The Therapeutic Potential Of Glycosaminoglycan Directed Metalloglycomics: Elucidating New Targets And Mechanisms For Polynuclear Platinum Complexes, James D. Hampton

Theses and Dissertations

Cancer remains a serious clinical problem and in order to continue to improve patient health outcomes, novel treatment strategies must continue to be developed. Platinum chemotherapies remain as one of the most widely successful classes of cancer therapeutic, with over 50% of cancer patients receiving a platinate at some point over the span of their treatment. However, intrinsic and extrinsic resistances limit their effectiveness, long term efficacy, and broad applicability to multiple cancer subtypes. Therefore, the development of new agents and strategies which can overcome these limitations are crucial for patient health. To this end a novel class of polynuclear …

Modeling Substance Use And Mental Disorder Comorbidity Using Latent Variable And Network Approaches, Courtney T. Blondino

Theses and Dissertations

Introduction. Substance use disorder (SUD) is a common condition that affects millions of Americans. Addressing SUD has been complicated by comorbid mental disorders and co-occurring substance use. Consequently, detailing and addressing SUD and comorbid SUD represent an important goal to improve the health of Americans.

Objective. The research goal of this dissertation was to characterize the comorbidity between substance use, including tobacco use, and mental disorder symptoms measured as negative affect and externalizing symptoms in a population-based sample using latent variable and network approaches.

Methods. Waves 1 – 3 from the Population Assessment of Tobacco and Health Study were used. …

Single-Molecule Investigation Of I-Motif Folding And Dynamics In Bioinspired Dna Platforms, Anoja Megalathan

Theses and Dissertations

Although the canonical right-handed B-DNA is the predominant form of DNA in cells, DNA can adopt other secondary structures such as hairpins, G-quadruplexes (G4), and intercalated motifs (i-motif). These secondary structures are typically formed in the regions with repeat sequences. Among many secondary structures DNA can adopt, G-quadruplexes and i-motifs (tetraplex structures formed in the G-rich and C-rich sequences, respectively) caught significant research interest in recent years due to the prevalence of G-rich and C-rich sequences in the human genome. While G-quadruplexes are extensively studied, little is known about i-motifs – especially their formation and stability under cellular environments. For …

Preclinical Pharmacokinetic Studies Of Pterostilbene, And Its Human Pharmacokinetic Prediction Using Physiologically Based Pharmacokinetic Modeling, Palak S. Phansalkar

Theses and Dissertations

This dissertation research aimed to determine the preclinical pharmacokinetics of pterostilbene in vitro and develop a physiologically based pharmacokinetic (PBPK) model to simulate the animal and human PK profiles for pterostilbene. The in vitro PK characteristics of pterostilbene, including Caco-2 cell permeability, plasma protein binding, and metabolic stability were determined using rat and human intestinal & hepatic S9 subcellular fractions. The in vitro metabolic parameters determined in rat subcellular fractions were extrapolated to in vivo values to predict the oral bioavailability (F_oral) in rats. The predicted F_oral was found to be 43.0 %, which is similar to …

Structural Reorganization Of The Cisternal Organelle In Neuroinflammatory Disease, Myshak S. Abdi

Theses and Dissertations

The axon initial segment (AIS), an axonal sub compartment located immediately distal to the soma, is an important structure in mediating action potential generation and modulation. The morphology of this domain can be altered by a wide variety of activity-dependent, environmental, and pathological triggers. Dysregulation of axonal calcium (Ca²⁺) concentrations, and subsequent enzymatic degradation of AIS cytoskeletal architecture have been reported to underlie structural modifications of the AIS. Moreover, pharmacological inhibition of neuronal Ca²⁺ channels have been shown to mitigate the disruptive effects of neuroinflammation on AIS structural integrity. Here we investigate the Cisternal Organelle (CO), a …

Conformational Modulation Of Α-Helical N-Acetylated Α-Synuclein, Ricardo Fernandez

Theses and Dissertations

Human N-acetylated α-synuclein (^NAcαSyn) has long been accepted as an intrinsically disordered protein (IDP) predominantly found in terminal nerve regions in healthy subjects. ^NAcαSyn structural fluidity enables the formation of transient or dynamic assemblies. Some of these assemblies may serve functional, yet undefined purposes. ^NAcαSyn is highly susceptible to the surrounding environment, leading to misfolding under high cytosolic oxidative stress conditions, which in turn assemble in the form of toxic oligomers or amyloid fibrils. These ^NAcαSyn inclusions along with their accretion and migration within neurons, are pathological hallmarks of Parkinson’s disease (PD), dementia, and multiple …

Copper Sulfide Manganese Nanoparticles For Multimodality Imaging And Therapy, Ali S. Gawi Ermi

Theses and Dissertations

Abstract

COPPER SULFIDE MANGANESE NANOPARTICLES FOR MULTIMODALITY IMAGING AND THERAPY

By Ali S. Gawi Ermi, MSc

Inorganic nanoparticles (NPs) are compatible with metal-based multi-modality molecular imaging and targeted therapy. Copper sulfide nanoparticles (CuS NPs) are attractive photoacoustic and photothermal agents and are amenable to incorporation of radionuclides and paramagnetic elements to facilitate image-guided therapy. The aim of this work is to develop manganese (Mn)- doped CuS NP, intrinsically radiolabeled with radionuclides such as (Zirconium-89 (⁸⁹Zr), Copper-64/67 (^64/67Cu) and Manganese-52/55 (^52/55Mn)). This novel approach combines Photoacoustic (PA), Positron emission tomography (PET), Single-photon emission computed tomography …

Effects Of Buprenorphine Treatment On Myelin Following Traumatic Brain Injury In A Rat Model, Jane Ryu

Theses and Dissertations

Traumatic brain injury (TBI) is a common phenomenon, accounting for significant cost and adverse health effects. While there is information about focal pathologies following TBI, knowledge of more diffuse processes is lacking, particularly regarding how analgesics affect this pathology. As Buprenorphine (Bup) is the most commonly used analgesic in experimental TBI models, the current study investigated the effects of the opioid analgesic Buprenorphine-sustained release-Lab (Bup-SR-Lab) on physiology and myelin alterations at 1d and 4w following central fluid percussion injury (cFPI) in adult male rats. Microscopic assessments were performed at 1 day and 4w post-injury. Myelin pathology was assessed by evaluating …

Mechanistic Insights Of Mitochondrial Reactive Oxygen Species In Alzheimer's Disease Models, Jakob C. Green

Theses and Dissertations

Alzheimer’s disease (AD) is a neurodegenerative disease that results in impaired cognition, disorientation, confusion, poor judgement, and behavioral changes. The mitochondrial cascade hypothesis (MCH), which postulates that accumulating oxidative stress and mitochondrial dysfunction plays an integral role in the development of the disease, potentially upstream, in conjunction with or independent of Aβ and tau. The literature supports the critical role of mitochondrial dysfunction in the progression and development of AD, but is inconclusive about what precise role, as initiator or delegate, it performs. Regardless, the impact that oxidative stress and mitochondrial dysfunction have on AD deserves further study and investigation. …

Influence Of Immigration Status On The 10-Year Trajectories Of Psychosocial Functioning In Individuals With Traumatic Brain Injury, Chimdindu Ohayagha

Theses and Dissertations

The population of racially/ethnically diverse groups within the U.S. is growing at an exponential rate. The U.S. Census Bureau estimated the number of foreign-born individuals in the U.S. to be nearly 40 million or 13% of the total population (Grieco et al., 2012). Racially/ethnically diverse groups in the U.S. have a higher incidence of traumatic brain injury (TBI; Gary et al., 2009). Although racial/ethnic disparities have been documented in numerous outcomes, research has yet to thoroughly explore differences in rehabilitation outcomes for immigrants relative to U.S.-born individuals. The purpose of this study was to compare the functional and mental health …

Evaluating Patient And Health Care Provider Acceptance Of A Personal Health Record In An Integrated Health Care System In The Kingdom Of Saudi Arabia, Consuela C. Yousef

Theses and Dissertations

With the shift to patient- and person-centered care, personal health records (PHRs) have been touted as a strategy to empower patients, improve patient-provider communication, and support self-management. Health care organizations around the world have implemented PHRs in a global push to meet three aims of health care—improve access to care, reduce costs, and increase the quality of care. The capabilities that PHRs support vary by organizations, yet basic functions include allowing patients to view their laboratory results, refill prescription medications, and request appointments. More advanced PHRs enable patient-centered communication through secure messaging.

As the burden of chronic disease grows, PHRs …

The Role Of Insurance Coverage In Outpatient Substance Use Disorder Treatment Referral, Utilization, And Outcomes, Huyen Pham

Theses and Dissertations

Opioid-related overdoses increased dramatically in recent years. Medicaid plays a predominant role in paying for opioid use disorder (OUD) treatment. However, there is a critical gap in understanding the role of Medicaid coverage in referrals to treatment, treatment utilization, and treatment retention. The three studies used observational and quasi-experimental (i.e., natural experiment) designs leveraging state and year variation in Medicaid expansion to characterize the role of Medicaid coverage in OUD treatment. We found that individuals with OUD with Medicaid insurance were more likely to use outpatient treatment, whereas those who were uninsured were more likely to use self-help groups only. …

Local Delivery Of Tumor Associated Macrophage Immunotherapy For The Treatment Of Metastases To The Lungs, Sulaiman Alhudaithi

Theses and Dissertations

Metastases are the leading cause of cancer-related deaths, and the lungs are one of the primary sites of metastases from several malignancies. Existing therapies fail to entirely eradicate tumors that disseminate and reside in lungs; therefore, patient prognosis significantly worsens. Conventional therapies utilized to treat lung tumors such as chemotherapy are administered systemically and typically exhibit poor lung biodistribution profiles, leading to many undesirable off target effects and suboptimal drug concentration in the tumor, which may promote resistance, further compromising the quality of life of secondary lung cancer patients. Immune cells that infiltrate the tumor microenvironment (TME) play a central …

A Novel Sulfated Trimer Of Quercetin For Pulmonary Delivery To Treat The Emphysematous Lung, Abhinav Mohan

Theses and Dissertations

Emphysema, a major manifestation of chronic obstructive pulmonary disease (COPD), affects millions of patients in the United States; yet, no present treatment is able to directly modify the disease process. In the recent past, a pathobiologic hypothesis surrounding the deficiency of vascular endothelial growth factor (VEGF), has surfaced as a cause of the alveolar structural destruction and loss in emphysema. Additionally, sirtuin 1 (SIRT1), a regulator of anti-oxidative proteins and cellular homeostasis, has been found to be reduced in the lungs of emphysematous patients. Given these disturbances, this research hypothesized that such pathobiologic deficiencies can be inhibited with a sulfated …

Urate Genetic Assessment In Asian And Pacific Islander Subgroups Of Pregnant Women: Implications For Personalized Medicine And Means To Reduce Health Disparities, Ali Alghubayshi

Theses and Dissertations

Gout is one of the most common rheumatic conditions and appears to have a higher prevalence in certain populations. Risk factors for gout and its precursor, hyperuricemia, are also significant risk factors for preeclampsia, major pregnancy-related morbidity. A retrospective cross-sectional study was conducted on 1059 pregnant women from different populations whom 100% reported their ethnicities from the Asian, Native Hawaiian, and Pacific Islander populations. Numerous uric acid (UA) genes and clinical conditions were addressed, and all study details were reviewed and exempted by the University of Hawaii human Studies Program (Protocol Number: 2018-00225). In this project, we hypothesized that UA …

Impact Of Physical Activity And Cardiorespiratory Fitness On Vascular Homeostasis In Premenopausal Women Consuming A Westernized High-Fat Meal, Lauren N. Pedersen

Theses and Dissertations

A large percentage of adults in industrialized nations consume a Westernized dietary pattern, which contributes to fasting dyslipidemia and increased risk for atherosclerotic cardiovascular disease. Evidence suggests that a single Westernized meal containing high saturated fat may induce alterations in blood lipids as well as disturb multiple factors regulating peripheral vascular homeostasis, including innate immune cell function, oxidative stress, and vascular function. Conversely, participation in acute and chronic exercise may beneficially impact an individual’s postprandial response. Therefore, this dissertation contains three manuscripts seeking to describe how acute exercise, cardiorespiratory fitness, and physical activity level impact the lipemic and vascular homeostatic …

Continuous Manufacturing Of Pharmaceuticals Using Novel Platforms, Sarah S. Aboelela

Theses and Dissertations

Pharmaceuticals have been synonymously manufactured in a centralized, batch mode with less attention to process and formulation understanding. However, due to rising drug costs, shortages, and robustness issues, in addition to the alarming lack of flexibility and agility, regulatory agencies have pushed towards switching to continuous processes. They believed in continuous manufacturing, providing cleaner, flexible, and more efficient processes. Hence, it was foreseen to reduce development and manufacturing costs, time, and environmental impact and ensured drug product quality. Over the last two decades, continuous manufacturing quality, environmental, and economic advantages have been evident through many case studies and approved products …

Investigating Cannabinoid Type-1 Receptor (Cb1r) Positive Allosteric Modulators (Pams) In Mouse Models Of Overt Cannabimimetic Activity, Subjective Drug Effects, And Neuropathic Pain, Jayden Elmer

Theses and Dissertations

Chronic pain affects between 20 and 30 percent of the adult population in western countries and represents a wide array of specific etiologies (Berge, 2011). Neuropathic pain secondary to traumatic nerve injury, chemotherapeutic toxicity, or diseases (e.g., diabetes mellitus) is often refractory to conventional analgesics, with patients receiving less than 50% pain relief compared to placebo (Finnerup et al. 2010). The endocannabinoid system has shown potential as a therapeutic target for neuropathic pain wherein CB1 agonism via administration of exogenous agonists or pharmacological blockade of endocannabinoid catabolic enzymes exhibits efficacy in reversing allodynia in the chronic constriction injury (CCI) model …

Exploring The Dopamine Transporter Utilizing A Two-Pronged Approach With Novel Cathinone Analogs And Mutant Dopamine Transporters, Charles B. Jones Iii

Theses and Dissertations

The dopamine transporter (DAT) is responsible for the removal of the neurotransmitter from the synaptic gap and a therapeutic target for a multitude of drugs. While the ortholog Drosophila melanogaster dopamine transporter (dDAT) and human serotonin transporter (hSERT) have resolved structures, the human dopamine transporter (hDAT) does not. A 3-D computational homology model of hDAT was constructed for the study of molecular interactions with agents within the central binding site (S1) of the transporter.

Synthetic cathiones are a class of abused stimulant drugs that primarily target DAT. Greater than 150 cathinones have been identified on the clandestine market but there …

Development Of Sam-Based Chemical Probes For Methyltransferases, Daniel V. Mongeluzi

Theses and Dissertations

Fig.1. SAM analog for the profiling of MTase activity. A. Chemical structure of probe 1; B. General scheme of the labeling and capture strategy.

A

B

Methylation is a fundamental mechanism used in the biological system to modify the structure and function of biomolecules such as proteins, DNA, RNA, and metabolites.¹ Methyl groups are installed by a large and diverse class of S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTases), which transfer the sulfonium methyl group of SAM to either carbon, nitrogen, oxygen, or other heteroatoms on biomolecules.² Dysregulated MTase activity contributes to numerous diseases, including cancer, metabolic disorders, neurodegenerative diseases. …

Intentions To Use Telerehabilitation For Communication And Treatment For Vision Impairments, Eric E. Hicks

Theses and Dissertations

BACKGROUND: Approximately 8.1 million people in the United States 18 and older have difficulty performing one or more daily activities because of vision impairment or blindness (Erickson, Lee, & von Schrader, 2020; Taylor, 2018). If the impairments caused by vision loss are not addressed, they can result in financial difficulties, suffering, disability, loss of productivity, and decreased quality of life (National Center for Chronic Disease Prevention and Health Promotion, 2011). Currently, in-person low vision rehabilitation services are the gold standard for teaching people how to adapt to and compensate for these deficits, however, the access and utilization of these services …

Sleep-Related Problems, Sleep-Related Distress, And Sleep-Related Functional Status Among Adult Inpatients Receiving Palliative Care, Lisa C. Sievers

Theses and Dissertations

Palliative care patients may be at a higher risk for sleep-related problems and their negative effects compared to the general population, yet limited sleep research has been done with this population. The purpose of this dissertation was to determine prevalence rates for excessive sleepiness, insomnia, restless legs syndrome (RLS), and high risk for sleep apnea (HRSA); examine relationships between the aforementioned sleep-related problems, sleep-related distress (SD), and sleep-related functional status (SFS); and to determine which sleep-related problem measures along with age and gender predicted SD and SFS among a sample of adult palliative care inpatients. Secondary aims were to understand …

A Deep Learning U-Net For Detecting And Segmenting Liver Tumors, Vidhya Cardozo

Theses and Dissertations

Visualization of liver tumors on simulation CT scans is challenging even with contrast-enhancement, due to the sensitivity of the contrast enhancement to the timing of the CT acquisition. Image registration to magnetic resonance imaging (MRI) can be helpful for delineation, but differences in patient position, liver shape and volume, and the lack of anatomical landmarks between the two image sets makes the task difficult. This study develops a U-Net based neural network for automated liver and tumor segmentation for purposes of radiotherapy treatment planning. Non-contrast simulation based abdominal CT axial scans of 52 patients with primary liver tumors were utilized. …

Dendrimer-Based Antibiotics For The Treatment Of Bacterial Biofilm In Cystic Fibrosis (Cf), Younan Ma

Theses and Dissertations

Pseudomonas aeruginosa (PA) is the predominant pathogen in chronic lung infections of cystic fibrosis (CF) patients. The most important mechanism of adaptation of PA to host defense and antibiotic treatment is the formation of biofilms within the mucus layer covering the lung bronchi. The effectiveness of antibiotics such as aminoglycosides is significantly attenuated by their limited penetration through thick mucus and embedded biofilm matrix in patients’ lung. Inhaled tobramycin (Tobra), which is the most commonly used antibiotics in the treatment of PA infections for CF patients, is usually found to be in very high concentration in patients’ lung, and yet …

Health Outcomes And Utilization Associated With Renal Diseases In Patients With Cancer In The United States, Mitisha Dedhia

Theses and Dissertations

Background: Adverse events and impairments associated with cancer and its treatments causes worse outcomes. Increased incidence of renal diseases among cancer patients is of particular concern. Objective: To determine the risk factors for renal disease in cancer patients and compare healthcare costs, utilization and health-related quality of life (HRQoL) of cancer patients with a renal disease and cancer patients without renal diseases. Methods: Medical Expenditure Panel Survey files from 2009 – 2018 for cancer patients was used for this study. Multiple logistic regression, generalized linear model, Poisson regression and multiple linear regression for analyses after adjusting for demographic, socioeconomic and …

Patient Blood Management Programs And Their Association With Patient And Organizational Outcomes, Sandra L. Lamm

Theses and Dissertations

Blood transfusions are the most common hospital procedure. However, many transfusions may be unnecessary. These unnecessary transfusion may expose patients to the potential risks of transfusion without improving patient outcomes Patient blood management (PBM) programs emphasize conserving a patient’s own blood resources and only transfusing the minimum amount needed. This study examined the organizational and environmental factors associated with a hospital having a PBM program, or having processes based on PBM, and their impact on organizational and patient outcomes potentially affected by blood transfusions.

A PBM survey was created for this study and used to gather information on hospitals having …

Formulation, Characterization And Pharmacokinetic Modelling Of Excipient Enhanced Growth Spray-Dried Inhalation Powders, Serena Bonasera

Theses and Dissertations

The overall aim of this research project was to evaluate effects of spray drying parameters and storage conditions on solid-state characteristics and aerosol performance of excipient enhanced growth (EEG) powders and to formulate a stable and highly dispersible tobramycin EEG powder to be delivered to pediatric cystic fibrosis subjects using a novel positive pressure dry powder inhaler.

Micrometer-sized albuterol sulfate EEG powders were produced using a medium-sized nebulizer and optimized spray drying conditions. Using trileucine as the dispersion enhancer improved the aerosol performance but showed increased moisture absorption compared to the L-leucine formulation.

The optimized spray drying conditions were then …

The Impact Of Healthcare Professional Students' Racial, Hiv-Related, And Abortion-Related Biases On Recommendations For Prenatal Care, Alison J. Patev

Theses and Dissertations

Black women and HIV-positive women have increased maternal mortality rates and other negative pregnancy outcomes, in part due to disparate prenatal care. Although women who seek abortions do not have the same negative outcomes, abortion stigma exists and is normalized in healthcare. Limited work has examined prenatal care provision for women in these groups, and even less work has explored the prenatal care provision by healthcare trainees (i.e., medical, nurse practitioner, and physician assistant students). Examining the role of bias on the prioritization of prenatal care items by healthcare trainees is imperative. Healthcare education sets the stage for future practice, …

Nebulizer-Based Systems To Improve Pharmaceutical Aerosol Delivery To The Lungs, Benjamin M. Spence

Theses and Dissertations

Combining vibrating mesh nebulizers with additional new technologies leads to substantial improvements in pharmaceutical aerosol delivery to the lungs across therapeutic administration methods. In this dissertation, streamlined components, aerosol administration synchronization, and/or Excipient Enhanced Growth (EEG) technologies were utilized to develop and test several novel devices and aerosol delivery systems. The first focus of this work was to improve the poor delivery efficiency, e.g., 3.6% of nominal dose (Dugernier et al. 2017), of aerosolized medication administration to adult human subjects concurrent with high flow nasal cannula (HFNC) therapy, a form of continuous-flow non-invasive ventilation (NIV). The developed Low-Volume Mixer-Heater (LVMH) …

Associations Between Social Determinants Of Health And Chlamydia Infections Among Georgia Counties, Bre'auna K. Beasley

Theses and Dissertations

Chlamydia is a growing public health concern that disproportionately impacts southern states. While social determinants of health are not direct causes of chlamydia infections, studies have found that these determinants do influence infections by creating environments that promote or hinder health seeking behaviors, as well as exposure to risk factors. Guided by the Social Ecological Model of Public Health and the Healthy People 2030 Social Determinants of Health Conceptual Framework, this dissertation study aimed to examine the associations between social determinants of health and chlamydia infections among Georgia counties. This study employed a correlational research design. Aggregate-level secondary data for …