Digital Commons Network^™

Loss-Of-Function Genomic Variants Highlight Potential Therapeutic Targets For Cardiovascular Disease, Jonas B. Nielsen, Oren Rom, Ida Surakka, Sarah E. Graham, Wei Zhou, Tanmoy Roychowdhury, Lars G. Fritsche, Sarah A. Gagliano Taliun, Carlo Sidore, Yuhao Liu, Maiken E. Gabrielsen, Anne Heidi Skogholt, Brooke Wolford, William Overton, Ying Zhao, Jin Chen, He Zhang, Whitney E. Hornsby, Akua Acheampong, Austen Grooms, Amanda Schaefer, Gregory J. M. Zajac, Luis Villacorta, Jifeng Zhang, Ben Brumpton, Mari Løset, Vivek Rai, Pia R. Lundegaard, Morten S. Olesen, Kent D. Taylor, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of …

Antibodies Against Lysophosphatidic Acid Protect Against Blast-Induced Ocular Injuries, Peethambaran Arun, Franco Rossetti, James C. Demar, Ying Wang, Andrew B. Batuure, Donna M. Wilder, Irene D. Gist, Andrew J. Morris, Roger A. Sabbadini, Joseph B. Long

Internal Medicine Faculty Publications

Exposure to blast overpressure waves is implicated as the major cause of ocular injuries and resultant visual dysfunction in veterans involved in recent combat operations. No effective therapeutic strategies have been developed so far for blast-induced ocular dysfunction. Lysophosphatidic acid (LPA) is a bioactive phospholipid generated by activated platelets, astrocytes, choroidal plexus cells, and microglia and is reported to play major roles in stimulating inflammatory processes. The levels of LPA in the cerebrospinal fluid have been reported to increase acutely in patients with traumatic brain injury (TBI) as well as in a controlled cortical impact (CCI) TBI model in mice. …

Web-Based Interactive Mapping From Data Dictionaries To Ontologies, With An Application To Cancer Registry, Shiqiang Tao, Ningzhou Zeng, Isaac Hands, Joseph Hurt-Mueller, Eric B. Durbin, Licong Cui, Guoqiang Zhang

Internal Medicine Faculty Publications

BACKGROUND: The Kentucky Cancer Registry (KCR) is a central cancer registry for the state of Kentucky that receives data about incident cancer cases from all healthcare facilities in the state within 6 months of diagnosis. Similar to all other U.S. and Canadian cancer registries, KCR uses a data dictionary provided by the North American Association of Central Cancer Registries (NAACCR) for standardized data entry. The NAACCR data dictionary is not an ontological system. Mapping between the NAACCR data dictionary and the National Cancer Institute (NCI) Thesaurus (NCIt) will facilitate the enrichment, dissemination and utilization of cancer registry data. We introduce …

Pregabalin-Induced Myopathy In A Double Lung Transplant Recipient, Vishwajit Hegde, Nidhi Shekar, Filip G. Garrett, Maher A. Baz, Michael I. Anstead

Internal Medicine Faculty Publications

Pregabalin is a gamma-aminobutyric acid (GABA) derivative that was commercially approved by the Food and Drug Administration (FDA) in 2004. It is commonly used in the treatment of diabetic neuropathy, peripheral neuropathy, and spinal cord injury. We present the case of a 36-year-old Caucasian male double lung transplant recipient who presented with an 18-month history of fatigue and muscle weakness. He had elevated creatinine kinase level and his muscle biopsy showed evidence of drug-induced myopathy that improved after the cessation of pregabalin. We present a case of drug-induced myopathy as a rare complication of pregabalin therapy in a double lung …

Predicting In-Hospital Mortality After An In-Hospital Cardiac Arrest: A Multivariate Analysis, Talal Alnabelsi, Rahul Annabathula, Julie Shelton, Marc Paranzino, Sarah Price Faulkner, Matthew Cook, Adam J. Dugan, Sethabhisha Nerusu, Susan S. Smyth, Vedant A. Gupta

Gill Heart & Vascular Institute Faculty Publications

Aim of the study: Most survivors of an in-hospital cardiac arrest do not leave the hospital alive, and there is a need for a more patient-centered, holistic approach to the assessment of prognosis after an arrest. We sought to identify pre-, peri-, and post-arrest variables associated with in-hospital mortality amongst survivors of an in-hospital cardiac arrest.

Methods: This was a retrospective cohort study of patients ≥18 years of age who were resuscitated from an in-hospital arrest at our University Medical Center from January 1, 2013 to September 31, 2016. In-hospital mortality was chosen as a primary outcome and unfavorable discharge …

Syphilis Hepatitis Presenting As A Mimic Of Primary Biliary Cholangitis, Cody Kern, Ahmed Elmoursi, Caroline Blake, Andrew Hoellein

Internal Medicine Faculty Publications

Syphilis hepatitis is a rare cause of acute liver injury. Primary biliary cholangitis (PBC) is a progressive autoimmune disease characterized by the typical presentation of a cholestatic liver injury and the presence of antimitochondrial antibodies (AMAs). We present a case of syphilis hepatitis that presented as a mimic to PBC with positive AMA. The eradication of syphilis led to the resolution of the liver injury and down trending of the antibody level. We recommend excluding syphilis in patients with high-risk behaviors presenting with a cholestatic liver injury and positive AMA before the diagnosis of PBC.

Development, Implementation And Outcomes Of A Quality Assurance System For The Provision Of Continuous Renal Replacement Therapy In The Intensive Care Unit, Eloy F. Ruiz, Victor M. Ortiz-Soriano, Monica Talbott, Bryan A. Klein, Melissa L. Thompson Bastin, Kirby P. Mayer, Emily B. Price, Robert Dorfman, Brandi N. Adams, Lisa J. Fryman, Javier A. Neyra, The University Of Kentucky Crrt Quality Assurance Group

Physical Therapy Faculty Publications

Critically ill patients with requirement of continuous renal replacement therapy (CRRT) represent a growing intensive care unit (ICU) population. Optimal CRRT delivery demands continuous communication between stakeholders, iterative adjustment of therapy, and quality assurance systems. This Quality Improvement (QI) study reports the development, implementation and outcomes of a quality assurance system to support the provision of CRRT in the ICU. This study was carried out at the University of Kentucky Medical Center between September 2016 and June 2019. We implemented a quality assurance system using a step-wise approach based on the (a) assembly of a multidisciplinary team, (b) standardization of …

Postoperative Hypocalcemia Following Parathyroidectomy For Giant Parathyroid Adenoma, Rishi Raj, Adele Amine, Demetrios Herodotou

Internal Medicine Faculty Publications

Objective
Giant parathyroid adenomas (GPAs) are a rare type of parathyroid adenoma (PA) weighing > 2 to 3 g. The objective of this manuscript is to report a case of giant parathyroid adenoma and highlight the risk of postoperative hypocalcemia.

Methods
We describe the presentation and work-up of a woman with GPA confirmed with histopathology as well as management of postoperative hypocalcemia.

Results
A 66-year-old Caucasian female with chronic fatigue was found to have elevated calcium levels at 13.7 mg/dL (normal, 8.9 to 10.2 mg/dL) and elevated parathyroid hormone levels at 1,240 pg/mL (normal, 12 to 72 pg/mL). Contrast enhanced computed …

An International Study Exploring The Experience Of Survivors Of Critical Illness As Volunteers Within Icu Recovery Services, Carly Robinson, Elizabeth Hibbert, Anthony J. Bastin, Joel Meyer, Ashley A. Montgomery-Yates, Tara Quasim, Andrew Slack, Mark E. Mikkelsen, Theodore J. Iwashyna, Kimberly J. Haines, Carla M. Sevin, Joanne Mcpeake, Leanne M. Boehm

Internal Medicine Faculty Publications

Objectives:
Many clinicians have implemented follow-up and aftercare to support patients following ICU. Some of this care is supported and facilitated by peer volunteers. There is limited contemporary work that has explicitly explored volunteer roles within ICU recovery services or the experience of volunteers undertaking these roles. We sought to explore the experience of survivors of critical illness, as volunteers, involved in ICU recovery services and understand their motivation for undertaking these roles.

Design:
Qualitative exploration using in-depth semistructured interviews. The study design used an inductive content analysis process. We also documented the roles that were adopted by volunteers in …

Combating Acquired Resistance To Mapk Inhibitors In Melanoma By Targeting Abl1/2-Mediated Reactivation Of Mek/Erk/Myc Signaling, Rakshamani Tripathi, Zulong Liu, Aditi Jain, Anastasia Lyon, Christina Meeks, Dana Richards, Jinpeng Liu, Daheng He, Chi Wang, Marika Nespi, Andrey Rymar, Peng Wang, Melissa Wilson, Rina Plattner

Pharmacology and Nutritional Sciences Faculty Publications

Metastatic melanoma remains an incurable disease for many patients due to the limited success of targeted and immunotherapies. BRAF and MEK inhibitors reduce metastatic burden for patients with melanomas harboring BRAF mutations; however, most eventually relapse due to acquired resistance. Here, we demonstrate that ABL1/2 kinase activities and/or expression are potentiated in cell lines and patient samples following resistance, and ABL1/2 drive BRAF and BRAF/MEK inhibitor resistance by inducing reactivation of MEK/ERK/MYC signaling. Silencing/inhibiting ABL1/2 blocks pathway reactivation, and resensitizes resistant cells to BRAF/MEK inhibitors, whereas expression of constitutively active ABL1/2 is sufficient to promote resistance. Significantly, nilotinib (2nd generation …

Salmonella Meningitis Complicated By Ventriculitis And Brain Abscesses In An Hiv Positive Adult Patient, Tamoor Ahmed, Taha Ahmed

Internal Medicine Faculty Publications

Salmonella meningitis is a rare complication of Salmonella sepsis and is mostly reported in infants and young children. The incidence of Salmonella bacteremia is increased in immunocompromised adult individuals, such as those having human immunodeficiency virus (HIV) infection. Ventriculitis and brain abscess as a complication of Salmonella intracranial infection is particularly rare, even in patients who are immunosuppressed. Herein, we report a case of Salmonella meningitis complicated by ventriculitis and two brain abscesses in an HIV positive adult patient requiring mini-craniectomy and drainage along with a prolonged course of antibiotic therapy with a favorable outcome.

Genome-Wide Dna Methylation Profiling In Human Breast Tissue By Illumina Truseq Methyl Capture Epic Sequencing And Infinium Methylationepic Beadchip Microarray, Nan Lin, Jinpeng Liu, James Castle, Jun Wan, Aditi Shendre, Yunlong Liu, Chi Wang, Chunyan He

Markey Cancer Center Faculty Publications

A newly-developed platform, the Illumina TruSeq Methyl Capture EPIC library prep (TruSeq EPIC), builds on the content of the Infinium MethylationEPIC Beadchip Microarray (EPIC-array) and leverages the power of next-generation sequencing for targeted bisulphite sequencing. We empirically examined the performance of TruSeq EPIC and EPIC-array in assessing genome-wide DNA methylation in breast tissue samples. TruSeq EPIC provided data with a much higher density in the regions when compared to EPIC-array (~2.74 million CpGs with at least 10X coverage vs ~752 K CpGs, respectively). Approximately 398 K CpGs were common and measured across the two platforms in every sample. Overall, there …

The Srg Rat, A Sprague-Dawley Rag2/Il2rg Double-Knockout Validated For Human Tumor Oncology Studies, Fallon K. Noto, Jaya Sangodkar, Bisoye Towobola Adedeji, Sam Moody, Christopher B. Mcclain, Ming Tong, Eric Ostertag, Jack Crawford, Xiaohua Gao, Lauren Hurst, Caitlin M. O'Connor, Erika N. Hanson, Sudeh Izadmehr, Rita Tohmé, Jyothsna Narla, Kristin Lesueur, Kajari Bhattacharya, Amit Rupani, Marwan K. Tayeh, Jeffrey W. Innis, Matthew D. Galsky, B. Mark Evers, Analisa Difeo, Goutham Narla, Tseten Y. Jamling

Markey Cancer Center Faculty Publications

We have created the immunodeficient SRG rat, a Sprague-Dawley Rag2/Il2rg double knockout that lacks mature B cells, T cells, and circulating NK cells. This model has been tested and validated for use in oncology (SRG OncoRat®). The SRG rat demonstrates efficient tumor take rates and growth kinetics with different human cancer cell lines and PDXs. Although multiple immunodeficient rodent strains are available, some important human cancer cell lines exhibit poor tumor growth and high variability in those models. The VCaP prostate cancer model is one such cell line that engrafts unreliably and grows irregularly in …

Axillary Artery Pseudoaneurysm Following Percutaneous Transaxillary Access For Impella Device Placement During Percutaneous Coronary Intervention, Anas A. Alharbi, Fahad S. Alqahtani, Peter Farjo, Jason A. Moreland

Internal Medicine Faculty Publications

Percutaneous transaxillary access is currently considered an acceptable alternative to transfemoral approach for large-bore access, especially in the setting of hostile iliofemoral arteries. Few published reports exist concerning complications of upper extremity access. We describe development of an axillary artery pseudoaneurysm and its management following transaxillary access. (Level of Difficulty: Advanced.)

The Β3-Adrenergic Receptor Agonist Mirabegron Improves Glucose Homeostasis In Obese Humans, Brian S. Finlin, Hasiyet Memetimin, Beibei Zhu, Amy L. Confides, Hemendra J. Vekaria, Riham H. El Khouli, Zachary R. Johnson, Philip M. Westgate, Jianzhong Chen, Andrew J. Morris, Patrick G. Sullivan, Esther E. Dupont-Versteegden, Philip A. Kern

Internal Medicine Faculty Publications

BACKGROUND. Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3-adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis.

METHODS. Before and after β3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and …

Protection Against Ionizing Radiation And Chemotherapy Toxicity Via Latexin Regulation, Gary Van Zant, Ying Liang, Yi Liu

Internal Medicine Faculty Patents

The present invention relates to methods for protecting against damage caused by radiation and/or chemotherapy, and methods for treating bone marrow damage by reducing/ inhibiting Latexin expression and/or Latexin activity. The methods comprise administering to a subject in need thereof a pharmaceutical composition comprising an antagonist that reduces expression and/or activity of latexin, wherein latexin is a latexin polynucleotide variant and/or a latexin polypeptide variant that binds to the antagonist.

Comparing The Outcomes Of Ceftaroline Plus Vancomycin Or Daptomycin Combination Therapy Versus Monotherapy In Adults With Complicated And Prolonged Methicillin-Resistant Staphylococcus Aureus Bacteremia Initially Treated With Supplemental Ceftaroline, Omar Ahmad, Timothy N. Crawford, Thein Myint

Internal Medicine Faculty Publications

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia confers considerable morbidity and mortality. Although vancomycin or daptomycin monotherapy is usually curative, prolonged bacteremia necessitating supplemental ceftaroline has occurred. The practice has led to the question of whether to continue with ceftaroline following bacteremia resolution.

METHODS: Adult patients hospitalized with MRSA bacteremia at the University of Kentucky Medical Center between January 2015 and December 2017 were retrospectively reviewed. Study subjects required supplemental ceftaroline due to 4 or more days of bacteremia despite vancomycin or daptomycin. They additionally had accompanying native valve infective endocarditis, osteomyelitis, or brain abscess. Patients were divided into two cohorts. …

Serum Amyloid A Is Not Incorporated Into Hdl During Hdl Biogenesis, Ailing Ji, Xuebing Wang, Victoria P. Noffsinger, Drew Jennings, Maria C. De Beer, Frederick C. De Beer, Lisa R. Tannock, Nancy R. Webb

Saha Cardiovascular Research Center Faculty Publications

Liver-derived serum amyloid A (SAA) is present in plasma where it is mainly associated with HDL and from which it is cleared more rapidly than are the other major HDL-associated apolipoproteins. Although evidence suggests that lipid-free and HDL-associated forms of SAA have different activities, the pathways by which SAA associates and disassociates with HDL are poorly understood. In this study, we investigated SAA lipidation by hepatocytes and how this lipidation relates to the formation of nascent HDL particles. We also examined hepatocyte-mediated clearance of lipid-free and HDL-associated SAA. We prepared hepatocytes from mice injected with lipopolysaccharide or an SAA-expressing adenoviral …

Hsp47 Promotes Cancer Metastasis By Enhancing Collagen-Dependent Cancer Cell-Platelet Interaction, Gaofeng Xiong, Jie Chen, Guoying Zhang, Shike Wang, Kunito Kawasaki, Jieqing Zhu, Yan Zhang, Kazuhiro Nagata, Zhenyu Li, Binhua P. Zhou, Ren Xu

Markey Cancer Center Faculty Publications

Increased expression of extracellular matrix (ECM) proteins in circulating tumor cells (CTCs) suggests potential function of cancer cell-produced ECM in initiation of cancer cell colonization. Here, we showed that collagen and heat shock protein 47 (Hsp47), a chaperone facilitating collagen secretion and deposition, were highly expressed during the epithelial-mesenchymal transition (EMT) and in CTCs. Hsp47 expression induced mesenchymal phenotypes in mammary epithelial cells (MECs), enhanced platelet recruitment, and promoted lung retention and colonization of cancer cells. Platelet depletion in vivo abolished Hsp47-induced cancer cell retention in the lung, suggesting that Hsp47 promotes cancer cell colonization by enhancing cancer cell–platelet interaction. …

Gynecologic Large Cell Neuroendocrine Carcinoma: A Review, Grant Burkeen, Aman Chauhan, Rohitashva Agrawal, Riva Raiker, Jill M. Kolesar, Lowell B. Anthony, B. Mark Evers, Susanne Arnold

Internal Medicine Faculty Publications

Large cell neuroendocrine carcinomas (LCNEC) are rare, aggressive high-grade neuroendocrine neoplasms within the neuroendocrine cell lineage spectrum. This manuscript provides a detailed review of published literature on LCNEC of gynecological origin. We performed a PubMed search for material available on gynecologic LCNEC. We analyzed 104 unique cases of gynecologic LCNECs, of which 45 were cervical primary, 45 were ovarian, 13 were uterine, and 1 was vaginal. A total of 45 cases of cervical LCNEC were identified with a median age of 36 years. Median overall survival was 16 months. We identified 45 ovarian LCNEC cases in the published literature with …

Safety, Feasibility, And Efficacy Of Early Rehabilitation In Patients Requiring Continuous Renal Replacement: A Quality Improvement Study, Kirby P. Mayer, Amanda R. Hornsby, Victor Ortiz Soriano, Timothy C. Lin, Jennifer T. Cunningham, Hanwen Yuan, Caroline E. Hauschild, Peter E. Morris, Javier A. Neyra

Physical Therapy Faculty Publications

Introduction: Early rehabilitation in critically ill patients is associated with improved outcomes. Recent research demonstrates that patients requiring continuous renal replacement therapy (CRRT) can safely engage in mobility. The purpose of this study was to assess safety and feasibility of early rehabilitation with focus on mobility in patients requiring CRRT.

Methods: Study design was a mixed methods analysis of a quality improvement protocol. The setting was an intensive care unit (ICU) at a tertiary medical center. Safety was prospectively recorded by incidence of major adverse events including dislodgement of CRRT catheter, accidental extubation, bleeding, and hemodynamic emergency; and minor adverse …