Weaving is defined as the crossing of two or more traffic streams traveling in the same direction along a significant length of the highway without the aid of traffic control devices. The traditional methods used for the design and operational analysis of a highway is the Highway Capacity Manual (HCM). These traditional methods in the manual use road geometry and traffic volumes as input and provide an estimate of the speed as an output. TRANSIMS is a new computer simulation package in transportation that can be used as an analysis as well as a planning tool. The Microsimulator in TRANSIMS deals with the actual simulation of traffic on roadways. The intent of this research is to evaluate TRANSIMS Microsimulator and compare it with the traditional Highway Capacity Manual in modeling the weaving sections on a freeway and make recommendations. This research will also compare the modeling strategy and provide analysis of the output. / Master of Science

Inherited cardiomyopathies are a set of pathological conditions that impact the structure and function of the heart. There are over 1,000 cardiomyopathy-causing mutations in genes encoding structural proteins in heart muscle cells, known as cardiomyocytes. The advents of human induced pluripotent stem cells (hiPSCs) and CRISPR/Cas9 technologies have opened a viable path for creating in vitro models to investigate therapeutic strategies for cardiac pathologies. However, hiPSC-derived cardiomyocytes (hiPSC-CMs) remain immature, limiting their capabilities to fully recapitulate disease phenotypes. Here, we report the variability in hiPSC-CM studies and discuss paths toward unification in hiPSC-CM model development, maturation, and assessment that we believe will drive progress in engineering mature cardiac tissue. We then utilized some of these models to investigate phenotypes of hypertrophic cardiomyopathy (HCM), showing that a beta-myosin heavy chain (MYH7) mutation leads to increased cell size, sarcomere content, contractility, mitochondria expression, and paracrine signaling of cardiomyocytes. While effects of HCM-causing mutations on cardiomyocyte function have been well-studied, it remains unclear how these mutations lead to a common HCM phenotype, fibrosis. Here, we used engineered cardiac microtissues (CMTs) comprised of MYH7-variant hiPSC-CMs and wild-type stromal cells, to dissect the multi-cellular interactions responsible for fibrosis. HCM-variant CMTs exhibited increased collagen deposition and tissue stiffening, resulting in a decrease in tissue contractility dependent on stromal cell proliferation. We show that this activation is paracrine driven through EGFR signaling and that EGF has synergistic effects with a well-known fibrosis mediator, TGF-β. Overall, our studies present a better understanding of how HCM-causing mutations impact cardiomyocyte function and how these changes impact stromal cell response leading to further disease progression. / 2025-08-31T00:00:00Z

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Abstrakt Hypertrophe Kardiomyopathie (HCM) ist eine genetisch bedingte Herzmuskelerkrankung mit einer Prävalenz von 0,2 bis 0,6% und einem SCD-Risiko von 0,5 bis 1% pro Jahr. HCM ist die häufigste Ursache für plötzlichen Herztod in jungem Alter. Seit Jahrzehnten wird bei HCM der optimale Vorhersagescore für SCD untersucht. Der erste validierte SCD-Sore bei HCM wurde im Jahr 2014 in die ESC-Leitlinien integriert. Ziel der Studie: Vergleich des berechneten SCD-Scores bei HCM aus dem Jahr 2014 vor und nach Alkohol- Septum-Ablation (PTSMA) mit dem erreichten Endpunkt (SCD). Methoden: 56 Patienten mit hypertropher obstruktiver Kardiomyopathie (HOCM) und Erst-PTSMA im Jahr 2009 wurden eingeschlossen: Alter 53,9 ± 11,5 Jahre, 7% positive Familienanamnese für SCD, 9% ungeklärte Synkope im letzten Jahr, 43% NSVT, maximale LV-Wanddicke 20,2 ± 4,3 mm, maximaler LVOT-Gradient 118 ± 42 mmHg, LA-Durchmesser 45,3 ± 6,4 mm. Ergebnisse: Vor dem ersten PTSMA hatten die HOCM-Patienten einen errechneten SCD-Wert von 4,2 ± 3,2%, nach PTSMA von 3,2 ± 2,2%. Wir beobachteten 2 (3,6%) SCD-Fälle in 5 Jahren. Die PTSMA führte zu einer signifikanten Reduktion des errechneten SCD-Scores von 1,0 ± 2,8%, p <0,05. Diese Reduktion war hauptsächlich durch die signifikante Reduktion des LVOT-Gradienten (durchschnittlich 54 ± 42 mmHg, p <0,05) zurückzuführen. Fazit: PTSMA ist eine etablierte Behandlung zur Verbesserung der Symptome bei HOCM-Patienten ohne Hinweis auf eine höhere Mortalität nach induziertem Infarkt. Der ESC-SCD-Score ist nur ein Hilfsalgorithmus für die individuelle Entscheidung bezüglich einer primärprophylaktischen AICD-Implantation. / Abstract Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease with a prevalence of 0.2-0.6% and an SCD risk of 0.5-1% per year. HCM is the leading cause of sudden cardiac death at a young age. For decades, the optimal prediction score for SCD has been investigated in HCM. The first validated score for SCD at HCM has been integrated into the ESC guidelines since 2014. Objective of the study: Comparison of the calculated SCD score for HCM from 2014 before and after alcohol septal ablation (PTSMA) with the endpoint reached (SCD). Methods: 56 patients with hypertrophic obstructive cardiomyopathy (HOCM) and first PTSMA in 2009 were included: age 53.9 ± 11.5 years, 7% positive family history for SCD, 9% unexplained syncope last year, 43% NSVTs, maximum LV wall thickness 20.2 ± 4.3 mm, maximal LVOT gradient 118 ± 42 mmHg, LA diameter 45.3 ± 6.4 mm. Results: Before the first PTSMA, the HOCM patients had a calculated SCD score of 4.2 ± 3.2%, after PTSMA 3.2 ± 2.2%. We observed 2 (3.6%) SCD patients in 5 years. PTSMA resulted in a significant reduction in the calculated SCD score of 1.0 ± 2.8%, p <0.05. This reduction was mainly due to the significant reduction in the LVOT gradient to 54 ± 42 mmHg (p <0.05). Conclusion: PTSMA is an established treatment to improve symptoms in HOCM patients without evidence of higher mortality after induced infarction. The ESC-SCD score is only an aid algorithm for individual decision to implante an ICD for primary prevention of SCD.

Weaving is defined as the crossing of two or more traffic streams traveling in the same direction along a significant length of the highway without the aid of traffic control devices . The traditional methods used for design and operational analysis of a highway is the Highway Capacity Manual (HCM). The traditional weaving methods in the highway capacity manual use road geometry and traffic volume as inputs and provide an estimate of speed as an output. CORSIM is a new computer simulation model developed by Federal Highway Administration (FHWA) for simulation of traffic behavior on integrated urban transportation networks of freeway and surface streets. The intent of this research is to identify the difference in the results by using the new CORSIM simulation and the traditional HCM approach in modeling the weaving sections on a freeway and make recommendations. The research will also compare the modeling strategy and provide analysis of the output. / Master of Science

Longitudinale Untersuchungen der kardialen Morphologie von knockin-Mäusen mit humanen Myosinmutationen / Longitudinal analyses of cardiac morphology in knockin mice carrying human myosin mutations

Cardiac diseases associated with mutations in Tn subunits include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM). Altered calcium handling in these diseases is evidenced by changes in the Ca2+ sensitivity of contraction. Mutations were generated to increase/ decrease the Ca2+ sensitivity of skinned fibers, and create the classified effects of DCM, HCM and RCM. This study mimicked the changes in Ca2+ sensitivity and relaxation properties of the muscle to determine if this was sufficient to recreate the disease. Four mutants (A23Q, S37G, V44Q, L48Q) were identified with RCM-like properties; a large increase in Ca2+ sensitivity, increased basal force and loss of ATPase inhibition. Two mutations were identified (E40A, I61Q) with DCM properties; decreased Ca2+ sensitivity in skinned fibers, decreased force recovery (%), and decreased activation of the ATPase at high Ca2+ levels (pCa 6-4). Also, the functional effects of four newly identified cTnC mutations associated with HCM were reported. Three of these HCM mutations A8V, C84Y, and D145E displayed HCM characteristics, increased Ca2+ sensitivity in skinned fibers and ATPase and A8V and D145E increased the force recovery. Only, D145E significantly increased the ATPase activation of the reconstituted thin filament. Also, Ca2+ affinity measurements using IAANS fluorescence were performed. No significant changes were found for E134D. The C84Y IAANS fluorescence measurements revealed that cTnC Ca2+ affinity of the cTn complex was unaltered. The Ca2+ affinity increased for D145E in isolated cTnC and the cTn complex, however in the regulated thin filament (RTF) with myosin subfragment-1 (S1) and rigor crossbridges the Ca2+ affinity values were similar to the fiber Ca2+ sensitivity. For A8V, the RTF significantly increased the Ca2+ affinity, and addition of S1 and rigor crossbridges caused the values to parallel the Ca2+ sensitivity values. In conclusion, direct and indirect protein-protein interactions contribute to the enhanced Ca2+ sensitivity of the HCM mutants. The cTnC mutant screen allowed selection of mutations that mimic the disease states: S37G (RCM) and, E40A (DCM); A8V (HCM) from the patient study for analysis in knock-in mice for futures studies to determine if these disease states can be recapitulated in vivo.

Knowing the performance of intersections is of utmost importance to engineers today. It affects the development, advancement, and future economic growth status of the city or place in which the intersections are located. The performance level is inferred from the levels of service of the intersections and one common way to measure the levels of service is to estimate delays for those intersections. Therefore, the estimation of delays at intersections is a very recurrent study done by traffic engineers. Different methods of calculating delays exist. Those methods are not ideal for estimating delay for all cases. The call for better methods for estimating delays for all cases is the source of much research that led to the new method that is scheduled to be included in the Highway Capacity Manual 2010, called the Incremental Queue Accumulation (IQA) method. Since it is a new method, it needs to be studied further to assess its benefits and shortcomings. The purpose of this study is to evaluate the accuracy of the IQA method. The intersection of University Parkway and Main Street in Orem, Utah was selected as the study site. Delays were estimated for northbound and southbound approaches of that intersection using both the current methods of estimating delays in the Highway Capacity Manual 2000 (HCM 2000) and the IQA methods. For both methods, both field and model analyses were done. The data were obtained from the video recorded in the BYU Transportation Lab. The IQA analysis was done cycle by cycle for each lane, and then the weighted average was acquired to get the delay for the 15 minutes of the approach. On the other hand, the HCM 2000 analysis was performed directly for the 15 minutes of the lane group and the approach. The results were compared to determine the accuracy of the IQA method. The findings indicate that the IQA method is promising; however, the method may need to be improved for right turn movements where right turn on red is allowed. Moreover, the IQA method should be checked further to determine its sensitivity to the saturation flow rate and arrival type.

Traffic simulation is a powerful tool that provides transportation engineers with the ability to test the feasibility and performance of a system before it is implemented and also helps in optimizing the proposed system. Over the past twenty years significant amount of work has been conducted on improving the quality and accuracy of transportation simulation models. Much of this work has been concentrated on microscopic simulation models because they provide traffic engineers greater opportunity to examine the inherently complex, stochastic, and dynamic nature of transportation systems when compared to traditional macroscopic models. In order to test the performance of some of the simulation models, a study is conducted on freeway weaving sections, which are considered to be one of the most complex regions to be modeled and analyzed. The intent of the research is to evaluate TRANSIMS, CORSIM, VISSIM and INTEGRATION and compare them with Highway Capacity Manual, which adopts a traditional methodology for carrying out the operational analysis of a highway system. The statistics collected for the simulation runs include weaving speeds, non-weaving speeds and density of the weaving section. / Master of Science

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