhet att byta till insulinpump.</p><p><strong>Slutsatser</strong><strong></strong></p><p>I dagsläget finns det skillnader i andelen insulinpumpanvändare mellan olika patientgrupper och skillnader finns även i de olika gruppernas benägenhet att byta från andra insulinbehandlingar till insulinpump. Beroende av patienters njurfunktion, kön, långtidsblodsocker, insulindos, diabetesduration och ålder har dessa olika sannolikheter att byta till insulinpump.<strong></strong></p>

The field of survival analysis has experienced tremendous growth during the latter half of the 20th century. The methodological developments of survival analysis that have had the most profound impact are the Kaplan-Meier method for estimating the survival function, the log-rank test for comparing the equality of two or more survival distributions, and the Cox proportional hazards (PH) model for examining the covariate effects on the hazard function. The accelerated failure time (AFT) model was proposed but seldom used. In this thesis, we present the basic concepts, nonparametric methods (the Kaplan-Meier method and the log-rank test), semiparametric methods (the Cox PH model, and Cox model with time-dependent covariates) and parametric methods (Parametric PH model and the AFT model) for analyzing survival data.<p> We apply these methods to a randomized placebo-controlled trial to prevent Tuberculosis (TB) in Ugandan adults infected with Human Immunodificiency Virus (HIV). The objective of the analysis is to determine whether TB preventive therapies affect the rate of AIDS progression and survival in HIV-infected adults. Our conclusion is that TB preventive therapies appear to have no effect on AIDS progression, death and combined event of AIDS progression and death. The major goal of this paper is to support an argument for the consideration of the AFT model as an alternative to the PH model in the analysis of some survival data by means of this real dataset. We critique the PH model and assess the lack of fit. To overcome the violation of proportional hazards, we use the Cox model with time-dependent covariates, the piecewise exponential model and the accelerated failure time model. After comparison of all the models and the assessment of goodness-of-fit, we find that the log-logistic AFT model fits better for this data set. We have seen that the AFT model is a more valuable and realistic alternative to the PH model in some situations. It can provide the predicted hazard functions, predicted survival functions, median survival times and time ratios. The AFT model can easily interpret the results into the effect upon the expected median duration of illness for a patient in a clinical setting. We suggest that the PH model may not be appropriate in some situations and that the AFT model could provide a more appropriate description of the data.