Translational Medical Research Commons^™

Scalable Feature Selection And Extraction With Applications In Kinase Polypharmacology, Derek Jones

Theses and Dissertations--Computer Science

In order to reduce the time associated with and the costs of drug discovery, machine learning is being used to automate much of the work in this process. However the size and complex nature of molecular data makes the application of machine learning especially challenging. Much work must go into the process of engineering features that are then used to train machine learning models, costing considerable amounts of time and requiring the knowledge of domain experts to be most effective. The purpose of this work is to demonstrate data driven approaches to perform the feature selection and extraction steps in …

Reducing Sepsis Mortality: A Cloud-Based Alert Approach, Janet A. Zink

Theses and Dissertations

The aim of this study is to examine the impact of a cloud-based CDS alerting system for SIRS, a precursor to sepsis, and sepsis itself, on adult patient and process outcomes at VCU Health System. The two main hypotheses are: 1) the implementation of cloud-based SIRS and sepsis alerts will lead to lower sepsis-related mortality and lower average length of stay, and 2) the implementation of cloud-based SIRS and sepsis alerts will lead to more frequent ordering of the Sepsis PowerPlan and more recording of sepsis diagnoses. To measure these outcomes, a pre-post study was conducted. A pre-implementation group diagnosed …

Effects Of The Na-Cl Co-Transporter (Ncc) In Western Diet Induced Metabolic And Cardiac Dysfunction, Zachary S. Cutter

Theses and Dissertations

Interleukin-18 (IL-18) is a pro-inflammatory cytokine known to be involved in maintaining metabolic homeostasis; however, also capable of inducing cardiac dysfunction. Additionally, IL-18, has been shown to bind to a novel receptor, the Na-Cl Co-transporter (NCC). We hypothesized that NCC mediates IL-18 metabolic and cardiac signaling in mice. Using male C57BL/6J mice, we compared the metabolic and cardiac function changes after at least 8 weeks of high-saturated fat high sugar diet (Western Diet) in NCC knockout (NCCKO), IL-18 knockout (IL-18KO), and wild-type mice. We show that NCCKO mice have significantly increased body weight gain from baseline, no difference in fasting …

Age-Dependent Changes In Oxygen Supply And Demand Of Rat Spinotrapezius Muscle, Sami C. Dodhy

Theses and Dissertations

Because of the aerobic nature of cellular metabolism in mammalian organisms, a continuous supply of oxygen is necessary to maintain normal physiological function. As organisms age, their metabolic rates generally decline and there are accompanying alterations in the structure and function of the microcirculation, as this part of the cardiovascular system is especially important for oxygen exchange. The overall Oxygen Transport System can be considered as being composed of two complementary components: one for Oxygen Demand and one for Oxygen Supply. The purpose of the current work is to describe the age-dependent changes in both oxygen demand and oxygen supply …

Type 1 Diabetes Alters Lipid Handling And Metabolism In Human Fibroblasts And Peripheral Blood Mononuclear Cells, Albert R. Jones Iv, Emily L. Coleman, Nicholas R. Husni, Jude T. Deeney, Forum Raval, Devin Steenkamp, Hans Dooms, Barbara S. Nikolajczyk, Barbara E. Corkey

Clinical and Translational Science Faculty Publications

Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca²⁺ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis factor α (TNFα). These data indicate that metabolic and signal transduction defects present in T1D can be elicited ex vivo in isolated cells. Changes that precede T1D, including inflammation, may activate atypical responses in people that are genetically predisposed to T1D. To identify such cellular differences …

Training Impact On Novice And Experienced Research Coordinators, Linda S. Behar-Horenstein, Jonell Efantis Potter Ph.D., Alena Prikhidko Phd, Candidate, Stephanie Swords Ma, Ccrp, Stephen Sonstein Phd, H Robert Kolb Rn Bs Ccrc

The Qualitative Report

Competency-based training and professional development is critical to the clinical research enterprise. Understanding research coordinators’ perspectives is important for establishing a common core curriculum. The purpose of this study was to describe participants’ perspectives regarding the impact of online and classroom training sessions. 27 participants among three institutions, completed a two-day classroom training session. 10 novice and seven experienced research coordinators participated in focus group interviews. Grounded theory revealed similarities in novice and experienced coordinator themes including Identifying Preferences for Instruction and Changing Self Perceptions. Differences, seen in experienced participants, focused on personal change, in the theme of Re-Assessing Skills. …

Hockey Fans In Training: A Pilot Pragmatic 1 Randomized Controlled Trial, Robert Petrella, Dawn P. Gill, Guangyong Zou, Ashleigh De Cruz, Brendan Riggin, Cassandra Bartol, Karen Danylchuk, Kate Hunt, Sally Wyke, Cindy M. Gray, Christopher Bunn, Merrick Zwarenstein

Lifestyle Research Team

Introduction Hockey Fans in Training (Hockey FIT) is a gender-sensitized weight loss and healthy lifestyle program. We investigated 1) feasibility of recruiting and retaining overweight and obese men into a pilot pragmatic randomized controlled trial and 2) potential for Hockey FIT to lead to weight loss and improvements in other outcomes at 12 wk and 12 months.

Methods Male fans of two ice hockey teams (35–65 yr; body mass index ≥28 kg·m−2) located in Ontario (Canada) were randomized to intervention (Hockey FIT) or comparator (wait-list control). Hockey FIT includes a 12-wk active phase (weekly, coach-led group meetings including provision of …

Hockey Fans In Training: A Pilot Pragmatic 1 Randomized Controlled Trial, Robert Petrella, Dawn P. Gill, Guangyong Zou, Ashleigh De Cruz, Brendan Riggin, Cassandra Bartol, Karen Danylchuk, Kate Hunt, Sally Wyke, Cindy M. Gray, Christopher Bunn, Merrick Zwarenstein

Lifestyle Research Team

Introduction Hockey Fans in Training (Hockey FIT) is a gender-sensitized weight loss and healthy lifestyle program. We investigated 1) feasibility of recruiting and retaining overweight and obese men into a pilot pragmatic randomized controlled trial and 2) potential for Hockey FIT to lead to weight loss and improvements in other outcomes at 12 wk and 12 months.

Methods Male fans of two ice hockey teams (35–65 yr; body mass index ≥28 kg·m−2) located in Ontario (Canada) were randomized to intervention (Hockey FIT) or comparator (wait-list control). Hockey FIT includes a 12-wk active phase (weekly, coach-led group meetings including provision of …

Hmgcs2 Is A Key Ketogenic Enzyme Potentially Involved In Type 1 Diabetes With High Cardiovascular Risk., Sanket Kumar Shukla, Weijing Liu, Kunal Sikder, Sankar Addya, Amrita Sarkar, Yidong Wei, Khadija Rafiq

Center for Translational Medicine Faculty Papers

Diabetes increases the risk of Cardio-vascular disease (CVD). CVD is more prevalent in type 2 diabetes (T2D) than type 1 diabetes (T1D), but the mortality risk is higher in T1D than in T2D. The pathophysiology of CVD in T1D is poorly defined. To learn more about biological pathways that are potentially involved in T1D with cardiac dysfunction, we sought to identify differentially expressed genes in the T1D heart. Our study used T1D mice with severe hyperglycemia along with significant deficits in echocardiographic measurements. Microarray analysis of heart tissue RNA revealed that the T1D mice differentially expressed 10 genes compared to …

Impact Of Kras/Nras Mutational Heterogeneity On Clinical Outcomes In Colorectal Cancer, Jonathan M. Loree

Dissertations and Theses (Open Access)

Introduction: Mutations in KRAS/NRAS (RAS) predict a lack of benefit from anti-EGFR agents in metastatic colorectal cancer (mCRC). As next generation sequencing (NGS) has advanced, we are discovering atypical and low allele frequency mutations. We aimed to evaluate how NGS can optimally define RAS mutant CRC and the role of relative mutant allele frequency (rMAF) as a biomarker.

Methods: Using institutional and public cohorts of mCRC patients with NGS results, we described the prevalence and clinical impact of atypical (not in current guidelines) and low rMAF RAS mutations (RAS MAF by the MAF of the mutated gene with …

Endocytic Trafficking Of The Amyloid Precursor Protein In Rat Cortical Neurons, Sahily Reyes

Dissertations and Theses (Open Access)

Amyloid-beta (Aβ) aggregation and deposition into extracellular plaques is a hallmark of the most common forms of dementia, including Alzheimer’s disease. The Aβ-containing plaques result from pathogenic cleavage of amyloid precursor protein (APP) by secretases resulting in intracellular production of Aβ peptides that are secreted and accumulate extracellularly. Despite considerable progress towards understanding APP processing and Aβ aggregation, the mechanisms underlying endosomal production of Aβ peptides and their secretion remain unclear. Using endosomes isolated from cultured primary neurons, we determined that the trafficking of APP from the endosomal membrane into internal vesicles of late endosome/multivesicular bodies (MVB) is dependent on …

Membrane Bound Il21 Promotes Natural Killer Cell Expansion Through Mir 124-3p Mediated Regulation, Anitha Somanchi

Dissertations and Theses (Open Access)

Natural Killer (NK) cells are cells of the innate immune system that act as first line of defense against viral infections and participate in tumor immune surveillance. NK cells do not cause graft versus host disease (GvHD), or require prior antigen exposure to exert anti-tumor activity, hence are an attractive choice for immunotherapy applications. Owing to small numbers of NK cells in peripheral blood (1-32%, with a 6% median), ex vivo expansion of NK cells is critical for NK cell adoptive immunotherapy, various expansion platforms have been explored over the decades. We developed a robust platform for ex vivo expansion …

Conference Proceedings: Aurora Scientific Day 2017

Journal of Patient-Centered Research and Reviews

This supplement includes select abstracts presented at the 43rd Annual Aurora Scientific Day research symposium on May 24, 2017. Aurora Scientific Day hosts a forum for original research conducted by faculty, fellows, residents, and other allied health professionals affiliated with Aurora Health Care, an integrated health system headquartered in Milwaukee, Wisconsin.

Generation Of A Patient-Derived Brain Metastasis Breast Cancer Cell Line Via Novel Orthotopic Injection Placement And Serial Mouse Transplantation To Develop Pdx Mouse Model, Amber L. Lacrosse, Denise M. Coley, Paul J. Mintz, Santhi D. Konduri, Richard A. Rovin, Amin B. Kassam

Journal of Patient-Centered Research and Reviews

Background: The incidence of brain metastasis appears to be increasing, potentially due to advanced technology that aids early diagnosis. Patient-derived xenografts (PDX) have high translational value, as these models retain key functional characteristics of the patient tumor. PDX models are useful to understand the molecular basis of tumorigenesis and to identify new treatment targets. However, generating a first-line PDX model is challenging as engraftment failure is high. Serial transplanting tumor tissue via mouse-to-mouse propagation increases engraftment rates and decreases PDX development time. Herein we report methods to generate a PDX cell line from patient-derived tumor tissue that includes the cerebral …

Preliminary Evaluation Of An Lyta Pcr Assay For Detection Of Streptococcus Pneumoniae In Urine Specimens From Hospitalized Patients With Community-Acquired Pneumonia, Subathra Marimuthu, James T. Summersgill, Kuldeep Ghosh, Leslie A Wolf

The University of Louisville Journal of Respiratory Infections

Community acquired pneumonia (CAP) due to Streptococcus pneumoniae still occurs in at risk populations, despite the availability of effective vaccines. Laboratory confirmation of S. pneumoniae remains challenging in cases of CAP despite advances in blood culture techniques and the availability of nucleic acid amplification tests such as PCR-based methods. Urine specimens are an attractive sample type because they are non-invasive compared to bronchial washes or whole blood specimens for patients with CAP. While urine specimens have been used successfully in antigen detection assays, they have not been extensively evaluated for PCR-based assays. In this preliminary study, we evaluated the potential …

Distributing Data And Analysis Software Containers For Better Data Sharing In Clinical Research, William A. Mattingly Phd, Stephen Furmanek, Christopher M. Sinclair, Timothy L. Wiemken Phd

The University of Louisville Journal of Respiratory Infections

Introduction: Data sharing in clinical research is critical for increasing knowledge discovery. Data and software tools should be FAIR: Findable, Accessible, Inter-operable and Re-usable. Many bottlenecks exist in the process of a clinical investigator using shared data including data acquisition and statistical analysis. The objective of this project is to develop a structure for sharing data and providing rapid automated statistical analysis through creation of a pre-packaged, open-source software container.

Methods: We use the open source software container technologies VirtualBox and Vagrant to create a template for sharing clinical data and analysis scripts as a single container. We use …

Rationale And Methods Of The Study Protocol: Streptococcus Pneumoniae Serotypes In Adults 18 Years And Older With Radiographically-Confirmed Community-Acquired Pneumonia (Cap), Ronika Alexander, Paula Peyrani, Julio A. Ramirez, Wesley H. Self Md, Mph, Carlos Grijalva, Francis Counselman, Gregory A. Volturo, Heidi Kabler, Luis Ostrosky-Zeichner, Richard Wunderink, Robert L. Sherwin, Senen Pena, Thomas File, Timothy L. Wiemken, Sharon Gray, Michael Pride, Kimbal D. Ford, Qin Jiang, Raul Isturiz

The University of Louisville Journal of Respiratory Infections

This study was an active, prospective surveillance study of adults 18 years and older hospitalized with community-acquired pneumonia (CAP) due to Streptococcus pneumoniae conducted at 21 hospitals in ten cities across the United States. This report describes the surveillance methodology applied between October 7, 2013 and September 30, 2016, including the identification and description of surveillance areas and populations at-risk for CAP hospitalization for estimation of incidence rates for selected study sites.

Streptococcus Pneumoniae Antigen, Missing Opportunities Of A Promising Point Of Care Diagnostic Test, Magdelina Słomka, Ruby Gupta, Baltej Singh, Venkatesh Gondhi, Siddartha Bhandary, Ekezie Francis, Jose Bordon

The University of Louisville Journal of Respiratory Infections

Background: The etiologic diagnosis of community acquired pneumonia (CAP) and community-acquired meningitis (CAM) are still far from optimal accuracy and turnaround time. The most common bacterial pathogen identified in both CAP and CAM is Streptococcus pneumoniae.

Methods: We reviewed the literature on S. pneumoniae antigen to highlight opportunities to optimize its use as a point of care diagnostic test to maximize quality of patient care, antimicrobial stewardship outcomes and cost saving. A PubMed search was performed using key words “S. pneumoniae antigen; rapid diagnostic tests for S. pneumoniae”. We selected articles in English and sorted into randomized …

Level Of Recall Bias Regarding Pneumococcal Vaccination History Among Adults Hospitalized With Community-Acquired Pneumonia: Results From The University Of Louisville Pneumonia Study, Sarah Van Heiden, Ruth Carrico, Timothy L. Wiemken, Ronika Alexander, John M. Mclaughlin, Qin Jiang, Paula Peyrani, William A. Mattingly, Stephen P. Furmanek, Connor L. English, Senen Pena, Raul Isturiz, Julio A. Ramirez

The University of Louisville Journal of Respiratory Infections

Background: Recall bias is likely to occur in vaccine effectiveness studies using self-reported vaccination history. The validity of patient-reported vaccination status for adults is not well defined. The objective of this study was to evaluate the validity of self-reported pneumococcal vaccination history among patients hospitalized with community-acquired pneumonia (CAP).

Methods: Prospective ancillary study of a population-based observational study of hospitalized patients with CAP in the city of Louisville. To be included in the analysis, patients had to (i) be reached by phone 30-days after discharge from the hospital and (ii) report that they remembered whether or not they received a …

One-Year Mortality In Patients With Community-Acquired Pneumonia, Paula Peyrani, Julio A. Ramirez

The University of Louisville Journal of Respiratory Infections

Pneumonia remains a common cause of morbidity and mortality in the US. Although, communityacquired pneumonia (CAP) has traditionally been considered an acute process, more recently, data have emerged showing that patients surviving an episode of CAP are at increased risk of death long after hospital discharged. In this descriptive review, we examine the current knowledge of long-term mortality and propose a hypothesis explaining the pathogenesis of long-term mortality in patients with CAP.