Class of 2012 Abstract / Specific Aims: The objective of this study is to evaluate consumers’ knowledge about over the counter (OTC) products containing acetaminophen (APAP).   Methods: Doctor of pharmacy student researchers set up a booth at consenting community pharmacies and invited consumers to participate in a 10-15 minute knowledge assessment. The booth contained a table displaying several OTC medication bottles/packages. Adult participants: a) answered baseline questions verbally about their APAP knowledge and associated risks; b) identified OTC products at the booth that contain APAP; and c) calculated and demonstrated dosing of APAP. The researchers asked follow-up questions and assessed the accuracy of the dosing. Participants received APAP educational brochures upon completion.      Main Results: Eighty percent of subjects reported not knowing what the abbreviation “APAP” means, and almost half of those who said that they knew what it means were incorrect. Very few participants were able to correctly identify the products containing APAP even with the product packaging information, with the percentage of incorrect responses as to whether a product contains APAP or not varying from 4.9% to 31.6%. More than 40% of the pediatric doses were incorrectly dosed for both of the pediatric formulations, even with the majority of subjects being parents. Conclusions: Consumers are not able to identify which over-the-counter products contain APAP even with the product packaging before them, and they do not know what the abbreviation “APAP” means. Better packaging and product ingredient information should be developed, and the abbreviation “APAP” should be avoided. Pediatric APAP products should be re-evaluated regarding safety and dosing.

Class of 2014 Abstract / Specific Aims: To determine the cost of treatment of oral and intravenous n-acetylcysteine (IV NAC) in acute acetaminophen (APAP) toxicity using the length of treatment and length of hospital stay. Methods: A retrospective chart review of Arizona Poison and Drug Information Center electronic records from 2009-2012 and January-June 2013 were evaluated. The following information was collected: age, sex, use oral or intravenous NAC, length of treatment, length of hospital stay (intensive care unit (ICU) and non-ICU) and use of antiemetic. The mean length of stay (MLOS) was calculated for each group as well as the cost of IV and oral NAC. These means were then compared using t-test for independent groups to test for significance. The average total cost of IV and oral NAC treatment was calculated by using monetary values from primary literature. A sensitivity analysis was performed to test the possible effects of an increase or decrease of the final costs by 5 to 10%. Main Results: Patients (≥18 yrs) being treated with IV or oral NAC for acute APAP toxicity (≤8 hours prior to ingestion) were included in this study. A total of 47 patients met the inclusion criteria. Length of hospital stay was shorter in patients receiving IV NAC (42.5% 24-24hr; 37.5% 48-72hr) compared to patients receiving oral NAC (28.6% 48-72hr, 71.4% >72hrs; p<0.001). Total cost of ICU/non-ICU stay in patients receiving IV NAC ($8,720/$3010) was less than patients receiving oral NAC ($12,321/$4703); however, cost of IV NAC-extended (37hrs) in ICU/non-ICU ($13,153/$5535) was greater than oral NAC. The sensitivity analysis performed demonstrated that an increase or a decrease by 5 to 10% in change of cost does not affect our final conclusion. Conclusion: The cost of treatment of IV NAC is lower due to shorter LOS of patients treated with IV NAC (p<0.001). However, when an extended course of treatment is medically necessary for patients on IV NAC then the cost of treatment with IV NAC exceeds the cost of treatment with oral NAC.

Acetaminophen, known as paracetamol in the UK and Tylenol in the United States, is a widespread and commonly used painkiller all over the world. Taken in large enough doses, however, it can cause fatal liver damage. In the U.S., 56000 people are admitted to hospital each year due to acetaminophen overdose and its related effects, at great cost to healthcare services. In this thesis we present a number of different models of acetaminophen metabolism and toxicity. Previously, models of acetaminophen toxicity have been complex and due to this complexity, do not lend themselves well to more advanced mathematical analysis such as the perturbation analysis presented later in this thesis. We begin with a simple model of acetaminophen metabolism, studying a single liver cell and performing numerical and sensitivity analysis to further understand the most important mechanisms and pathways of the model. Through this we identify key parameters that affect the total toxicity in our model. We then proceed to perform singular perturbation analysis, studying the behaviour of the model over different timescales, finding a number of key timescales for the depletion and subsequent recovery of various cofactors as well as critical dose above which we see toxicity occurring. Later in the thesis, this model is used to model metabolism in a spheroid cell culture, examining the difference spatial effects have on metabolism across a 3D cell culture. We then present a more complex model, examining the difference the addition of an adaptive response to acetaminophen overdose from the Nrf2 signalling pathway, has on our results. We aim to reproduce an unexplained result in the experimental data of our colleagues, and so analyse the steady states of our model when subjected to an infused dose, rather than a bolus one. We identify another critical dose which leads to GSH depletion in the infused dose case and find that Nrf2 adaptation decreases toxicity and model sensitivity. This model is then used as part of a whole-body PBPK model, exploring the effects that the distribution of the drug across the bloodstream and different organs has. We explore the affects of that a delay in up-regulation from the Nrf2 pathway has on the model, and find that with rescaled parameters we can qualitatively reproduce the results of our collaborators. Finally, we present the results of in vitro work that we have undertaken, the aim of which was to find new parameters for the model in human hepatocytes, rather than from rodent models, and find a new value for a parameter in our model from human cell lines.

No description available.

Ecto-nucleotidase triphosphate diphosphohydrolase-2 (NTPDase2) is an ecto-enzyme that is expressed on portal fibroblasts in the liver that modulates P2 receptor signaling by regulating local concentrations of extracellular ATP and ADP. NTPDase2 has protective properties in liver fibrosis and may impact bile duct epithelial turnover. Here, we study the role of NTPDase2 in acute liver injury using an experimental model of acetaminophen (APAP) intoxication in mice with global deletion of NTPDase2. Acute liver toxicity was caused by administration of acetaminophen in wild type (WT) and NTPDase2-deficient (Entpd2 null) mice. The extent of liver injury was compared by histology and serum alanine transaminase (ALT). Markers of inflammation, regeneration and fibrosis were determined by qPCR). We found that Entpd2 expression is significantly upregulated after acetaminophen-induced hepatotoxicity. Entpd2 null mice showed significantly more necrosis and higher serum ALT compared to WT. Hepatic expression of IL-6 and PDGF-B are higher in Entpd2 null mice. Our data suggest inducible and protective roles of portal fibroblast-expressed NTPDase2 in acute necrotizing liver injury. Further studies should investigate the relevance of these purinergic pathways in hepatic periportal and sinusoidal biology as such advances in understanding might provide possible therapeutic targets.

L’anxiété et l’insomnie représentent des affections parmi les plus répandues, avec plusieurs conséquences négatives pour les personnes qui en souffrent, leur famille et la société en général. Parmi les solutions les plus communément utilisées pour la prise en charge de l’anxiété et de l’insomnie, nous avons l’option pharmacologique qui, malgré une certaine efficacité initiale présente plusieurs conséquences à long terme comme la présence d’effets indésirables et l’installation progressive du phénomène de tolérance. Une autre possibilité thérapeutique est la psychothérapie et dans cette catégorie, le traitement de choix recommandé pour la solution à long terme de ces troubles est représenté par la thérapie cognitivo- comportementale. Mais, malheureusement, les ressources pour l’administrer sont limitées et couteuses et les temps d’attente sont souvent longs. Il a été alors question de trouver des alternatives pour permettre à plus de personnes souffrant d’anxiété et d’insomnie d’avoir accès rapidement à des solutions pour leur problème. C’est ainsi que notre réflexion s’est tournée vers les nouvelles technologies qui se sont répandues à grande échelle dans la population et qui montrent progressivement leur utilité pour remédier à la difficulté d’accès à certaines ressources traditionnelles dans la prise en charge de problématiques reliées à la santé mentale. Notre équipe, déjà impliquée dans le développement de plusieurs approches thérapeutiques par internet, a pris l’initiative de tester l’efficacité de l’application Muzzz, conçue pour réduire l’anxiété et améliorer le sommeil et qui consiste en l’écoute de suggestions positives inspirées du training autogène de Schultz. Ces suggestions ont la particularité d’être progressivement masquées par une musique relaxante et deviennent donc préconscientes. Muzzz est une dérivée du programme APAP (Augmentation de la Psychothérapie Par Amorçage Préconscient) dont le concept, basé sur l’écoute de suggestions positives personnalisées masquées par de la musique relaxante, a été évalué positivement en termes de validité et de faisabilité dans l’étude de Borgeat et collaborateurs réalisée en 2013 [augmentation des cognitions positives (d = 0,53) et diminution des cognitions négatives (d = 0,73) au Test d’Auto-Évaluation des Pensées en Interaction Sociale (TAPIS)]. Pour évaluer l’efficacité de l’application, 20 personnes (parmi lesquelles 10 hommes et 10 femmes, qui avaient un âge moyen de 41,25 ans, variant de 20 à 67 ans avec écart-type de 15,82) ont été recrutées dans les CLSC (centre local de services communautaires) Saint-Michel et Rosemont de la région de Montréal et ont été invitées à utiliser l’application pendant 4 semaines, dans un contexte de psychoéducation. Les effets ont été mesurés en les soumettant à l’index d’anxiété de Beck (mesure principale) ainsi qu’à l’index de sévérité de l’Insomnie et au questionnaire pour les inquiétudes du Penn State (mesures secondaires), respectivement au début de l’étude, puis après 2 et 4 semaines. L’anxiété, l’insomnie et les inquiétudes ont aussi été mesurées quotidiennement avec l’application Emax qui sert à recueillir les données en temps réel. Nous avons aussi évalué les processus cognitifs avec la mesure idiosyncratique de la conviction dans les pensées au début et à la fin de l’étude. Les résultats ont montré une réduction statistiquement significative de l’anxiété (d=0,78) au terme de la période d’intervention. Le même résultat a été observé avec les autres variables avec une amélioration de la qualité du sommeil (d=0,78) et une réduction des inquiétudes (d=0,77) toutes deux significatives. Une amélioration des cognitions, reflétée par la diminution significative des valeurs de la mesure idiosyncratique de la conviction dans les pensées (d=1,59), a aussi été observée. L’utilisation de l’application Muzzz dans un contexte de psychoéducation a montré son utilité pour soulager temporairement les symptômes de personnes souffrant d’anxiété et d’insomnie, dans l’attente de consulter un professionnel de la santé. Notre étude ne disposait que d’une faible taille d’échantillon. Ces résultats devraient donc être confirmés par d’autres études futures de plus grande ampleur. / Anxiety and insomnia are among the most common mental health disorders with negative consequences for patients, their families and society as a whole. Pharmacological treatment options with initial efficacy are available but are associated with unwanted side effects and tolerance in the longer term. Cognitive-behavioral therapy is a treatment of choice that provides an effective and longer-term solution, but availability is limited with long waiting-lists. Alternative effective options are needed to address the needs of all those suffering from anxiety and insomnia in a cost effective and timely manner. In particular, the development of new applications of technologies that are already widely used in the general population hold the potential to address the lack of access to traditional resources for those with mental health problems. Our team took the initiative to evaluate the efficacy of the Muzzz app, which consists of listening to positive suggestions inspired by Schultz's autogenic training., and is designed to reduce anxiety and to improve sleep These suggestions are masked by relaxing music and delivered in a subliminal format as a derivative of the APAP (Augmentation of Psychotherapy through Alternative Preconscious Priming) program. The APAP program developed by Borgeat et al. (2013) consists of listening of positive personalized suggestions masked by relaxing music, which has previously shown effectiveness in increasing positive cognitions (d = 0.53) and decreasing negative cognitions (d = 0.73). To assess the effectiveness of the Muzzz app and its application among those with anxiety and insomnia a total of 20 participants (10 men and 10 women were recruited at the Saint-Michel and Rosemont CLSCs (local community service centers) and invited to use the app for 4 weeks in a psychoeducational context. To measure the effects of the app they were administered the Beck Anxiety Inventory, the Insomnia Severity Index and the Penn State Worry Questionnaire at the beginning of the study and then at 2 and 4 weeks respectively. Anxiety, insomnia and worry was also assessed with the Emax app which is used to collect data in real time. In addition, change in cognitions were assessed with the Idiosyncratic Measure of Convictions in Thoughts at the beginning and at the end of the study. The results showed a statistically significant reduction in anxiety (d=0.78) at the end of the intervention period. In addition, there was a significant improvement in the quality of sleep (d=0.78) and reduction in worries (d=0.77). Finally, a significant improvement in cognitions was observed with the decrease in negative cognitions as assessed by the Idiosyncratic Measure of Convictions in Thoughts (d=1.59). We can therefore conclude that the use of the Muzzz app in a psychoeducational context is effective for temporarily relieving symptoms of people with anxiety and insomnia, while they are on waiting-list to see a healthcare professional. Results are limited by a relatively small size and await confirmation in future larger-scale studies.

This thesis is a multi-sited survey providing insight into integral performing arts institutions and how they engage in the distribution of cosmopolitan cultural capital to middlebrow audiences. It additionally provides a taxonomy of the different types of performances present across three sites: MSC OPAS, Arts Midwest, and the Association of Performing Arts Presenters’ Annual Conference in New York (APAP/NYC). My research methods include ethnography, interviewing, and textual analysis, but my investigation of these sites began with several leading questions: How do audiences read live performances for cosmopolitanism? How is that cosmopolitanism produced in key performing arts organizations? How is performance both a product that is marketed to venues and audiences and the means of marketing itself? Cosmopolitanism is an integral component to marketing, delivering, and enjoying live touring commercial performances. Performing arts presenters like OPAS, and presenting organizations, including Arts Midwest and APAP, engage cosmopolitanism on multiple levels as they work to provide regional audiences with otherwise unattainable “world-class” performances. Cosmopolitanism is present and presented every step of the way and the industry continues to advance cosmopolitan goals. This works shifts from analyzing cosmopolitan tourists to understanding touring cosmopolitanism because touring performances provide cosmopolitan cultural capital to community audiences located outside these urban centers. Touring performances provide opportunities for residents outside large metropolitan areas to engage in a global culture of performance and insert themselves into an imagined community of cosmopolitans. This is due in part to touring artists who deliver “world-class” performances to audiences that would otherwise entirely lack a connection to arts opportunities that accompany metropolitan centers and cosmopolitan communities. Cosmopolitanism is operationalized in performances of rurality, organizational culture and sociability, and exoticizing marketing strategies. I not only explore how cosmopolitanism is operationalized across these sites, but also how performance, in several of its variations, is operationalized, negotiated, and, of course, presented. More specifically, I examine artistic, interpersonal, organizational, and economic performances, as they are present across the three sites.