The Left Atrial Appendage, once thought to be "a relatively insignificant portion of cardiac anatomy," has currently been realized to possess "important pathological associations [1a]" particularly in its role in promoting serious, frequent thromboembolic events common in individuals suffering from Atrial Fibrillation. Prior approaches to mitigating these events have either required invasive procedures, proved less than fully effective, or presented with problematic sequelae of their own. This work will present a new procedure that addresses both the prevention of the thromboembolic events and the correction of the shortcomings of the major prior methods utilized. A compliant hydrogel that can conform to the geometry of the appendage is proposed as a more effective method of occluding the chamber. This material would be transported to the LAA in liquid form via a multi-lumen catheter, and then solidify within the chamber to form a solid plug. Previous research has identified a candidate hydrogel, comprised of PEG-tetra-thiol and Dextran vinyl sulfone as a candidate hydrogel for this application. Experimental work has investigated fluid properties of the material, as well as degradation and swelling properties of the material. Results from this experimentation were used for fluid transport analysis, and for evaluation of anchoring force of the hydrogel within the chamber. Finally, subfunctions of the occlusion procedure were modeled and tested. During the actual procedure, a catheter balloon will isolate the appendage from the rest of the heart. A model was developed to study interactions between the appendage and this balloon. Additionally, due to fast solidification time, hydrogel components in the surgical procedure will be mixed in a mixing chamber at the tip of the catheter. Potential mixing chamber designs were modeled, and a ternary diffusion model was developed to better understand hydrogel mixing. Prototypes for both these subfunctions were built and tested as well. Additional analysis looked at the overall occlusion procedure, and how various subfunctions interacted with each other. / text

The chelicerates (e.g., spiders, mites, scorpions, harvestmen and horseshoe crabs) are oneof the oldest arthropod clades, arising in the Cambrian. The chelicerates display a conserved body plan comprising of an anterior prosoma and a posterior opisthosoma. The prosoma comprises the segments bearing the chelicerae, pedipalps and the four pairs of walking legs. The opisthosoma is more variable, and either contains no appendages (e.g., in harvestmen), or extremely derived appendages (e.g., the spinnerets of spiders and the pectines of scorpions). Recent evolutionary developmental (evo devo) studies on arachnids and other arthropods have shown that a conserved suite of developmental genes pattern the chelicerate body plan, with slight modifications in their expression patterns correlating with morphological diversification and evolution of segments and the appendages that they bear. Although a few tractable evo devo chelicerate models are currently in use, there is a noted paucity of evo devo studies on mites, let alone embryological studies on mites using modern microscopic techniques. The following dissertation aimed at filling the gap in the current knowledge of mite evolution and development by studying the development of the emerging mite model mite Archegozetes longisetosus. Four main aims that focused on answering questions surrounding mite and chelicerate evolution were the subjects of the dissertation research. These aims included a.) determining the segmental composition of the mite opisthosoma, b.) determining how the segment of the suppressed fourth pair of walking legs is formed during embryogenesis, c.) determining how can the appendage-patterning genes, i.e., the "limb gap genes," aide in elucidating arthropod phylogeny and d.) determining how the evolutionarily conserved Hox genes pattern the reduced mite opisthosoma. The findings from this project include that the acariform mite opisthosoma has been reduced to two terminal segments, that the formation of the segments bearing the fourth pair of walking legs is tied to opisthosomal segmentation in A. longisetosus, that mites retain chelicerae comprised of three segments, that only the proximal elements of the fourth pair of walking legs are patterned during development in A. longisetosus, and that the mite homologues of the Hox genes Ultrabithorax and Abdominal-B are only expressed in a single segment in the opisthosoma in A. longisetosus. These findings are placed within a comparative framework to aid in the understanding of the evolution of arthropod and chelicerate body plans.

Atrial fibrillation (AFIB) is the most common heart rhythm abnormality and is associated with significant morbidity and mortality. While the treatment of AFIB involves strategies of rate with or without rhythm control, it is also essential to strategize appropriate therapies to prevent thromboembolic complications arising from AFIB. Previously, anticoagulation was the main treatment option which exposed patients to higher than usual risk of bleeding. However, with the advent of new technology, novel therapeutic options aimed at surgical or percutaneous exclusion or occlusion of the left atrial appendage in preventing thromboembolic complications from AFIB have evolved. This review evaluates recent advances and therapeutic options in treating AFIB with a special focus on both surgical and percutaneous interventions which can reduce and/or eliminate thromboembolic complications of AFIB.

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<p>Regeneration is a remarkable feat of developmental regrowth and patterning. The blastema is a mass of progenitor cells that enables complete regeneration of amputated salamander limbs or fish fins. Despite years of study, methodologies to identify and track blastemal cell progenies have been deficient, restricting our understanding of appendage regeneration at a cellular and molecular level. To bridge this knowledge gap, gene expression analysis, the generation of transgenic and mutant zebrafish, qualitative and quantitative analyses, morphological measurements, and chemical treatments were used to assess molecular and cellular processes involved in fin regeneration. Two main findings arose from these methods. The first provides evidence that connective tissue progenitors are rapidly organized into a scalable blueprint of lost structures, and that amputation stimulates resident cells to reset proximodistal positional information. The second identifies a fibroblast subpopulation near uninjured fin joints that contributes to the blastemal progenitor population. These findings reveal insights on cellular and molecular mechanisms of appendage regeneration and provide a basis for work exploring how cells in an adult vertebrate bone appendage coordinately rebuild a new structure.</p> / Dissertation

Understanding the hemodynamics of the cardiovascular system and associated diseases is important for mitigating health risks. We applied flow diagnostic techniques to investigate pulsatile flow characteristics past sidewall cavities, which have implications to two biomedical problems in the cardiovascular system: sidewall aneurysms and the left atrial appendage. Superhydrophobically-coated mesh diverters and synthetic slippery surfaces were studied for their effects on flow diversion and cavity flow enhancements. The study of pulsatile flow over a coated mesh diverter showed that the formation of the primary vortex was prevented which prevents flow stagnation and downwash flow in the cavity. The second study indicates that the healthy heart cycle is essential to reducing flow stasis inside the left atrial appendage. After applying a synthetic slippery surface to the interior of a side wall cavity model, this surface reduced the wall shear stress and allowed vortical flow to reach deeper into the cavity.

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<p>Stroke is a devastating event for a patient. Patients undergoing cardiac surgery are at risk of both peri-operative and delayed stroke. This thesis comprises 8 chapters that highlight the rate of stroke in cardiac surgery patients and its risk predictors. It justifies the need for a randomized controlled trial of left atrial appendage (LAA) occlusion on top of usual antithrombotic therapy for stoke prevention in patients with atrial fibrillation or flutter.</p> <p>Chapter 1 is a preface that provides the rationale for undertaking each of the studies included within this thesis.</p> <p>Chapter 2 presents a large cohort study that examines the predictors of early and long-term stroke in patients undergoing cardiac surgery with emphasis on the impact of atrial fibrillation as well as the CHADS₂ score.</p> <p>Chapter 3 has been published in the journal <em>Circulation </em>in a modified form. A review of the current literature is presented, highlighting that although LAA occlusion holds promise for stroke prevention in AF, there is currently insufficient evidence that it can replace the gold standard of oral anticoagulation.</p> <p>Chapter 4 is a long-term follow-up study of the first Left Atrial Appendage Occlusion Study. This trial included patients undergoing coronary artery bypass grafting with or without AF. By performing a long-term follow-up of these patients, an estimate of stroke risk and risk of developing new AF was obtained.</p> <p>In Chapter 5, the results of LAAOS II are presented. This registry and pilot trial was used to assess the rate of recruitment into a novel design of a trial comparing LAA occlusion to antithrombotic therapy, LAA amputation safety, and the rate of a composite outcome of death, myocardial infarction, stroke, non-cerebral systemic emboli, and major bleeding.</p> <p>Chapter 6 presents the design for the LAAOS III trial. The data presented in the previous chapters is used to create the definitive trial of LAA occlusion on top of usual antithrombotic therapy using a prospective, randomized open trial with blinded end-point study (i.e., PROBE) design.</p> <p>Chapter 7 presents the health economic analysis plan for LAAOS III.</p> <p>Finally, Chapter 8 presents the conclusion, limitations, and implications of the research presented in my PhD thesis</p> / Doctor of Philosophy (PhD)