Periodic Breathing and Behavioral Awakenings at High Altitude.

Objectives. To study the relationship between nocturnal periodic breathing episodes and behavioral awakenings at high altitude. Methods. Observational study. It is 6-day ascent of 4 healthy subjects from Besisahar (760 meters) to Manang (3540 meters) in Nepal in March 2012. A recording pulse oximeter was worn by each subject to measure their oxygen saturation and the presence of periodic breathing continuously through the night. An actigraph was simultaneously worn in order to determine nocturnal behavioral awakenings. There were no interventions. Results. 187-hour sleep at high altitude was analyzed, and of this, 145 hours (78%) had at least one PB event. At high altitude, 10.5% (95% CI 6.5-14.6%) of total sleep time was spent in PB while 15 out of 50 awakenings (30%, 95% CI: 18-45%) occurring at high altitudes were associated with PB (P < 0.001). Conclusions. Our data reveals a higher than expected number of behavioral awakenings associated with PB compared to what would be expected by chance. This suggests that PB likely plays a role in behavioral awakenings at high altitude.

THE DESIGN AND SYNTHESIS OF SILOXANE PRECURSORS FOR CHIRAL PERIODIC MESOPOROUS ORGANOSILICA MATERIALS

The development of cost-effective and reliable methods for the synthesis and separation of asymmetric compounds is paramount in helping to meet society’s ever-growing demand for chiral small molecules. Of these methods, chiral heterogeneous supports are particularly appealing as they allow for the reuse of the chiral source. One such support, based on the synergy between chiral organic units and structurally stable inorganic silicon scaffolds are periodic mesoporous organosilicas (PMOs). In the work described herein, I examine some of the factors governing the transmission of chirality between chiral dopants and prochiral bulk phases in chiral PMO materials. In particular, the exploration of 1,1’-binaphthalene-bridged chiral dopants with a focus on the point of attachment into the materials. Moreover, the effects of ordering in the materials are examined and reveal that chirality transfer is more facile in materials with molecular-scale order then those containing amorphous walls. Secondly, the issues surrounding the synthesis and purification of aryl-triethoxysilanes as siloxane precursors are addressed. Both the introduction of a two-carbon linker and the direct attachment of allyl and mixed allyldiethoxysilane species are explored. This work demonstrates that allyldiethoxysilanes are ideal, in that they are stable enough to permit facile synthesis, while still being able to hydrolyze completely to produce well-ordered materials. Lastly, the production of new bulk phases for chiral PMO materials is examined by introducing new prochiral nitrogen-containing siloxane precursors. Biphenyldiamine and bipyridine-bridged siloxane precursors are readily synthesized on reasonable scales. Their use as the bulk siloxane precursor in the production of PMO materials however, is precluded by insufficient gelation and additional siloxane precursors are necessary for the production of ordered materials. In addition to the research detailed above that forms the body of this thesis, two short works are appended. The first details the production of polythiophene assemblies mediated through coordination nanospaces, while the second explores the production of N-heterocyclic carbene functionalized gold nanoparticles through ligand exchange.

UPTAKE OF THE PERIODIC HEALTH EXAM AMONG ADULTS WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITIES FROM 2003 TO 2015

Background: Over the past decade, annual heath exams have been de-emphasized for the general population but emphasized for adults with intellectual and developmental disabilities (IDD). The purpose of this project was to determine if there has been an increase in the uptake of the health exam among adults with IDD in Ontario, to what extent, and the effect on the quality of preventive care provided. Methods: Using administrative health data, the proportion of adults (18-64 years old) with IDD who received a health exam (long appointment, general assessment, and “true” health exam), a high value on the primary care quality composite score (PCQS), and a health exam or high PCQS each year was compared to the proportion in a propensity score matched sample of the general population. Negative binomial and segmented negative binomial regression controlling for age and sex were used to determine the relative risk of having a health exam/high PCQS/health exam or PCQS over time. Results: Pre joinpoint, the long appointment and general assessment health exam definitions saw a decrease and the “true” health exam saw an increase in the likelihood of adults having a health exam. Post joinpoint, all health exam definitions saw a decrease in the likelihood of adults having a health exam. Pre joinpoint, all PCQS measures (high PCQS, long appointment or high PCQS, “true” health exam or high PCQS) saw an increase in the likelihood for adults to achieve a high PCQS or high PCQS/have a health exam. Post joinpoint, all PCQS measures saw a decrease in the likelihood for adults to achieve a high PCQS or high PCQS/have a health exam. Achieving a high PCQS was strongly associated with having a health exam regardless of health exam definition or IDD status. Conclusions: Despite the publication of guidelines, only a small proportion of adults with IDD are receiving health exams. This indicates that the publication of guidelines alone was not sufficient to change practice. More targeted measures, such as the implementation of an IDD-specific health exam fee code, should be considered to increase the uptake of the health exam among adults with IDD.

Discrete-time positive periodic systems with state and control constraints

The aim of this paper is to provide an efficient control design technique for discrete-time positive periodic systems. In particular, stability, positivity and periodic invariance of such systems are studied. Moreover, the concept of periodic invariance with respect to a collection of boxes is introduced and investigated with connection to stability. It is shown how such concept can be used for deriving a stabilizing state-feedback control that maintains the positivity of the closed-loop system and respects states and control signals constraints. In addition, all the proposed results can be efficiently solved in terms of linear programming.

Report on the Status of Findings and Recommendations from the City of Lambs Grove Periodic Examination Report dated September 4, 2014 for the period June 1, 2015 through February 29, 2016

Report on the Status of Findings and Recommendations from the City of Lambs Grove Periodic Examination Report dated September 4, 2014 for the period June 1, 2015 through February 29, 2016

Proficiency and mechanisms of perturbation of mature T-cell homeostasis by the TCL1 family of oncogenes

In the first part of this thesis, the oncogenic potential of TCL1A family genes was comparatively evaluated by using gamma-retroviral vectors to introduce human TCL1A, MTCP1, and TML1 into hematopoietic stem cells/hematopoietic progenitor cells (HSC/HPC) of wild type mice that were transplanted into wild type recipients. TCL1A and MTCP1 recipient mice predominantly developed B-cell malignancies after a median survival of 388 days and 394 days, respectively. The presented data indicates that TCL1A and MTCP1 are oncogenes with comparable oncogenic potential and shows for the first time that MTCP1 is not only a T-cell oncogene, but is able to transform B cells as well. The third family member TML1 induced the development of immature T-cell malignancies in only a few mice. This study provides first evidence for its oncogenic function. Additionally, the transforming potential of compartment-targeted TCL1A variants was evaluated by retroviral expression of a membrane localizing myristoylated (myr-TCL1A) and a nuclear localizing (nls-TCL1A) variant. Recipients of HSC/HPC transduced with myr-TCL1A and nls-TCL1A predominantly developed B-cell malignancies after a median survival of 360 days and 349 days, respectively. There was a significantly shorter latency period for nls-TCL1A compared to the previously described generic TCL1A. Gene expression analysis revealed higher similarities between expression profiles of tumors induced by TCL1A and nls-TCL1A. Together these data implicate that TCL1A’s predominant oncogenic function might rely on its nuclear presence. The second part of this thesis aims to understand if and how TCR stimulation affects the transforming potential of TCL1A. Mature OT-1 T cells carrying monoclonal TCR’s that specifically recognize ovalbumin (OVA) were retrovirally transduced with TCL1A and repeatedly stimulated in vivo with OVA-peptides. TCR stimulated recipient mice of TCL1A transduced T cells showed a significantly accelerated leukemic outgrowth and a reduced median survival of 305 days, when compared to unstimulated recipients (417 days). These data strongly implicate a pro-leukemogenic cooperation of TCL1A and TCR signals that might be actionable in upcoming interventional designs.

A Periodic State Space Model to Monthly Long-term Temperature Data

This work presents a periodic state space model to model monthly temperature data. Additionally, some issues are discussed, as the parameter estimation or the Kalman filter recursions adapted to a periodic model. This framework is applied to monthly long-term temperature time series of Lisbon.

Nonlinear periodic problems with a jumping reaction

We consider a periodic problem driven by the scalar $p-$Laplacian and with a jumping (asymmetric) reaction. We prove two multiplicity theorems. The first concerns the nonlinear problem ($1

Managing and utilizing information flow for new products’ periodic account sales process

The goal was to understand, document and module how information is currently flown internally in the largest dairy organization in Finland. The organization has undergone radical changes in the past years due to economic sanctions between European Union and Russia. Therefore, organization’s ultimate goal would be to continue its growth through managing its sales process more efficiently. The thesis consists of a literature review and an empirical part. The literature review consists of knowledge management and process modeling theories. First, the knowledge management discusses how data, information and knowledge are exchanged in the process. Knowledge management models and processes are describing how knowledge is created, exchanged and can be managed in an organization. Secondly, the process modeling is responsible for visualizing information flow through discussion of modeling approaches and presenting different methods and techniques. Finally, process’ documentation procedure was presented. In the end, a constructive research approach was used in order to identify process’ related problems and bottlenecks. Therefore, possible solutions were presented based on this approach. The empirical part of the study is based on 37 interviews, organization’s internal data sources and theoretical framework. The acquired data and information were used to document and to module the sales process in question with a flowchart diagram. Results are conducted through construction of the flowchart diagram and analysis of the documentation. In fact, answers to research questions are derived from empirical and theoretical parts. In the end, 14 problems and two bottlenecks were identified in the process. The most important problems are related to approach and/or standardization for information sharing, insufficient information technology tool utilization and lack of systematization of documentation. The bottlenecks are caused by the alarming amount of changes to files after their deadlines.

Efficient split eld FDTD analysis of third-order nonlinear materials in two-dimensionally periodic media

In this work the split-field finite-difference time-domain method (SF-FDTD) has been extended for the analysis of two-dimensionally periodic structures with third-order nonlinear media. The accuracy of the method is verified by comparisons with the nonlinear Fourier Modal Method (FMM). Once the formalism has been validated, examples of one- and two-dimensional nonlinear gratings are analysed. Regarding the 2D case, the shifting in resonant waveguides is corroborated. Here, not only the scalar Kerr effect is considered, the tensorial nature of the third-order nonlinear susceptibility is also included. The consideration of nonlinear materials in this kind of devices permits to design tunable devices such as variable band filters. However, the third-order nonlinear susceptibility is usually small and high intensities are needed in order to trigger the nonlinear effect. Here, a one-dimensional CBG is analysed in both linear and nonlinear regime and the shifting of the resonance peaks in both TE and TM are achieved numerically. The application of a numerical method based on the finite- difference time-domain method permits to analyse this issue from the time domain, thus bistability curves are also computed by means of the numerical method. These curves show how the nonlinear effect modifies the properties of the structure as a function of variable input pump field. When taking the nonlinear behaviour into account, the estimation of the electric field components becomes more challenging. In this paper, we present a set of acceleration strategies based on parallel software and hardware solutions.

Unfolding Operator Method for Thin Domains with a Locally Periodic Highly Oscillatory Boundary

We analyze the behavior of solutions of the Poisson equation with homogeneous Neumann boundary conditions in a two-dimensional thin domain which presents locally periodic oscillations at the boundary. The oscillations are such that both the amplitude and period of the oscillations may vary in space. We obtain the homogenized limit problem and a corrector result by extending the unfolding operator method to the case of locally periodic media.

A Novel integration approach : perturbation studies in vitro using PDK1 inhibitors in glioblastoma multiforme

Os objetivos a atingir em 2020 no que respeita ao processo de investigação e desenvolvimento de medicamentos estão claramente focados na redução em termos temporais na investigação pré-clínica e clínica e na diminuição da taxa de atrito entre as novas moléculas. De forma a atingir estes objetivos, um novo conceito tem sido desenvolvido e aplicado a este complexo e moroso processo, este é a Farmacologia Quantitativa e de Sistemas. Além disso, esta abordagem inovadora pode ser crucial para o tratamento de determinados tipos de tumores cerebrais letais – Glioblastoma Multiforme (GBM) – que permanecem um desafio terapêutico, e por tanto, uma doença com um destino fatal para os doentes. Por estas razões, esta dissertação de mestrado apresenta uma especial relevância, tendo por objetivos avaliar o potencial impacto e importância biológica da variação de parâmetros farmacológicos, para além da potência, no contexto da resposta celular ao fármaco, pela avaliação da perturbação induzida em células do GBM por inibidores do PDK1 e pela realização de uma caracterização multiparamêtrica dose-resposta destas novas moléculas. A presente dissertação assume em Portugal a vanguarda na área da Farmacologia Quantitativa e de Sistemas aplicada ao processo de investigação e desenvolvimento de medicamentos. Em última estância, esta dissertação poderá contribuir para uma melhor previsão dos fármacos durante este processo, significando assim possíveis vantagens para os utentes, indústrias farmacêuticas, institutos de investigação, governo e institutos superiores.