Medicine and Health Sciences Commons^™

Urinary Bile Acid Indices As Prognostic Biomarkers For The Complications Of Liver Diseases, Wenkuan Li

Theses & Dissertations

Hepatobilary diseases cause the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues, which may lead to an unfavorable prognosis. In this study, we compared the urinary BA profile in 257 patients with hepatobilary diseases during a 7-year follow-up period. We investigated the use of the urinary BA profile to develop logistic regression models to predict the prognosis of hepatobiliary diseases in terms of developing disease-related complications, especially for ascites. The urinary BA profile was characterized by calculating BA indices, which quantify the composition, metabolism, hydrophilicity, and toxicity of the BA profile. All patients had high …

Apixaban To Prevent Thrombosis In Adult Patients Treated With Asparaginase, Krishna Gundabolu

Theses & Dissertations

The outcomes of pediatric acute lymphoblastic leukemia (ALL) have improved dramatically after intensification of the multi-agent chemotherapy backbone over a period of time starting from 1960’s, and asparaginase (ASP) is an important part of this success story. Adoption of such strategy in adult ALL and other high grade lymphoid neoplasms had been difficult due to higher anticipated toxicities including thrombosis. Many thrombosis prevention strategies including antithrombin (AT) replacement, Enoxaparin, unfractionated heparin (UFH) was studied but there is no firmly established evidence-based approach yet. We report the safety and efficacy of thrombosis prophylaxis with apixaban 2.5 mg orally twice daily for …

A Collection Of Research In Transplantation Surgery: The Importance Of Assessing Outcomes In A Field Dependent On The Availability Of Limited Resources, Amy J. Hargrove

Theses & Dissertations

This thesis is a collection of three independent projects related to transplantation surgery. In summary, project I involves an assessment of long-term quality of life outcomes of intestinal transplantation in pediatric patients who are now in adulthood, with comparison to other solid organ transplant patients. Health related quality of life surveys were completed in 14 adult patients who underwent intestine, liver, or kidney transplants as children. Project II evaluates pre-surgical characteristics of patients undergoing liver transplant to assess predictive factors for the need of venovenous bypass utilization intraoperatively by assessing trends at the University of Nebraska Medical Center in 95 …

Proof Of Concept: The Use Of Renal Biomarkers In Critically Ill Pediatric Patients For Therapeutic Drug Monitoring, Christopher Lee Shaffer

Theses & Dissertations

Acute kidney injury (AKI) is a serious and common complication in critically ill pediatric patients. The incidence of pediatric AKI continues to increase, especially in patients who undergo surgical correction of congenital heart defects. Serum creatinine and urine output are the most commonly used tools to assess renal function, with international guidelines standardizing AKI-definitions based upon these parameters. However, changes in serum creatinine can occur 24 hours or later after a renal insult event, delaying the diagnosis and potential interventions to reverse injury. It is critical to identify endogenous renal biomarkers within the pediatric population that are both timely and …

Molecular Pathogenesis Of A Novel Subgroup Of Peripheral T-Cell Lymphomas, Jiayu Yu

Theses & Dissertations

Peripheral T-cell Lymphoma (PTCL) consists of numerous distinct disease entities. With the current diagnostic criteria over a third of the cases cannot be further classified and are called "not otherwise specified" (PTCL-NOS). Using gene expression profiling (GEP) of tumors, we identified two novels PTCL-NOS molecular subgroups either characterized by high expression of GATA3 (33%), which is associated with Th2 cell differentiation, or high expression of TBX21 (49%) which regulates Th1 cell maturation. Therefore, stratifying patients for diagnosis and identifying the underlying genetic basis to improve clinical therapy becomes critical to prognosis.

First, we performed DNA copy number analysis by using …

Insights Into Cutaneous Squamous Cell Carcinoma Pathogenesis And Metastasis Using A Bedside-To-Bench Approach, Marissa Lobl

Theses & Dissertations

Cutaneous squamous cell carcinoma (SCC) is the second most common skin cancer, affecting 1,000,000 people in the United States annually and causing approximately 9,000 deaths. SCC and basal cell carcinoma are the most common types of skin cancer arising in the superficial squamous cells or deeper basal cells of the epidermis, respectively. SCC is more likely to invade and metastasize, while basal cell cancer tends to grow locally. While the majority of cases of SCC are cured by surgery alone, approximately 2-5% of SCCs metastasize, at which point outcomes may be poor. Specific patient groups, particularly immunosuppressed patients, have a …

Gene Expression Profiling Of Mapk Pathway Inhibitor Resistance In Cutaneous Melanoma: Can Bioinformatics Be Used To Select Better Melanoma Cell Lines?, Stephen Luebker

Theses & Dissertations

Melanoma is the deadliest form of skin cancer, and incidence has continued to increase. Half of all melanomas have a BRAF V600E mutation and respond to MAPK pathway inhibitors, including BRAF inhibitor therapy or BRAF/MEK inhibitor combination therapy, but nearly all patients develop treatment resistance. Melanoma cell lines produce variable results as models of MAPK pathway inhibitor resistance. To better understand how the genomic similarity of a melanoma cell line to patient-derived tumors affects resistance mechanisms, differences in DNA mutations and copy-number alterations were compared between melanoma cell lines profiled by the Cancer Cell Line Encyclopedia and cutaneous melanoma tumors …

Superoxide And Pulmonary Hypertension, Tammy Wichman

Theses & Dissertations

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disease, which is progressive and fatal despite advances in therapy. Animal models have shown that oxidative stress may be pathogenic in PAH. We hypothesize that oxidative stress, as measured by increased levels of a specific reactive oxygen species, superoxide (O₂^•-), mayplay a role in PAH in humans. Using a novel application of electron paramagnetic resonance (EPR) spectroscopy, we initially evaluated whether levels of O₂^•- from whole blood collected from the pulmonary artery collected during right heart catheterization (RHC) would correlate with O₂^•- levels in peripheral …

Association Of New And/Or Progressive Multiple Organ Dysfunction Syndrome With Mortality And New Morbidity Among Children Encountering Septic Shock, Rachel L. Waworuntu

Capstone Experience

Despite reductions in sepsis mortality, there remains a substantial morbidity burden among children who survive sepsis. Furthermore, the majority develop multiple organ ‘group has historically been analyzed as a single cohort. Using the Life After Pediatric Sepsis Evaluation (LAPSE) investigation database, we studied the association of new and progressive multiple organ dysfunction syndrome (NPMODS) with morbidity and mortality among children with septic shock. We hypothesized that NPMODS represents a distinct phenotype based on evolving organ dysfunction. There was evidence of an association but it did not reach the 0.05 level of significance. We also hypothesized and confirmed that children with …

Mucin And Splice Variant Profiles Of Pancreatic Adenocarcinoma Predict Patient Survival And Subtyping, Christopher M. Thompson

Theses & Dissertations

PDAC is a pancreatic epithelial malignancy and demonstrates aggressive progression and bleak patient prognosis. Despite decades of research, the evolution of novel diagnostics and intervention modalities for PDAC is stagnant. This dissertation explores the characteristic aberrant and elevated expression of mucins in PDAC. Beginning with the hypothesis that mucins are associated with disease aggressiveness, analysis of PDAC patient survival in TCGA revealed no associations between single mucin expression and patient survival. This led to the underlying issue of PDAC tumor cellularity since this disease demonstrates variability in the proportion of cancer cells within the tumor. Tumor purity assessed with the …

Fire Service Covid-19 Infection Prevention And Control Policy Comparison, Saaddedine Dichari

Theses & Dissertations

To date, there have been over 2.7 million deaths and more than 126 million cases attributed to the COVID-19 pandemic (JHU, 2021). This pandemic has affected nearly every aspect of daily life. Among those impacted are U.S. firefighters, as they provide many services beyond simply extinguishing structure fires and are frequently dual certified as emergency medical technicians. Many of the victims of this pandemic have relied on first responders to provide them with emergency medical care and hospital transport. When caring for these infected patients, firefighters have an increased risk of exposure and must be provided with adequate …

Biomedical Porcine Models For The Study Of Surgical Hemostasis, Hindlimb Ischemia, And Pancreatic Cancer, Shruthishree Aravind

Theses & Dissertations

Murine models have dominated the world of biomedical research and comparative medicine since their development in the early 1900s. [1] While they may be suitable models to study proteomics and genomics, they may not serve as effective translational models. [2-4] Murine models do not accurately model the pathophysiology of human disease and are limited by their size, application of medical imaging and intervention, which reduces their overall preclinical predictive value. [2-4]

Porcine models on the other hand, are slowly and steadily bridging the gap between murine models and human patients. [5] Pigs …

The Driving Simulator Visual Field In Glaucoma – A Novel Task To Test Available Field Of View, Deepta Ghate

Theses & Dissertations

Glaucoma causes peripheral vision loss and impaired driving performance. We developed a novel driving simulator visual field task (DSVF) in a panoramic driving simulator to map the available field of view under different perceptual task loads in naturalistic settings. Our hypothesis is that “available field of view” will decrease with increasing task load in both glaucoma subjects and controls. This is a cross-sectional study with 28 glaucoma subjects and 19 controls. DSVF (60̊ x 20̊ visual field at 2.5 m) was tested in a high-fidelity interactive driving simulator in 4 different scenarios: a) no distractions b) no driving condition with …

Reach, Effectiveness, Adoption, And Maintenance Of Mobile Electronic Clinical Decision Support Tools Deployed As Part Of National Quality Improvement Projects, Ellen K. Kerns

Theses & Dissertations

Electronic clinical decision support (ECDS) tools are often developed within quality improvement (QI) projects to increase adherence with the latest clinical practice guidelines. However, the potential reach and maintenance of ECDS use beyond the time and location of their associated project are very limited. Deploying ECDS using a mobile app (mECDS) has shown the potential to be a viable method of overcoming these limitations. However, it is unclear what pattern the reach and adoption of such a tool might follow and what effect this use has on clinical practice. Our team developed an app which contained two different mECDS tools …

The Role Of Vgll4 And Mark2-Hdac Axis In Mitosis And Cancer, Yongji Zeng

Theses & Dissertations

The Hippo pathway is an evolutionarily conserved signaling pathway that plays important roles in stem cell biology, tissue homeostasis, and cancer development. The Hippo core signaling pathway features a kinase cascade consisting of mammalian sterile-20 like protein 1/2 (Mst1/2) and large tumor suppressor 1/2 (Lats1/2). Inactivation of the Hippo pathway is correlated with the promotion of proliferation and anti-apoptosis through activation of the transcriptional co-activator Yes-associated protein (YAP). YAP functions through binding with TEA-domain transcription factors (TEAD1–4) to activate target genes.

Vestigial-like 4 (Vgll4) functions as a transcriptional co-repressor in the Hippo-Yes associated protein (YAP) pathway. Vgll4 inhibits cell proliferation …

The Effect Of Polyunsaturated And Saturated Fatty Acids On Seizure Presence And Severity In A Cohort Of Subjects In An Epilepsy Monitoring Unit, Jana K. Wells

Theses & Dissertations

Ketogenic diet therapies (KDTs) have been used to treat epilepsy for nearly 100 years. Although effective, restrictive diet patterns and unknown impacts on long-term health outcomes often prevent their use as first-line therapy. To date, a distinct mechanism of action for KDTs has not been determined and evidence suggests fatty acids (FAs) may play a role in eliciting anti-seizure effects. This dissertation aimed to provide insights into the effect of polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFAs) on seizure presence and severity through the analysis of dietary intake in a cohort of patients admitted to an epilepsy monitoring …

Multimodal Neuroimaging Of Hiv And Aging, Brandon Lew

Theses & Dissertations

HIV infection remains a significant contributor to disease burden, and with the success of antiretroviral therapies, the population of people with HIV is aging. A growing literature suggests a relationship between HIV-infection and a profile of age advancement, most notably in molecular studies of epigenetics. However, despite the widely-known high prevalence of HIV-related brain atrophy, functional deficits, and HIV-associated neurocognitive disorder (HAND), epigenetic age advancement has not been linked to HIV-related changes in neuroimaging metrics.

We applied three neuroimaging methods, structural MRI, resting state functional MRI, and resting state MEG, to study the brain structure and function of 121 virally-suppressed …

Secreted Mucin 5ac-Mediated Epithelial And Stromal Modulations Augment Pancreatic Cancer Aggressiveness, Koelina Ganguly

Theses & Dissertations

The mucosal layer that shields the epithelium of the body cavities is made up of high molecular weight, heavily glycosylated proteins called mucins that are broadly categorized into transmembrane and secreted members. Aberrant expression of secreted mucin MUC5AC has been implicated in lung, stomach, and colon cancer pathologies. MUC5AC is expressed de novo in the pancreas upon oncogenic insult, and its abundance in pancreatic tumor and circulation correlates to disease progression. However, few studies have explored beyond the diagnostic and prognostic significance of MUC5AC in pancreatic cancer (PC).

In this dissertation, we sought to investigate the mechanistic contribution of MUC5AC …

Clinical Consequences And Determinants Of False Positive Blood Cultures In Adult Hospitalized Patients, Sidra Liaquat

Theses & Dissertations

Blood cultures are the gold standard for detecting blood stream infections. However, in the US, 0.6-6% of all blood cultures get contaminated leading to adverse clinical outcomes such as unnecessarily prolonged hospital stay and antibiotic therapy. Using electronic medical records, we explored the clinical outcomes and patient-specific risk factors of contaminated blood cultures in an era where rapid blood culture testing was being utilized to provide blood culture results within hours. Rapid blood culture test results can help clinicians in early and more effective management of patients with contaminated blood cultures, thus improving clinical outcomes. We also studied the impact …

Development Of Long-Acting Antiviral Drug Nanoformulations, Denise Cobb

Theses & Dissertations

Antiretroviral therapy (ART) has improved the quality and duration of life for people living with human immunodeficiency virus (HIV) infection. However, opportunities to improve its profile abound. ART is limited by putative viral reservoir penetrance, emergence of viral mutations, inherent toxicities, and regimen non-adherence. These highlight the need improved drug delivery schemes. Previously, our lab has demonstrated that targeting mononuclear phagocytes for antiretroviral drug delivery extends drug half-life and improves penetrance into viral reservoirs, addressing these limitations of ART. Herein, we developed synthetic and biologic antiretroviral (ARV) drug nanocarriers improve the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ARVs through …

Impact Of Proton Pump Inhibitor Use On Effectiveness Of Immune Checkpoint Inhibitors In Advanced Cancer Patients, Ken Chen

Capstone Experience

Background: Gut microbiome plays a critical role in modulating therapeutic effect of immune checkpoint inhibitors (ICIs). Proton pump inhibitors (PPIs) may affect the gut microbiome by altering gut pH.

Objective: To evaluate if concurrent use of PPI 0-30 days before or after initiation of ICIs (nivolumab or pembrolizumab) is associated with poorer overall survival (OS) and progression-free survival (PFS) for patients with stage IV non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, transitional cell carcinoma or head and neck squamous cell carcinoma compared with no PPI use.

Methods: This was a single-center retrospective cohort study of advanced cancer patients …

Pandemic Driven Innovation: Development Of An Alternative Respiratory Pathogen Self-Collection Device, Thang Nguyen

Theses & Dissertations

The SARS-CoV-2 virus outbreak has underscored numerous weak links in our biodefense countermeasures against highly communicable diseases. Many believe it was our lack of an effective testing model that allowed the virus to become a global pandemic within a short period. The gold standard collection method for the SARS-CoV-2 virus involves mechanical debridement of the nasopharyngeal cavity with a stiff swab applicator, which has been known to cause pain and injury to patients, subsequently resulting in low patient acceptance of the procedure. Due to the invasive nature of the nasopharyngeal swab collection method, it may not be conducive to the …

Glycemic Variability In Patients With Stage Ii-Iii Colon Cancer, Natalie Mandolfo

Theses & Dissertations

Patients with cancer experience metabolic changes such as hypoglycemia, hyperglycemia, and glycemic variability; collectively termed malglycemia. Glycemic variability, defined as fluctuations in glucose, is a marker of metabolic instability. Higher glycemic variability is associated with adverse health outcomes in the general population and in those with diabetes. Little is known about glycemic variability in patients with cancer, especially those with solid tumor malignancies. Glycemic variability is associated with increased infection, shorter periods of remission, and higher mortality in patients with hematological cancer. This body of work describes the concept and measurement of glycemic variability to assess glycemic control in patients …

Impact Of Immunotherapy On The Survival Of Pancreatic Adenocarcinoma Patients: An Analysis Of The National Cancer Database, Saber A. Amin

Theses & Dissertations

Pancreatic adenocarcinoma (PDAC) represents 7.2% of all cancer deaths, and by 2030, it will become the second leading cause of death due to cancer. The median overall survival (OS) is 17-23 months in resectable and 4-6 months in metastatic PC [8-9]. The 5-year survival of resectable PC is 22%, and unresectable PC is 8%. A majority of patients treated with standard treatments such as surgery, chemotherapy, and radiation therapy eventually succumb to the disease due to widespread micrometastases at the time of diagnosis. Due to the minimal effect of the current treatments, novel treatment strategies such as immunotherapeutics have been …

Multiquantal Glutamate Release From Rod Photoreceptors, Cassandra L. Hays

Theses & Dissertations

Neurons communicate via Ca²⁺-dependent release of neurotransmitters packaged into vesicles (quanta). Some CNS neurons, especially sensory synapses, can release multiple vesicles at a time, increasing information transmission and overcoming the unreliability of a stochastic process. Ribbon-bearing neurons, including retinal photoreceptors, face the challenge of encoding sensory receptor potentials into an ever-changing train of vesicle release events. We studied release of glutamate using voltage clamp to measure anion currents activated during glutamate reuptake into presynaptic terminals (I_A(glu)) of salamander and mouse rods, finding that each employ distinct mechanisms for multiquantal release. In amphibian rods, we found that …

Leveraging Aqueous Humor Dynamics And Ocular Biometrics For Improving Therapeutic Outcomes In Glaucoma, Vikas Gulati

Theses & Dissertations

Glaucoma laser and incisional surgical treatments are associated with a known risk of complications. The ability to better predict treatment outcomes and individualize treatment recommendations can enhance the benefit to risk ratio of a treatment option. The work presented in this dissertation explores the interplay of biometrics, race and aqueous humor dynamics and their influence on treatment outcomes. In the first chapter, we demonstrate that pre-operative aqueous humor dynamics (higher aqueous flow, lower outflow facility and lower uveoscleral outflow) are predictive of greater intraocular pressure lowering after selective laser trabeculoplasty. The second chapter describes significant race-based differences in aqueous humor …

Urinary Bile Acid Indices As Diagnostic And Prognosic Biomarkers For Liver Diseases, Jawaher Alamoudi

Theses & Dissertations

Hepatobiliary diseases result in the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues which may contribute to an unfavorable prognosis. We compared the urinary BA profile between 300 patients with hepatobiliary diseases vs. 103 healthy controls. Also, we investigated the use of the urinary BA profile to develop survival models to predict the prognosis of hepatobiliary diseases. The urinary BA profile, a set of non-BA parameters, and the adverse events of liver transplant and/or death were monitored in patients with cholestatic liver diseases for up to 7 years. The BA profile was characterized by calculating …

Development Of An Lc-Esi-Ms/Ms Method For Determination Of A Novel Pyrrolomycin (Mp-1) And Application To Pre-Clinical Adme Studies, Wafaa N. Aldhafiri

Theses & Dissertations

A rapid, selective, and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitation of a novel Pyrrolomycin (MP-1) in mouse plasma. MP-1 was extracted from plasma utilizing a structural analog (PL-3) as the internal standard (IS). Analyte separation was achieved using a Waters Acquity UPLC®BEH C18 column (1.7 µm, 100 x 2.1 mm) protected with Acquity UPLC C18 guard column. Mobile phase consisted of 0.1% acetic acid in water (10%) and methanol (90%) at a total flow rate of 0.25 mL/min. The mass spectrometer was operated at unit resolution in the multiple reaction …

Structural Magnetic Resonance Imaging As A Diagnostic Biomarker Of Hiv-Associated Neurocognitive Disorders (Hand), Mikki Schantell

Capstone Experience

Objective: The goal of this study was to do an exploratory analysis to determine if gray matter brain volumes and cortical thickness measures obtained from structural magnetic resonance imaging (sMRI) can discriminate people with HIV-associated neurocognitive disorders (HAND), neurocognitively unimpaired people with HIV (NU PWH), and HIV-negative controls (HIV- controls) using linear discriminant analyses.

Methods: A total of 231 participants, including 110 PWH and 121 HIV- controls, completed a neuropsychological (NP) battery and an sMRI protocol. The bilateral gray matter volumes and cortical thickness brain regions were analyzed using 18 linear discriminant models to assess the discriminability of gray matter …

Effects Of Acute Intracranial Pressure Changes On Optic Nerve Head Morphology In Humnans And Pig Model, Sachin Kedar

Theses & Dissertations

The optic nerve head (ONH) is located at the interface of intracranial and intraocular compartments. It is comprised of lamina cribrosa (LC), a fenestrated connective tissue tethered to the posterior sclera across the scleral canal. Since LC is exposed to intraocular pressure (IOP) anteriorly and intracranial pressure (ICP) posteriorly, it is an ideal site for noninvasively detecting intracranial pressure (ICP) fluctuation. We hypothesized that the pressure differential between IOP and ICP across LC, will determine LC position and meridional diameter of scleral canal (also called Bruch’s membrane opening- BMOD). We tested our hypothesis in 19 human subjects undergoing medically necessary …