Medicine and Health Sciences Commons^™

Frailty In Patients Undergoing Left Ventricular Assist Device Implantation, Candice Falls

Theses and Dissertations--Nursing

Heart failure is a progressive condition that affects over 5.7 million Americans and costs associated with heart failure account for 2-3 % of the national health care budget. The high rates of morbidity and mortality along with increased costs from readmissions associated with advanced heart failure have led to the exploration of advanced treatments such as left ventricular assist devices (LVADs). LVADS have demonstrated morbidity and mortality benefit but cost remains extensive with costs per quality-adjusted years > $400,000. With this in mind, it is important to identify those who are most likely to benefit from an LVAD to avoid unfavorable …

Caregivers’ Influence On Patients’ Heart Failure Self-Care, Hospital Readmission And Mortality, Linda Clements

Theses and Dissertations--Nursing

Background: Heart failure (HF) is a leading cause of hospitalization, readmissions, and death in the United States. Patients hospitalized for HF are at risk for readmission, in- hospital mortality, and early post-discharge death. In the United States, inpatient care has been estimated to cost $83,980 over the lifetime of each patient with HF. The majority of patients with HF depend on caregiver support for successful HF self-care, which is essential for optimal patient outcomes. Support from caregivers is thought to be important for better self-care, and lower readmission and mortality rates. Yet, there are few studies considering the influence of …

The Impact Of Maternal Nutrition During Pregnancy On Inflammation And Birth Outcomes, Lori Ogden

Theses and Dissertations--Nursing

More than 85% of American adults do not consume recommended amounts of fruits or vegetables. Preterm birth and hypertensive disorders of pregnancy are common adverse conditions affecting pregnancy and are leading causes of maternal and fetal morbidity and mortality. Preterm birth affects nearly 10% of all births in the United States and is on the rise, as are hypertensive disorders, which have increased by 25% over the last two decades. Pregnancy is a state of controlled inflammation, and dysregulation has been linked to preterm birth and other adverse gestational outcomes. A healthy diet is recommended in pregnancy, but little is …

Gay Men And Satisfaction With Health Care Interactions, Michael Huggins

Theses and Dissertations--Nursing

The purpose of this research was to determine relationships among depression, anxiety, self-rated physical and mental health, self-advocacy, internalized homophobia, and quality of patient-provider communication to satisfaction with health care interactions. These were measured while controlling for select demographic variables: age; ethnicity; urban or rural domicile; relationship status; household income; highest educational attainment; health insurance; disclosure to health care provider as a gay man; reason for last healthcare visit; and, general health self-rating. The specific aims of this study were to: 1) identify general characteristics of gay men in this sample; 2) examine how levels of satisfaction with health care …

Barriers And Facilitors Of Healthcare Use Among People Who Inject Drugs, C. Brooke Kuns-Adkins

Theses and Dissertations--Nursing

Hepatitis C Virus (HCV) is an infection that can have grave consequences when left untreated. Hepatitis C can be easily eradicated with direct acting antiviral therapy. People who inject drugs (PWID) and inmates are among those with the highest incidence of HCV. However, cure rates among this population remains low. This is, in part, related to an interruption in the HCV care cascade such that only 30% of PWID are linked to care and only 8% of those receive treatment. Inadequate screening and failure to be linked to HCV care remain the largest impediments to treatment success. There is limited …

Actinomycin Familial Diversity Driven By Phenoxazinone-Core Reactivity, Matthew Richard Mcerlean

Theses and Dissertations--Pharmacy

Actinomycins are a class of compounds consisting of phenoxazinone-like core attached to two peptidolactone rings, denoted as α and β. A unique component of a few families—actinomycins G, Y, and Z—is a chlorinated β-ring threonine residue. Families G and Y also contained an actinomycin that possess a β-ring heterocycle (actinomycins G₅ and Y₅, respectively); prior to this work, no β-ring heterocycle-containing actinomycins were reported for the Z family. Unlike other actinomycin derivatives, Y₅’s cytotoxicity was abolished while still maintaining some antibacterial potency.

We constructed a model compound to probe the physical properties of the actinomycin …

Developing A Workflow To Evaluate Medications For Repurposing Using Health Claims Data: Application To Substance Use Disorders, Emily Ruth Hankosky

Theses and Dissertations--Pharmacy

Healthcare big data are a growing source of real-world data with which to identify and validate medications with repurposing potential. Previously, we developed a claims-based workflow to evaluate medications with potential to treat stimulant use disorders. In order to test the workflow, the framework was applied in the context of opioid use disorders (OUDs), for which there are medications with known efficacy. Using the Truven Marketscan Commercial Claims Database, a nested case-control analysis was conducted to determine the association between OUD medications (buprenorphine, naltrexone) and remission. Cases were defined as enrollees with a remission diagnosis and matched (1:4) to controls …

Phase Behavior Of Amorphous Solid Dispersions: Miscibility And Molecular Interactions, Kanika Sarpal

Theses and Dissertations--Pharmacy

Over the past few decades, amorphous solid dispersions (ASDs) have been of great interest to pharmaceutical scientists to address bioavailability issues associated with poorly water-soluble drugs. ASDs consist of an active pharmaceutical ingredient (API) that is typically dispersed in an inert polymeric matrix. Despite promising advantages, a major concern that has resulted in limited marketed formulations is the physical instability of these complex formulations. Physical instability is often manifested as phase heterogeneity, where the drug and carrier migrate and generate distinct phases, which can be a prelude to recrystallization. One important factor that dictates the physical stability of ASDs is …

The Development Of Novel Proteasome Inhibitors For The Treatment Of Multiple Myeloma And Alzheimer’S Disease, Min Jae Lee

Theses and Dissertations--Pharmacy

Over a decade, proteasome inhibitors (PIs), bortezomib, carfilzomib (Cfz) and ixazomib, have contributed to a significant improvement in the overall survival for multiple myeloma (MM) patients. However, the response rate of PI was fairly low, leaving a huge gap in MM patient care. Given this, mechanistic understanding of PI resistance is crucial towards developing new therapeutic strategies for refractory/relapsed MM patients.

In this dissertation work, we found H727 human bronchial carcinoid cells are inherently resistant to Cfz, yet susceptible to other PIs and inhibitors targeting upstream components of the ubiquitin-proteasome system (UPS). It indicated H727 cells may serve as a …

Carbapenem-Resistant Enterobacteriaceae: Epidemiology, Genetics, In Vitro Activity, And Pharmacodynamic Modeling, Brandon Kulengowski

Theses and Dissertations--Pharmacy

Background: Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) such as Escherichia coli and Klebsiella pneumoniae are among the most urgent threats of the infectious disease realm. The incidence of these infections has been increasing over the years and due to very limited treatment options, mortality is estimated at about 50%. By 2050, mortality from antimicrobial resistant infections is expected to surpass cancer at 10 million deaths annually.

Methods: We evaluated 18 contemporary antimicrobials against 122 carbapenem-resistant Enterobacteriaceae using a variety of antimicrobial susceptibility testing methods according to Clinical Laboratory Standards Institute guidelines. Time-kill studies were performed on clinical isolates with variable …

Therapeutic Video Games And The Simulation Of Executive Function Deficits In Adhd, Markus Tiitto

Theses and Dissertations--Pharmacy

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by difficulty paying attention, impulsivity, and hyperactivity. Diagnosis of ADHD rose 42% from 2003–2004 to 2011–2012. In 2011, 3.5 million children were treated with drugs. Optimizing therapy can take a year, and may not be completely effective.

A clinical trial is currently being conducted of a device/drug combination using the computer game Minecraft, to determine how certain activities affect executive function, working memory, and restraint in patients diagnosed with ADHD. The human subjects’ responses are being modeled using artificial neural networks (ANNs), an artificial intelligence method that can be utilized …

Pharmacokinetic And Pharmacodynamic Evaluation Of Cocaine Hydrolases For The Treatment Of Cocaine Overdose And Cocaine Addiction Using Rodent Models, Xirong Zheng

Theses and Dissertations--Pharmacy

Overdose and addiction are two medical complications of cocaine abuse. To date, there is no FDA approved pharmacotherapy specific for cocaine abuse. Cocaine hydrolases (CocHs) have been extensively investigated for its potential in anti-cocaine therapy. Previous studies have demonstrated that CocHs efficiently hydrolyze cocaine to generate biologically inactive metabolites both in vivo and in vitro. However, it has not been studied whether there is gender difference in the therapy using CocHs. In addition, the effectiveness of CocHs is unknown for treating cocaine toxicity when alcohol is co-administered.

The main purpose of this dissertation is to characterize and evaluate efficient …

Mechanisms And Thermodynamics Of The Influence Of Solution-State Interactions Between Hpmc And Surfactants On Mixed Adsorption Onto Model Nanoparticles, Salin Gupta Patel

Theses and Dissertations--Pharmacy

Nanoparticulate drug delivery systems (NDDS) such as nanocrystals, nanosuspensions, solid-lipid nanoparticles often formulated for the bioavailability enhancement of poorly soluble drug candidates are stabilized by a mixture of excipients including surfactants and polymers. Most literature studies have focused on the interaction of excipients with the NDDS surfaces while ignoring the interaction of excipients in solution and the extent to which the solution-state interactions influence the affinity and capacity of adsorption. Mechanisms by which excipients stabilize NDDS and how this information can be utilized by formulators a priori to make a rational selection of excipients is not known.

The goals of …

Discovery Of Novel Pharmacotherapeutics For Substance Use Disorders, Na-Ra Lee

Theses and Dissertations--Pharmacy

Substance use disorders are serious health concerns in the United States. Furthermore, the National Survey on Drug Use and Health reports a continuous increase in substance use disorders in the United States during the last 10 years. However, there are not many effective pharmacotherapeutics available for substance use disorders. The current dissertation is focused on research aimed at discovering pharmacotherapeutics for substance use disorders. First part of dissertation focused on discovering methamphetamine (METH) use disorder therapeutics targeting specific mechanism of METH action on dopaminergic neurons. The second part of dissertation focused on opioids and cocaine use disorder therapeutics targeting rewarding …

Trends And Patterns In Use Of Medications For Opioid Use Disorder In A Commercially Insured Population In The U.S., Catherine Serratore

Theses and Dissertations--Pharmacy

Opioid use disorder (OUD) and opioid overdose are pervasive public health problems in the U.S. Medications for opioid use disorder (MOUD) have been shown effective to reduce OUD morbidity and mortality. Two distinct approaches to MOUD are currently used: agonist therapy (methadone or buprenorphine) or antagonist therapy (naltrexone). Limited information is available about the patterns of use, adherence to therapy, and characteristics of those who use agonist vs. antagonist therapy. The objective of this study is to assess recent trends in MOUD, adherence in use of MOUD, and the characteristics of those who use agonist vs. antagonist therapy in a …

Development Of Mithramycin Analogues With Improved Efficacy And Reduced Toxicity For Treatment Of Ets-Dependent Tumors In Ewing Sarcoma And Prostate Cancer, Joseph Michael Eckenrode

Theses and Dissertations--Pharmacy

Introduction: Genetic rearrangements in Ewing sarcoma, prostate, and leukemia cells result in activation of oncogenic ETS transcription factor fusions. Mithramycin (MTM) has been identified as an inhibitor of EWS-FLI1 transcription factor, a gene fusion product responsible for oncogenesis in Ewing sarcoma. Despite preclinical success, a phase I/II clinical trial testing MTM therapy in refractory Ewing sarcoma was terminated. Liver and blood toxicities resulted in dose de-escalation and sub-therapeutic exposures. However, the promise of selectively targeting oncogenic ETS transcription factors like EWS-FLI1 prompted us to undertake the discovery of more selective, less toxic analogues of MTM. MTM is a potent inhibitor …

Computational Modeling Guided Discovery Of Novel Inhibitors Of Mpges-1 And Butyrylcholinesterase As Drug Candidates, Shuo Zhou

Theses and Dissertations--Pharmacy

Ever since the advent of computer-aided drug design (CADD), in silico simulation methods have greatly accelerated the drug discovery process and lead to the discovery of numerous drug candidates. With the exponential growth of computational power, we nowadays simulate biologic systems at a scale unimaginable a decade ago and thus provides perspectives for drug design. In this dissertation research, combining in silico simulation methods like molecular docking and molecular dynamics (MD) simulation with organic synthesis, in vitro/in vivo experiments and clinical data mining, we developed new drug discovery strategies. These strategies were applied in our drug discovery projects and led …

Toward An Enzyme-Coupled, Bioorthogonal Platform For Methyltransferases: Probing The Specificity Of Methionine Adenosyltransferases, Tyler D. Huber

Theses and Dissertations--Pharmacy

Methyl group transfer from S-adenosyl-l-methionine (AdoMet) to various substrates including DNA, proteins, and natural products (NPs), is accomplished by methyltransferases (MTs). Analogs of AdoMet, bearing an alternative S-alkyl group can be exploited, in the context of an array of wild-type MT-catalyzed reactions, to differentially alkylate DNA, proteins, and NPs. This technology provides a means to elucidate MT targets by the MT-mediated installation of chemoselective handles from AdoMet analogs to biologically relevant molecules and affords researchers a fresh route to diversify NP scaffolds by permitting the differential alkylation of chemical sites vulnerable to NP MTs that are unreactive to …

Investigation Of Factors Influencing Protein Stability In Lyophilized Formulations Using Solid-State Nmr Spectroscopy, Ashley Lay-Fortenbery

Theses and Dissertations--Pharmacy

Many proteins are unstable in solution and must be formulated in the solid state. This has led to an increase in the use of lyophilized dosage forms. Lyophilization is a complicated processing method consisting of three major steps: freezing, primary drying, and secondary drying. This can lead to several formulation stability challenges including changes in ionization within the matrix, phase separation of the protein drug from added stabilizers, sufficient mobility within the system for movement of reactive species and protein side chains, and crystallization of excipients upon storage. Solid-State Nuclear Magnetic Resonance Spectroscopy (SSNMR) is used to characterize many important …

Estimating Disease Severity, Symptom Burden And Health-Related Behaviors In Patients With Chronic Pulmonary Diseases, Radmila Choate

Theses and Dissertations--Epidemiology and Biostatistics

Chronic pulmonary diseases include a wide range of illnesses that differ in etiology, prevalence, symptomatology and available therapy. A common link among these illnesses is their impact on patients’ vital function of breathing, high symptom burden and significantly impaired quality of life.

This dissertation research evaluates disease severity, symptom burden and health behaviors of patients with three different chronic pulmonary conditions. First, alpha-1 antitrypsin deficiency (AATD) is an inherited condition that typically is associated with an increased risk of early onset pulmonary emphysema. This study examines differences in demographic, health, and behavioral characteristics and compares clinical outcomes and health related …

Understanding The Contributions Of Alzheimer’S Disease & Cardiovascular Risks To Cerebral Small Vessel Disease Manifest As White Matter Hyperintensities On Magnetic Resonance Imaging (Mri), Omar M. Al-Janabi

Theses and Dissertations--Clinical and Translational Science

Introduction: Alzheimer’s Diseases (AD) & cerebral small vessel disease associated with cardiovascular risk factors (cSVD) frequently coexist, differentially affecting both imaging and clinical features associated with aging and dementia. We hypothesized that Magnetic Resonance Imaging (MRI) can be used in novel ways to identify relative contributions of AD & cardiovascular risks to cSVD and brain atrophy, generating new biomarkers & insights into mixed disease states associated with cognitive decline and dementia.

Methods: Three experiments were conducted to address the overarching hypothesis. First, we visually rated the clinical MRI of 325 participants from a community-based cross-sectional sample to elucidate the relative …

A Pilot Study Of A Multiple Health Behavior Change Intervention For Smokers, Srihari Seshadri

Theses and Dissertations--Clinical and Translational Science

Background: Being both obese and a smoker increases the probability of developing type 2 diabetes, cardiovascular disease, and cancer, diseases that impact Kentucky residents disproportionately. Kentucky (KY) has a high incidence of obesity (34.2%) and smoking (24.5 %). Weight gain associated with smoking cessation also can undermine health benefits of quitting, and may lead to smoking relapse.

Aim: The aim of the pilot study was to implement and evaluate a Multiple Health Behavioral Change (MHBC) program that combines Cooper Clayton Method to Stop Smoking (CCMSS) and the Diabetes Prevention Program (DPP) for weight control.

Method: A 15-week intervention was administered …

Protocolized Volume De-Resuscitation In Critically Ill Patients, Brittany Dawn Bissell

Theses and Dissertations--Clinical and Translational Science

While early fluid resuscitation may be a necessary component to decrease mortality in the majority of critically ill patients admitted to the intensive care unit, the benefit of continued administration after the first 24 hours is less clear. Paradoxically, a positive fluid balance secondary to intravenous fluid receipt has been associated with diverse and persistent perpetuating detriment on a multitude of organ systems. Continued clinical harm has been demonstrated on pulmonary and renal function as well as patient outcomes such as rates of mortality and length of stay. Despite the growing body of evidence supporting the potential adverse aspects of …

The Impact Of Dysphagia And Gastrostomy On Quality Of Life In Caregivers Of Patients With Amyotrophic Lateral Sclerosis, Emily Clare Sither Goggin

Theses and Dissertations--Communication Sciences and Disorders

There is little research studying the relationship between caregiver quality of life and gastrostomy, a palliative intervention recommended to manage dysphagia and malnutrition in patients diagnosed with Amyotrophic Lateral Sclerosis (ALS). To facilitate a more comprehensive assessment of treatment effectiveness and to better guide patients and their families, this study investigated the relationship between gastrostomy, caregiver strain, and patient disease-related factors. Patients with bulbar-onset ALS and their caregivers were recruited regardless of their decision to accept or decline future gastrostomy. Caregivers completed the Modified Caregiver Strain Index (MCSI) to assess levels of caregiver strain as an index of quality of …

Changes In Muscle Size, Quality And Power Are Related To Physical Function In Patients With Critical Illness, Kirby Mayer

Theses and Dissertations--Rehabilitation Sciences

Patients admitted to intensive care unit (ICU) are known to develop significant impairments in physical function. Patients with critical illness suffer up to 30% reductions in muscle size within the first ten days of admission to the ICU. Muscle strength testing, Medical Research Council-sum score, is current gold-standard to diagnosis ICU-acquired weakness and predicts risk of mortality and long-term physical function. Muscle power different from muscle strength in that it accounts for velocity of movement, is potentially a better independent predictor of function that has not been studied in this population. In addition, we hypothesize that muscle size and quality …

Pyocyanin, A Virulence Factor Produced By Sepsis-Causing Pseudomonas Aeruginosa, Promotes Adipose Wasting And Cachexia, Nika Larian

Theses and Dissertations--Pharmacology and Nutritional Sciences

Sepsis is a leading cause of death among critically ill patients that results in metabolic alterations including hypercatabolism, lipoatrophy, and muscle wasting, contributing to the development of cachexia. Septic cachexia is associated with loss of body weight, fat mass, and lean mass and dysregulated immune function. There are currently no efficacious treatment strategies for septic cachexia, and nutritional interventions have limited success in preventing hypercatabolic wasting. Pyocyanin is a virulence factor produced by sepsis-causing Pseudomonas aeruginosa that has been shown to activate the aryl hydrocarbon receptor (AhR), increase inflammation, and produce reactive oxygen species. Thus, pyocyanin represents a novel mechanistic …

Azithromycin Therapy Reduces Cardiac Inflammation And Mitigates Adverse Cardiac Remodeling After Myocardial Infarction, Ahmed Hamish Neamah Al-Darraji

Theses and Dissertations--Pharmacology and Nutritional Sciences

Introduction: Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Induced by cardiomyocyte death, MI initiates a prolonged and uncontrolled inflammatory response which impairs the healing process. Immune cells, such as macrophages, play a central role in organizing the early post-MI inflammatory response and the subsequent repair phase. Two activation states of macrophages have been identified with distinct and complementary functions (inflammatory vs. reparatory). This bimodal pattern of macrophage activation is an attractive therapeutic target to favorably resolve post-MI inflammation and enhance recovery. It has been demonstrated that azithromycin (AZM), a commonly used antibiotic with immunomodulatory effects, …

Pathological Tau As A Cause, And Consequence, Of Cellular Dysfunction, Shelby Meier

Theses and Dissertations--Physiology

Tauopathies are a group of neurodegenerative diseases characterized by the abnormal deposition of the protein tau, a microtubule stabilizing protein. Under normal physiological conditions tau is a highly soluble protein that is not prone to aggregation. In disease states alterations to tau lead to enhanced fibril formation and aggregation, eventually forming neurofibrillary tangles (NFTs). The exact cause for NFT deposition is unknown, but increased post-translational modifications and mutations to the tau gene can increase tangle formation.

Tauopathic brains are stuck in a detrimental cycle, with cellular dysfunction contributing to the development of tau pathology and the development of tau pathology …

Effects Of Pituitary Pars Intermedia Dysfunction And Prascend® Treatment On Endocrine And Immune Function In Senior Horses, Ashton B. Miller

Theses and Dissertations--Veterinary Science

Pituitary pars intermedia dysfunction (PPID) is one of the most common endocrine diseases affecting senior horses. PPID causes abnormally high concentrations of adrenocorticotropic hormone (ACTH) in the plasma and a very distinct, long, shaggy haircoat (hypertrichosis). At present, the recommended treatment for PPID is daily oral administration of pergolide mesylate. Due to the increased ACTH levels associated with PPID, it is commonly thought that these horses are immunosuppressed and at increased risk of opportunistic infections, although current research in this area is sparse. Additionally, it is not well-understood how treatment with Prascend^® (pergolide tablets) affects endocrine measures other than …

The Impact Of A Fruit And Vegetable Farmers' Market Voucher Prescription Program On A Low-Income Rural Population, Kevin Anthony Richie

Theses and Dissertations--Nutrition and Food Systems

Objective: Measures the impact of the Farmers’ Market Voucher program on weight, body mass index, waist circumference, during the 2016 summer on a rural, low-income population residing in Appalachian Kentucky.

Background: Rural communities often have limited access to fresh fruits and vegetables (FV) which contributes to low levels of consumption. FV are calorie poor, nutrient dense and are inversely associated with inflammation markers, obesity, hypertension, and high blood glucose levels. Appalachian rural communities have a higher prevalence of obesity, diabetes, strokes, and death by heart attack when compared to the U.S. Farmers’ markets

Methods: Pre-experimental intervention design examining FV consumption …