The field of prenatal screening and diagnosis has developed rapidly over the past half-century, enabling possibilities for detecting anomalies in reproduction that were never before contemplated. A simple blood sample can aid in the identification of several conditions in the fetus early in the pregnancy. If a fetus is found to be affected by Down syndrome, anencephalus, spina bifida, or Edward's syndrome, a decision must then be made whether to continue or terminate the pregnancy. As prenatal screening becomes increasingly commonplace and part of routine maternal care, researchers are faced with the challenge of understanding its effects at the level of the population and monitoring trends over time. Greater uptake of prenatal screening, when followed by prenatal diagnosis and termination, has important implications for both congenital anomaly surveillance and infant and fetal mortality indicators. Research in Canada suggests that this practice has led to reductions in the congenital-anomaly specific infant mortality rate and increases in the stillbirth rate.(1, 2) The current study is a population-based, epidemiological exploration of demographic predictors of maternal serum screening (MSS) and amniocentesis uptake, with special attention to variations in birth outcomes resulting from different patterns of use. To accomplish our objectives, multiple data sources (vital statistics, hospital and physician services, cytogenetic and MSS laboratory information) were compiled to create a comprehensive maternal-fetal-infant dataset. Data spanned a six-year period (2000-2005) and involved 93,171 pregnancies. A binary logistic regression analysis found that First Nations status, rural-urban health region of residence, maternal age group, and year of test all significantly predicted MSS use. Uptake was lower in women living in a rural health region, First Nations women, and those under 30 years of age. The study dataset identified ninety-four terminations of pregnancy following detection of a fetal anomaly (TOPFA), which led to a lower live birth prevalence of infants with Down syndrome, Trisomy 18, and anencephalus. While a significant increasing trend was observed for the overall infant mortality rate in Saskatchewan between 2001-2005, a clear trend in one direction or the other could not be seen in regards to infant deaths due to congenital anomaly. First Nations status and maternal age were important predictors of both MSS and amniocentesis testing, and appeared to influence the decision to continue or terminate an affected pregnancy. The fact that First Nations women were less likely to screen (9.6% vs. 28.4%) and to have diagnostic follow-up testing (18.5% vs. 33.5%), meant that they were less likely to obtain a prenatal diagnosis when the fetus had a chromosomal anomaly compared to other women (8.3% vs. 27.0%). This resulted in a lower TOPFA rate compare to the rest of the population (0.64 vs. 1.34, per 1,000 pregnancies, respectively) and a smaller difference between the live birth prevalence and incidence of Down syndrome and Trisomy 18 for First Nations women. Women under 30 years of age were much less likely to receive a prenatal diagnosis when a chromosomal anomaly was present (18.4% vs. 31.8%). While risk for a chromosomal anomaly is considerably lower for younger mothers, 53.5% of all pregnancies with chromosomal anomalies and 40.7% of DS pregnancies belonged to this group. Consistent with other studies pregnancy termination rates following a prenatal congenital anomaly diagnosis are high (eg. 74.1% of prenatally diagnosed Down syndrome or Trisomy 18 cases), but these rates may be misleading in that they are based on women who chose to proceed to prenatal diagnosis. The fact that two-thirds (67.3%) of Saskatchewan women who received an increased-risk result declined amniocentesis, helps to put this finding into context. Strong surveillance systems and reasonable access to research datasets will be an on-going challenge for the province of Saskatchewan and should be viewed as a priority. Pregnancies and congenital anomalies are two particularly challenging outcomes to study in the absence of perinatal and congenital anomaly surveillance systems. Still pregnancies that never reach term must be accounted for, in order to describe the true state of maternal-fetal-infant health and to study its determinants. While our study was able to identify some interesting trends and patterns, it is only a snapshot in time. Key to the production of useful surveillance and evaluation is timely information. The current system is not timely, nor is it user-friendly for researchers, health regions or governments. Data compilation for the current study was a gruelling and cumbersome process taking more than five years to complete. A provincial overhaul is warranted in both the mechanism by which researchers access data and in the handling of data. The Better Outcomes Registry & Network (BORN) in Ontario is an innovative perinatal and congenital anomaly surveillance system worthy of modelling.(3) Academic papers in non-ethics' journals typically focus on the technical or programmatic aspects of screening and do not effectively alert the reader to the complex and profound moral dilemmas raised by the practice. A discussion of ethics was felt necessary to ensure a well-rounded portrayal of the issue, putting findings into context and helping to ensure their moral relevance did not remain hidden behind the scientific complexities. Here I lay out the themes of the major arguments in a descriptive manner, recognizing that volumes have been written on the ethics of both screening and abortion. A major ethical tension arising within the context of population based prenatal screening is the tension between community morality and the principle of respect for personal autonomy. Prenatal screening and selective termination have been framed as a purely private or medical matter, thereby deemphasizing the social context in which the practice has materialized and the importance of community values. I consider how a broader sociological perspective, one that takes into account the relevance of community values and limitations of the clinical encounter, could inform key practice and policy issues involving prenatal screening. It is my position that the community's voice must be invited to the conversation and public engagement processes should occur prior to any additional expansion in programming. I end with a look at how the community’s voice might be better heard on key issues, even those issues that at first glance seem to be the problems of individuals. As Rayna Rapp (2000) (4) poignantly observed, women today are 'moral pioneers' not by choice, but by necessity. By elucidating the effects of prenatal screening and the extent of the practice of selective termination in the province, the true occurrence of important categories of congenital anomalies in our province can be observed. Without this knowledge it is very difficult to identify real increases or decreases in fetal and infant mortality over time as the etiologies are complex. Evidence suggests a large and increasing impact of TOPFA on population-based birth and mortality statistics nationally, whereas in Saskatchewan the effect appears to be less pronounced. Appreciation of the intervening effect of new reproductive technologies will be increasingly important to accurate surveillance, research, and evaluation as this field continues to expand.

A new Laser Induced Fluorescence Capillary Zone Electrophoresis (LIF-CZE) bioassay to detect and study the catalytic activity of the sulfur assimilating enzyme commonly found in E. coli species; alkanesulfonate monooxygenase (EC 1.14.14.5) is described for the first time. This technique enables the possibility for direct injection onto a capillary for detection without the need for pre-concentration of sample and with minimal sample preparative steps prior to analysis. In this bioassay, a group of Fischer based cyanine dyes and two Oxazine (Nile red) derivatives were designed for further optimization as key Vis-NIR fluorescent substrate. In developing this technique, the test dyes were first assessed for their photophysical properties, based on four criteria; (1) photostable (2) solvatochromism (3) binding affinity towards both the monooxygenase active site and serum albumin and (4) chemical stability in strong electric field strength. Applying key dye characterization procedures including; molar absorptivity determination, quantum yield determination, photostability, solvatochromism and protein interaction studies it was determined that the Fischer indolium cyanine dyes were most suitable for the method development. The data revealed that under the test conditions, reduced flavin, the oxidative monooxygenase catalytically specifically converts the alkylsulfonate substituted cyanine dyes to the corresponding aldehyde. This new bioassay has proven to be quick, portable, sensitive, reliable and the exhibit the possibility of ‘on-the-spot’ detection; advantages not readily realized with other commonly applied techniques such as PCR, SPR, ELISA and GC used to study bacterial sulfur assimilation processes. In addition, recent literature results proposed by other research groups developing similar techniques showed strong reliance on GC analyses. Those assays involve the use of low molecular weight straight chain non-emissive alkanesulfonate substrates. Once enzyme catalysis occurs the aldehyde is formed becomes rather volatile and requires complex and tedious headspace sampling for GC analyses. This feature limits the in vitro applicability and eliminated the possibility in vivo development. Our goal is to further develop, optimize and present this CZE based bioassay as a suitable alternative to the current trends in the field while creating a more robust and sensitive in vitro monooxygenase detection method with the possibilities of in vivo application.

Background: Clinical studies have shown that tea consumption leads to decreased iron absorption. This finding is however, not supported by epidemiological studies, where no relationship between an increased tea consumption and a lower iron status in a population at risk of iron depletion has been found. Objectives: The main aim of this study was to compare the effects of black tea and Rooibos consumption on the iron status of primary school children in a rural setting in Potchefstroom, South Africa. Methods: One hundred and seventy five children, aged six to fifteen years, participated in this single blind, randomised, parallel intervention trial. Subjects were randomly allocated to receive two 200ml servings of either black tea or Rooibos with milk and sugar. These beverages were consumed during breaks and at the same time as the food h m the school-feeding scheme. The trial proceeded for sixteen weeks. The children received antihelminthic treatment (500mg mebendazole) at baseline. Haemoglobii haematocrit, serum iron, ferritin and transferfin were measured and total iron binding capacity and transferrin saturation were calculated. Trained fieldworkers measured dietary intakes by means of 24-hour dietary recalls and anthropometrists took anthropometric measurements. All the above mentioned data were gathered at the beginning and at the end of the intervention period. Results: Measurements indicated a study population that is malnourished in terms of anthropometrical indices and nutrient intakes. Biochemical markers of iron status also indicated that the population could be at risk of iron depletion. Changes in red blood cell count, haemoglobin, haematocrit, mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV), serum iron, transferrin, transferrin saturation, ferritin and total iron binding capacity (TIBC) did not differ significantly between the two groups. Mean red blood cell count, haematocrit, MCV, transferrin and TIBC increased significantly h m baseline to end in both groups (all p<0.0001) and MCH decreased significantly (p<.0001). Mean haemoglobin increased significantly with black tea consumption (p=0.002), although not with the consumption of Rooibos (p=0.073). Conclusion: Black tea or Rooibos consumption has similar effects on the iron status of primary school children. Iron status was not compromised by black tea in comparison with Rooibos. This questions the proposed limitation of black tea consumption as a public health strategy in order to combat iron deficiency in a population with marginal iron status. / Thesis (M.Sc. (Nutrition))--North-West University, Potchefstroom Campus, 2004.

Infection is a leading cause of death in hemodialysis patients, partly due to dysfunctional immunity. Frequent dialysis therapy improves patient outcomes and quality of life. We hypothesize that extended home hemodialysis (EHHD) also improves immune function compared to conventional in-hospital hemodialysis (CHD); therefore, we designed a prospective matching-cohort clinical study to assess serum inflammatory markers and the functional capacity of monocyte-derived dendritic cells (MDDCs) and T-lymphocytes. Serum CRP was decreased in EHHD patients suggesting that extended dialysis may decrease inflammatory solute/cytokine levels. Compared to controls, MDDCs from hemodialysis patients had similar endocytic capacity, expression of co-stimulatory molecules, and T-cell activation capacity. However, CHD was associated with the highest expression of CD83 and CD40. Activated T-cells in CHD patients also produced significantly more immunosuppressive IL-10 compared to EHHD patients and controls. Therefore, EHHD may improve immune function by decreasing inflammation, MDDC pre-activation, and synthesis of immunosuppressive cytokines.

Drug transport across the intestinal epithelium is roughly predicted from permeability values obtained from Caco-2 cell monolayers. This thesis examines the important role of pH and extracellular additives for increasing the reliability and predictivity of the in vitro screening system, Caco-2. It was shown that the passive transport of ionizable compounds may be biased by a false efflux or uptake component, when applying a physiological pH-gradient across the membrane. pH also affected the amount of compound available at the transporter-binding site. Therefore, pH dependence should be considered in studies of such compounds and of drug-drug interactions involving efflux transporters. It was also shown that proton-dependent apical uptake or basolateral efflux should be studied both with and without a pH gradient over the whole monolayers. The two extracellular additives, bovine serum albumin (BSA) and the solubilizing agent, Cremophor® EL, also influenced Caco-2 permeabilities. BSA applied to the receiver side increases, and to the donor side decreases drug permeation according to the drug’s protein binding capacity. Thus, the absorptive transport for both passive and active compounds is favoured, giving a physiologically sound improvement of the Caco-2 cell model. Inclusion of BSA increased both the predictivity and quality of permeability studies, particularly of highly lipophilic, BCS class II compounds. Passive and active transport processes could also be distinguished after accounting for unbound concentrations. The overall effect of Cremophor® EL on the permeability to a drug was compound-specific and probably dependent on micellar incorporation. Cremophor® EL can therefore not be recommended. Neither pH nor BSA affect the functionality of transporters such as P-glycoprotein. However, efflux ratios of ionizable or protein bound drugs are altered in the presence of a pH-gradient or BSA, indicating that an experimental system without protein or pH gradient can over- or underestimate active and passive efflux in drug transport.

Vitamin D deficiency and insufficiency are now seen as a contemporary health problem in Australia with possible widespread health effects not limited to bone health1. Despite this, the Vitamin D status (measured as serum 25-hydroxyvitamin D (25(OH)D)) of ambulatory adults has been overlooked in this country. Serum 25(OH)D status is especially important among this group as studies have shown a link between Vitamin D and fall risk in older adults2. Limited data also exists on the contributions of sun exposure via ultraviolet radiation and dietary intake to serum 25(OH)D status in this population. The aims of this project were to assess the serum 25(OH)D status of a group of older ambulatory adults in South East Queensland, to assess the association between their serum 25(OH)D status and functional measures as possible indicators of fall risk, obtain data on the sources of Vitamin D in this population and assess whether this intake was related to serum 25(OH)D status and describe sun protection and exposure behaviors in this group and investigate whether a relationship existed between these and serum 25(OH)D status. The collection of this data assists in addressing key gaps identified in the literature with regard to this population group and their Vitamin D status in Australia. A representative convenience sample of participants (N=47) over 55 years of age was recruited for this cross-sectional, exploratory study which was undertaken in December 2007 in south-east Queensland (Brisbane and Sunshine coast). Participants were required to complete a sun exposure questionnaire in addition to a Calcium and Vitamin D food frequency questionnaire. Timed up and go and handgrip dynamometry tests were used to examine functional capacity. Serum 25(OH)D status and blood measures of Calcium, Phosphorus and Albumin were determined through blood tests. The Mean and Median serum 25-Hydroxyvitamin D (25(OH)D) for all participants in this study was 85.8nmol/L (Standard Deviation 29.7nmol/L) and 81.0nmol/L (Range 22-158nmol/L), respectively. Analysis at the bivariate level revealed a statistically significant relationship between serum 25(OH)D status and location, with participants living on the Sunshine Coast having a mean serum 25(OH)D status 21.3nmol/L higher than participants living in Brisbane (p=0.014). While at the descriptive level there was an apparent trend towards higher outdoor exposure and increasing levels of serum 25(OH)D, no statistically significant associations between the sun measures of outdoor exposure, sun protection behaviors and phenotypic characteristics and serum 25(OH)D status were observed. Intake of both Calcium and Vitamin D was low in this sample with sixty-eight (68%) of participants not meeting the Estimated Average Requirements (EAR) for Calcium (Median=771.0mg; Range=218.0-2616.0mg), while eighty-seven (87%) did not meet the Adequate Intake for Vitamin D (Median=4.46ug; Range=0.13-30.0ug). This raises the question of how realistic meeting the new Adequate Intakes for Vitamin D is, when there is such a low level of Vitamin D fortification in this country. However, participants meeting the Adequate Intake (AI) for Vitamin D were observed to have a significantly higher serum 25(OH)D status compared to those not meeting the AI for Vitamin D (p=0.036), showing that meeting the AI for Vitamin D may play a significant role in determining Vitamin D status in this population. By stratifying our data by categories of outdoor exposure time, a trend was observed between increased importance of Vitamin D dietary intake as a possible determinant of serum 25(OH)D status in participants with lower outdoor exposures. While a trend towards higher Timed Up and Go scores in participants with higher 25(OH) D status was seen, this was only significant for females (p=0.014). Handgrip strength showed statistically significant association with serum 25(OH)D status. The high serum 25(OH)D status in our sample almost certainly explains the limited relationship between functional measures and serum 25(OH)D. However, the observation of an association between slower Time Up and Go speeds, and lower serum 25(OH)D levels, even with a small sample size, is significant as slower Timed Up and Go speeds have been associated with increased fall risk in older adults3. Multivariable regression analysis revealed Location as the only significant determinant of serum 25(OH)D status at p=0.014, with trends (p=>0.1) for higher serum 25(OH)D being shown for participants that met the AI for Vitamin D and rated themselves as having a higher health status. The results of this exploratory study show that 93.6% of participants had adequate 25(OH)D status-possibly due to measurement being taken in the summer season and the convenience nature of the sample. However, many participants do not meet their dietary Calcium and Vitamin D requirements, which may indicate inadequate intake of these nutrients in older Australians and a higher risk of osteoporosis. The relationship between serum 25(OH)D and functional measures in this population also requires further study, especially in older adults displaying Vitamin D insufficiency or deficiency.

Particles and macromolecular components, including biopolymers (protein and carbohydrate), are viewed as the main foulants in the complex feed submerged membrane filtration systems such as membrane bioreactor (MBR). This work focused on two aspects of fouling in complex fluids: 1- Assessing fouling propensity and mechanisms for various model solutions. 2- Using of two specific solutions modelling biomass found in MBR for a better understanding of the fouling mechanisms in submerged MBR processes. Filtrations were carried out with 0.22 ??m PVDF hollow fibre membrane. Alginate was used as a model for polysaccharide, bovine serum albumin (BSA) as a model for protein, (un)washed yeast and bentonite were representing suspended solid contents. According to the data obtained during this study the fouling propensity of each model solution was classified as follow in a decreasing order: Alginate &gt unwashed yeast &gt washed yeast &gt BSA &gt bentonite for one-component solutions; and Alginate-washed yeast &gt Alginate-BSA &gt Alginate-bentonite &gt Alginate-unwashed yeast for two-component solutions. Introducing the alginate increased the reversible fouling (except BSA). Passive adsorption had a significant effect on fouling of alginate even before the beginning of the filtration. Washed yeast and a mixture of washed yeast + BSA were then used as model solutions to simulate the activated sludge found in MBR. The concentration of washed yeast and BSA used in this study were calculated in order for the characterisations of the two model solution to match (in terms of biopolymer contents) those of MBR biomasses reported in the literature. By rinsing, backwashing and chemical cleaning of the membrane, three fouling layers of upper, intermediate and lower were defined respectively. Results obtained from the analysis of the biopolymers found in the cleaning solutions allow a better understanding of the fouling mechanisms occurring for the two model solutions used in this study: for washed yeast, the lower layer and for washed yeast + BSA , the upper and intermediate layers were found to have relatively high biopolymeric composition. This was explained by higher concentration of solids on the membrane surface and by higher biopolymer interactions when washed yeast was mixed with BSA.

Diss. (sammanfattning) Umeå : Univ., 2008. / Härtill 4 uppsatser.

Submitted by Aelson Maciera (aelsoncm@terra.com.br) on 2017-10-06T18:08:45Z No. of bitstreams: 1 DissACP.pdf: 6605106 bytes, checksum: c63dcdec106579e271edaa4dc5a8bdcf (MD5) / Approved for entry into archive by Ronildo Prado (bco.producao.intelectual@gmail.com) on 2017-11-28T12:14:39Z (GMT) No. of bitstreams: 1 DissACP.pdf: 6605106 bytes, checksum: c63dcdec106579e271edaa4dc5a8bdcf (MD5) / Approved for entry into archive by Ronildo Prado (bco.producao.intelectual@gmail.com) on 2017-11-28T12:14:55Z (GMT) No. of bitstreams: 1 DissACP.pdf: 6605106 bytes, checksum: c63dcdec106579e271edaa4dc5a8bdcf (MD5) / Made available in DSpace on 2017-11-28T12:26:25Z (GMT). No. of bitstreams: 1 DissACP.pdf: 6605106 bytes, checksum: c63dcdec106579e271edaa4dc5a8bdcf (MD5) Previous issue date: 2017-02-24 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Nowadays, cancer is one of the most feared diseases, affecting each day more and more people worldwide. The importance of new cancer treatment researches is very clear since the ones that has been used are not very effective and may lead to drug resistance, implying in a constant dose increasing which can lead to toxicity issues. Collateral effects and the instability generated in the patient’s organism are also reasons why the necessity of discovering new cancer treatments is imminent. A treatment alternative that has aroused interest is the use of monoclonal antibodies as immunotherapics, since they act by stimulating the patient’s immune system neutralizing the tumor cells in a very efficient and specific way. This kind of antibody can be produced by culturing hybrid animal cells, better known as hybridoma, under strictly controlled conditions so they can be studied and used in human beings. For this reason, the major goal of this project was the production of murine monoclonal antibodies using hybridoma cell culture in order to stablish an efficient culture methodology for hybridomas PC-61 or DTA1 producers of monoclonal antibodies anti-CD25 and anti-GITR, respectively, with high quality and enough amounts using Fetal Bovine Serum (FBS) free medium to, in the future, carry out animal model studies of their potential as therapeutic agents for cancer treatment. Both hybridomas were cultivated on a small scale with RPMI medium and addition of SFB, for comparative purposes and only one was selcted for the second step. The sequential adaptation methodology test, consisted in a gradual percent’s reduction of medium with serum at the same time that increase the percentage of commercial medium without serum, and was selected the medium without SFB in which the hybridoma was better adapted. After was carried out on a laboratory scale in a system type spinner flask (500 ml) with the commercial medium selected in the previous step, in controlled conditions of temperature (37 ° C) and pH (7.2). Based on analyzes of cell culture results, amino acid consumption and monoclonal antibodies quantification , SFM commercial medium SFB-free provided better results for culturing the PC-61 hybridoma, allowing the pilot scale culture reached even higher cell densities than in the standard medium with addition of FBS. / O câncer é uma das doenças mais temidas da atualidade, e atinge cada vez mais pessoas em todo o mundo. A importância de pesquisas sobre novos tratamentos na luta contra o câncer é clara e consensual, uma vez que os que vem sendo utilizados, não são muito eficientes, causam resistência à medicação utilizada o que implica na utilização de doses crescentes que por sua vez podem gerar problemas de toxicidade. Os efeitos colaterais e a instabilidade gerada no organismo do paciente, também são fatores da necessidade de pesquisar novos caminhos para o tratamento do câncer. Uma das alternativas de tratamento que tem despertado interesse é a utilização de anticorpos monoclonais (mAbs) como imunoterápicos, os quais agem estimulando o próprio sistema imune do paciente neutralizando a ação das células tumorais de forma eficiente e específica. A produção de tais anticorpos pode ser feita mediante o cultivo de células animais híbridas, mais conhecidas como hibridomas, sobre condições estritamente controladas para que possam ser estudados e utilizados em humanos. Por essa razão definiu-se como objetivo desse trabalho a produção anticorpos monoclonais murinos por meio de cultivo de hibridomas com a finalidade de estabelecer uma metodologia eficiente de cultivo dos hibridomas PC-61 ou DTA1 secretores dos mAbs anti-CD25 e antiGITR respectivamente, com qualidade e em quantidades suficientes utilizando meios livres de soro fetal bovino (SFB), para a seguir efetuar estudos em modelo animal de seu potencial como agentes terapêuticos no tratamento de câncer. Os dois hibridomas foram cultivados em pequena escala utilizando meio RPMI-1640 e adição de SFB, para fins comparativos e somente um foi selecionado para a próxima etapa. O teste da metodologia de adaptação sequencial, onde houve a redução gradativa da porcentagem de meio RPMI-1640 com 10% de SFB e o aumento da porcentagem de meio comercial sem SFB, e foi selecionado o meio livre de SFB em que o hibridoma melhor se adaptou. Posteriormente foi realizado o cultivo do hibridoma em escala laboratorial em sistema de frasco agitado biorreator do tipo Spinner (500 mL) com o meio livre de SFB selecionado na etapa anterior, sob condições bem controladas de temperatura (37ºC), pH (7,2). Com base nas análises dos resultados dos cultivos celulares, metabolismo de aminoácidos e quantificação de mAbs, o meio comercial SFM livre de SFB proporcionou melhor resultados para o cultivo do hibridoma PC-61, permitindo que o cultivo em escala laboratorial atingisse densidades celulares ainda maiores que no meio padrão com adição de SFB. Como consequência desse vasto crescimento celular em quantidades abundantes de mAbs foram conseguidas para iniciar num futuro próximo ensaios em modelos animais.

La prédiction du devenir du greffon et de sa survie permettrait d’optimiser la prise en charge des patients transplantés. Le suivi des patients transplantés rénaux inclue des mesures répétées de marqueurs longitudinaux tels que la créatinine sérique et l’exposition aux médicaments immunosuppresseurs. L’approche statistique récemment proposée des modèles conjoints permet d’analyser la relation entre un processus longitudinal et la survenue d’un événement clinique. Dans la première partie de ce travail de thèse, nous avons utilisé les modèles conjoints à classes latentes pour étudier l’impact du profil de créatinine sérique au cours des 18 premiers mois post-greffe sur la survie du greffon à long terme. Dans la cohorte étudiée, trois groupes homogènes caractérisés par une trajectoire spécifique de l’évolution de la créatinine sérique en fonction du temps et un risque d’échec de greffe spécifique ont été identifiés. Les probabilités individuelles de l’échec de greffe pendant les 10 premières années post-transplantation ont été calculées sur la base du modèle conjoint développé. Chez les patients qui n’avaient pas développé d’anticorps anti-HLA spécifiques du donneur, le risque d’échec de greffe en fonction du temps était prédit avec un niveau de performance satisfaisant en termes de spécificité, sensibilité et précision.L’utilité clinique de cet outil devra être évaluée avec une approche dynamique. Dans une seconde partie, les modèles non linéaires à effets mixtes combinés avec l’approche des modèles de mélange a été utilisée pour analyser (i) l’association entre la variabilité de l’exposition au tacrolimus au cours du temps et l’adhésion au traitement rapportée par le patient et (ii) l’impact de cette variabilité d’exposition sur le risque de rejet aigu. Ce modèle a montré un effet significatif de la variabilité de l’exposition au cours du temps du tacrolimus sur la survenu de rejet aigu au-delà de 3 mois post-transplantation. Au contraire, aucune association entre l’adhésion et la variabilité de l’exposition au tacrolimus d’une part, et le risque de rejet aigu d’autre part n’a été observée dans cette étude qui n’incluait que des patients modérément non-adhérents. Ce résultat pose la question de l’impact d’une non adhésion modérée sur le devenir du greffon. / Prediction of graft outcome would be useful to optimize patient care. Follow-up of kidneytransplant patients include repeated measurements of longitudinal markers, such as serum creatinine and immunosuppressive drug exposure. Recently proposed joint models areappropriate to analyze relationship between longitudinal processes and time-to-event data. In the first part of present work, we used the approach of joint latent class mixed models tostudy the impact of time-profiles of serum creatinine collected within the first 18 months after kidney transplantation on long-term graft survival. The studied cohort was parted into three homogenous classes with a specific time-evolution of serum creatinine and a specific risk of graft failure. The individual predicted probabilities of graft failure up to 10 years posttransplantation, calculated from this joint model were satisfying in terms of sensitivity, specificity and overall accuracy, for patients who had not developed de novo donor specificanti-HLA antibodies. The clinical usefulness of developed predictive tooI needs to beevaluated with a dynamic approach. In the second part, non-linear mixed effects models witha mixture of distribution for random effects were used to investigate (i) the associationbetween variability over time of tacrolimus exposure and self-reported drug adherence and(ii) the impact of this variability on the acute rejection risk. This model found a significantimpact of tacrolimus time-exposure variability on acute rejection onset beyond 3 months posttransplantation. On the contrary, no association between adherence and (i) variability oftacrolimus time-exposure and (ii) acute rejection was observed in our study which included moderate non-adherent patients only. This result questions the impact of moderate nonadherence on graft outcome.