Commonly prescribed small molecule drugs can have net-positive and well-understood safety profiles when prescribed individually, but unexpected consequences when taken at the same time. Detection of these drug-drug interactions (DDIs) continues to be a critical and unmet area of translational research. The Centers for Disease Control and Prevention (CDC) estimate that one third of Americans are concurrently taking two or more prescription drugs, and DDIs are estimated to be responsible for 17% of all drug adverse events. The consequences of DDIs can be relatively minor (headache, skin rash) or much more severe (bleeding, liver toxicity). At a cellular level, DDIs can occur as a result of both drugs competing for metabolism (known as pharmacokinetic interactions) or targeting the same protein target or biological pathway (pharmacodynamic interactions). Clinical trials typically focus on the effects of individual drugs, leaving DDIs to usually be discovered only after the drugs have been approved. One of the most carefully studied drug adverse events is long QT syndrome (LQTS), an unexpected change in the heart's electrical activity that can lead to a potentially fatal ventricular tachycardia known as torsades de pointes (TdP). Some patients have genetic mutations that lead to congenital forms of LQTS, while drug-induced LQTS typically occurs via block of the hERG potassium channel (KCNH2) responsible for ventricular repolarization. After a number of high profile drugs were withdrawn from the market due to discovered risk of TdP, the FDA issued guidelines so that pharmaceutical companies could anticipate and test for this side effect before a new drug is approved. These recommendations have helped prevent new QT-prolonging drugs from entering the market, but nonetheless over 180 approved drugs have been associated with drug-induced LQTS. While information on individual QT-prolonging drugs is thus readily available to clinicians, little has remained known about DDIs (QT-DDIs). There are many more commonly prescribed drugs that are safe when given individually but could increase TdP risk when administered together. This troubling situation is compounded by the fact that traditional post-market surveillance algorithms are poorly equipped to sensitively and specifically detect DDIs. Data science – the application of rigorous analytical methods to large datasets – offers an opportunity for predicting previously unknown QT-DDIs. Some biomedical datasets (such as drug-target binding affinities and experiments to determine protein-protein interactions) have been collected explicitly for research, while other valuable datasets (such as electronic health records) were initially recorded for billing purposes. Each data modality has its own important set of advantages and disadvantages, and integrative data science approaches can incorporate multiple types of data to help account for these limitations. In this thesis we develop new data sciences techniques that combine clinical, biological, chemical, and genetic data. These approaches are explicitly designed to be robust to biased and missing data. We apply these new methodologies to (1) predict new QT-DDIs, (2) validate them experimentally, and (3) investigate their molecular and genetic mechanisms. We exemplify this approach in the discovery of a previously unknown QT-DDI between ceftriaxone (cephalosporin antibiotic) and lansoprazole (proton pump inhibitor); importantly, both drugs have no cardiac indications and are safe when given individually. The clinical data mining, drug target prediction, biological network analysis, genetic ancestry prediction, and experimental validation methods described in this thesis form the basis for a comprehensive pipeline to predict QT-DDIs rapidly and robustly. They also provide an opportunity for further enriching our understanding of LQTS biology and ultimately enabling the design of safer drugs.

O objetivo deste trabalho é apresentar alguns testes de cointegração fracionária para séries integradas de ordem d (dR), i.e., séries I(d), comparando-os com os testes de cointegração, cujo parâmetro d assume valores inteiros. O procedimento para os testes de cointegração fracionária utiliza reamostragens de bootstrap com reposição para gerar séries sob a hipótese nula de não cointegração. Estas reamostragens são então utilizadas para calcular os p-valores de algumas estatísticas de testes de regressão, tais como a estatística de Durbin-Watson e a estimativa do parâmetro de memória longa (d) residual. O poder destes testes é apresentado e comparado com os testes de cointegração, mostrando sua consistência. A aplicação destes testes a dados reais compara o modelo de correção de erros de cointegração com o modelo de correção de erros de cointegração fracionária utilizando a medida de erros quadráticos médios dos modelos ajustados. / The purpose of this project is to present some fractional cointegration tests for integrated time series of order d (dR), i.e., I(d) time series, comparing them to cointegration tests, where the parameter d assumes integer values. The tests procedure is done by using bootstrap samples to obtain series under the null hypothesis of non-cointegration. These samples are then used to estimate the p-value of some regression-based test statistics, such as the Durbin-Watson statistic and estimates of residual d parameter. The application of these tests to real series compares the error correction model of cointegration to the error correction model of fractional cointegration by evaluating the mean squared errors over the residuals from the fitted models.

Doctor of Philosophy / Department of Human Ecology-Personal Financial Planning / Dorothy Durband / D. Elizabeth Kiss / Using constructs derived from expected utility theory and data from the RAND American Life Panel 2012 Well Being 186 and 193 surveys, this study explored the extent to which financial knowledge, financial risk tolerance, and the uncertainty regarding the future need for long-term care were associated with long-term care insurance (LTCI) ownership by baby boomers (N = 1,152). Although extensive studies have been conducted regarding long-term care (LTC) issues facing baby boomers in the United States (U.S.), no studies have been found that investigate whether or not these specific factors were predictive of LTCI ownership by baby boomers. Regression analysis was used to estimate the relationship between the dependent and the independent variables in this study. Consistent with the hypotheses of this study, LTCI knowledge was statistically significantly associated with LTCI ownership by baby boomers. Subjective financial knowledge regarding LTCI had the greatest influence on LTCI ownership. An examination of items used to measure uncertainty regarding the future need of LTC indicated that merely thinking about needing LTC at some point in the future positively influenced LTCI ownership. Baby boomers with higher household income were also more likely to own LTCI. Results of this study may contribute to the existing literature on LTCI ownership among baby boomers. As the need for, and cost of, LTC are expected to increase as the U.S. population ages, study results may also provide information for financial advisors and other stakeholders to better engage baby boomers in ways that promote comprehensive risk management decision making in retirement planning. More specifically, study results may provide stakeholders with information to better understand factors that influence LTCI ownership by baby boomers.

The hydrology of southwestern British Columbia is influenced by the region’s mountainous topography and climate oscillations generated from the Pacific Ocean. While much of the region is characterized as a temperate rainforest, recent summers are defined by record-breaking droughts that focus attention on the threat to regional water supply security likely to accompany future climate changes. The limited length and distribution of hydrological records in southwestern British Columbia provide poor context for resource managers tasked with developing policy and water management strategies. The purpose of the dissertation was to describe long-term variability in several key hydroclimatic variables and hydroecological interactions that may be used in updated water resource policy and management strategies. Specifically, the research focused on developing long-term proxy records of April 1 snow water equivalent (SWE), summer streamflow, spring lake levels, and salmon abundance from tree ring records. A secondary goal of the dissertation was to identify the role and influence of several key climate oscillations on regional long-term hydroclimatic and ecological variability. Freshet contributions from melting snow are critical for sustained summer streamflow in southwestern British Columbia. Even so, few manual snow survey stations exist within the region are of sufficient length to understand the full range of natural SWE variability. Long-term April 1 SWE records were constructed by establishing statistical relationships with the radial growth of high-elevation trees and April 1 SWE records. Explaining 51% and 73% of the total variance in the instrumental SWE records in coastal and continental settings, the reconstructions provide high-resolution descriptions of April 1 SWE over the past three centuries and help position the remainder of the dissertation. Negative phases of the Pacific Decadal Oscillation (PDO) and El Niño-Southern Oscillation (ENSO) were shown to strongly influence April 1 SWE totals. Both reconstructions illustrate repeated step-changes in April 1 SWE during the last 300 years and show that coastal areas may be more sensitive to annual variability than snowpack that accumulates in more continental locations. Water shortages in the Metro Vancouver area in recent summers are linked to low total winter snowpack and early spring melt. Dendrohydrological analysis of dry-season streamflow was conducted to determine if the instrumental range has been underestimated over the past several centuries. A regionalized record of July-August streamflow for the Capilano and Seymour watersheds, which supply the Metro Vancouver area, was modelled from present to 1711using tree-rings. Explaining 54% of total variance over the instrumental period, the models show that below-average streamflow events are becoming more frequent. When compared to those characterizing the past 300 years, streamflow totals from 1977 to present have consistently fallen well-below the average long-term discharge. Further analyses indicated that negative ENSO and PDO conditions strongly influenced July-August runoff trends since 1711, as have climate regimes related to the Pacific North American pattern (PNA). The increased frequency in recent years of reduced summer runoff in southwestern British Columbia has led many communities to rely on natural and dammed reservoirs to supplement their water needs. Where communities rely on natural lakes, this dependence may have socioeconomic consequences if lake levels fall below those necessary to supply built infrastructure. Unfortunately, there are few lake level records in southwestern British Columbia and none of sufficient duration to understand the full range of variability in natural lake systems. Harrison Lake is the only natural lake with a lake level record exceeding 50 years. Using the average April water level dataset, a dendrohydrological model was constructed that explained 49.5% of total variance. The model was used to reconstruct a proxy record of April water levels spanning the interval from 1711 to 1980. Averaging 9.37 m in depth, lake levels in Harrison Lake ranged from 8.9 to 10.0 m over the past 300 years. These variations were shown to be statistically associated with negative and positive phases of ENSO and positive phases of PDO. April water levels in Harrison Lake have been, on average, 0.13 m lower since the mid-1930s compared to the previous 200 years. This reduction in storage capacity amounts to a loss of almost 300-million litres of stored water since the start of instrumental records. Salmon play a vital economic, cultural, and social role in many southwestern British Columbia communities. There is concern that salmon populations in the region are under threat, as changing climates alter and impact their spawning habitat. While various lines of research have sought to determine the response of salmon to these changing conditions, population records that extend only to 1951 hinder a complete understanding of the impacts. Two dendroecological models were constructed to provide a longer-term perspective of regional salmon-climate relationships. Explaining 48.2% and 48.9% of variance in observed Chinook and Coho salmon abundance since 1951, the models were used to construct proxy escapement records extending to the 1700s. Spectral analysis revealed that the reconstructions account for generational life histories and that low-frequency climate variability was associated with fluctuations in abundance. Both the Chinook and the Coho reconstructions show phase dependent relationships to climate oscillations generated from the Pacific Ocean. The Coho record is strongly linked to negative winter and spring ENSO, while the Chinook record was shown to be associated with negative PDO conditions. The identified relationships to teleconnections generated in the Pacific Ocean to our record indicates that both species are sensitive to oceanic interactions prior to entering natal habitats. Taken together, the reconstructions illustrate that the observational record encompasses a period of lower-than-average abundance and that neither accounts for the full range of variability in annual abundance when considered over the past three centuries. The proxy tree-ring records presented in this dissertation provide new information about climate-water resource relationships in southwestern British Columbia. Significant phase-dependent associations, especially to negative phases of the PDO and ENSO, were shown to exert long-term influences on the state of several critical hydroclimatic variables over the last 300 years. Additionally, the research illustrates that over the instrumental period, both streamflow and lake volumes in the region have consistently remained below those characterizing the previous two to three centuries. These findings are of direct use to resource managers tasked with developing new policy and strategies under present and future climate change, in that they offer singular insights into the full range of natural hydroclimatic variability in southwestern British Columbia. / Graduate

BACKGROUND: Breast cancer is the most commonly diagnosed cancer and second leading cancer death cause among females in the U.S.A. About 1 in 8 women in U.S will develop invasive breast cancer over the course of her lifetime. In 2013, 234,580 new invasive breast cancer cases are expected to occur in women within the US and approximately 64,640 non-invasive carcinomas in situ were diagnosed in 2013, most of which were ductal carcinoma in situ (DCIS). Along with technological advances, a wide variety of candidate biomarkers have been proposed for cancer diagnosis and prognosis, including DNA content and non-coding RNA. Current techniques for detecting DNA content abnormalities in formalin-fixed, paraffin-embedded (FFPE) tissue samples by flow cytometric analysis have used cells recovered from ≥50µm whole tissue sections. Here, in our first study, a novel core punch sampling method was investigated for assessing DNA content abnormalities and intratumoral heterogeneity in FFPE specimens. Secondly, long non-coding RNAs (lncRNAs) has been examined. LncRNA participates in a broad spectrum of biological activities by diverse mechanisms and its dysregulation is associated with tumorgenesis. Some lncRNAs may function as oncogenes (O) and others as tumor suppressor genes (TSG). To date, lncRNA has been investigated primarily by qRT-PCR and RNA sequencing. This study has examined the relationship of lncRNA expression patterns to breast tumor pathology by chromogenic in situ hybridization (CISH). METHODS: Firstly, FFPE breast carcinoma specimens were selectively targeted using 1.0 mm diameter punch needles. Extracted cores were assayed by flow cytometry using a modified-Headley method. Secondly, the lncRNA expression levels of 6 lncRNAs: HOTAIR, H19, KCNQ1OT1, MEG3, MALAT11 and Zfas1, was examined by RNAscope® CISH using FFPE breast tissue microarrays (TMAs) comprising normal adjacent epithelia (NA), DCIS, and invasive carcinoma (IC) from 46 patients. LncRNA associate polycomb complex protein EZH2 was evaluated by immunohistochemistry (IHC). LncRNA data was also compared to standard breast tumor data including ER, PR, Her2 and Ki67 IHC. SYSTAT version 11 statistical package was used to perform for all the tests. RESULTS: Following optimization experiments of the core punch flow cytometric approach, DNA index and percent S-phase fraction intratumoral heterogeneities were detected in 10/23 (44%) and 11/23 (47%) specimens respectively. The lncRNA CISH study utilized a TMA that contained 36 spots of NA breast tissues, 34 DCIS spots and 43 IC spots. HOTAIR CISH staining was significantly stronger in IC than DCIS (p CONCLUSION: Core-punching is an effective alternative to whole specimen sectioning and shows that macro-level genomic heterogeneity is common even within a single FFPE block. The interrelationship of DNA content heterogeneity to other forms of heterogeneity requires further study. RNAscope CISH supports bright-field microscopy investigations of lncRNA expression in FFPE tissue specimens. HOTAIR, H19 and KCNQ1OT1 may be potential breast cancer biomarkers, both HOTAIR and H19 may be a marker for DCIS at increased risk of progression to invasive cancer. HOTAIR, in particular, may be a predictor for invasive cancer grade.

Employee turnover costs long-term care facilities billions of dollars on an annual basis. The purpose of this correlational study was to examine the relationships between employee turnover intention of certified nursing assistants (CNAs) in the long-term care industry and employee compensation, engagement, job satisfaction, motivation, and work environment. The predictor variables were employee compensation, engagement, job satisfaction, motivation, and work environment. The criterion variable was employee turnover intention. The population of interest consisted of CNAs who were residents of Florida, over the age of 18 years, and employed in the long-term care industry. The theoretical framework that grounded this study was the motivational-hygiene theory. For this study, a sample of 157 participants completed an electronic survey. Multiple linear regression analyses predicted the dependent variables, R-² = .34, F(5, 151) = 15.22, p < .0001. The multiple regression model with 4 of the 5 predictors accounted for significantly more variance in turnover intention than would be expected by chance. Correlation tests resulted in statistically significant inverse relationships between employee turnover intention and employee compensation, engagement, job satisfaction, and work environment. The negative correlation observed between motivation and turnover intention was not statistically significant. The findings in this study may contribute to positive social change by reducing turnover intention while improving the quality of care and reducing costs of care that affect the lives of the long-term care residents, concerned family members, and significant others.

Turnover among direct-care workers in long-term care (LTC) facilities is high, and has a significant impact on residents, leaders, and owners of LTC facilities. The overall turnover costs are also substantial and constitute a significant financial burden in LTC facilities. This systematic review of the literature examined, retention strategies for direct-care workers in the LTC workforce. The information may be used to develop and provide practice recommendations that will help improve retention rates among direct-care workers in LTC facilities. The project design involved a systematic examination of English-only studies from 2001-2004, retrieved from 3 major databases: CINAHL with Medline simultaneous, ProQuest, and Ovid resources. The review led to the identification of 858 publications out of which 17 articles met the inclusion criteria. The manifested variables were critically analyzed and grouped into 8 categories: job training, management style, acknowledgement of accomplishments, career advancements, benefits, peer mentoring, competitive wages and work load. The findings from this systematic review of the literature suggest that several factors affect turnover rates in the LTC setting, including job training, management style, acknowledgement of accomplishments, career advancements, benefits, peer mentoring, competitive wages and work load. This project aims to provide insight to project developers, administrators, researchers, and policy makers concerning factors that affect retention. The information can be used as a catalyst for positive social change and reduce the turnover crisis among direct-care workers in the long-term care setting.

Urinary incontinence affects up to 70% of residents living in a long-term care facility and can affect their quality of life. Specifically, urinary incontinence has a direct impact on older adults in regards to self-esteem, pressure ulcer development, falls, urinary tract infections, and psychosocial wellbeing. The goal of this quality improvement pilot project was to determine if an electronic health record (EHR) assessment tool could help older adults remain continent longer and assist in maintaining an independent lifestyle. Orem's self-care deficit theory and social cognitive theory were used to determine how the electronic health record incontinence template could be used to monitor residents for incontinence and affect the incidence of incontinence. Out of 25 residents, 13 met the requirements for inclusion in the pilot study. Quantitative data were collected and documented in the EHR for 4 weeks and compared to the immediate 4 week period post-implementation of the EHR template. Descriptive analyses of pre- and post-implementation EHR assessments showed there were no EHR assessments completed pre-implementation and 2 residents out of 13 had EHR assessments completed post-implementation. The available data suggested that the EHR template, if edited, could be effective for tracking incontinence. The template needed to address bladder incontinence only rather than bowel and bladder. Feedback from nursing staff indicated that a future study should be conducted over a longer period than 4 weeks to see if results would remain consistent. Nurses working in the long term care environment would benefit from reading this project. This study contributes to social change as evidenced by the residents who remained continent longer by having individual toileting plans partially developed by the template; therefore, they remained a viable part of the community.

A persistent truck driver shortage and high driver turnover at common carriers limit the effectiveness of some U.S. supply chains. Most driver vacancies result from job hopping, especially among younger drivers. A multiple case study was conducted to explore strategies that some leaders of U.S. common carriers have used to retain millennial-age long-haul truck drivers. Data sources consisted of semistructured, in-person and phone/videoconference interviews; participant observations; and company documents. The sample population was 9 leaders from 6 different common carriers with operations in the southwestern region of the United States who successfully retained millennial long-haul drivers. The conceptual framework was person-organization fit theory. Data were compiled and organized, disassembled into fragments, reassembled into a sequence of groups, and interpreted for meaning. Methodological triangulation and member checking were used to validate the trustworthiness of those interpretations. Five major themes emerged from data analysis: strategic recruiting, competitive compensation, limiting driver time away from home, facilitating driver comfort while away from home, and demonstrating a company culture of driver appreciation. Potentially, carrier leaders can use the lessons learned from this research to reduce driver turnover rates and operating costs and to improve freight reliability for U.S. supply chains. The implications for positive social change include the potential to lower freight costs to shippers and consumers, improve job satisfaction for long-haul drivers, and improve highway safety for truck drivers and motorists.

Ananda Devi [1957 - ], a French-language author and poet from Mauritius, adds depth to the lyricism already inherent in her writing by drawing upon that country's multicultural heritage, which includes African, Hindu, and French, and its Creole language. Le Long Désir (2003) defies genre, being neither strictly poetry nor prose, and presents more a collection of prose poems than a structured story with a tangible plot. The poetic aspect of her text, accomplished through this Creole as well as experimentation with grammatical structures and the display of the text on the page, inclines me as a translator to prioritize the lyricism of her text over its content, though cer-tainly I have endeavored to bring both into my English translation of selected sections of the book. Its unifying theme of the struggle of women with violence, anguish and self-definition is brought to the fore by running motifs of animalistic behavior, putrefaction, and darkness, which are accompanied by equally vivid instances of fragility and beauty, signaling the plurality of the situation of women. The challenges of translating the Creole, of preserving her imagery's fresh-ness as well as the content's poignancy, and other myriad deliberations make the labor of produc-ing The Long Desire, the English translation, that much more rewarding; for it is well worth bringing a glimpse of life as a Mauritienne to an English-speaking audience, if not for the noble purpose of increasing our awareness of the world, then at least to taste the enchanting complexity of the text itself.