Semiparametric Estimation of Models for Natural Direct and Indirect Effects

In recent years, researchers in the health and social sciences have become increasingly interested in mediation analysis. Specifically, upon establishing a non-null total effect of an exposure, investigators routinely wish to make inferences about the direct (indirect) pathway of the effect of the exposure not through (through) a mediator variable that occurs subsequently to the exposure and prior to the outcome. Natural direct and indirect effects are of particular interest as they generally combine to produce the total effect of the exposure and therefore provide insight on the mechanism by which it operates to produce the outcome. A semiparametric theory has recently been proposed to make inferences about marginal mean natural direct and indirect effects in observational studies (Tchetgen Tchetgen and Shpitser, 2011), which delivers multiply robust locally efficient estimators of the marginal direct and indirect effects, and thus generalizes previous results for total effects to the mediation setting. In this paper we extend the new theory to handle a setting in which a parametric model for the natural direct (indirect) effect within levels of pre-exposure variables is specified and the model for the observed data likelihood is otherwise unrestricted. We show that estimation is generally not feasible in this model because of the curse of dimensionality associated with the required estimation of auxiliary conditional densities or expectations, given high-dimensional covariates. We thus consider multiply robust estimation and propose a more general model which assumes a subset but not all of several working models holds.

Graves' ophthalmopathy: natural history and treatment outcomes

The pathogenesis of Graves' ophthalmopathy has not been yet clarified, and from a therapeutic standpoint Graves' ophthalmopathy remains an enigma. The natural course and effects of different treatment regimens are poorly documented.

STATE-AND-TRANSITION MODELING AND ADAPTIVE MANAGEMENT: TOOLS FOR FUTURE CO-DEVELOPMENT OF MADAGASCAR’S NATURAL RESOURCES AND PEOPLE

Madagascar’s terrestrial and aquatic ecosystems have long supported a unique set of ecological communities, many of whom are endemic to the tropical island. Those same ecosystems have been a source of valuable natural resources to some of the poorest people in the world. Nevertheless, with pride, ingenuity and resourcefulness, the Malagasy people of the southwest coast, being of Vezo identity, subsist with low development fishing techniques aimed at an increasingly threatened host of aquatic seascapes. Mangroves, sea grass bed, and coral reefs of the region are under increased pressure from the general populace for both food provisions and support of economic opportunity. Besides purveyors and extractors, the coastal waters are also subject to a number of natural stressors, including cyclones and invasive, predator species of both flora and fauna. In addition, the aquatic ecosystems of the region are undergoing increased nutrient and sediment runoff due, in part, to Madagascar’s heavy reliance on land for agricultural purposes (Scales, 2011). Moreover, its coastal waters, like so many throughout the world, have been proven to be warming at an alarming rate over the past few decades. In recognizing the intimate interconnectedness of the both the social and ecological systems, conservation organizations have invoked a host of complimentary conservation and social development efforts with the dual aim of preserving or restoring the health of both the coastal ecosystems and the people of the region. This paper provides a way of thinking more holistically about the social-ecological system within a resiliency frame of understanding. Secondly, it applies a platform known as state-and-transition modeling to give form to the process. State-and-transition modeling is an iterative investigation into the physical makeup of a system of study as well as the boundaries and influences on that state, and has been used in restorative ecology for more than a decade. Lastly, that model is sited within an adaptive management scheme that provides a structured, cyclical, objective-oriented process for testing stakeholders cognitive understanding of the ecosystem through a pragmatic implementation and monitoring a host of small-scale interventions developed as part of the adaptive management process. Throughout, evidence of the application of the theories and frameworks are offered, with every effort made to retool conservation-minded development practitioners with a comprehensive strategy for addressing the increasingly fragile social-ecological systems of southwest Madagascar. It is offered, in conclusion, that the seascapes of the region would be an excellent case study worthy of future application of state-and-transition modeling and adaptive management as frameworks for conservation-minded development practitioners whose multiple projects, each with its own objective, have been implemented with a single goal in mind: preserve and protect the state of the supporting environment while providing for the basic needs of the local Malagasy people.

Defining the role of IL-15 trans-presentation by distinct cell-types during the development and homeostasis of Natural Killer and invariant Natural Killer T cells

The immuno-regulatory functions displayed by NK and iNKT cells have highlighted their importance as key lymphocytes involved in innate and adaptive immunity. Therefore, understanding the dynamics influencing the generation of NK and iNKT cells is extremely important. IL-15 has been shown to provide a critical signal throughout the development and homeostasis of NK and iNKT cells; however, the cellular source of IL-15 has remained unclear. In this investigation, I provide evidence that the cell-type providing IL-15 to NK and iNKT cells via trans-presentation is determined by the tissue site and the maturation status of NK and iNKT cells. For NK cells, I revealed the non-hematopoietic compartment provides IL-15 to NK cells in the early stages of development while hematopoietic cells were crucial for the generation and maintenance of mature NK cells. Regarding iNKT cells in the thymus, IL-15 trans-presentation by non-hematopoietic cells was crucial for the survival of mature iNKT cells. In the liver, both hematopoietic and non-hematopoietic compartments provided IL-15 to both immature and mature iNKT cells. This IL-15 signal helped mediate the survival and proliferation of both NK and iNKT cells as well as induce the functional maturation of mature iNKT cells via enhanced T-bet expression. In conclusion, my work illustrates an important notion that the immunological niche of NK and iNKT cells is tightly regulated and that this regulation is meticulously influenced by the tissue microenvironment.

Origins and evolution of VNTR loci: The apolipoprotein B 3$\sp\prime$ VNTR

I studied the apolipoprotein (apo) B 3$\sp\prime$ variable number tandem repeat (VNTR) and did computer simulations of the stepwise mutation model to address four questions: (1) How did the apo B VNTR originate? (2) What is the mutational mechanism of repeat number change at the apo B VNTR? (3) To what extent are population and molecular level events responsible for the determination of the contemporary apo B allele frequency distribution? (4) Can VNTR allele frequency distributions be explained by a simple and conservative mutation-drift model? I used three general approaches to address these questions: (1) I characterized the apo B VNTR region in non-human primate species; (2) I constructed haplotypes of polymorphic markers flanking the apo B VNTR in a sample of individuals from Lorrain, France and studied the associations between the flanking-marker haplotypes and apo B VNTR size; (3) I did computer simulations of the one-step stepwise mutation model and compared the results to real data in terms of four allele frequency distribution characteristics.^ The results of this work have allowed me to conclude that the apo B VNTR originated after an initial duplication of a sequence which is still present as a single copy sequence in New World monkey species. I conclude that this locus did not originate by the transposition of an array of repeats from somewhere else in the genome. It is unlikely that recombination is the primary mutational mechanism. Furthermore, the clustered nature of these associations implicates a stepwise mutational mechanism. From the high frequencies of certain haplotype-allele size combinations, it is evident that population level events have also been important in the determination of the apo B VNTR allele frequency distribution. Results from computer simulations of the one-step stepwise mutation model have allowed me to conclude that bimodal and multimodal allele frequency distributions are not unexpected at loci evolving via stepwise mutation mechanisms. Short tandem repeat loci fit the stepwise mutation model best, followed by microsatellite loci. I therefore conclude that there are differences in the mutational mechanisms of VNTR loci as classed by repeat unit size. (Abstract shortened by UMI.) ^

Origin and evolution of reactive and noble gases dissolved in matrix pore water

Reactive and noble gases dissolved in matrix pore water of low permeable crystalline bedrock were successfully extracted and characterized for the fist time based on drillcore samples from the Olkiluoto investigation site (SW Finland). Interaction between matrix pore water and fracture groundwater occurs predominately by diffusion. Changes in the chemical and isotopic composition of gases dissolved in fracture groundwater are transmitted and preserved in the pore water. Absolute concentrations, their ratios and the stable carbon isotope signature of hydrocarbon gases dissolved in pore water give valuable indications about the evolution of these gases in the nearby-flowing fracture groundwaters. Inert noble gases dissolved in matrix pore water and their isotopes combined with their in-situ production and accumulation rates deliver information about the residence time of pore water.

Theoretical framework for the assessment of vulnerability to natural hazards and climate change [in Europe]

Reducing risk that emerges from hazards of natural origin and societal vulnerability is a key challenge for the development of more resilient communities and the overall goal of sustainable development. The following chapter outlines a framework for multidimensional, holistic vulnerability assessment that is understood as part of risk evaluation and risk management in the context of Disaster Risk Management (DRM) and Climate Change Adaptation (CCA). As a heuristic, the framework is a thinking tool to guide systematic assessments of vulnerability and to provide a basis for comparative indicators and criteria development to assess key factors and various dimensions of vulnerability, particularly in regions in Europe, however, it can also be applied in other world regions. The framework has been developed within the context of the research project MOVE (Methods for the Improvement of Vulnerability Assessment in Europe; ) sponsored by the European Commission within the framework of the FP 7 program.