Medicine and Health Sciences Commons^™

Pkpd-Model Based Preclinical Characterization Of The Activity Of Spectinamide 1599 Against Mycobacterial Subpopulations. And The Identification Of Potential Partners For Combination Therapy, Zaid Hanif Temrikar

Theses and Dissertations (ETD)

Tuberculosis is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent prior to COVID19. Mycobacterium tuberculosis (Mtb) is the causative agent of TB. The interaction between Mtb and the immune system leads to development of diverse environmental niches and physiology within the lung of the TB patients. Mtb is thought to adapt and thrive in such an environment by transforming to different phenotypic variants. Such variants are difficult to kill and are thought to prolong TB pharmacotherapy. Spectinamide 1599 is a synthetic modification of spectinomycin that has demonstrated excellent …

Investigation Of Clinically Relevant Fluconazole Resistance Mechanisms In The Fungal Pathogen Candida Parapsilosis, Laura Anne Doorley

Theses and Dissertations (ETD)

Invasive candidiasis is a severe fungal infection associated with significant morbidity and mortality, particularly among the critically ill and immunocompromised. Candida parapsilosis is the most common non-albicans species causing invasive Candida infections in pediatric and neonatal populations worldwide and is particularly common in the countries of South America, Western Asia, Mediterranean Europe, and Southern Africa. For many of these countries, fluconazole and other triazoles are the first line antifungal agents used for effective treatment of invasive Candida infection. Until recently, rates of fluconazole resistance among C. parapsilosis isolates were relatively low, therefore the determination of clinically relevant resistance mechanisms in …

A Design, Development, And Evaluation Of Bio-Patch For Myocardial Tissue Repair, Yaya Zhang

Theses and Dissertations (ETD)

Introduction. Ischemic heart disease (IHD) is a major concern of human health issue. The structural repair and functional recovery of injured hearts is a major challenge in the clinical setting. Preclinical studies over last 10 years have demonstrated the potential of using stem cells to treat IHD, but the efficacy of this therapy is jeopardized by uncontrollable migration and low survival of the injected stem cells. An approach based on tissue engineering enabling target-specific stem cell delivery such as cardiac patches has emerged as an alternative solution for stem cell therapy for IHD. It employs scaffold materials to engulf various …

Physiologically-Based Pharmacokinetic (Pbpk) Modeling For The Preclinical Development Of Spectinamide Antibiotics, Keyur R. Parmar

Theses and Dissertations (ETD)

Despite being an ancient disease caused by Mycobacterium tuberculosis (Mtb) and after decades of research, tuberculosis (TB) still affects millions of people every year worldwide. In 2018, the World Health Organization (WHO) reported that 10 million people developed tuberculosis and 1.5 million died of the disease. With the increase in the multidrug-resistant (MDR) and extensively drug-resistant (XDR) cases, the treatment for TB with the standard first and second-line therapy is becoming increasingly difficult. Therefore, there is an urgent need to find new anti-TB drugs as combination partners of existing and experimental classes of antimicrobial agents to shorten and simplify the …

Ribonucleotide Reductase Subunit Switching In Hepatoblastoma Drug Response And Relapse, Anthony Brown

Theses and Dissertations (ETD)

Hepatoblastoma is the most common primary liver cancer in infants and young children. Despite being a very rare cancer that accounts for only 0.5-2% if all childhood cancer cases, HB has the largest increase in incidence among childhood cancers in the United States and worldwide. The five-year survival rate of children with the aggressive forms of HB, including those that have developed metastatic or recurrent diseases, is less than 40% due to the lack of effective treatment. We aim to identify targetable mechanisms underlying the progression and drug resistance of high-risk HB. Our recent work on HB mouse and organoid …

Nursing Perspectives And Opinions On Early Or Delayed Sepsis Treatment: A Mixed Methods Approach, Pamela L. Harris

Theses and Dissertations (ETD)

Purpose. Each year at least 1.7 million adults in America develop sepsis. Sepsis can lead to life threatening organ dysfunction, severe hypotension, and death when severe sepsis or septic shock is involved. Sepsis is responsible for 50% of acute kidney injury (AKI), which is the most common form of organ dysfunction seen in critical care. Sepsis associated AKI results in loss of, or decreased renal function, is associated with adverse long-term outcomes, and carries a higher mortality rate than non-septic AKI, sepsis without AKI, or septic shock without AKI. Surviving sepsis guidelines suggests a 1-hour window from the time of …

Otulin's Novel Regulatory Mechanisms In Genotoxic And Inflammatory Nf-Kb Signaling, Mingqi Li

Theses and Dissertations (ETD)

Triple negative breast cancer (TNBC) is aggressive but cannot be treated with hormone therapy or molecular therapy due to the lack of a target. Chemotherapy is a systemic treatment that works by attacking rapidly growing cells, which is initially more effective for TNBC patients than those individuals with the hormone receptor-positive breast cancer. However, patients with TNBC tend to develop resistance to chemo drugs, called chemoresistance. After years of effort, the signaling pathways involved in TNBC chemoresistance are gradually revealed, including the nuclear factor-kappa B (NF-kB) pathway. Transcription factor NF-kB is widely involved in cancer development and progression, and its …

Targeting Myeloid Protein Kinase C Signaling To Overcome Immune Suppression And Improve Immunotherapy In Cancer, Mehdi Chaib

Theses and Dissertations (ETD)

Checkpoint immunotherapy unleashes T cell antitumor potential which has revolutionized cancer treatment showing unprecedented long-term responses. However, most patients do not respond to immunotherapy which often correlates with a dysfunctional or immunosuppressive myeloid compartment. Immunosuppressive myeloid cells comprise Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) and can suppress T cells via production of immunosuppressive factors. Conversely, efficient cytotoxic T cell priming is dependent on the ability of antigen-presenting cells (APCs), mainly conventional dendritic cells (cDCs) and macrophages, to present or cross-present tumor antigens to T cells. Thus, targeting immunosuppressive myeloid cells while simultaneously enhancing APCs represents a promising strategy …

Targeting Protein Degradation To Uncover Novel Oncoprotein Drivers Of Acute Leukemia, Fatemeh Keramatnia

Theses and Dissertations (ETD)

Acute Lymphoblastic Leukemia (ALL), the most common childhood cancer and the second most common acute leukemia in adults, arises from clonal expansion of undifferentiated lymphoid precursor cells in bone marrow. Despite the extensive knowledge on its cytogenetic and molecular biology, ALL treatment remains highly challenging especially after relapse. Conventional chemotherapy has shown significant improvement in overall survival rates of pediatric patients up to 90%, however, treatment failure due to ALL relapse occurs in 15-20% of the cases. On the other hand, adults and elderly patients with ALL are considered difficult to treat populations with the 5-year overall survival of 30–40%. …

Evaluation And Feasibility Of A Head Positioning Intervention In Patients With Intraparenchymal Hemorrhage, Wendy L. Dusenbury

Theses and Dissertations (ETD)

Stroke caused by intraparenchymal hemorrhage (IPH) is most commonly the result of hypertension-induced blood vessel rupture in the brain and is associated with devastating disability and high rates of death. To date, no intervention has improved outcomes in IPH stroke patients; however, head elevation may be one of the most important first steps to promote clinical stability in the hyperacute stage of IPH stroke because of the risk of increased intracranial pressure (ICP) in these patients. Nursing research completed in the late 1970s and early 1980s in patients with increased ICP due to traumatic brain injury showed that elevating the …

Iatrogenic Electrocautery Damage And Cellular-Based Corrosion Of Total Joint Arthroplasty Biomaterials, Kirsten Carol Miller

Theses and Dissertations (ETD)

Introduction. The number of patients undergoing a Primary Total Knee Arthroplasty (PTKA) has been increasing steadily each year. Of those PTKA patients, 20% report long-term pain and/or some functional deficit. Cobalt-Chromium-Molybdenum (CoCrMo) alloy is one of the most used materials in Total Joint Arthroplasty (TJA) implants due the material’s high strength, high corrosion resistance, and biocompatibility. The release of metal ions and potential occurrence of metallosis in TJA has been shown to be detrimental to the longevity of the implant. The mechanisms leading to this increase in metal ion concentrations have been up for debate, with some believing it is …

Near-Field Electrospinning And Characterization Of Biodegradable Small Diameter Vascular Grafts, William E. King Iii

Theses and Dissertations (ETD)

The ideal “off the shelf” tissue engineering, small-diameter (< 6 mm inner diameter (ID)) vascular graft hinges on designing a template that facilitates transmural ingrowth of capillaries to regenerate an endothelized neointimal surface. Previous traditionally electrospun (TES) approaches to create bioresorbable vascular grafts lack the pore sizes required to facilitate transmural capillary ingrowth required for successful in situ neovascular regeneration. Therefore, the ability to create scaffolds with program-specific architectures independent of fiber diameter via the relatively recent sub-technique of near-field electrospinning (NFES) represents a promising solution to create tissue engineering vascular grafts. These programmed large pore sizes are anticipated to promote in situ regeneration and improve the outcomes as well as the quality of life of patients with arterial disease.

In this dissertation, we manufactured via NFES as well as characterized biodegradable polydioxanone (PDO) small-diameter vascular grafts. Chapter 1 introduces the need for off-the-shelf, small-diameter vascular grafts to facilitate in situ regeneration, the process and pore size limitations of TES vascular grafts, and the promising use of NFES to develop precisely tailored PDO vascular grafts. Chapter 2 describes the process of NFES and details the current progress in NFES of biomedical polymers as well as the major limitations that exist in the field. Chapters 3, 4, and 5 contain primary research …

Audiovisual Integration During Novel Word Learning Among School-Aged Children With Cochlear Implants, Kristen Elizabeth Thompson Thornton

Theses and Dissertations (ETD)

Objective. It is well established that being able to see someone’s mouth move as they speak boosts speech perception for children with cochlear implants (CIs). Thus, children with CIs are often instructed to orient themselves toward the person they are listening to, to gain access to visual speech cues. Children with CIs who are better “audiovisual integrators,” or those who experience an auditory-visual (AV) enhancement effect (higher performance for AV information than auditory-alone (AO) or visual-alone (VO)), are more likely to have better speech and language outcomes after receiving their CI than children with poorer AV integration skills. While AV …

Joint Coordination Variability In Anterior Cruciate Ligament Reconstructed Subjects During Stair Ambulation Using A Vector Coding Technique, Bryan R. Simrak

Theses and Dissertations (ETD)

Anterior cruciate ligament (ACL) rupture is a common injury, with an estimated incidence of 120,000 to 200,000 per year in the United States. ACL reconstruction surgery is the standard treatment for this injury to restore knee joint stability and function. While surgical reconstruction has been shown to restore laxity of the knee, current literature lacks consensus on return to normal knee joint kinematics following surgery. Additionally, re-injury is a major risk for those who return to sports activity after reconstruction surgery. Dynamical systems methods for quantifying joint coordination variability have been explored as a method for detecting differences between ACL …

Failure Of Primary Total Knee Arthroplasty: Establishing A Baseline For Retrieval Analysis Using Well-Functioning Necropsy Specimens, Meredith Perkins

Theses and Dissertations (ETD)

Introduction. Total knee arthroplasty (TKA) is an effective treatment for end-stage osteoarthritis of the knee. While many patients have positive functional and pain outcomes following primary TKA, a subset of patients have suboptimal outcomes, such as unexplained pain or aseptic loosening of the implant components necessitating revision of the index procedure. The understanding of the exact etiology of these suboptimal outcomes of primary TKA is in its infancy. In order to elucidate the etiology of failure in primary TKAs, a baseline for the factors contributing to arthroplasty failure and dissatisfaction must first be established. The purpose of this study …

Retrieval Analysis Of Necropsy Total Hip Replacements: Considerations Beyond The Implant, Julie Alyse Lowell

Theses and Dissertations (ETD)

Introduction. Total hip arthroplasty (THA) surgery is one of the most commonly performed and successful orthopedic procedures in the United States. More than 300,000 primary THAs and 40,000 revision THAs performed in the United States every year. While the need for revision surgeries can stem from a variety of causes, there have been, to the author’s knowledge, no studies attempting to correlate the concentrations of certain inflammatory cytokines to metal ion concentrations found in the tissue surrounding the implant, amount of polyethylene wear, or strength of the interface of the modular taper. The purpose of this study was to begin …

A Novel Distractive And Mobility-Enabling Lumbar Spinal Orthosis For Treating Mechanical Low Back Pain, Daniel Clay Hillyard

Theses and Dissertations (ETD)

Introduction: Lumbar spinal orthoses (LSOs) are often used as non-surgical treatment and serve to support the spine and alleviate low back pain. More recently, dynamic orthoses claiming to decompress the spine have been introduced. Currently, there is an unserved population of people that suffer from mechanical low back pain (LBP) conditions, such as degenerative disc disease or lumbar foraminal stenosis, that would benefit from spinal decompression and mobility. A previously-developed prototype of dynamic mobility orthosis (DMO1) was designed that provided a distractive load across the lumbar spine but required higher sagittal bending moments and was unable to maintain spinal off-loading …

Quantifying Joint Coordination Variability In Anterior Cruciate Ligament-Reconstructed Individuals During Walking, Kylie Davis

Theses and Dissertations (ETD)

The knee is the second most common joint to sustain injury. An estimated 200,000 anterior cruciate ligament (ACL) ruptures occur each year in the United States alone, and about 100,000 ACL reconstruction (ACLR) surgeries are performed annually. There is a significant risk of developing osteoarthritis of the knee after incurring an ACL injury, and the incidence of ipsilateral or contralateral injury is six times greater in individuals who have a surgically repaired ACL. Past studies have analyzed kinetic and kinematic characteristics of individual lower extremity joints to reveal differences between subjects with and without ACLR. Despite reports of altered kinematic …

Design, Validation, And Clinical Testing Of A Novel Fastening Device For A Scoliosis Brace, Cody Keith Bateman

Theses and Dissertations (ETD)

Each year, thirty thousand children in the US were put into a scoliosis brace. The primary function of scoliosis braces was to reduce and prevent progression of the spinal deformity as the patient grew by application of corrective forces to the spine. Straps, often made of Velcro, were attached to the back of the brace that applied forces to the spine when the straps were tightened. Braces were prescribed to be worn up to 23 hours a day. Studies have concluded that discomfort increased with increasing strap tension and pad pressure. They have also shown an increase in strap tension …

The Effect Of Hamstring Lengthening On Pelvic Tilt And Lumbar Lordosis, Michael Scott Braman

Theses and Dissertations (ETD)

A direct correlation between hamstring tightness and severity of lower back pain (LBP) has been previously reported. Hamstring contraction creates knee flexion, hip extension and posterior pelvic tilt. Posterior pelvic tilt causes the lumbar spine to flatten (hypolordosis) which places pressure on the anterior structures of the spine, including the intervertebral disc. This increased pressure may predispose individuals to disc degeneration and associated pain. For this reason, hamstring stretching is often prescribed to alleviate LBP, however, the effect of hamstring lengthening on the kinematics of the lumbar spine and pelvis is not well understood. Accurate measurement of lumbar spine movement …

A Subject Specific Surface Electromyography Model For Estimating L4/L5 Compressive Loading, Pablo Joaquin Dopico

Theses and Dissertations (ETD)

Introduction: Low Back Pain (LBP) is a leading cause of activity limitation worldwide and results in 149 million lost work days annually in the United States. The total costs of LBP are estimated to be $100 to $200 billion annually. Specific causes of LBP account for less than 15% of LBP cases. Heavy loading of the lumbar spine and tight hamstrings have been identified as risk factors for LBP. Tight hamstrings pull the pelvis posteriorly and reduce the lordosis of the spine, resulting in increased loading of the lumbar vertebral bodies of the spine. While this mechanism has been described, …

Scoliosis Analog Model For The Evaluation Of Bracing Technology, Chloe Ly Chung

Theses and Dissertations (ETD)

Thoracolumbar braces are commonly used to treat Adolescent Idiopathic Scoliosis (AIS). Braces serve to reduce and prevent progression of the spinal curve by applying corrective forces. The magnitude and direction of these corrective forces applied by the brace to the spine remain unknown. Additionally the brace fitting process involves making alterations to the brace that affect its corrective force capacity. The objective was to design and validate an analog model of a mid-thoracic single curve scoliotic deformity for quantifying structural properties of the brace and the force response of the brace on the spine. This model was used to investigate …

Kinematic And Kinetic Effects Of Alterations In Lumbar Lordosis In People With Tight Hamstrings, Dema Assaf

Theses and Dissertations (ETD)

The etiology of nonspecific low back pain is sparsely understood. To better understand the contributing factors to nonspecific low back pain, there are often common concurrent pathologies that are investigated to determine their functional relationship to low back pain. One such pathology, investigated further in this thesis, is tight hamstrings. Specifically, the effect of hamstring length on pelvic position during gait and activities of daily living under normal and altered spinal position were investigated as part of this study in a motion analysis lab.

First, a marker validation study was conducted to ensure the accuracy of sagittal spinal measures of …

Adverse Effects Of Asparaginase In Pediatric Patients With Acute Lymphoblastic Leukemia, Chengcheng Liu

Theses and Dissertations (ETD)

Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. Asparaginase is a critical treatment component for ALL. However, its use is complicated by adverse effects, such as hypersensitivity, osteonecrosis and pancreatitis.

Hypersensitivity to asparaginase typically requires discontinuation of current formulation and substitution with other formulations, but the differential diagnosis can be challenging, and the diagnostic utility of antibody tests is unclear. We comprehensively analyzed anti-Elspar (native E.coli asparaginase) IgG antibodies in 410 pediatric patients treated on an asparaginaseintensive front-line clinical trial. Of 169 patients (41.2%) who exhibited clinical allergy, 147 (87.0%) were positive for anti-Elspar antibody. Of …

Total Knee Arthroplasty Wear Is Caused By Malrotation And Excessive Laxity, Erik Woodard

Theses and Dissertations (ETD)

Total knee arthroplasty is a proven technique which combines specially designed components and surgical processes to treat cartilage degeneration and alleviate pain in arthritic knees. However, this technique is limited by component design and surgical precision. Due to these limitations, knee arthroplasty components will eventually wear out, causing rejection and necessitating the need for a replacement. For this reason, it would be beneficial to experts if the primary causes of this wear could be identified in order to minimize the number of replacements.

This study aims to determine if a correlation exists between instability of a knee joint and the …

In Vitro Manual Therapy And Biorobotic Simulation Of Glenohumeral Joint Mobilization Techniques, Hunter Johnson Smith

Theses and Dissertations (ETD)

Physical therapists (PT) employ mobilization techniques for restoring range of motion to joints. Few studies have attempted to quantify the biomechanics of manual therapy on the glenohumeral (GH) joint. The objectives of this study were to develop an in vitro protocol to determine the biomechanical effects of joint mobilization on the GH joint, and to then simulate these mobilizations in the University of Tennessee Health Science Center (UTHSC) Joint Implant Biomechanics Laboratory’s Robotic Testing Platform (RTP).

The GH joint is an incredibly shallow socket joint. This gives the joint an unusually large range of motion (ROM) compared to other ball …

Effect Of Fixation Using Locked Compression Plate Versus Lag Screws On Biomechanics Of Talonavicular Joint: A Human Cadaveric Foot Model, Rahul Sudheer Ghotge

Theses and Dissertations (ETD)

Introduction: Talonavicular fusion is a surgery used for treating many hind foot pathologies. A problem associated with the procedure is non-union which may be due to inadequate stabilization. The objective of our study was to compare the effect of two surgical fixation techniques on the motion and biomechanics of the talonavicular joint in a human cadaveric foot model.

Materials and Methods: Thirteen human cadaveric foot specimens were prepared, mounted in a multi-axis programmable robot, and loaded using four loading scenarios. Each of the four loading scenarios consisted of a constant Achilles tendon load of 350N followed by either internal or …

The Use Of Preclinical Models To Improve The Treatment Of Retinoblastoma, Katie Marie Nemeth

Theses and Dissertations (ETD)

Rodent models play an essential role in the development of new chemotherapeutics and dosing regimes. It is often difficult to carryout a clinical study for pediatric cancers due to the small patient population. Retinoblastoma, a pediatric cancer of the eye, is one example of a pediatric cancer that can benefit from preclinical studies. Over the years various retinoblastoma rodent models have been developed used to test various combination of broad-spectrum systemic chemotherapy. It was found form these studies that the combination of topotecan and carboplatin was effective. However both drugs cause myelosuppression and therefore administrating both of these drugs systemically …

Preosteoblast Behavior On A Synthetic Calcium Phosphate Scaffold Coated With Cell Derived Matrix, Daniel A. Young

Theses and Dissertations (ETD)

Bone grafts are commonly used for the treatment of large bone defects. Biodegradable, synthetic bone grafts combined with cells and growth factors as a tissue engineered construct can provide benefits over the common autografts and allografts currently used. Calcium phosphate (CaP) materials offer high biocompatibility and chemical similarity to natural bone tissue. Biodegradable beta-tricalcium phosphate (β-TCP) scaffolds with an interconnected porous network have been created to promote tissue ingrowth and regeneration in vitro and in vivo. Extracellular matrix (ECM) coated on titanium and polymer scaffolds has been shown to improve cell response to those material surfaces. Here, we attempted …

Chitosan/Ellagic Acid Composite Materials For Local Cancer Therapy, Sung Woo Kim

Theses and Dissertations (ETD)

Current advances in the drug delivery have improved the therapeutic efficacy of the drug and minimized risks of side effects associated with toxicity of the drug. Implantable polymeric delivery system has gained increasing attentions for controlled drug release and localized treatments. In comparison to conventional chemotherapy, polymeric delivery systems are implantable at a local targeted site and biodegradable after a sufficient therapeutic span. The objectives of this project were to fabricate and characterize an implantable polymeric vehicle for a local chemotherapy and investigate its biological properties against cancer cells including human WM115 melanoma, human U87 glioblastoma, and rat C6 glioma …