I confronted empirical habitat data (1994-2004) and population data (1988-2005) with ecological theory on habitat dynamics, recruitment, survival, and dispersal to develop predictive relationships between landcover variation and population dynamics. I focus on Florida Scrub-Jays, although one chapter presents a model for the potential influence of habitat restoration on viability of the Florida Grasshopper Sparrow. Both species are unique to Florida landscapes that are dominated by shrubs and grasses and maintained by frequent fires. Both species are declining, even in protected areas, despite their protected status. I mapped habitat for both species using grid polygon cells to quantify population potential and habitat quality. A grid cell was the average territory size and the landcover unit in which habitat-specific recruitment and survival occurred. I measured habitat-specific recruitment and survival of Florida Scrub-Jays from 1988-2008. Data analyses included multistate analysis, which was developed for capture-recapture data but is useful for analyzing many ecological processes, such as habitat change. I relied on publications by other investigators for empirical Florida Grasshopper Sparrow data. The amount of potential habitat was greatly underestimated by landcover mapping not specific to Florida Scrub-Jays. Overlaying east central Florida with grid polygons was an efficient method to map potential habitat and monitor habitat quality directly related to recruitment, survival, and management needs. Most habitats for both species were degraded by anthropogenic reductions in fire frequency. Degradation occurred across large areas. Florida Scrub-Jay recruitment and survival were most influenced by shrub height states. Multistate modeling of shrub heights showed that state transitions were influenced by vegetation composition, edges, and habitat management. Measured population declines of 4% per year corroborated habitat-specific modeling predictions. Habitat quality improved over the study period but not enough to recover precariously small populations. The degree of landcover fragmentation influenced mean Florida Scrub-Jay dispersal distances but not the number of occupied territories between natal and breeding territories. There was little exchange between populations, which were usually further apart than mean dispersal distances. Florida Scrub-Jays bred or delayed breeding depending on age, sex, and breeding opportunities. I show an urgent need also for Florida Grasshopper Sparrow habitat restoration given that the endangered bird has declined to only two sizeable populations and there is a high likelihood for continued large decline. A major effect of habitat fragmentation identified in this dissertation that should apply to many organisms in disturbance prone systems is that fragmentation disrupts natural processes, reducing habitat quality across large areas. Humans have managed wildland fire for > 40,000 years, so it should be possible to manage habitat for many endangered species that make Florida's biodiversity unique. This dissertation provides methods to quantify landscape units into potential source and sink territories and provides a basis for applying adaptive management to reach population and conservation goals.

Tuberculosis is an ancient infectious disease and a leading cause of death globally. Preclinical research is important for defining drugs and regimens which should be carried forward to human studies. This thesis aims to characterize the population pharmacokinetics and exposure-response relationships of anti-tubercular drugs alone and in combinations, and to suggest experimental designs for preclinical settings. The population pharmacokinetics of rifampicin, isoniazid, ethambutol and pyrazinamide were described for the first time in two mouse models. This allowed for linking the population pharmacokinetic model to the Multistate Tuberculosis Pharmacometric (MTP) model for biomarker response, which was used to characterize exposure-response relationships in monotherapy. Pharmacodynamic interactions in combination therapies were quantitatively described by linking the MTP model to the General Pharmacodynamic Interaction (GPDI) model, which provided estimates of single drug effects together with a quantitative model-based evaluation framework for evaluation of pharmacodynamic interactions among drugs in combinations. Synergism (more than expected additivity) was characterized between rifampicin and ethambutol, while antagonism (less than expected additivity) was characterized between rifampicin and isoniazid in combination therapies. The new single-dose pharmacokinetic design with enrichened individual sampling was more informative than the original design, in which only one sample was taken from each mouse in the pharmacokinetic studies. The new oral zipper design allows for informative pharmacokinetic sampling in a multiple-dose administration scenario for characterizing pharmacokinetic-pharmacodynamic relationships, with similar or lower bias and imprecision in parameter estimates and with a decreased total number of animals required by up to 7-fold compared to the original design. The optimized design for assessing pharmacodynamic interactions in the combination therapies, which was based on EC20, EC50 and EC80 of the single drug, provided lower bias and imprecision than a conventional reduced four-by-four microdilution checkerboard design at the same total number of samples required, which followed the 3Rs of animal welfare. In summary, in this thesis the population pharmacokinetic-pharmacodynamic models of first-line drugs in mice were characterized through linking each population pharmacokinetic model to the MTP model. Pharmacodynamic interactions were quantitatively illustrated by the MTP-GPDI model. Lastly, experimental designs were optimized and recommended to both pharmacokinetic and pharmacodynamic studies for preclinical settings.

Sous l'ère moderne, où le commerce n'a plus de frontières physiques, les catastrophes causant des dommages à grande échelle se sont multipliées. Lorsque de telles catastrophes surviennent, l'utilisation de procédures de recours collectif pour juger de l'ensemble des litiges semble être la solution indiquée. Pourtant, l'expérience nous démontre qu'il n'en est rien... Bien que le même événement cause des dommages à de multiples victimes, le recours judiciaire demeure l'exercice d'un droit personnel. Le tribunal devra alors rechercher l'application de règles matérielles spécifiques à ce recours. En l'absence de règles spécifiques, les règles de conflit de lois du tribunal saisi seront applicables. Or, ces règles ne sont pas uniformes et entraînent une multiplicité de lois applicables. Conséquemment, il est opportun de s'interroger sur la pertinence de réunir des recours individuels en un seul recours. L'expérience américaine nous démontre les difficultés engendrées par la multiplicité de lois applicables à un recours collectif, bien que des solutions législatives et jurisprudentielles aient été proposées. Ces solutions demeurent imparfaites, tant au niveau de leur constitutionalité que du respect des droits fondamentaux. Devant la complexité occasionnée par le regroupement de ces litiges, les tribunaux sont réfractaires à leur autorisation, dès lors qu'une multiplicité de lois applicables est démontrée. Ainsi, la solution juridique la mieux adaptée aux recours collectifs internationaux demeure celle de saisir les tribunaux, de plusieurs recours collectifs distincts; chacun regroupé en fonction de la loi applicable à chaque recours, déterminée, au préalable, par l'analyse des règles de conflit de lois du tribunal saisi. / When a catastrophic accident occurs, involving numerous victims from different states, we could, instinctively believe that justice will be best served by consolidation of all claims arising from such event. However, this idea isn’t completely right... Ironically, while catastrophic accident is a collective event, the claims pertaining such event remain a personal right of action. Therefore, the court might select the law applicable to each claim in accordance with its own conflict of laws rules. Because those rules aren't similar among states, the law applicable to each claim will differ accordingly. Consequently, the judge hearing a multi-state class action pertaining the same event will need to deal with multiplicity of laws. Historically, American federal courts have almost systematically rejected consolidation of claims when a multiplicity of laws appears. Many solutions to overwhelm problems arising from multiplicity of laws have been raised by the legal communauty. To date, none of those solutions seems perfect. It brings the conclusion that the idea of an international class action to resolve in a single lawsuit, all claims resulting from a single accident, might be an utopia. However, efficiency of class actions proceedings remains. As soon as litigants determine, prior to the certification request, the law applicable to each individual claims, in accordance with the relevant conflict-of-laws rules, in order to join all claims that are similarly conducted by the same law. In doing so, problems related to diversity of laws in class actions are avoided.

With approximately nine million new cases and the attributable cause of death of an estimated two millions people every year there is an urgent need for new and effective drugs and treatment regimens targeting tuberculosis. The tuberculosis drug development pathway is however not ideal, containing non-predictive model systems and unanswered questions that may increase the risk of failure during late-phase drug development. The aim of this thesis was hence to develop pharmacometric tools in order to optimize the development of new anti-tuberculosis drugs and treatment regimens. The General Pulmonary Distribution model was developed allowing for prediction of both rate and extent of distribution from plasma to pulmonary tissue. A distribution characterization that is of high importance as most current used anti-tuberculosis drugs were introduced into clinical use without considering the pharmacokinetic properties influencing drug distribution to the site of action. The developed optimized bronchoalveolar lavage sampling design provides a simplistic but informative approach to gathering of the data needed to allow for a model based characterization of both rate and extent of pulmonary distribution using as little as one sample per subject. The developed Multistate Tuberculosis Pharmacometric model provides predictions over time for a fast-, slow- and non-multiplying bacterial state with and without drug effect. The Multistate Tuberculosis Pharmacometric model was further used to quantify the in vitro growth of different strains of Mycobacterium tuberculosis and the exposure-response relationships of three first line anti-tuberculosis drugs. The General Pharmacodynamic Interaction model was successfully used to characterize the pharmacodynamic interactions of three first line anti-tuberculosis drugs, showing the possibility of distinguishing drug A’s interaction with drug B from drug B’s interaction with drug A. The successful separation of all three drugs effect on each other is a necessity for future work focusing on optimizing the selection of anti-tuberculosis combination regimens. With a focus on pharmacokinetics and pharmacodynamics, the work included in this thesis provides multiple new methods and approaches that individually, but maybe more important the combination of, has the potential to inform development of new but also to provide additional information of the existing anti-tuberculosis drugs and drug regimen.

Sous l'ère moderne, où le commerce n'a plus de frontières physiques, les catastrophes causant des dommages à grande échelle se sont multipliées. Lorsque de telles catastrophes surviennent, l'utilisation de procédures de recours collectif pour juger de l'ensemble des litiges semble être la solution indiquée. Pourtant, l'expérience nous démontre qu'il n'en est rien... Bien que le même événement cause des dommages à de multiples victimes, le recours judiciaire demeure l'exercice d'un droit personnel. Le tribunal devra alors rechercher l'application de règles matérielles spécifiques à ce recours. En l'absence de règles spécifiques, les règles de conflit de lois du tribunal saisi seront applicables. Or, ces règles ne sont pas uniformes et entraînent une multiplicité de lois applicables. Conséquemment, il est opportun de s'interroger sur la pertinence de réunir des recours individuels en un seul recours. L'expérience américaine nous démontre les difficultés engendrées par la multiplicité de lois applicables à un recours collectif, bien que des solutions législatives et jurisprudentielles aient été proposées. Ces solutions demeurent imparfaites, tant au niveau de leur constitutionalité que du respect des droits fondamentaux. Devant la complexité occasionnée par le regroupement de ces litiges, les tribunaux sont réfractaires à leur autorisation, dès lors qu'une multiplicité de lois applicables est démontrée. Ainsi, la solution juridique la mieux adaptée aux recours collectifs internationaux demeure celle de saisir les tribunaux, de plusieurs recours collectifs distincts; chacun regroupé en fonction de la loi applicable à chaque recours, déterminée, au préalable, par l'analyse des règles de conflit de lois du tribunal saisi. / When a catastrophic accident occurs, involving numerous victims from different states, we could, instinctively believe that justice will be best served by consolidation of all claims arising from such event. However, this idea isn’t completely right... Ironically, while catastrophic accident is a collective event, the claims pertaining such event remain a personal right of action. Therefore, the court might select the law applicable to each claim in accordance with its own conflict of laws rules. Because those rules aren't similar among states, the law applicable to each claim will differ accordingly. Consequently, the judge hearing a multi-state class action pertaining the same event will need to deal with multiplicity of laws. Historically, American federal courts have almost systematically rejected consolidation of claims when a multiplicity of laws appears. Many solutions to overwhelm problems arising from multiplicity of laws have been raised by the legal communauty. To date, none of those solutions seems perfect. It brings the conclusion that the idea of an international class action to resolve in a single lawsuit, all claims resulting from a single accident, might be an utopia. However, efficiency of class actions proceedings remains. As soon as litigants determine, prior to the certification request, the law applicable to each individual claims, in accordance with the relevant conflict-of-laws rules, in order to join all claims that are similarly conducted by the same law. In doing so, problems related to diversity of laws in class actions are avoided.

Health and public health services in England are under increasing financial pressure. At the same time, nearly 40% of the total disease burden is potentially amenable to known causes with two of the leading behavioural risk factors being unhealthy diets and physical inactivity. To better inform decision makers and improve health in England, this thesis aims to develop a cost-effectiveness model that can directly compare diet and physical activity interventions. Published public health economic models were reviewed and the strengths and weaknesses of the modelling structures were explored. A pre-existing multistate life table model, PRIMEtime, was developed into PRIMEtime Cost Effectiveness (PRIMEtime CE). Disease specific NHS England costs were derived from NHS England Programme Budgeting Data and unrelated disease costs from NHS cost curves. Social care costs were quantified using a Department of Health tool for estimating wider societal costs. Disease specific utility decrements were adopted from a catalogue of EuroQoL five dimensions questionnaire scores. The cost effectiveness of reformulating food to have less salt and of expanding access to leisure centres in England were modelled from an NHS and social care perspective over a 10 year time horizon, including government and industry costs. Salt reformulation was dominant with an estimated cost per quality adjusted life year (QALY) of -£17,000 (95% uncertainty interval, -£40,000 to £39,000), compared with £727,000 (£514,000 to £1,064,000) for increasing access to leisure centres. Sensitivity analyses and cross validation testing of outcomes demonstrated how cost per QALY estimates were sensitive to the choice of model scope, parameters, and structure. PRIMEtime CE is a tool for decision makers to compare interventions affecting diet and physical activity, enabling them to make better informed choices about how to spend finite resources. Future work will focus on making the model freely available and expanding its risk factors to enable comparisons of other public health interventions.

La surveillance des infections acquises en réanimation (IAR) représente un outil majeur dans la stratégie de lutte contre les infections nosocomiales. Nous avons enrichi la base de données de surveillance REA-RAISIN avec des données médico-administratives du PMSI afin de disposer d’informations sur l’hospitalisation complète et d’analyser des facteurs de risques supplémentaires. L’étude descriptive détaillée des 11 années de notre cohorte a permis de montrer des variations temporelles et les groupes les plus à risque. L’estimation de l’impact de ces IAR sur la mortalité et la durée de séjour nécessite des techniques statistiques multiples afin de prendre en compte les biais dont la durée d’apparition de l’IAR et le risque compétitif. Cet impact dépend du type d’IAR. La mortalité est très impactée par les bactériémies, peu par les pneumopathies et pas par les infections urinaires. L’augmentation de la durée de séjour est la plus importante pour les pneumopathies, suivie des infections urinaires et est modérée pour les bactériémies. L’étude du portage de S. aureus méticillino-résistant est parue insuffisante pour détecter des épidémies. / Monitoring the infection acquired in intensive care units (ICU-AI) is a strategic tool for the control of hospital-associated infections. We enhanced the national surveillance database REA-RAISIN with the local diagnosis-related group database. This allows us to have data on the whole hospitalization and assess additional risk factors. The assessment of the impact of these ICU-AI on mortality and length of stay needs appropriate and multiple statistical analysis to take in account various potential bias, including time-dependent bias and competitive risk. This impact is a function of the kind of IAR. Mortality is most affected by bacteremia, more lightly by pneumonia and stay equivalent for patients with or without urinary tract infections. On the other hand, excess of length of stay was the most important for patients with pneumonia and urinary tract infections but moderate for those with bacteremia.Finally, studying the carriage of methicillin-resistant S. aureus appeared insufficient to detect outbreaks and does not measure the risk associated with SASM carriage.

New analytical and technological tools have the potential to yield unprecedented insights into the life histories of migratory species. I used Bayesian population models and Global Positioning System-acceleration tracking devices to understand the demographic mechanism and likely drivers underpinning the Greenland White-fronted Goose (Anser albifrons flavirostris) population decline. I used a 27-year capture-mark-recapture dataset from the main wintering site for these birds (Wexford, Ireland) to construct multistate models that estimated age- and sex-specific survival and movement probabilities and found no sex-bias in emigration or ‘remigration’ rates (chapter 2). These formed the foundation for an integrated population model, which included population size and productivity data to assess source-sink dynamics through estimation of age-, site-, and year-specific survival and movement probabilities, the results of which suggest that Wexford is a large sink and that a reduction in productivity (measured as recruitment rate) is the proximate demographic mechanism behind the population decline (chapter 3). Low productivity may be due to environmental conditions on breeding areas in west Greenland, whereby birds bred at youngest ages when conditions were favourable during adulthood and the breeding year (chapter 4), and possibly mediated by links with the social system, as birds remained with parents into adulthood, forfeiting immediate reproductive success, although a cost-benefit model showed the ‘leave’ strategy was marginally favoured over the ‘stay’ strategy at all ages (chapter 5). Foraging during spring does not appear to limit breeding, as breeding and non-breeding birds did not differ in their proportion of time feeding or energy expenditure (chapter 6). Two successful breeding birds were the only tagged individuals (of 15) to even attempt to nest, suggesting low breeding propensity has contributed to low productivity. Although birds wintering in Ireland migrated further to breeding areas than those wintering in Scotland, there were no differences in feeding between groups during spring migration (chapter 7). These findings suggest that Greenland White-fronted Geese are not limited until arrival on breeding areas and the increasingly poor environmental conditions there (chapter 8). More broadly, these findings demonstrate the application of novel tools to diagnose the cause of population decline.

Changes in the marital status in the age group from 15 to 59 years in the Czech Republic after 1930 Abstract The aim of this thesis is to analyze the changes in population structure according to the individual marital statuses. For this analysis sex-specific and age-specific nuptuality rates and multistate life tables were use, in order to be able to describe transitions between the individual marital statuses. In the first part of this thesis the data sources and the methods of creating the transversal increment- decrement life tables were described. Following chapters deal with the historical development of the Czech Republic population since the year 1930 and the trends of nuptuality, divorce and mortality. Second part is dedicated to the analysis of the transitions between the individual marital statuses. The findings of this thesis conclude that people in the individual marital states tend to react similarly to the historical events in Czech Republic, unless some events are purposefully aiming to influence only a part of the population. Key words: nuptuality rate, divorce rate, mortality rate, marital status, multistate demography, transversal increment-decrement life tables, Czech Republic

Puisque de plus en plus d’enfants sont exposés à la séparation de leurs parents, plusieurs d’entre eux doivent partager leur temps entre les logements et la supervision de leur mère et leur père. Qu’on nomme cette réalité « garde », « résidence » ou « temps parental », elle complique grandement la description et la mesure des structures familiales dans lesquelles évoluent les enfants. Dans ce contexte, la thèse comporte deux objectifs principaux. Le premier consiste à préciser l’évolution historique des différents concepts légaux et sociologiques en jeu et à montrer comment le flou terminologique entourant la garde entraîne des problèmes lors de la mesure des arrangements résidentiels des enfants. Pour exposer la problématique, je tente de déterminer la prévalence de la double résidence égalitaire en faisant une évaluation critique des sources de données disponibles au Québec et au Canada. En fin de compte, en raison des lacunes de ces diverses sources et de leurs résultats parfois divergents, il s’avère pratiquement impossible de répondre à la question : « Combien d’enfants vivent en garde partagée (ou en double résidence) ? ». Le second objectif, qui occupe la majeure partie de la thèse, vise à illustrer le caractère dynamique des arrangements de temps parental, un aspect souvent ignoré dans la littérature scientifique. À partir des données des treize premiers passages de l’Étude longitudinale du développement des enfants du Québec (ÉLDEQ) (n=2120), je distingue quatre arrangements de temps parental postséparation : 1) la résidence maternelle (avec peu ou pas de contacts père-enfant) ; 2) la résidence maternelle (avec contacts père-enfant réguliers) ; 3) la double résidence ; 4) la résidence paternelle. En ordonnant les informations disponibles à différents points dans le temps pour un même enfant, j’ai pu reconstituer des trajectoires de temps parental complètes. Les analyses réalisées sur ces trajectoires sont rapportées dans deux articles. Je m’intéresse, dans le premier article, aux caractéristiques familiales liées à l’établissement d’un arrangement donné au moment de la séparation ainsi qu’à la durée de cet arrangement. J’y montre par exemple que la part du temps parental assumée par le père au moment de la séparation est positivement associée au niveau de scolarité des parents, au travail à temps plein des mères et au sentiment de plaisir parental des pères. On y constate aussi que les arrangements initiaux ne sont pas tous aussi durables les uns que les autres. Même si les facteurs associés à cette durée sont plus difficiles à discerner, le niveau de scolarité des parents semble être important dans le processus. Dans le second article, je construis des tables de survie multiétats afin de résumer les trajectoires de temps parental de la perspective d’un enfant « moyen ». Je cherche entre autres à déterminer combien de temps les enfants passent dans chacun des quatre arrangements définis plus tôt et à identifier les facteurs sociodémographiques associés à cette répartition. J’y conclus que le temps passé en double résidence par un enfant moyen est faible, mais qu’il augmente avec le niveau de scolarité des deux parents. La double résidence est cependant une composante centrale de la paternité postrupture. Malgré une grande fluidité dans les trajectoires de temps parental, l’arrangement établi au moment de la séparation demeure un bon prédicteur de l’expérience parentale ultérieure. Les enfants initialement en double résidence, par exemple, perdent rarement contact avec leur père au cours des cinq années qui suivent la séparation, et ce, même si plusieurs d’entre eux finiront par habiter principalement avec leur mère. / As more children are exposed to the separation of their parents, many of them have to share their time between the homes and the supervision of their mother and father. Whether this reality is referred to as “custody”, “residence” or “parenting time”, it greatly complicates the description and measurement of the family structures in which children evolve. In this context, the thesis has two main objectives. The first is to clarify the historical evolution of the various legal and sociological concepts involved and to show how the terminological confusion surrounding child custody raises problems when trying to measure children’s living arrangements. In particular, I try to determine the prevalence of egalitarian dual residence by critically assessing the various data sources available in Quebec and Canada. In the end, because of the shortcomings of these various sources and their sometimes divergent results, it is virtually impossible to answer the question: “How many children live in shared physical custody (or dual residence) ?” The second objective, which comprises most of the thesis, aims to illustrate the dynamic nature of parenting-time arrangements, an element often overlooked in the scientific literature. With data from the first thirteen waves of the Quebec Longitudinal Study of Child Development (QLSCD) (n = 2120), I distinguish four postseparation parenting-time arrangements: 1) mother residence (with little or no father-child contact); 2) mother residence (with regular father-child contact); 3) dual residence; 4) father residence. By ordering the information available at different time points for each child, I was able to reconstruct complete parenting-time trajectories. The analyzes carried out on these trajectories are reported in two articles. In the first article, I look at family characteristics related to the establishment of specific arrangements at separation and at the duration of this arrangement. For instance, I show that the share of parenting time assumed by fathers following separation is positively associated with parents’ education level, mothers’ full-time employment and father’s feeling of parental enjoyment. The article also shows that initial arrangements are not all as durable as each other. Although the factors associated with this duration are difficult to identify, the parents’ level of education appears to be play an important role. In the last article, I build multistate life tables in order to summarize parenting-time trajectories from the perspective of an average child. I try to determine, inter alia, how much time children spend in each of the four arrangements defined earlier and what sociodemographic factors are associated with this distribution of time. I show that time spent in dual residence by an average child is low, but that it increases with the education level of both parents. Dual residence is, however, a central component of postseparation fatherhood. Despite great fluidity in parenting-time trajectories, arrangements established at separation remain good predictors of the subsequent parenting experience. Children initially in dual residence, for instance, seldom lose contact with their father during the first five years following separation even if many of them eventually end up living mainly with their mother.