Translational Medical Research Commons^™

Receptor Tyrosine Kinases-Mediated Acquired Parp Inhibitor Resistance In Breast Cancer, Mei-Kuang Chen

Dissertations and Theses (Open Access)

Leveraging compromised DNA damage repair (DDR) pathways commonly found in tumor cells, a classic strategy in cancer therapy is inducing excessive DNA damage to cause cancer cell death. Small molecule poly(ADP-ribose) polymerase (PARP) inhibitors (PARP-is) have been approved for clinical use in treating breast cancer and ovarian cancer patients bearing DDR-deficient tumors with mutations in breast cancer susceptibility genes (BRCA^m). However, accumulating evidences show that both intrinsic and acquired resistances to PARP-is exist in clinic and pre-clinical animal models. Therefore, I developed panels of cells with acquired PARP-is resistance from PARP-is-sensitive triple negative breast cancer (TNBC) cell …

Development Of Fully Balanced Ssfp And Computer Vision Applications For Mri-Assisted Radiosurgery (Mars), Jeremiah Sanders

Dissertations and Theses (Open Access)

Prostate cancer is the second most common cancer in men and the second-leading cause of cancer death in men. Brachytherapy is a highly effective treatment option for prostate cancer, and is the most cost-effective initial treatment among all other therapeutic options for low to intermediate risk patients of prostate cancer. In low-dose-rate (LDR) brachytherapy, verifying the location of the radioactive seeds within the prostate and in relation to critical normal structures after seed implantation is essential to ensuring positive treatment outcomes.

One current gap in knowledge is how to simultaneously image the prostate, surrounding anatomy, and radioactive seeds within the …

A Call For Grounding Implicit Bias Training In Clinical And Translational Frameworks, Nao Hagiwara, Frederick W. Kron, Mark W. Scerbo, Ginger S. Watson

Psychology Faculty Publications

Since the publication of Unequal Treatment in 2003,¹ the number of studies investigating the implicit bias of health-care providers and its troubling consequences has increased exponentially. Bias can occur in all three psychological components: affects (ie, prejudice), cognition (ie, stereotypes), and behaviour (ie, discrimination). Implicit bias refers to prejudicial attitudes towards and stereotypical beliefs about a particular social group or members therein. These prejudicial attitudes and stereotypical beliefs are activated spontaneously and effortlessly, which often result in discriminatory behaviours.² This definition is consistent with how implicit bias is defined in psychology³ and in literature on health disparities. …

How Immune T-Cell Augmentation Can Help Prevent Covid-19: A Possible Nutritional Solution Using Ketogenic Lifestyle, Ravi K. Kamepalli Md,Fidsa,Cwsp

The University of Louisville Journal of Respiratory Infections

No abstract provided.

Covid-19, Colleagues, Confusion, And Conversations, Nathanael R. Sanchez M.D., Katherine S. Lee , M.D., Karen Weaver M.D.

Clinical Research in Practice: The Journal of Team Hippocrates

During the COVID-19 pandemic, doctors in a community hospital reflect on their decision-making regarding treatment options for COVID-19. Whether to use hydroxychloroquine is the treatment discussed in most detail.

When Rationing Becomes Part Of Clinical Decision-Making, Christopher A. Hopper, Mitra Bahaee

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical practice-based reflection on Noack DP, Newton G. Compared to maximal current management standards, oscillating positive expiratory pressure devices have not been shown to improve clinically relevant outcomes in COPD patients with acute exacerbation. Clin. Res. Prac. 2017;3(2):eP1516. doi: 10.22237/crp/149886732.

Clinical Decision Science Suggests Different Research Questions Need To Be Asked Related To Informed Consent, John K. Geddes

Clinical Research in Practice: The Journal of Team Hippocrates

The author examines the literature relating to informed consent for early cardiac catheterization to treat Non-ST-segment elevation acute coronary syndrome, and considers whether Clinical Decision Science might provide new directions for applying the clinical research literature.

Valbenazine Has A Small But Meaningful Benefit For Tardive Dyskinesia, Joseph Friedli, Ryan Quick, Reem Sobh, Samantha Cowing

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of

Hauser RA, Factor SA, Marder SR, et al. KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia. Am J Psychiatry. 2017;174(5):476-484. https://doi.org/10.1176/appi.ajp.2017.16091037

and

Factor SA, Remington G, Comella CL, et al. The Effects of Valbenazine in Participants with Tardive Dyskinesia: Results of the 1-Year KINECT 3 Extension Study. J Clin Psychiatry. 2017;78(9):1344-1350. https://doi.org/10.4088/JCP.17m11777

exploring the efficacy of a newer therapy for tardive dyskinesia, and describing recommendations for a patient with acute medical problems and longstanding tardive dyskinesia.

From The Editor: Defining The Scholarship Of Clinical Decision Science, James Peter Meza

Clinical Research in Practice: The Journal of Team Hippocrates

The Editor refines the focus of the journal to a new area of scholarship, Clinical Decision Science, exploring how the complex interacting aspects of clinical care are described, understood, shared, and explained in the context of the doctor-patient relationship.

Copd Exacerbation Caused By Sars-Cov-2: A Case Report From The Louisville Covid-19 Surveillance Program, Forest W. Arnold, Kamran Mahmood, Angeline Prabhu, Darmaan Aden, Anupama Raghuram, Mark Burns, Leslie A. Beavin, Donghoon Chung, Kenneth E. Palmer, Julio A. Ramirez

The University of Louisville Journal of Respiratory Infections

A 53-year-old male with a history of chronic obstructive pulmonary disease (COPD) on home oxygen presented to the hospital with worsening shortness of breath plus cough. He was admitted to the intensive care unit for COPD exacerbation and respiratory failure. A routine evaluation was performed, including a nasopharyngeal swab for a respiratory viral panel, which was negative. His symptoms improved over 48 hours, after which time a surveillance test for SARS-CoV-2 returned as positive. After clinical improvement, he was discharged to home isolation.

How To Prevent Covid-19 In Nurses And Physicians In The Hospital Setting: Universal Test-And-Isolate For All Patients Admitted To Hospitals, Julio A. Ramirez, Ruth Carrico, Forest W. Arnold, Paul Schulz

The University of Louisville Journal of Respiratory Infections

No abstract provided.

Defining The Burden Of Covid-19 In The Kentuckiana Area: Incidence, Epidemiology & Clinical Outcomes Of Patients With Covid-19, Julio A. Ramirez

The University of Louisville Journal of Respiratory Infections

Rationale: Early evaluation of the burden of disease that COVID-19 may produce in a community is critical to appropriately allocate resources for COVID-19 prevention and treatment.

Objective: The primary objective of this study is to define the incidence, epidemiology, and clinical outcomes of patients with COVID-19 in the Louisville, Kentucky, and southern Indiana region (Kentuckiana) of the USA.

Methods: This will be a retrospective observational study of patients in the Kentuckiana region with the diagnosis of COVID-19.

Louisville Coronavirus Surveillance Program, Julio A. Ramirez, Kenneth E. Palmer, Ruth Carrico, Forest W. Arnold, Donghoon Chung, Leslie A Wolf

The University of Louisville Journal of Respiratory Infections

An important feature of COVID-19, the disease produced by the new coronavirus SARS-CoV-2, is the high number of health care workers (HCWs) that acquire the disease. In an initial report of 138 patients hospitalized with COVID-19 pneumonia in China, 40 patients (29%) were HCWs. One reason why HCWs are at higher risk of acquiring COVID-19 is that some patients with COVID-19 are admitted to the hospital without the classical presentation and are therefore not tested for the disease early during hospitalization. Presently in the US, it is recommended to test for COVID-19 when physicians suspect the disease. This subjective approach …

Reversing Heart Failure With A Ventricular Anchoring Device: Another Hope For Myopathic Mitral Regurgitation., J. Eduardo Rame

Center for Translational Medicine Faculty Papers

No abstract provided.

Endemic Human Coronaviruses In Hospitalized Adults With Community-Acquired Pneumonia: Results From The Louisville Pneumonia Study, Forest W. Arnold, Mark V. Burns, Kamran Mahmood, Darmaan Aden, Stephen P. Furmanek, Mahder A. Tella, Connor Glick, Anupama Raghuram, Leslie A. Beavin, Rodrigo Cavallazzi, Dawn Balcom, Leslie A. Wolf, Kenneth E. Palmer, Ruth Carrico, Julio A. Ramirez, The Center Of Excellence For Research In Infectious Diseases (Cerid) Coronavirus Study Group

The University of Louisville Journal of Respiratory Infections

Introduction: There are four endemic serotypes of human coronavirus (HCoV) that may cause community-acquired pneumonia (CAP) in humans. The clinical syndrome of CAP due to HCoVs is not well characterized. The objectives of this study were to evaluate incidence, epidemiology, and outcomes of CAP in adults due to HCoV and to compare them with CAP due to influenza.

Methods: The Louisville Pneumonia Study (LPS) is a prospective observational study of hospitalized adult patients with CAP in the city of Louisville. Patients enrolled in the LPS in whom a respiratory viral panel polymerase chain reaction (PCR) was obtained were evaluated. Incidence, …

Community-Acquired Pneumonia Due To Endemic Human Coronaviruses Compared To 2019 Novel Coronavirus: A Review, Julio A. Ramirez, Ruth Carrico, Rodrigo Cavallazzi, Leslie A. Beavin, Anupama Raghuram, Mark V. Burns, Kamran Mahmood, Darmaan Aden, Angeline Prabhu, Dawn Balcom, Stephen P. Furmanek, Leslie A Wolf, Kenneth E. Palmer, Mahder A. Tella, Connor Glick, Forest W. Arnold, The Center Of Excellence For Research In Infectious Diseases (Cerid) Coronavirus Study Group

The University of Louisville Journal of Respiratory Infections

The human coronaviruses (HCoVs) are an important etiology of community-acquired respiratory tract infections. Community-acquired pneumonia (CAP) may be caused by serotypes of endemic HCoVs or highly pathogenic HCoVs. In this review, we compared clinical characteristics, management, outcomes, and infection control practices for patients with CAP due to endemic HCoVs versus patients with CAP due to 2019 novel coronavirus (SARS-CoV-2).

Dna Dependent Protein Kinase (Dna-Pk) Enhances Hiv Transcription By Promoting Rna Polymerase Ii Activity And Recruitment Of Transcription Machinery At Hiv Ltr., Sonia Zicari, Adhikarimayum Lakhikumar Sharma, Geetaram Sahu, Larisa Dubrovsky, Lin Sun, Han Yue, Tejaswi Jada, Alex Ochem, Gary Simon, Michael Bukrinsky, Mudit Tyagi

Center for Translational Medicine Faculty Papers

Despite reductions in mortality from the use of highly active antiretroviral therapy (HAART), the presence of latent or transcriptionally silent proviruses prevents HIV cure/eradication. We have previously reported that DNA-dependent protein kinase (DNA-PK) facilitates HIV transcription by interacting with the RNA polymerase II (RNAP II) complex recruited at HIV LTR. In this study, using different cell lines and peripheral blood mononuclear cells (PBMCs) of HIV-infected patients, we found that DNA-PK stimulates HIV transcription at several stages, including initiation, pause-release and elongation. We are reporting for the first time that DNA-PK increases phosphorylation of RNAP II C-terminal domain (CTD) at serine …

In Clinical Practice, Patients Have Names, James Peter Meza

Clinical Research in Practice: The Journal of Team Hippocrates

In order to better reflect this robust description of clinical practice, we have initiated the use of pseudonyms for patients in our publications.

Improving Community Advisory Board Engagement In Precision Medicine Research To Reduce Health Disparities, Erin Connors, Rebecca Selove, Juan Canedo, Maureen Sanderson, Pamela Hull, Marilyn Adams, Ila Mcdermott, Calvin Barlow, Denice Johns-Porter, Caree Mcafee, Karen Gilliam, Oscar Miller, Nora Cox, Mary Kay Fadden, Stephen King, Hilary Tindle

Journal of Health Disparities Research and Practice

Community Advisory Boards (CABs) are used in efforts to reduce health disparities; however, there is little documentation in the literature regarding their use in precision medicine research. In this case study, an academic-CAB partnership developed a questionnaire and patient educational materials for two precision smoking cessation interventions that involved use of genetic information. The community-engaged research (CEnR) literature provided a framework for enhancing benefits to CAB members involved in developing research documents for use with a low-income, ethnically diverse population of smokers. The academic partners integrated three CEnR strategies: 1) in-meeting statements acknowledging their desire to learn from community partners, …

Parp1-Targeted Radiotherapies, Stephen Jannetti

Dissertations, Theses, and Capstone Projects

Poly-ADP-ribosylation reactions were first reported by Chambon in 1963 as enzymatic activity that increases incorporation of ATP in the presence of nicotinamide mononucleotide. In the decades since that publication, Poly(ADP-ribose)polymerase 1 (PARP1) and the PARP family enzymes have been widely studied. PARP enzymes are currently known to play various roles in mammals, including anti-aging processes, interactions with Breast Cancer Suppressor Protein-1 (BRCA1), and DNA damage repair. A significant focus of PARP1 research has been elucidating its role in DNA damage repair. PARP1 is recruited to repair single strand DNA (ssDNA) breaks, which can become double stranded DNA (dsDNA) breaks if …

Mitochondrial Quality Control In Age-Related Pulmonary Fibrosis., Willy Roque, Karina Cuevas-Mora, Freddy Romero

Center for Translational Medicine Faculty Papers

Idiopathic pulmonary fibrosis (IPF) is age-related interstitial lung disease of unknown etiology. About 100,000 people in the U.S have IPF, with a 3-year median life expectancy post-diagnosis. The development of an effective treatment for pulmonary fibrosis will require an improved understanding of its molecular pathogenesis and the "normal" and "pathological' hallmarks of the aging lung. An important characteristic of the aging organism is its lowered capacity to adapt quickly to, and counteract, disturbances. While it is likely that DNA damage, chronic endoplasmic reticulum (ER) stress, and accumulation of heat shock proteins are capable of initiating tissue repair, recent studies point …

Effects Of Deceptive Footwear Condition On Subjective Comfort And Running Biomechanics, Zoe Y.S. Chan, Ivan P.H. Au, Janet H. Zhang-Lea, Reed Ferber, Gary Shum, Winko W. An, Roy T.H. Cheung

Human Physiology Faculty Scholarship

Comfort is a major criterion for footwear selection. Previous studies have suggested that physical properties were not enough to predict comfort and psychological factors could also affect the perception. To understand comfort, this study examined the effect of controlled shoe description and price cue on the perception of comfort. Furthermore, this study also examined the running biomechanics in response to footwear conditions of differing comfort. Fifteen runners completed treadmill running tests in two conditions: Shoe A and Shoe B. The same pair of neutral running shoes was used in both conditions, yet, Shoe B was described to be the “latest …

Opioid Tolerance Influences Outcomes After Lumbar Fusion In Patients With Degenerative Pathology, Noah Levy, Max Detweiler, Dhruv K.C. Goyal, Ariana Reyes, Alexander R. Vaccaro

Phase 1

Introduction: Extended opioid use prior to surgery has been implicated in poorer postoperative outcomes. However, it remains unclear if there is a significant difference in postoperative outcomes among preoperative opioid-naïve and opioid-tolerant patients who undergo lumbar spinal fusion. The purpose of this study was to determine the effect of preoperative opioid use on patient-reported outcome measures in patients undergoing lumbar spinal fusion.

Methods: This retrospective cohort analysis identified 260 patients who underwent lumbar spinal fusion at a high-volume, single institution. There were two cohorts: patients who were opioid-naïve (defined as total opioid consumption of ≤ 7 days in …

Prediction Of Neonatal Birthweight Associated With Maternal Obesity And Diabetes, Laura Gleason, Rebekah Mccurdy, Md, Mph

Phase 1

Introduction: To design a model that will predict neonatal birth weight within obese mothers by diabetic status.

Methods: A secondary data analysis of an RCT (NCT 02909582) was utilized to create a neonatal birth weight prediction model. Women (n=325) with a BMI > 35 kg/m2 from a tertiary academic institution, 2016 – 2019, were included to estimate the risk of large for gestational age (LGA) infants and neonatal birth weight based on maternal prepregnancy BMI and diabetic status. LGA was defined as an infant birth weight > 90th percentile. Analysis included Chi-square, t-test, multivariate logistic and linear regression.

Results: Mean birthweight did …

Understanding The Relationship Between Drug Overdose Death Rates And Socioeconomic Factors, William Duan, Dennis J. Hand

Phase 1

Drug-overdose deaths increased rapidly recently. What are the causes? We believe socioeconomical factors play critical roles. Secondary data analyses are done on the US population, using mortality-data files from the National Vital Statistics System. Deaths are grouped by race, age, sex, education and marital status. We believe that the percentage-of-total-death (PoTD) value, which equals to the number-of-overdose-deaths divided by the total-number-of-deaths in the corresponding group, more accurately reflect the severity of overdose-deaths. Analysis of 2017 data reveals that among all age groups, PoTD is highest in the age 25-34 group, with dramatic differences between white (PoTD 24%) and black (PoTD …

The Role Of Rassf5 On Cell Growth And Hippo Signaling In Rhabdomyosarcoma, Megan Garver, Lee Helman, Md, Katrina Slemmons, Phd

Phase 1

Introduction: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Dysregulation of the Hippo pathway, a signaling cascade that regulates many biological processes, is associated with many human cancers. The goal of my project was to delete RASSF5, a regulator of the Hippo pathway, in RMS cells utilizing CRISPR/Cas9 and then to evaluate how the absence of RASSF5 affects RMS cell growth and Hippo signaling, with and without DNMTi Tx.

Methods: A lipofectamine transfection was performed in two different RMS cell lines, Rh30 & RD, in which two different CRIPSR/Cas9 vectors with RASSF5 guide RNA were introduced. …

Characteristics And Outcomes Of Patients Discharged Directly Home From A Medical Intensive Care Unit, Michele Fiorella, Ms, Preeyal M. Patel, Ann Zheng, Lauren Mcdonnell, Msn, Acnp, Mina Yasuoka, Msn, Erika J. Yoo, Md

Phase 1

RATIONALE: Discharging patients directly from ICUs is an increasingly common practice, largely due to decreased availability of ward beds. The purpose of this study was to describe the population and evaluate the outcomes of patients discharged directly from the MICU.

METHODS: We conducted a retrospective chart review of direct discharges to home from June 2018 to June 2019 from two MICUs. Patients were separated into two groups based on wait time (<24 hours or ≥ 24 hours) between ward transfer order and actual discharge. The primary outcome was 30-day hospital readmission. Risk was adjusted using Mortality Probability Model (MPM-III); ICU workload at admission and discharge was estimated using the nine equivalents of nursing manpower use score (NEMS). Patient characteristics were compared using t-test and Fisher exact or X².

RESULTS: There was no difference in severity-of-illness or admission NEMS between the two groups. Patients who waited <24 hours for discharge were more likely to be admitted from home. Patients who waited ≥24 hours prior to discharge had significantly longer mean hospital LOS compared to those who waited <24 hours (4.63 days vs. 2.65 days, p<0.001). There was no significant difference in 30-day readmission between patients who were discharged after waiting <24 hours vs. waiting ≥24 hours (p=0.70).

CONCLUSION: Patients who returned directly home from the MICU …

Treatment Of Persistent Air Leaks Using Endobronchial Valves, Michael Zimmerman, Cole Zingas, Achala Donuru, Scott W. Cowan, Nathaniel Evans Iii, Boyd Hehn

Phase 1

Introduction: Persistent air leaks (PAL) are from bronchopleural fistula resulting from communication between the bronchial tree and pleural space. Endobronchial valves (EBVs) are unidirectional valves placed bronchoscopically preventing airflow to the diseased lung lobe. For non-operable patients with PALs, EBVs offer a potential non-invasive treatment approach to stop air leak and allow lung healing. The purpose of this study is to retrospectively analyze EBV placement to treat non-operable adult patients with PALs.

Methods: We retrospectively analyzed all adult patients that underwent EBV placement for PAL treatment at our institution from January 2016 to June 2019. All patients failed conservative …

Late Complications Of Free Flaps In Head And Neck Microvascular Reconstruction, Swapna Vasudevan, Cory Bovenzi, Md

Phase 1

Introduction: Late free flap complications (LFFC) in head and neck reconstructive surgery occur over 72 hours postoperatively and result in flap loss in 97% of cases. Due to the rarity of LFFC, there is minimal research regarding risk factors for their development. Identifying risk factors for LFFC will result in improved monitoring of patients to prevent flap loss. This study aims to identify risk factors for the development of LFFC.

Methods: The target population of this retrospective cohort study was 116 patients who had undergone an Orbital Exenteration at Thomas Jefferson University Hospital (TJUH) and had LFFC. Data was …

Effects Of Corneal Transplant On Rates Of Retinal Detachment, Daniel S. Mackinnon, Zeba A. Syed, Md, Durga Borkar, Hannah Levin

Phase 1

Introduction: Corneal transplant remains the gold standard treatment for irreversible corneal damage. The purpose of this study is to evaluate retinal detachment rates and clinical outcomes after penetrating keratoplasty (PK) and endothelial keratoplasty (EK). We hypothesized that corneal transplants would increase the rate of RD.

Methods: This retrospective cohort study utilized corneal transplant data from all surgical visits from PK or EK between April 1, 2012 and August 31, 2018. Individual charts were reviewed from patients who had a subsequent retinal detachment. Incidence of retinal detachment following PK or EK was the main outcome measured.

Results: A total of …