Class of 2017 Abstract / Objectives: To assess the incidence of medication-induced corrected QT (QTc) interval in patients taking two or more QTc prolonging medications and to identify which risk factors are associated with QTc prolongation. Methods: This retrospective chart review examined QTc prolongation in adult patients admitted to Banner University Medical Center South Campus (BUMC South) received at least two QTc prolonging medications. Patients were assessed for risk factors of QTc prolongation, number of QTc prolonging drugs received, and presence of QTc prolongation. Results: Of the patients who received two, three, or four or more QTc prolonging drugs, 43.4%, 67.3%, and 45.5%, experienced QTc prolongation, respectively (p < 0.05). Those who received three QTc prolonging drugs had a greater incidence of QTc prolongation compared to those who received two (p = 0.0089) or four or more (p = 0.049) QTc prolonging drugs. There was no difference in incidence of QTc prolongation in those receiving two versus four drugs (p = 0.084). The incidence of QTc prolongation was associated with risk factors including a history of cardiovascular diseases, electrolyte disturbances, and being female (p < 0.05). Conclusions: An increase in the number of QTc prolonging drugs received was not associated with a corresponding increase in the incidence of QTc prolongation. Being female, having electrolyte disturbances, or a history of cardiovascular disease may increase the risk of QTc prolongation.

Class of 2015 Abstract / Objectives: The goals of this study were to determine how frequently azithromycin and moxifloxacin were used in combination with other drugs that cause QTc prolongation, describe the effects these combinations have on QTc interval length, determine the incidence of QTc prolongation in patients on these medication combinations, and identify risk factors associated with QTc interval prolongations in patients on these medication combinations. Methods: A retrospective chart review was performed on patients who received at least two doses of azithromycin or moxifloxacin. It was noted whether these patients received other medications that prolonged the QTc interval. ECG information was grouped into daily phases depending on whether the patient was at baseline, receiving antibiotic therapy, QTc prolonging medication therapy, or concomitant therapy. These data were compared using a repeated measures ANOVA. Results: Patients received concomitant antibiotic-QTc prolong medication therapy in 70% of cases analyzed. In all patients on concomitant therapy there was no significant difference in any measured ECG data (all p-values > 0.26). In those who were on azithromycin and experienced QTc prolongation there was a significant difference in RR interval length (p=0.034). In those that experienced QTc prolongation on moxifloxacin there was a significant difference in QT (p=0.0033) and QTcF (p=0.0089) length. Conclusions: These medication combinations are used frequently in the hospital. These medications may not increase the QTc interval length in the general population but more research is warranted in this area to confirm this finding.

While some composers at the beginning of the twentieth century drifted away from tonal hierarchical structures, Gustav Holst and Ralph Vaughan Williams sought ways of integrating tonal ideas with new materials. By analyzing the music of Holst and Vaughan Williams using a technique expressly designed for the analysis of tonal musical structure—Schenkerian Analysis—this study looks at ways in which the composers combined old and new techniques and what that means with regards to our understanding of their music. To do this, the current study focuses on the sacred choral repertory because it can form a stylistic bridge between nineteenth-century tonality and the composers’ more experimental works. This repertory also provides an opportunity for interpreting text-music connections that help us understand the music at a deeper level. In order to establish groundwork for the analytical methodology, I begin the study with background information on the composers and previous research done on their music, after which I summarize their most pertinent stylistic features (including their use of diatonic modes and other pitch collections, their harmonic, melodic, and contrapuntal techniques, and their formal structures). I then discuss how an analyst can determine prolongational structure in Holst’s and Vaughan Williams’s music by establishing the tonic or pitch-class center, establishing the context for harmonic and melodic stability, and following predictable formal patterns. Finally, I apply the analytical methodology in detail to Vaughan Williams’s Benedicite and Holst’s The Hymn of Jesus, two substantial single-movement choral works that represent both the conservative (Benedicite) and experimental (The Hymn of Jesus) sides of the composers’ style. I also compare the analyses with the texts and show how the composers portrayed religious ideas, even at deeper levels of the prolongational structure. The modified Schenkerian analytical techniques used in these analyses show that even though Holst and Vaughan Williams used a number of twentieth-century compositional techniques, their prolongational structures still follow expected patterns and closely resemble traditional structures.

<div>The human ether-a-go-go-related gene (hERG, KCNH2) potassium channel has been implicated in diverse physiological and pathological processes. The KCNH2 gene encodes a rectifier voltage-gated potassium channel (Kv 11.1) that governs the chief repolarizing current, IKr, which is essential for normal electrical activity in excitable cells such as cardiomyocytes. It is also involved in cell growth and apoptosis regulation in non-excitable cells, such as tumor cells. Dysfunction of hERG is associated with potentially lethal complications, including diseases and sudden death under certain circumstances. While the mechanisms regulating KCNH2 expression remain unclear, recent data suggested that microRNAs (miRNAs) are involved, particularly in the context of several pathologic effects. </div><div>miRNA is a class of RNA defined by its conserved, short, non-coding nature. miRNAs are important regulators of gene expression at the post-transcriptional level that bind through complimentary annealing to the 3’ untranslated regions (3’ UTRs) of target mRNAs, resulting in mRNA destabilization and translational repression. The primary objectives of this research were to 1) identify miRNAs regulating KCNH2 expression in cancer, 2) investigate the potential association between miR-362-3p expression and risk of drug-induced QT interval lengthening, and 3) identify miRNAs potentially regulating KCNH2 expression and function in cardiac cells. </div><div>Through bioinformatics approaches, five miRNAs were identified to potentially regulate KCNH2 expression and function in breast cancer cells. The five identified miRNAs were validated through a Dual-Luciferase Assay using the KCNH2 3′ UTR. Only miR-362-3p was validated to bind to the KCNH2 3’ UTR, decreasing luciferase activity by 10% ± 2.3 (P < 0.001, n = 3) when compared to cells transfected with luciferase plasmid alone. miR-362-3p was also the only miRNA that its expression positively correlated with overall survival of patients with breast cancer from The Cancer Genome Atlas-Cancer Genome (TCGA) database by log-rank test (HR: 0.39, 95% CI: 0.18 to 0.82, P = 0.012). Cell proliferation was assessed by MTS assay (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) 48 hours following transfection in breast cancer cell lines, including SK-BR-3 and MCF-7. miR-362-3p significantly decreased proliferation of SK-BR-3 and MCF-7 cells by 23% ± 8.7 (P = 0.014, n = 3) and 11.7% ± 1.0 (P < 0.001, n = 3), respectively. Cell cycle phases in SK-BR-3 and MCF-7 cells were differentiated by flow cytometry 48 hours following transfection. miR-362-3p and hERG siRNA (positive control) significantly increased the accumulation of cells in G0/G1 phase in MCF-7 by 11.7% (from 51.1% ± 0.64 to 57.1 ± 0.96, P = 0.002, n = 3) and 10% (from 51.1% ± 0.64 to 56.8 ± 0.96, P < 0.001, n = 3), respectively. </div><div>The demonstrated ability of miR-362-3p to regulate hERG in breast cancer cells coupled with previously published data that indicated an alteration of miR-362-3p expression during HF and a potential association between its expression and QT interval prolongation suggesting an important role for this miRNA in regulation of hERG function during HF. Therefore, the contribution of miR-362-3p to hERG function was investigated in patients administered the QT prolonging drug ibutilide, known to inhibit hERG. A total of 22 patients completed a prospective, parallel-group comparative study during which they received subtherapeutic doses (0.003 mg/kg) of ibutilide. The study was originally designed to investigate the influence of heart failure with preserved ejection fraction (HFpEF) on response to drug-induced QT prolongation. Blood for determination of serum Ibutilide concentrations and miR-362-3p expression, along with electrocardiograms (ECGs) were serially collected over a span of 12 hours. ΔΔ-Fridericia-heart rate corrected QT (ΔΔ QTF) intervals were utilized for all analyses to account for baseline and diurnal variation. </div><div>To assess the ability of miR-362-3p to predict ibutilide QT-induced ΔΔQTF changes, nonlinear mixed effects pharmacokinetic/ pharmacodynamic (PKPD) modeling was performed to assess the contribution of miR-362-3p to drug-induced QT interval lengthening. The model that best fit serum ibutilide concentrations versus time was a 3-compartment model with first order elimination and proportional residual errors, while the model that best described the ibutilide concentration- ΔΔQTF relationship was an Emax model with an effect compartment. In addition to miR-362-3p expression, several demographic and clinical data were evaluated as potential covariates on PK and PD parameter estimates. Of tested covariates, heart failure (HF) status on Emax (ΔOFV = -4.1; P < 0.05), and miR-362-3p expression on EC50 (ΔOFV = -9.9; P < 0.05) were incorporated in the final PKPD model. The mean individual Emax was significantly higher in HF patients when compared to non-HF patients (P = 0.015), while EC50 was negatively correlated with miR-362-3p expression (P < 0.0001, R2 0.93). </div><div>Previous evidence indicates that miR-362-3p is altered in patients with HF. In addition, several miRNAs commonly regulate the same ion channel. Therefore, we have developed a large-scale high-throughput bioassay (HT-bioassay) to explore and identify other miRNAs potentially involved in KCNH2 expression and function in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) during sustained β-adrenergic receptor (βAR) stimulation or overexpression of activated calcium/calmodulin-dependent protein kinase 2 (CaMKII), which are classical consequences of HF. </div><div>Through bioinformatic approaches, putative miRNA binding sites (n=327) were identified in the KCNH2 3′ UTR. Fragments containing these putative binding sites were synthesized, cloned into linearized plasmids, and amplified. The plasmid pool was transfected into hiPS-CM cells either treated with βAR stimulation or overexpressing CaMKII. Next-generation sequencing was performed to identify: 1) expression of putative miRNA binding sites and 2) endogenous miRNAs versus control. Eight predicted binding sites were found to be significantly downregulated in the CAMKII group (P <0.05, log fold change -0.287 to -0.59), and six significantly downregulated in the sustained βAR group (P <0.05, log fold change -0.29 to -0.72). Two binding sites were significantly reduced in both treatment groups (P < 0.05, log fold change between -0.38 and -0.61).</div><div>Thirty-one miRNAs were predicted to bind to the 16 binding sites identified from the bioassay. Of these, seven were selected for further screening using dual luciferase assays. None of the putative miRNAs reduced luciferase activity. However, hERG expression was assessed by immunoblot analysis following transfection of the seven miRNAs into HEK293 cells stably expressing hERG (HEK293-hERG). Six of the seven miRNA mimics reduced hERG protein expression. An additional validation step was performed by assessing hERG-related current density by whole cell electrophysiology, in which three of the six miRNAs inhibited hERG protein transfected into HEK293-hERG cells. Those same three miRNA mimics significantly decreased Ikr current (P <0.05). </div><div>Finally, expression of the miRNAs identified by HT-bioassay was examined in the patients enrolled in the clinical trial in which genome-wide next generation sequencing was performed on miRNAs extracted from whole blood samples. Of the 31 miRNAs identified from HT-bioassay, six were found to be expressed in patients (n = 12). A correlation analysis was performed between levels of the expressed miRNAs and corresponding QTF interval lengthening with ibutilide. Of the six miRNAs, only miR-4665-5p was significantly associated with QTF interval (P = 0.0379). </div><div>In summary, miR-362-3p was identified to regulate hERG, and reduces proliferation of breast cancer cells through a mechanism that may be partially mediated by hERG inhibition. While miR-362-3p may have modest effects in cancer, in Aim 2 we demonstrated that it along with HF status accounts for a significant amount of variability in QTF prolongation following ibutilide administration. However, it is common for several miRNAs to regulate a single ion channel. Therefore, an HT-bioassay was developed to identify all miRNAs that potentially regulate KCNH2 during HF. In addition to miR-362-3p, thirty-one miRNAs were predicted to regulate KCNH2; one miRNA (miR-4665-5p) was significantly associated with QTF prolongation. The potential for miR-362-3p and HT-bioassay-identified miRNAs to reduce hERG-related current and influence susceptibility to drug-induced QT interval prolongation warrants further investigation. </div><div><br></div>

This thesis investigates the psychological implications of prolongation, a structural phenomenon of tonal music, which is described in the musicological literature as an elaborative process in which some pitch events - such as chords and notes - remain as if they were sounding even though they are not physically present.

L’étude de la durée des délégations de service public a été pour longtemps marginalisée bien que cette notion constitue un élément essentiel du contrat. Néanmoins, depuis le début des années 1990 et notamment avec l’adoption de la loi Sapin, la conception de la fixation de la durée et de l’encadrement de sa prolongation a connu une importance grandissante. Elle a été conçue comme le moyen le plus apte à garantir la lutte contre la corruption et les rentes de situations. Cependant les modalités de la détermination de la durée ont été rattachées à des notions variables tel l’amortissement, ce qui a rendu la fixation préalable de la durée d’une impossibilité évidente. De ce fait, cette fixation telle qu’exercée aujourd’hui en matière des délégations de service public, souffre d’une grave incohérence tant dans sa conceptualisation que dans son application. Par conséquent, cette théorie n’a pas réussi à préserver le service public et à trouver une sorte de compromis entre le délégant et le délégataire qui tient compte primordialement de l’intérêt du service et de l’usager. Il semble que seule la théorie de la durée variable, liée aux résultats de l’exploitation saurait remédier aux difficultés que soulève une constante variation des circonstances. Dans cette perspective, désencombrer la durée nous pousse à amplifier le contrôle et à élargir l’imperium du magistrat pour assurer la sauvegarde du service public. / The study of the duration of delegation of public services has long been marginalized despiet it being an essential element of the contract. However, since the early nineties, and with the adoption of the Sapin law, the concept of the determination of the duration and of the frames setting out its extension has received increased attention. It has been seen as the most appropriate means to guarantee the fight against corruption. Nonetheless, the modalities of determination of the duration have been linked to multiple notions such as amortization, which has rendered an early determination of the duration impossible. As a consequence, the determination of the duration, as practised today, suffers from serious incoherences in both concept and application. Therefore, this theory has failed to protect public services and permit compromise between the delegate and the person being delegated to, primarily taking into account the best interests of the service and the user. It appears that only a theory of a variable duration, linked to the results of the operation would remedy the difficulties raized by the ever-changing circonstances. In this perspective, simplifiying the duration would lead to increased control and power of the judge in order to safeguard public services.

This study examined a sentence-initial one-second sound prolongation as a possible fluency-inducing condition in people who stutter. The effects of this prolongation technique on the single sentence utterances of five people who stutter (PWS) and five age- and gender-matched controls were investigated. Variables tested included stuttering percentages, speaking rate, duration of phonated intervals, and correlation between upper lip and lower lip/jaw. Results showed a non-significant trend for less stuttering to occur when participants used the prolongation technique. Significant findings included longer durations of phonated intervals and more negatively correlated upper- and lower-lip movements during the prolongation condition. Rate of speech was not affected. These findings suggest that the prolongation technique caused measurable changes in speech motor control, possibly leading to greater fluency for PWS.

Background: Drugs are an important part of treating diseases but can also come with its risks. To reduce the risks, a system assisted pharmaceutical validation (SAPVAL) is being developed at Uppsala University Hospital. This will include the generation of alerts regarding different risks, sent to a clinical pharmacist who assesses whether the alerts should be forwarded to a physician or not. One of the risks included is QT prolongation, a relatively uncommon condition which however can result in sudden cardiac death. Aim: The aim was to map the management and the consequences of QT-related risk prescriptions and to determine the clinical relevance of QT-related alerts. Method: A retrospective cross-sectional study was performed at Uppsala University Hospital. It included the review of patients´ electronic health records (EHR) and determination of risk periods. The clinical relevance of the alerts was assessed by a physician and a developed flowchart. Results: 65 patients (age=71 ± 15 years, 54% women), and their 85 QT-related alerts were included, with a median risk period of 145 days. Within the risk period, 46 patients had an ECG taken with 35% having one or more prolonged QTc ≥ 480 ms. The risk of QT prolongation had been noticed or mitigated for 23% of the 65 patients. 89% of the alerts were concluded to be clinically relevant. Conclusion: The management and documentation of QT-related risks could be improved. It is also important to further study QT-related risk factors to better assess which patients are at the highest risk.

No description available.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.