528 research outputs found
Liam Rector, 14th Annual ODU Literary Festival
No full textLiam Rector is the author of The Sorrow of Architecture, a book of poems. He\u27s also the editor of The Day I Was Older: On the Poetry of Donald Hall. He has taught at Old Dominion University, George Mason, Goucher College, and Phillips Academy at Andover. In addition, he has administered literary programs at the Folger Academy of American Poets. Currently, Liam Rector is executive director of Associated Writing Programs, which has lately taken a leading role in defending the 1st amendment. Rector has been awarded both NEA and Guggenheim fellowships for poetry
Liam Rector, 12th Annual ODU Literary Festival
No full textLiam Rector is the author of a book of poetry, The Sorrow of Architecture, 1984, and editor of The Day I Was Older: On the Poetry of Donald Hall, 1989, and is currently working on a second book of poems, tentatively titled The Persistence of Virginia. He is executive director of the Associated Writing Programs, located at Old Dominion University
Plasma lipoproteins : genetic influences and relevance to atherosclerotic and infectious diseases
No full textPlasma lipoproteins, such as low-density lipoprotein (LDL), high-density lipoprotein (HDL), and lipoprotein(a) are highly heritable traits and important biomarkers for atherosclerotic cardiovascular disease (ASCVD). LDL and lipoprotein(a) are atherogenic plasma lipoproteins that are often both elevated among individuals with familial hypercholesterolemia; a common, autosomal co-dominant disorder characterized by pathogenic DNA variants in the LDLR, APOB, and PCSK9 genes. These pathogenic variants impair the removal of LDL from the blood and lead to severe hypercholesterolemia and increased risk of ASCVD. Despite the ability to identify individuals with a genetic cause for familial hypercholesterolemia or elevated lipoprotein(a), one of the most challenging aspects in the clinical management of this patient population is the remarkable diversity of ASCVD risk.
Alternatively, HDL has been thought to protect against atherosclerosis because low levels of HDL are strongly associated with increased risk of ASCVD. Several recent clinical trials have unsuccessfully attempted to raise HDL cholesterol to reduce the risk of ASCVD. These results have left unanswered questions about the primary function(s) of HDL. Plasma lipoproteins undergo extensive changes in structure, function, and metabolism during severe infections such as sepsis. However, the implications and causality of these changes to clinical outcomes is poorly understood.
The central objective was to explore the contribution of genetic variation in plasma lipoprotein traits and metabolism on lipid disorders such as familial hypercholesterolemia, elevated lipoprotein(a), and serious infections such as sepsis. Here, we used genetic epidemiology and mouse models of disease to assess how common and rare germline genetic variation affects the risk of atherosclerotic cardiovascular diseases and infectious diseases. Specifically, 1) can background genetic variation related to LDL and lipoprotein(a) modify the risk of ASCVD for individuals with familial hypercholesterolemia? and 2) are associations between HDL and risk of infectious disease causal?
Several broad conclusions can be made. First, background polygenic factors influencing LDL-C and lipoprotein(a) levels modify the penetrance and expressivity of familial hypercholesterolemia. Second, the primordial function of HDL may be related to immunoregulation and resolution of infection. Third, cholesteryl ester protein is an important regulator of HDL levels during sepsis and may be a therapeutic target.Medicine, Faculty ofMedicine, Department ofGraduat
Indigenous cardiovascular health : assessing disease, risk factors, and patient care
No full textBackground: Indigenous Peoples are extremely diverse and have unique cultural and social histories that have allowed them to remain resilient through decades of colonialism aimed to disrupt the health of their communities. Chronic diseases, including cancer, diabetes, and atherosclerotic cardiovascular disease (ASCVD) are leading causes of morbidity and mortality and disproportionately impacts Indigenous populations. In high income countries, such as Canada, Indigenous populations experience ASCVD rates 1.5 to 2.5 times higher than their non-Indigenous counterparts. There are several factors which contribute to this disproportionate burden of ASCVD, including systematic racism and discrimination in healthcare, however, social determinants of health, such as these, are often overlooked when designing and implementing healthcare strategies in the current western-based medical system.
Methods: To generate background knowledge, we conducted a comprehensive narrative review examining existing studies and grey literature on the prevalence of ASCVD in Indigenous populations in Canada and discuss recommendations for future addressment strategies (Chapter 1). To understand major risk factors for ASCVD, we conducted a systematic review and meta-analysis estimating the prevalence of hypercholesterolemia in Indigenous populations (Chapter 2). Addressing the need to understand how Indigenous patients view equitable cardiovascular care, we conducted a prospective observational study assessing the cardiovascular care of Indigenous patients with premature ASCVD (Chapter 3).
Results: Our findings reveal significantly higher rates of ASCVD in Indigenous populations compared to non-Indigenous populations. While hypercholesterolemia and familial hypercholesterolemia, significant risk factors for ASCVD, were found to be inadequately studied in Indigenous populations, we estimated the pooled-prevalence of hypercholesterolemia to be 28.9%, demonstrating it is extremely common in Indigenous populations. To address ASCVD, Indigenous populations should be provided access to evidence-based cardiovascular care which we found increases medication uptake and significantly improves lipid profiles, decreasing risk of recurrent cardiovascular events for Indigenous patients.
Conclusion: Indigenous populations are significantly impacted by ASCVD and major risk factors, including hypercholesterolemia. We recommend the establishment of collaborative alliances with Indigenous communities to augment the accessibility of screening and testing services, thereby enhancing Indigenous Peoples' awareness of ASCVD, and major associated risk factors, and affording them the autonomy to participate in screening initiatives at their discretion.Medicine, Faculty ofMedicine, Department ofGraduat
Premature atherosclerotic cardiovascular disease : challenges in risk assessment and prevention
No full textAtherosclerotic cardiovascular disease (ASCVD), the leading cause of death globally, is largely preventable through the implementation of a healthy lifestyle or effective and safe treatments. The global effort to improve screening and prevention has led to a decrease in the overall incidence of ASCVD and its major component, coronary artery disease (CAD). However, rates of premature ASCVD have remained stagnant or even rising. There are different reasons hypothesized to contribute to this lack of improvement amongst younger people, including rise in the prevalence of cardiovascular risk factors, challenges in risk assessments, and younger patients being less likely to seek medical attention or participate in population-based prevention programs.
The objectives of this work were to evaluate trends in cardiovascular health, barriers to the prevention of premature CAD, and a possible solution in the form of a family-based screening program. We used an observational cohort study design to analyze data collected in a) a prospective observational study of patients with premature CAD and their first-degree relatives (FDRs) and b) pan-provincial administrative data databases to investigate several questions essential for guiding preventive efforts.
From this work several conclusions can be made. First, despite the high and further increasing burden of cardiovascular risk factors, very few patients with premature CAD received lipid lowering therapy (LLT) before presentation. Despite the nearly universal eligibility for lipid screening and frequent interactions with healthcare, half of these patients were not eligible for preventive LLT due to low or moderate calculated cardiovascular risk. Females, smokers, and rural residents were less likely to receive LLT and novel risk enhancers did not affect the likelihood of LLT initiation. Adherence to LLT was low in primary and secondary preventive settings leading to non-achievement of treatment targets. Finally, a screening program that includes clinical assessment and cardiovascular imaging of FDRs has a high diagnostic yield and impacts patient management.
In summary, rates of premature cardiovascular disease are static, are associated with cardiovascular risk factors, and have a large familial component which can be addressed by screening first degree relatives of patients but adherence to therapy remains a challenge.Medicine, Faculty ofMedicine, Department ofGraduat
Prediction and mechanisms of doxorubicin-induced cardiotoxicity : role of RARG and cardioprotective effects of SGLT2 inhibitor
No full textDoxorubicin is a commonly used chemotherapy drug that treats both adult and childhood cancers, but its clinical usefulness is limited by doxorubicin-induced cardiotoxicity (DIC). The incidence of DIC increases up to 65% at cumulative doses of 550 mg/m², which leads to irreversible heart failure and death. Since some patients suffer from DIC even at low doses, genetic differences may account for some of the inter-individual variability in risk for DIC and several associated genetic variants have been identified. Among these variants, RARG-S427L is one of the top variants that shows strong evidence of association with DIC. Sodium-glucose transport protein 2 inhibitors (SGLT2i) are effective glucose-lowering medications that are indicated for type 2 diabetes mellitus treatment. SGLT2i have also been demonstrated to be cardioprotective for heart failure. We still lack ways to predict and prevent DIC. The goal of this dissertation is to investigate the impacts and mechanism of RARG-S427L variant in DIC and the potential cardioprotective effects of SGLT2i against DIC. I hypothesized that RARG-S427L increases the risk of DIC and the SGLT2i (empagliflozin) protects against DIC. To conduct this work, I developed a patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) model of DIC and used this to show that RARG-S427L increases susceptibility to DIC by orchestrating a DNA repair response to doxorubicin. Furthermore, co-treatment with empagliflozin reduced doxorubicin-induced cell death and up-regulated fatty acid metabolism-related gene expression. In summary, our findings reveal the roles of RARG-S427L in transcriptional response to doxorubicin in cardiomyocytes and identify empagliflozin as a potential cardioprotective agent against DIC, with implications for personalized risk prediction and the potential usage of empagliflozin to prevent this adverse drug reaction.Medicine, Faculty ofMedicine, Department ofGraduat
Modelling adverse drug reactions using induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs)
No full textAdverse drug reactions (ADRs) constitute the fourth leading cause of death and their incidence is steadily increasing. Cardiovascular toxicity is one of the most common and serious ADR and is the leading cause of drug discontinuation. The overarching goal of this thesis is to investigate cardiac ADRs using human pluripotent stem cell derived cardiomyocytes (hPSC-CMs). Doxorubicin is a chemotherapy drug administered to adult and pediatric patients for the treatment of hematological and solid tumors, however, it can cause doxorubicin induced cardiotoxicity (DIC). We generated induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from patients who received doxorubicin as part of their chemotherapy regimen. iPSC-CMs from individuals who developed DIC displayed significantly greater sensitivity to doxorubicin compared to iPSC-CMs from patients who did not experience DIC. Several variants associated with DIC have been identified, with RARG –S427L having the strongest genetic evidence. iPSC-CMs together with genome editing, provide a powerful platform to establish causal relationships between genetic variants and ADRs. We used CRISPR/Cas9 to investigate the functional impact of RARG-S427L on DIC in isogenic patient derived iPSC-CMs that differed only at the RARG locus. Genetic correction of RARG-S427L decreased susceptibility to in vitro DIC, whereas introduction of RARG-S427L had the opposite effect. We also used this platform to identify novel cardioprotectants that can be used clinically to prevent DIC. Empagliflozin, a sodium-glucose co-transporter 2 inhibitor, is an FDA-approved medication for the treatment of diabetes that shows cardiovascular benefits. iPSC-CMs treated with empagliflozin exhibited reduced doxorubicin induced cell death. Finally, we showed that enriched cardiomyocyte subtype populations are necessary for accurate drug screening and disease modelling. Ibrutinib is an anticancer drug indicated for the treatment of B cell malignancies; however, it can cause atrial fibrillation. We used atrial and ventricular hPSC-CMs to study ibrutinib induced atrial fibrillation. Ibrutinib had an arrhythmogenic impact on hPSC atrial derived cardiomyocytes, while ventricular hPSC remained unaffected. Collectively, our findings demonstrate that hPSC-CMs represent a powerful platform for disease modelling and drug screening that is amenable to personalized risk prediction for the prevention of adverse drug reactions.Medicine, Faculty ofMedicine, Department ofGraduat
Connecting the clinic to the bench : modelling the functional effects of a titin variant associated with atrial and ventricular arrhythmias
No full textAtrial fibrillation (AF) is a common arrhythmia linked to increased risk of stroke, heart failure, and death. In AF patients without known clinical risk factors, genetic factors are likely contributors to disease pathogenesis. Studies into the genetic risk factors of AF showed a strong association between truncating variants in the titin gene and increased risk of AF in structurally normal hearts. Titin truncating variants (TTNtv) are a well-established cause of dilated cardiomyopathy (DCM), and recent studies have also shown an increased risk of atrial and ventricular fibrillation (VF) in DCM patients with TTNtv. The effect of TTNtv on risk of AF compared to modifiable risk factors is unclear. Furthermore, the cellular effects of TTNtv in atrial and ventricular arrhythmias without dilated cardiomyopathy is unknown. The objectives of this dissertation were 1) to evaluate the association between titin variants and increased risk of AF compared to modifiable risk factors and 2) to examine the cellular effects of TTNtv identified in atrial and ventricular fibrillation patients without structural disease. We used genetic epidemiology approaches and data from UK Biobank to assess the risk of AF in titin variant carriers, and we used patient-specific induced pluripotent stem cell-derived atrial- and ventricular-like cardiomyocytes and engineered heart tissue constructs to model a TTNtv implicated in AF and VF. We demonstrated an additive effect between titin variant status and modifiable risk factors on the risk of AF. In the AF model, the TTNtv led to sarcomere disarray, reduced contractility, increased arrhythmogenicity, and transcriptional changes implicating substrate alterations. In the VF model, the TTNtv resulted in calcium transient shortening and impaired electrophysiological response to β-adrenergic stimulation. These findings highlight the utility of genetic testing to identify TTNtv carriers who are at increased risk of developing AF and the importance of clinical risk factor management to reduce AF risk. Furthermore, we provide evidence of functional abnormalities associated with TTNtv in vitro that implicate atrial myopathic remodelling as well as altered electrophysiology and β-adrenergic response in patient-specific models of AF and VF, respectively, that deepen our understanding of titin’s role in the pathogenesis of atrial and ventricular arrhythmias.Medicine, Faculty ofMedicine, Department ofGraduat
Project Triton : A study into delivering targeted information to an individual based on implicit and explicit data.
No full textThe World Wide Web is frequently seen as a source of knowledge, however much of this remains undiscovered by its users. In recent times, recommender systems (e.g. Digg and Last.fm) have attempted to bridge this gap, alerting users to previously untapped knowledge. As more socially oriented services appear on the Web (e.g. Facebook and MySpace), it has never been easier to obtain information pertaining to an individual’s interests. At present, solutions for automated data recommendation tend to be highly topic specific (recommending only a certain topic such as news) and often only allow access to the system using monolithic interfaces. This report hopes to detail the stages from research to evaluation involved in creating an extensible framework, which will operate without the need for human intervention. The framework will feature several proof-of-concept plugins residing in a custom workflow, which target information that is useful to the user. Information will be retrieved automatically through plugins involved with data gathering (such as feed processing and page scraping), while users’ interests will be obtained implicitly (for example, using header information to derive location) or explicitly (taking advantage of Social Network APIs such as Facebook Connect). Finally, Third Parties will be able to integrate the framework into their own solutions using the customisable XML API (written in PHP), so that their products can provide custom user interfaces without style constraints
Design, fabrication and molecular modeling of protein subunits for use in a novel hydrogel:
No full textUse of bioinspired, genetically engineered proteins in tissue engineering scaffolds represents a new opportunity for engineering these constructs. However, the production and rational modification of new, artificial proteins is hindered by significant gaps in knowledge regarding expression of artificial gene constructs in E. coli and their molecular modeling. This thesis focuses on the production of a novel hydrogel scaffold composed of four self-assembling protein modules and their rational modification using Molecular Dynamics (MD) simulations. Two of the modules are based on the ABA triblock copolymer design. In this triblock, a hydrophilic, random coiled region is flanked by 28 amino-acid α−helical endblocks. The purpose of these endblocks is to function as virtual crosslinkers and support network formation. The length of the endblocks can be changed by the addition of two unlinked, fiber-forming peptides and thus potentially alter the gelation and melting points of the hydrogel. We evaluate the efficacy of production of these endblocks by two separate expression strategies in E. coli and demonstrate their ability to form hydrogels. Furthermore, we analyze the Gibbs free energy of formation of oligomeric intermediates that arise early on during fibrillogenesis from the unlinked peptides using the MM/PBSA module of Amber 9. Thermodynamic data demonstrates changes in the primary structure of these peptides affect the stability of the intermediate that seeds fiber formation. This analysis also suggests a shift in the fiber forming mechanism from monomer addition to protofibril addition. We offer how this data can be used to improve interhelical interactions between endblocks and unlinked peptides and how to develop coarse-grain models of fiber formation.Ph.D.Includes bibliographical referencesby Christopher Liam Gaugha
- …
