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.

Introdução: A cardiotoxicidade aguda e subaguda pode ser caracterizada pelo prolongamento do intervalo QT corrigido (QTc) e demais medidas derivadas do intervalo QTc, como: a dispersão do intervalo QTc (QTdc) e a dispersão transmural da repolarização (DTpTe). No entanto, ainda não foi determinado se pacientes com neoplasia de mama submetidas ao esquema quimioterápico com antraciclina, ciclofosfamida e taxano (ACT) podem apresentar prolongamento do intervalo QTc, da QTdc e da DTpTe. Os objetivos deste estudo foram 1. avaliar o efeito da quimioterapia ACT no intervalo QTc, 2. avaliar o efeito da quimioterapia ACT na QTdc e na DTpTe, 3.avaliar os biomarcadores cardioespecíficos como a troponina e o peptídeo natriurético do tipo B (BNP), e 4. avaliar manifestações clínicas de cardiotoxicidade, como a presença de: arritmias cardíacas, insuficiência cardíaca (ICC), angina e morte cardiovascular em pacientes com neoplasia de mama. Métodos: Trata-se de um estudo de coorte prospectivo em que 23 pacientes com neoplasia de mama não metastática foram acompanhadas durante o tratamento quimioterápico com o esquema ACT. As medidas do intervalo QTc, da QTdc e da DTpTe foram determinadas pelo eletrocardiograma (ECG) de 12 derivações antes do início da quimioterapia (basal), após a primeira fase com antraciclina e ciclofosfamida (AC), e ao final do tratamento com taxano (T). Biomarcadores como troponina e BNP também foram analisados. Resultados: Quando comparado aos valores basais, houve prolongamento do intervalo QTc após a primeira fase da quimioterapia - AC, 439,7 ms ± 33,2 vs 472,5 ms ± 36,3, (p = 0,001) e ao final do tratamento com taxano, 439,7 ms ± 33,2 vs 467,9 ms ± 42,6, (p < 0,001). A dosagem média de troponina sérica, quando comparada aos valores basais, apresentou elevação após o término da primeira fase da quimioterapia - AC, 6,0 pg/mL [min-max. 6,0 - 22,0] vs 23,0 pg/mL [min-max. 6,0 - 85,0], (p < 0,001) e ao final do tratamento com taxano, 6,0 pg/mL [min-max. 6,0 - 22,0] vs 25,0 pg/mL [min-max. 6,0 - 80,0], (p < 0,001). A QTdc, a DTpTe e os níveis séricos de BNP não mostraram diferenças com significância estatística. Durante o seguimento clínico não houve nenhum óbito e nenhuma constatação de angina, ICC e arritmias cardíacas. Conclusão: Em pacientes com neoplasia de mama não metastática submetidas à quimioterapia com esquema ACT, houve prolongamento do intervalo QTc e elevação dos níveis séricos de troponina / Background: Acute and subacute cardiotoxicity are characterized by prolongation of the corrected QT interval (QTc) and other measures derived from the QTc interval, such as the QTc dispersion (QTdc) and the transmural dispersion of repolarization (DTpTe). Although anthracyclines prolong the QTc interval, it is unknown whether breast cancer patients who undergo a chemotherapy regimen with anthracycline (A; doxorubicin), cyclophosphamide (C) and taxane (T; ACT regimen) may present with QTc, QTdc and DTpTe prolongation. Methods: Twenty-three patients with breast cancer were followed up in a prospective study during ACT chemotherapy. QTc, QTdc and DTpTe measurements were determined by a 12-lead electrocardiogram (EKG) prior to chemotherapy (baseline), after the first phase of anthracycline and cyclophosphamide (AC), and after T treatment. Biomarkers such as troponin and B-type natriuretic peptide (BNP) were also measured. Results: When compared to baseline values, the QTc interval showed a statistically significant prolongation after the AC phase (439.7 ± 33.2 msec vs 472.5 ± 36.3 msec, p = 0.001) and after T treatment (439.7 ± 33.2 msec vs 467.9 ± 42.6 msec, p < 0.001). Troponin levels were elevated after the AC phase (23.0 pg/mL [min-max: 6.0 - 85.0] vs 6.0 pg/mL [min-max: 6.0 - 22.0], p < 0.001) and again after T treatment (25.0 pg/mL [min-max: 6.0 - 80.0] vs 6.0 pg/mL [min-max: 6.0 - 22.0], p < 0.001) compared to the baseline values. Conclusion: In patients with non-metastatic breast cancer who underwent ACT chemotherapy, a statistically significant QTc prolongation and an elevation in serum troponin levels were observed

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.

Introdução: A cardiotoxicidade aguda e subaguda pode ser caracterizada pelo prolongamento do intervalo QT corrigido (QTc) e demais medidas derivadas do intervalo QTc, como: a dispersão do intervalo QTc (QTdc) e a dispersão transmural da repolarização (DTpTe). No entanto, ainda não foi determinado se pacientes com neoplasia de mama submetidas ao esquema quimioterápico com antraciclina, ciclofosfamida e taxano (ACT) podem apresentar prolongamento do intervalo QTc, da QTdc e da DTpTe. Os objetivos deste estudo foram 1. avaliar o efeito da quimioterapia ACT no intervalo QTc, 2. avaliar o efeito da quimioterapia ACT na QTdc e na DTpTe, 3.avaliar os biomarcadores cardioespecíficos como a troponina e o peptídeo natriurético do tipo B (BNP), e 4. avaliar manifestações clínicas de cardiotoxicidade, como a presença de: arritmias cardíacas, insuficiência cardíaca (ICC), angina e morte cardiovascular em pacientes com neoplasia de mama. Métodos: Trata-se de um estudo de coorte prospectivo em que 23 pacientes com neoplasia de mama não metastática foram acompanhadas durante o tratamento quimioterápico com o esquema ACT. As medidas do intervalo QTc, da QTdc e da DTpTe foram determinadas pelo eletrocardiograma (ECG) de 12 derivações antes do início da quimioterapia (basal), após a primeira fase com antraciclina e ciclofosfamida (AC), e ao final do tratamento com taxano (T). Biomarcadores como troponina e BNP também foram analisados. Resultados: Quando comparado aos valores basais, houve prolongamento do intervalo QTc após a primeira fase da quimioterapia - AC, 439,7 ms ± 33,2 vs 472,5 ms ± 36,3, (p = 0,001) e ao final do tratamento com taxano, 439,7 ms ± 33,2 vs 467,9 ms ± 42,6, (p < 0,001). A dosagem média de troponina sérica, quando comparada aos valores basais, apresentou elevação após o término da primeira fase da quimioterapia - AC, 6,0 pg/mL [min-max. 6,0 - 22,0] vs 23,0 pg/mL [min-max. 6,0 - 85,0], (p < 0,001) e ao final do tratamento com taxano, 6,0 pg/mL [min-max. 6,0 - 22,0] vs 25,0 pg/mL [min-max. 6,0 - 80,0], (p < 0,001). A QTdc, a DTpTe e os níveis séricos de BNP não mostraram diferenças com significância estatística. Durante o seguimento clínico não houve nenhum óbito e nenhuma constatação de angina, ICC e arritmias cardíacas. Conclusão: Em pacientes com neoplasia de mama não metastática submetidas à quimioterapia com esquema ACT, houve prolongamento do intervalo QTc e elevação dos níveis séricos de troponina / Background: Acute and subacute cardiotoxicity are characterized by prolongation of the corrected QT interval (QTc) and other measures derived from the QTc interval, such as the QTc dispersion (QTdc) and the transmural dispersion of repolarization (DTpTe). Although anthracyclines prolong the QTc interval, it is unknown whether breast cancer patients who undergo a chemotherapy regimen with anthracycline (A; doxorubicin), cyclophosphamide (C) and taxane (T; ACT regimen) may present with QTc, QTdc and DTpTe prolongation. Methods: Twenty-three patients with breast cancer were followed up in a prospective study during ACT chemotherapy. QTc, QTdc and DTpTe measurements were determined by a 12-lead electrocardiogram (EKG) prior to chemotherapy (baseline), after the first phase of anthracycline and cyclophosphamide (AC), and after T treatment. Biomarkers such as troponin and B-type natriuretic peptide (BNP) were also measured. Results: When compared to baseline values, the QTc interval showed a statistically significant prolongation after the AC phase (439.7 ± 33.2 msec vs 472.5 ± 36.3 msec, p = 0.001) and after T treatment (439.7 ± 33.2 msec vs 467.9 ± 42.6 msec, p < 0.001). Troponin levels were elevated after the AC phase (23.0 pg/mL [min-max: 6.0 - 85.0] vs 6.0 pg/mL [min-max: 6.0 - 22.0], p < 0.001) and again after T treatment (25.0 pg/mL [min-max: 6.0 - 80.0] vs 6.0 pg/mL [min-max: 6.0 - 22.0], p < 0.001) compared to the baseline values. Conclusion: In patients with non-metastatic breast cancer who underwent ACT chemotherapy, a statistically significant QTc prolongation and an elevation in serum troponin levels were observed

Epileptic seizures are often un-witnessed and can result in hypoxic brain damage or can be fatal due to injuries, status epilepticus or sudden unexpected death in epilepsy (SUDEP). The first aim of this thesis was to investigate some of the physiological parameters that accompany an epileptic seizure and may be useful in a seizure alarm system. The second aim was to investigate aspects of cardiac dysfunction during clinical and sub-clinical seizures that may be potential contributing factors in SUDEP. Percentage heart rate change and oxygen saturation were studied prospectively during 527 epileptic seizures in 50 patients aged from one-day full term neonate to 60 years with a variety of seizure types (absences, generalised tonic clonic seizures, myoclonic seizures, tonic seizures and focal seizures) and in normal physiological events (e.g. coughing, turning in bed). Higher percentage heart rate change occurred during epileptic seizures (21.8%) than during normal physiological events (16.4%) p<0.001. Diagnostic testing of clinically significant seizures i.e seizures that could potentially lead to serious consequences if left undetected (n=61) had a sensitivity of 91% and specificity of 75% when percentage heart rate change and hypoxaemia parameters were combined. Percentage heart rate change and oxygen saturation could be used as reliable indicators of a seizure when set at specific levels and distinguish clinically significant seizures from normal physiological events. These parameters can now be used to develop a reliable alarm system to detect epileptic seizures at night. Prolongation of QTc and increased vagal tone may be possible mechanisms underlying SUDEP. Corrected Q-T cardiac repolarisation time 5 minutes before and throughout 156 epileptic seizures were analysed using four corrective formulae (Bazett, Hodge, Fridericia and Framingham). All formulae indicated statistically significant lengthening of the corrected Q-T during epileptic seizures (p<0.001) compared to pre-seizure values. All formulae agreed that the greatest lengthening of the corrected QT beyond normal limits occurred during right temporal lobe seizures in two patients. Reflex and tonic vagal activity utilising R-R intervals was assessed in 33 sub-clinical seizures occurring during stages 3 or 4 sleep and was compared to matched counts of R-R interval non-ictal baseline studies from the same stage of sleep in each patient. Altered vagal activity occurred during total sub-clinical seizures compared to baseline studies (p<0.001). Lengthening of the corrected Q-T and changes in cardiac vagal tone during epileptic seizures may have a role in the patho-physiology of SUDEP.

This thesis explores two novel ways of reducing the data complexity of tactile sensing. The thesis begins by examining the state-of-the art in tactile sensing, not only examining the sensor construction and interpretation of data but also the motivation for these designs. The thesis then proposes two methods for reducing the complexity of data in tactile sensing. The first is a low-power tactile sensing array exploiting a novel application of a pressure-sensitive material called quantum tunnelling composite. The properties of this material in this array form are shown to be beneficial in robotics. The electrical characteristics of the material are also explored. A bit-based structure for representing tactile data called Bitworld is then defined and its computational performance is characterised. It is shown that this bit-based structure outperforms floating-point arrays by orders of magnitude. This structure is then shown to allow high-resolution images to be produced by combining low resolution sensor arrays with equivalent functional performance to a floating-point array, but with the advantages of computational efficiency. Finally, an investigation into making Bitworld robust in the presence of positional noise is described with simulations to verify that such robustness can be achieved. Overall, the sensor and data structure described in this thesis allow simple, but effective tactile systems to be deployed in robotics without requiring a significant commitment of computational or power resources on the part of a robot designer.

QTc-Zeit Verlängerungen sind aufgrund potentieller Übergänge in lebensbedrohliche Tachyarrhythmien Gegenstand vieler Arbeiten. Einer der Häufigsten Risikofaktoren ist die Einnahme von typischen bzw. atypischen Antipsychotika. Mehrere Studien belegen darüber hinaus genetische Einflüsse und zeigen, dass das homozygote Vorhandensein von rs12143842(T) und rs10494366(G) in NOS1AP einen verlängernden Einfluss auf die QTc-Zeit hat. Zudem scheinen oben genannte Polymorphismen von NOS1AP bei der Entwicklung schizophrener Psychosen eine Rolle zu spielen. In bisherigen Studien wurde immer nur getrennte Analysen hinsichtlich der genannten Risikofaktoren vorgenommen. In dieser Arbeit soll erstmals der gemeinsame Einfluss von Psychopharmaka und den zwei beschriebenen Polymorphismen von NOS1AP bei Patienten mit Schizophrenie untersucht werden. / The prolongation of the QTc-Time interval is a well examined phenomenon due to the risk of suffering a life threatening tachyarrhythmia. In patients with schizophrenia, several risk factors have been identified one of which is taking antipsychotic medication. Genetic variation in NOS1AP polymorphisms rs12143845 (T) and rs10494366 (G) are also found to be significant risk factors. Furthermore, NOS1AP is associated with a higher risk of developing schizophrenic psychosis. This study aims to detect the impact on QTc prolongation in an analysis of combined risk factors in patients with schizophrenia.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Clustering gene expression data such that the diameters of the clusters formed are no greater than a specified threshold prompted the development of the Quality Threshold Clustering (QTC) algorithm. It iteratively forms clusters of non-increasing size until all points are clustered; the largest cluster is always selected first. The QTC algorithm applies in many other domains that require a similar quality guarantee based on cluster diameter. The worst-case complexity of the original QTC algorithm is (n5). Since practical applications often involve large datasets, researchers called for more efficient versions of the QTC algorithm. This dissertation aimed to develop and evaluate efficient variations of the QTC algorithm that guarantee a maximum cluster diameter while producing partitions that are similar to those produced by the original QTC algorithm. The QTC algorithm is expensive because it considers forming clusters around every item in the dataset. This dissertation addressed this issue by developing methods for selecting a small subset of promising items around which to form clusters. A second factor that adversely affects the efficiency of the QTC algorithm is the computational cost of updating cluster diameters as new items are added to clusters. This dissertation proposed and evaluated alternate methods to meet the cluster diameter constraint while not having to repeatedly update the cluster diameters. The variations of the QTC algorithm developed in this dissertation were evaluated on benchmark datasets using two measures: execution time and quality of solutions produced. Execution times were compared to the time taken to execute the most efficient published implementation of the QTC algorithm. Since the partitions produced by the proposed variations are not guaranteed to be identical to those produced by the original algorithm, the Jaccard measure of partition similarity was used to measure the quality of the solutions. The findings of this research were threefold. First, the Stochastic QTC alone wasn’t computationally helpful since in order to produce partitions that were acceptably similar to those found by the deterministic QTCs, the algorithm had to be seeded with a large number of centers (ntry ≈ n). Second, the preprocessed data methods are desirable since they reduce the complexity of the search for candidate cluster points. Third, radius based methods are promising since they produce partitions that are acceptably similar to those found by the deterministic QTCs in significantly less time.