Gain of function of cardiac voltage-gated sodium channel (Nav1.5) leads to Long QT Syndrome Type 3 (LQT3). LQT3 phenotype can be exacerbated by expanding the perinexus, which is an intercellular nanodomain with high density of Nav1.5 in the intercalated disc. Following this finding, we found that elevating extracellular sodium and widening the perinexus synergistically exacerbated LQT3 phenotype, Importantly, we also found that perinexal expansion increases the susceptibility to cardiac arrest in aged LQT3, which demonstrated that perinexal expansion is an arrhythmogenic risk especially in aged LQT3 patients. Furthermore, we observed that the perinexus narrows with aging and conceals LQT3 phenotype, which suggests that perinexal narrowing may have a cardio-protective role during aging in LQT3. Surprisingly, following the finding of the synergistic effect of extracellular sodium elevation and perinexal widening on LQT3 phenotype in drug-induced LQT3 guinea pig hearts, we found that this synergistic effect was not observed in genetically-modified LQT3 mouse hearts, which is due to high sodium also increasing transient outward potassium current (Ito). In summary, the whole project investigated the role of the perinexus in LQT3 from different conditions including sodium, aging and species. The findings in this project discovered the importance of perinexal expansion in LQT3 and also the involvement of Ito in sodium regulating LQT3 phenotype in hearts which functionally express Ito channels. Therefore, a LQT3 animal model which has similar electrophysiology close to human may be a great option for translational purpose. / Doctor of Philosophy / Long QT Syndrome Type 3 (LQT3) is an inherited heart disease with the phenotype of long QT interval in ECG. It has been found that LQT3 phenotype gets worse when a very tiny space in the heart, termed as the perinexus, is wide due to cardiac edema. Following this finding, we also found that increasing sodium concentration together with wide perinexus can further exacerbate LQT3 phenotype in guinea pig hearts. Furthermore, we found that widening the perinexus in aged LQT3 hearts causes cardiac death but not in adult, which suggests that perinexal widening worsens LQT3 phenotype and even leads to cardiac death in aged hearts. Besides, we found that the perinexus narrows with aging and there is no difference in LQT3 phenotype between adult and aged hearts, which suggests that the narrow perinexus during aging may protect the hearts from cardiac death in LQT3. Surprisingly, we discovered that increasing sodium and widening the perinexus together fails to exacerbate LQT3 phenotype when compared with widening the perinexus alone in LQT3 mouse hearts, which is due to high sodium increasing transient outward potassium current (Ito). Notably, Ito channels are not functionally expressed in guinea pig hearts. In summary, the whole project investigated the role of the perinexus in LQT3 from different conditions including sodium, aging and species. The findings in this project discovered the importance of perinexal expansion in LQT3 and also the involvement of Ito in sodium regulating LQT3 phenotype in hearts. Therefore, a LQT3 animal model which has similar electrophysiology close to human may be a great option for translational purpose.

The first study investigates the factors that impact the duration of U.S. fresh fruit and vegetable imports. We employ both survival analysis (Kaplan Meier estimates and Cox proportional hazards model) as well as count data models. Our results indicate that SPS treatment requirements positively impact the duration of trade while new market access has the opposite effect. Other factors typically included in trade duration models (such as: GDP, transportation costs, tariff rates, etc.) were also investigated. We also employ a probit model to understand the factors impacting the probability that a country selects into exporting fresh fruits and vegetables to the United States. The second study estimates the goods-time elasticity of substitution for Food Stamp/SNAP participants versus non participants. We find that the elasticity of substitution for SNAP participants is not statistically different from zero. This indicates that SNAP participants have Leontief production function in household food production, implying that increasing the amount of SNAP benefits paid to participants will not lead to more food production if the time households dedicate to food preparation remains unchanged. This finding extends the analysis done by Baral, Davis and You (2011) and offers insights for policies related to the SNAP program. / Master of Science

Many common statistical techniques for modeling multidimensional dynamic data sets can be seen as variants of one (or multiple) underlying linear/nonlinear model(s). These statistical techniques fall into two broad categories of supervised and unsupervised learning. The emphasis of this dissertation is on unsupervised learning under multiple generative models. For linear models, this has been achieved by collective observations and derivations made by previous authors during the last few decades. Factor analysis, polynomial chaos expansion, principal component analysis, gaussian mixture clustering, vector quantization, and Kalman filter models can all be unified as some variations of unsupervised learning under a single basic linear generative model. Hidden Markov modeling (HMM), however, is categorized as an unsupervised learning under multiple linear/nonlinear generative models. This dissertation is primarily focused on hidden Markov models (HMMs). On the first half of this dissertation we study enhancements on the theory of hidden Markov modeling. These include three branches: 1) a robust as well as a closed-form parameter estimation solution to the expectation maximization (EM) process of HMMs for the case of elliptically symmetrical densities; 2) a two-step HMM, with a combined state sequence via an extended Viterbi algorithm for smoother state estimation; and 3) a duration-dependent HMM, for estimating the expected residency frequency on each state. Then, the second half of the dissertation studies three novel applications of these methods: 1) the applications of Markov switching models on the Bifurcation Theory in nonlinear dynamics; 2) a Game Theory application of HMM, based on fundamental theory of card counting and an example on the game of Baccarat; and 3) Trust modeling and the estimation of trustworthiness metrics in cyber security systems via Markov switching models. As a result of the duration dependent HMM, we achieved a better estimation for the expected duration of stay on each regime. Then by robust and closed form solution to the EM algorithm we achieved robustness against outliers in the training data set as well as higher computational efficiency in the maximization step of the EM algorithm. By means of the two-step HMM we achieved smoother probability estimation with higher likelihood than the standard HMM. / Ph. D.

Introduction: Adverse Childhood Experiences (ACEs) are known to increase risk of mental health challenges throughout development, and sleep is known to decrease risk of mental health challenges. These have not been studied in tandem in younger cohorts. We investigated whether interactions between sleep duration and sleep regularity would moderate the impact of ACE exposure on risk for the development of mental health disorders. Methods: We conducted secondary cross-sectional analyses on the 2020-2021 waves of the National Survey of Children's Health (NSCH) (n = 92,669). We used logistic and ordinal regression to replicate known main effects of ACEs (total, household, community, and single) and sleep (duration and irregularity) on mental health diagnostic status and symptom severity, and we examined the interaction of ACEs and sleep on mental health diagnostic status. To correct for multiple comparisons, all original models were performed with one half of the dataset and then replicated in the second half. Follow-up analyses by age cohort (0-5, 6-11, 12-17 years) further examined interaction effects across development. Poverty level, parental education status, child age, child sex, neighborhood safety, neighborhood support, and race/ethnicity were included as covariates, as indicated in a priori acyclic graph (DAG) modeling. Results: Known main effects for ACE and sleep on mental health diagnoses were replicated across all models. Interactions between ACE exposure and adequate sleep duration or increased sleep irregularity were not clinically significant, although some were statistically significant due to large sample size, such that adequate sleep duration was associated with marginally increased risk of mental health diagnosis (Omnibus B = 0.048, p < 0.0001) and greater bedtime irregularity was associated with marginally decreased risk of mental health diagnosis (Omnibus B = -0.030, p < 0.001). Discussion: Main effects in this analysis are consistent with previous literature on ACEs, sleep, and mental health. However, interaction effects were largely small and clinically insignificant. Dichotomous and categorical parent-report items assessing sleep health may not be sensitive to interaction effects, compared with continuous data or physiological measurements. Further, examining mental health symptoms (rather than diagnosis status) may also allow for more nuanced understanding of potential interaction effects.

The performance of a mobile satellite communications link can be determined by the propagation path between a satellite and mobile users. Some of the most important factors are multipath propagation and vegetative shadowing. System designers should have the most reliable information about the statistics of fade duration in order to determine fade margin or to compensate for the fades using modulation and coding scheme. This report describes a simulator, PROSIM, developed at Virginia Tech for simulating a propagation model in land mobile satellite communications. The simulator is based on a random number generator that generates data sets to compute statistics of the propagation channel. Performance of the simulator was evaluated by comparing statistics from an analytical model and experimental data provided by W. Vogel of Univ. of Texas at Austin and J. Goldhirsh of the Applied Physics Laboratory. New expressions for phasor plot and its mathematical expression for lognormal channel were derived and were simulated. Finally, the advantages of the simulator using random number generator in simulating the propagation model are described. / Master of Science

No / The first purpose of this paper is to assess the short-run forecasting capabilities of two competing financial duration models. The forecast performance of the Autoregressive Conditional Multinomial–Autoregressive Conditional Duration (ACM-ACD) model is better than the Asymmetric Autoregressive Conditional Duration (AACD) model. However, the ACM-ACD model is more complex in terms of the computational setting and is more sensitive to starting values. The second purpose is to examine the effects of market microstructure on the forecasting performance of the two models. The results indicate that the forecast performance of the models generally decreases as the liquidity of the stock increases, with the exception of the most liquid stocks. Furthermore, a simple filter of the raw data improves the performance of both models. Finally, the results suggest that both models capture the characteristics of the micro data very well with a minimum sample length of 20 days.

Yes / Spatial dispersion of repolarization is known to play an important role in arrhythmogenesis. Electrotonic modulation of repolarization by the activation sequence has been observed in some species and tissue preparations, but to varying extents. Our study sought to determine the mechanisms underlying species- and tissue-dependent electrotonic modulation of repolarization in ventricles. Epi-fluorescence optical imaging of whole rat hearts and pig left ventricular wedges were used to assess epicardial spatial activation and repolarization characteristics. Experiments were supported by computer simulations using realistic geometries. Tight coupling between activation times (AT) and action potential duration (APD) were observed in rat experiments but not in pig. Linear correlation analysis found slopes of −1.03 ± 0.59 and −0.26 ± 0.13 for rat and pig, respectively (p < 0.0001). In rat, maximal dispersion of APD was 11.0 ± 3.1 ms but dispersion of repolarization time (RT) was relatively homogeneous (8.2 ± 2.7, p < 0.0001). However, in pig no such difference was observed between the dispersion of APD and RT (17.8 ± 6.1 vs. 17.7 ± 6.5, respectively). Localized elevations of APD (12.9 ± 8.3%) were identified at ventricular insertion sites of rat hearts both in experiments and simulations. Tissue geometry and action potential (AP) morphology contributed significantly to determining influence of electrotonic modulation. Simulations of a rat AP in a pig geometry decreased the slope of AT and APD relationships by 70.6% whereas slopes were increased by 75.0% when implementing a pig AP in a rat geometry. A modified pig AP, shortened to match the rat APD, showed little coupling between AT and APD with greatly reduced slope compared to the rat AP. Electrotonic modulation of repolarization by the activation sequence is especially pronounced in small hearts with murine-like APs. Tissue architecture and AP morphology play an important role in electrotonic modulation of repolarization.

Yes / There is limited information regarding the views of patients, as healthcare consumers, on visual field testing, and no information regarding their preferences for future test developments. This study aimed to increase knowledge of patients' subjective experience of visual field assessment and to explore their opinions and priorities regarding current active areas of research and development. Online questionnaire with purposive sampling design. Adults who regularly perform visual field tests in Australia who report having glaucoma or being at risk of glaucoma. An anonymous survey, implemented using the Qualtrics webtool, with both closed and open ended questions designed to explore opinions regarding visual field testing, visit attendance for perimetry, as well as priorities for developments. The survey assessed three domains: 1) opinions regarding visual field test duration and visit frequency; 2) subjective experience; and 3) perspectives on future developments for perimetry. 152 complete survey responses were obtained. The median (IQR) age of participants was 66 (60-72) years. Most participants (70%) had experience of performing more than 11 visual field tests. Participants recalled that they completed visual field tests in median of 6 minutes (IQR: 5-8 minutes) and were willing to accept additional time (median: 5, IQR: 3-6 minutes) to obtain more information. Participants were prepared to increase both the number of visual field tests per eye and the frequency of visual field tests (median: 3, IQR: 2-4 visits per year), in order to gain more information about their visual status. Regarding future developments, the most preferred option was "similar test times but an increase in the level of information about my visual field", which ranked significantly higher than all other options including "shorter test times that maintain the currently available level of information about my visual field." Our study confirms, in a different population and healthcare system, previous research reporting patient perspectives on visual field assessment. We further reveal that healthcare consumers show a strong preference for accurate information about their vision and report being prepared to undergo longer visual field tests or more visual field tests to achieve that outcome.

Yes / Evidence has shown that older adults have lower accuracy in Theory-of-Mind (ToM) tasks compared to young adults, but we are still unclear whether the difficulty in decoding mental states in older adults stems from not looking at the critical areas, and more so from the ageing Asian population. Most ToM studies use static images or short vignettes to measure ToM but these stimuli are dissimilar to everyday social interactions. We investigated this question using a dynamic task that measured both accuracy and error types, and examined the links between accuracy and error types to eye gaze fixation at critical areas (e.g. eyes, mouth, body). A total of 82 participants (38 older, 44 young adults) completed the Movie for the Assessment of Social Cognition task on the eye tracker. Results showed that older adults had a lower overall accuracy with more errors in the ipo-ToM (under-mentalising) and no-ToM (lack of mentalisation) conditions compared to young adults. We analysed the eye gaze data using principal components analysis and found that increasing age and looking less at the face were related to lower MASC accuracy in our participants. Our findings suggest that ageing deficits in ToM are linked to a visual attention deficit specific to the perception of socially relevant nonverbal cues. / This study was funded by the Ministry of Higher Education Malaysia (FRGS/1/2016/SS05/SYUC/03/2) awarded to M.H.Y.

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