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Life Stressors And Immune Aging: Protective Effects Of Cognitive Reappraisal, Rebecca G. Reed, Steven R. Presnell, Ahmad Al-Attar, Charles T. Lutz, Suzanne C. Segerstrom May 2023

Life Stressors And Immune Aging: Protective Effects Of Cognitive Reappraisal, Rebecca G. Reed, Steven R. Presnell, Ahmad Al-Attar, Charles T. Lutz, Suzanne C. Segerstrom

Markey Cancer Center Faculty Publications

Stressful life events may accelerate aspects of immune aging, but habitual use of an adaptive emotion regulation strategy, cognitive reappraisal, may attenuate these effects. This study examined whether cognitive reappraisal moderates the associations between life stressor frequency and stressor desirability on aspects of immune aging, including late-differentiated CD8+ T and natural killer (NK) cells and inflammatory markers (IL-6, TNF-α, and CRP), both between and within people in a longitudinal sample of 149 older adults (mean age = 77.8, range: 64–92 years). Participants reported stressful life events, use of cognitive reappraisal, and provided blood semiannually for up to 5 years to …


Identification Of Molecular Markers Associated With Copd In Non-Smokers And Smokers: A Bioinformatics Analysis, Agede O. Ayodele, Isa M. Wasagu, Ademola E. Fawibe, Alakija K. Salami May 2023

Identification Of Molecular Markers Associated With Copd In Non-Smokers And Smokers: A Bioinformatics Analysis, Agede O. Ayodele, Isa M. Wasagu, Ademola E. Fawibe, Alakija K. Salami

The University of Louisville Journal of Respiratory Infections

Background

Even though the proportional burden of COPD among never-smokers is significant in both developing and developed nations, accounting for around 30% of all COPD in the community, there is little awareness of the prevalence of COPD in this population. Understanding the molecular processes that underlie COPD in nonsmokers is essential.

Methods

Dataset (GSE146560) was acquired from the Gene Expression Omnibus (GEO). The limma and clusterProfiler software tools were used to identify differentially expressed genes (DEGs) and conduct a functional enrichment analysis respectively.

Results

In all, 10,583 DEGs were found, of which 1,065 were up-regulated and 9,518 were down-regulated. The …


Adipocytes And Innate Immunity In Systemic Sclerosis, Nancy Wareing May 2023

Adipocytes And Innate Immunity In Systemic Sclerosis, Nancy Wareing

Dissertations and Theses (Open Access)

Systemic sclerosis (SSc; scleroderma) is a chronic systemic autoimmune and connective tissue disorder characterized by vasculopathy, autoimmune phenomena, and widespread fibrosis. Skin thickening and tightening is the cardinal feature of SSc and is responsible, in part, for the considerable morbidity of this disease. There are currently no targeted treatments for skin manifestations in SSc, primarily due to our fragmented understanding of its pathophysiologic mechanisms. In PART I, we report a previously unappreciated link between aberrant expression of the developmental gene sine oculis homeobox homolog 1 (SIX1) in skin-associated adipocytes in SSc skin and the early loss of dermal white adipose …


Prevalence Of Antimicrobial Resistance And Association With Patient Outcomes In A Rural Kenyan Hospital, Ian C. Drobish, Immaculate K. Barasa, George Otieno, Moses Odhiambo Osoo, Solomon K. Thuo, Kaya S. Belknap, Arianna Mclain Shirk, S. Taylor Mcclanahan, Elizabeth Irungu, Felix Riunga May 2023

Prevalence Of Antimicrobial Resistance And Association With Patient Outcomes In A Rural Kenyan Hospital, Ian C. Drobish, Immaculate K. Barasa, George Otieno, Moses Odhiambo Osoo, Solomon K. Thuo, Kaya S. Belknap, Arianna Mclain Shirk, S. Taylor Mcclanahan, Elizabeth Irungu, Felix Riunga

Internal Medicine, East Africa

Data on antimicrobial resistance (AMR) and association with outcomes in resource-variable intensive care units (ICU) are lacking. Data currently available are limited to large, urban centers. We attempted to understand this locally through a dual-purpose, retrospective study. Cohort A consisted of adult and pediatric patients who had blood, urine, or cerebrospinal fluid cultures obtained from 2016 to 2020. A total of 3,013 isolates were used to create the Kijabe Hospital’s first antibiogram. Gram-negative organisms were found to be less than 50% susceptible to third- and fourth-generation cephalosporins, 67% susceptible to piperacillin–tazobactam, 87% susceptible to amikacin, and 93% susceptible to meropenem. …


Leveraging The Electronic Health Record To Implement Emergency Department Delirium Screening, Ilianna Santangelo, Christopher R Carpenter, Shan W Liu, Kyler M Godwin, Aanand D Naik, Hardeep Singh, Maura Kennedy May 2023

Leveraging The Electronic Health Record To Implement Emergency Department Delirium Screening, Ilianna Santangelo, Christopher R Carpenter, Shan W Liu, Kyler M Godwin, Aanand D Naik, Hardeep Singh, Maura Kennedy

Faculty, Staff and Students Publications

OBJECTIVE: The aim of this study is to understand how emergency departments (EDs) use health information technology (HIT), and specifically the electronic health record (EHR), to support implementation of delirium screening.

METHODS: We conducted semi-structured interviews with 23 ED clinician-administrators, representing 20 EDs, about how they used HIT resources to implement delirium screening. Interviews focused on challenges participants experienced when implementing ED delirium screening and EHR-based strategies they used to overcome them. We coded interview transcripts using dimensions from the Singh and Sittig sociotechnical model, which addresses use of HIT in complex adaptive health care systems. Subsequently, we analyzed data …


Immune Profiling Of Adeno-Associated Virus Response Identifies B Cell-Specific Targets That Enable Vector Re-Administration In Mice, Samantha Fleury, Shuyun Deng, Shirin Nouraein, Susan Butler, Sangsin Lee, Courtney Chambers, H Courtney Hodges, Jerzy O Szablowski, Junghae Suh, Omid Veiseh May 2023

Immune Profiling Of Adeno-Associated Virus Response Identifies B Cell-Specific Targets That Enable Vector Re-Administration In Mice, Samantha Fleury, Shuyun Deng, Shirin Nouraein, Susan Butler, Sangsin Lee, Courtney Chambers, H Courtney Hodges, Jerzy O Szablowski, Junghae Suh, Omid Veiseh

Faculty, Staff and Students Publications

Adeno-associated virus (AAV) vector-based gene therapies can be applied to a wide range of diseases. AAV expression can last for months to years, but vector re-administration may be necessary to achieve life-long treatment. Unfortunately, immune responses against these vectors are potentiated after the first administration, preventing the clinical use of repeated administration of AAVs. Reducing the immune response against AAVs while minimizing broad immunosuppression would improve gene delivery efficiency and long-term safety. In this study, we quantified the contributions of multiple immune system components of the anti-AAV response in mice. We identified B-cell-mediated immunity as a critical component preventing vector …


Effect Of P2y12 Inhibitors On Organ Support-Free Survival In Critically Ill Patients Hospitalized For Covid-19: A Randomized Clinical Trial, Michelle N Gong, Harmony R Reynolds, Mary Cushman, Andrew D Althouse, Patrick R Lawler, Bryan J Mcverry, Keri S Kim, Lisa Baumann Kreuziger, Scott D Solomon, Mikhail N Kosiborod, Scott M Berry, Grant V Bochicchio, Marco Contoli, Michael E Farkouh, Joshua D Froess, Sheetal Gandotra, Yonatan Greenstein, Erinn M Hade, Nicholas Hanna, Kristin Hudock, Robert C Hyzy, Fátima Ibáñez Estéllez, Nicole Iovine, Ashish K Khanna, Pooja Khatri, Bridget-Anne Kirwan, Matthew E Kutcher, Eric Leifer, George Lim, Renato D Lopes, Jose L Lopez-Sendon, James F Luther, Lilia Nigro Maia, John G Quigley, Lana Wahid, Jennifer G Wilson, Ryan Zarychanski, Andrei Kindzelski, Mark W Geraci, Judith S Hochman, Activ-4a Investigators May 2023

Effect Of P2y12 Inhibitors On Organ Support-Free Survival In Critically Ill Patients Hospitalized For Covid-19: A Randomized Clinical Trial, Michelle N Gong, Harmony R Reynolds, Mary Cushman, Andrew D Althouse, Patrick R Lawler, Bryan J Mcverry, Keri S Kim, Lisa Baumann Kreuziger, Scott D Solomon, Mikhail N Kosiborod, Scott M Berry, Grant V Bochicchio, Marco Contoli, Michael E Farkouh, Joshua D Froess, Sheetal Gandotra, Yonatan Greenstein, Erinn M Hade, Nicholas Hanna, Kristin Hudock, Robert C Hyzy, Fátima Ibáñez Estéllez, Nicole Iovine, Ashish K Khanna, Pooja Khatri, Bridget-Anne Kirwan, Matthew E Kutcher, Eric Leifer, George Lim, Renato D Lopes, Jose L Lopez-Sendon, James F Luther, Lilia Nigro Maia, John G Quigley, Lana Wahid, Jennifer G Wilson, Ryan Zarychanski, Andrei Kindzelski, Mark W Geraci, Judith S Hochman, Activ-4a Investigators

Faculty, Staff and Students Publications

IMPORTANCE: Platelet activation is a potential therapeutic target in patients with COVID-19.

OBJECTIVE: To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19.

DESIGN, SETTING, AND PARTICIPANTS: This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients.

INTERVENTION: Participants were randomly assigned to receive a P2Y12 …


The Impact Of Initial Specimen Diversion Systems On Blood Culture Contamination May 2023

The Impact Of Initial Specimen Diversion Systems On Blood Culture Contamination

Faculty, Staff and Students Publications

Blood culture contamination is associated with increased antimicrobial use, length of stay, and hospital cost. To address this problem, blood culture diversion has been developed as an additional measure to reduce contamination to targeted goals. Three different versions were proposed, including an open technique and 2 commercially available devices. This study aims to review the existing literature and analyze evidence for these 3 techniques.


Extracorporeal Membrane Oxygenation Characteristics And Outcomes In Children And Adolescents With Covid-19 Or Multisystem Inflammatory Syndrome Admitted To Us Icus, Cameron C Young, Timothy P Mccadden, Margaret M Newhams, Suden Kucukak, Elizabeth H Mack, Julie C Fitzgerald, Courtney M Rowan, Aline B Maddux, Amanda R Kolmar, Katherine Irby, Sabrina Heidemann, Stephanie P Schwartz, Michele Kong, Hillary Crandall, Kevin M Havlin, Aalok R Singh, Jennifer E Schuster, Mark W Hall, Kari A Wellnitz, Mia Maamari, Mary G Gaspers, Ryan A Nofziger, Peter Paul C Lim, Ryan W Carroll, Alvaro Coronado Munoz, Tamara T Bradford, Melissa L Cullimore, Natasha B Halasa, Gwenn E Mclaughlin, Pia S Pannaraj, Natalie Z Cvijanovich, Matt S Zinter, Bria M Coates, Steven M Horwitz, Charlotte V Hobbs, Heda Dapul, Ana Lia Graciano, Andrew D Butler, Manish M Patel, Laura D Zambrano, Angela P Campbell, Adrienne G Randolph May 2023

Extracorporeal Membrane Oxygenation Characteristics And Outcomes In Children And Adolescents With Covid-19 Or Multisystem Inflammatory Syndrome Admitted To Us Icus, Cameron C Young, Timothy P Mccadden, Margaret M Newhams, Suden Kucukak, Elizabeth H Mack, Julie C Fitzgerald, Courtney M Rowan, Aline B Maddux, Amanda R Kolmar, Katherine Irby, Sabrina Heidemann, Stephanie P Schwartz, Michele Kong, Hillary Crandall, Kevin M Havlin, Aalok R Singh, Jennifer E Schuster, Mark W Hall, Kari A Wellnitz, Mia Maamari, Mary G Gaspers, Ryan A Nofziger, Peter Paul C Lim, Ryan W Carroll, Alvaro Coronado Munoz, Tamara T Bradford, Melissa L Cullimore, Natasha B Halasa, Gwenn E Mclaughlin, Pia S Pannaraj, Natalie Z Cvijanovich, Matt S Zinter, Bria M Coates, Steven M Horwitz, Charlotte V Hobbs, Heda Dapul, Ana Lia Graciano, Andrew D Butler, Manish M Patel, Laura D Zambrano, Angela P Campbell, Adrienne G Randolph

Faculty, Staff and Students Publications

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) has been used successfully to support adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related cardiac or respiratory failure refractory to conventional therapies. Comprehensive reports of children and adolescents with SARS-CoV-2-related ECMO support for conditions, including multisystem inflammatory syndrome in children (MIS-C) and acute COVID-19, are needed.

DESIGN: Case series of patients from the Overcoming COVID-19 public health surveillance registry.

SETTING: Sixty-three hospitals in 32 U.S. states reporting to the registry between March 15, 2020, and December 31, 2021.

PATIENTS: Patients less than 21 years admitted to the ICU meeting Centers for Disease Control criteria …


Endogenous Interleukin-10 Contributes To Wound Healing And Regulates Tissue Repair, Benjamin Padon, Tanuj J Prajapati, Fayiz Faruk, Oluyinka O Olutoye, Ling Yu, Paul Bollyky, Sundeep G Keswani, Swathi Balaji May 2023

Endogenous Interleukin-10 Contributes To Wound Healing And Regulates Tissue Repair, Benjamin Padon, Tanuj J Prajapati, Fayiz Faruk, Oluyinka O Olutoye, Ling Yu, Paul Bollyky, Sundeep G Keswani, Swathi Balaji

Faculty, Staff and Students Publications

INTRODUCTION: Interleukin-10 (IL-10) is essential in fetal regenerative wound healing and likewise promotes a regenerative phenotype in adult dermal wounds. However, the role of endogenous IL-10 in postnatal dermal wound healing is not well-established. We sought to determine the function of endogenous IL-10 in murine full thickness excisional wounds that are splinted to prevent contracture and mimic human patterns of wound closure.

METHODS: Full-thickness excisional wounds were made in wildtype (WT) and IL-10

RESULTS: We observed no difference in wound healing rate between WT and IL-10

CONCLUSIONS: These data suggest that endogenous IL-10 expression does not alter closure of full …


Bladder Mucosal Cystitis Cystica Lesions Are Tertiary Lymphoid Tissues That Correlate With Recurrent Urinary Tract Infection Frequency In Postmenopausal Women, Priyanka Parameswaran, Siobhan Sutcliffe, Jerry L Lowder, Indira U Mysorekar May 2023

Bladder Mucosal Cystitis Cystica Lesions Are Tertiary Lymphoid Tissues That Correlate With Recurrent Urinary Tract Infection Frequency In Postmenopausal Women, Priyanka Parameswaran, Siobhan Sutcliffe, Jerry L Lowder, Indira U Mysorekar

Faculty, Staff and Students Publications

PURPOSE: We identify correlates and clinical outcomes of cystitis cystica, a poorly understood chronic inflammatory bladder change, in women with recurrent urinary tract infections.

MATERIALS AND METHODS: A retrospective, observational cohort of women with recurrent urinary tract infections who underwent cystoscopy (n=138) from 2015 to 2018 were identified using electronic medical records. Cystitis cystica status was abstracted from cystoscopy reports and correlations were identified by logistic regression. Urinary tract infection-free survival time associated with cystitis cystica was evaluated by Cox proportional hazards regression. Exact logistic regression was used to identify factors associated with changes to cystitis cystica lesions on repeat …


Why The Vonoprazan Helicobacter Pylori Therapies In The Us-European Trial Produced Unacceptable Cure Rates May 2023

Why The Vonoprazan Helicobacter Pylori Therapies In The Us-European Trial Produced Unacceptable Cure Rates

Faculty, Staff and Students Publications

INTRODUCTION: Helicobacter pylori infects a large percentage of the world's population and is etiologically related to gastric cancer. The U.S. Food and Drug Administration recently approved two 14-day vonoprazan-containing regimens (vonoprazan-amoxicillin with or without clarithromycin) for H. pylori infections in the United States/Europe.

METHODS: We critically reviewed the trial methods to discover why the results were unacceptable low [i.e., no regimen achieved clinically acceptable (≥ 90%) or even conditionally acceptable cure rates (≥ 85%)]. Cure rates with antibiotic susceptible strains were 84.7 for vonoprazan triple therapy, 78.5 for vonoprazan-amoxicillin, and 78.7 for lansoprazole triple therapy, respectively. As was previously shown …


Adad2 Functions In Spermiogenesis And Pirna Biogenesis In Mice, Kanako Kojima-Kita, Kenjiro Shirane, Hsin-Yi Chang, Toru Nishimura, Takayuki Koyano, Zhifeng Yu, Julio M Castañeda, Makoto Matsuyama, Satomi Kuramochi-Miyagawa, Martin M Matzuk, Masahito Ikawa May 2023

Adad2 Functions In Spermiogenesis And Pirna Biogenesis In Mice, Kanako Kojima-Kita, Kenjiro Shirane, Hsin-Yi Chang, Toru Nishimura, Takayuki Koyano, Zhifeng Yu, Julio M Castañeda, Makoto Matsuyama, Satomi Kuramochi-Miyagawa, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

BACKGROUND: Adenosine deaminase domain containing 2 (ADAD2) is a testis-specific protein composed of a double-stranded RNA binding domain and a non-catalytic adenosine deaminase domain. A recent study showed that ADAD2 is indispensable for the male reproduction in mice. However, the detailed functions of ADAD2 remain elusive.

OBJECTIVES: This study aimed to investigate the cause of male sterility in Adad2 mutant mice and to understand the molecular functions of ADAD2.

MATERIALS AND METHODS: Adad2 homozygous mutant mouse lines, Adad2

RESULTS: Adad2–/– and Adad2Δ/Δ mice exhibit male-specific sterility due to abnormal spermiogenesis. ADAD2 interacts with multiple RNA-binding proteins involved in …


Synthesis, Radiolabeling And Evaluation Of A Suite Of Tracers With 44Sc For Detecting Extracellular Dna, Zhiyao Li May 2023

Synthesis, Radiolabeling And Evaluation Of A Suite Of Tracers With 44Sc For Detecting Extracellular Dna, Zhiyao Li

McKelvey School of Engineering Graduate Student Theses & Dissertations

Neutrophil extracellular traps involve the rapid translocation of DNA to the outside of the cell under certain stimuli. This structure forms a fibrous network that is able to limit the spread of pathogens and to kill microorganisms. It has also been shown to be present in various pathological processes such as inflammation, autoimmune diseases, and cancer metastasis. Currently, the formation process of NETs in vivo is being extensively studied. However noninvasive detection and quantitation has yet to be achieved. A class of PET tracers are described here that consists of a DNA dye as the backbone that is labeled with …


A Novel Neuroinvasive Infection Modality For Francisella Tularensis Elicits Neuroinflammation Resulting In Cellular Damage, Mireya Griselle Ramos-Muniz May 2023

A Novel Neuroinvasive Infection Modality For Francisella Tularensis Elicits Neuroinflammation Resulting In Cellular Damage, Mireya Griselle Ramos-Muniz

Open Access Theses & Dissertations

Francisella tularensis (Ft.) is a gram-negative coccobacillus bacterium that causes the zoonotic disease tularemia in humans. Ft. causes the most severe, often fatal, form of the disease through inhalation. However, Ft. is most commonly transmitted through direct contact with infected animal carcasses such as rodents and rabbits, consumption of contaminated food or water, or through arthropod bites, particularly ticks. Due to its extremely low infectious dose, high mortality rate, and potential use as a biological warfare agent, Ft. is classified by the CDC as a "Tier 1 select agent". Ft. infection triggers an overactive inflammatory response, termed a "cytokine storm", …


Gwas And Meta-Analysis Identifies 49 Genetic Variants Underlying Critical Covid-19, Erola Pairo-Castineira, Konrad Rawlik, Andrew D Bretherick, Ting Qi, Yang Wu, Glenn A Mcconkey, Lucija Klaric, Fiona Griffiths, Wilna Oosthuyzen, Athanasios Kousathanas, Anne Richmond, Jonathan Millar, Clark D Russell, Tomas Malinauskas, Ryan Thwaites, Kirstie Morrice, Sean Keating, David Maslove, Alistair Nichol, Malcolm G Semple, Julian Knight, Manu Shankar-Hari, Charlotte Summers, Charles Hinds, Peter Horby, Lowell Ling, Danny Mcauley, Hugh Montgomery, Peter J M Openshaw, Colin Begg, Timothy Walsh, Albert Tenesa, Carlos Flores, José A Riancho, Augusto Rojas-Martinez, Pablo Lapunzina, Genomicc Investigators, Scourge Consortium, Isaricc Investigators, 23andme Covid-19 Team, Jian Yang, Chris P Ponting, James F Wilson, Veronique Vitart, Malak Abedalthagafi, Andre D Luchessi, Esteban J Parra, Raquel Cruz, Angel Carracedo, Angie Fawkes, Lee Murphy, Kathy Rowan, Alexandre C Pereira, Andy Law, Benjamin Fairfax, Sara Clohisey Hendry, J Kenneth Baillie May 2023

Gwas And Meta-Analysis Identifies 49 Genetic Variants Underlying Critical Covid-19, Erola Pairo-Castineira, Konrad Rawlik, Andrew D Bretherick, Ting Qi, Yang Wu, Glenn A Mcconkey, Lucija Klaric, Fiona Griffiths, Wilna Oosthuyzen, Athanasios Kousathanas, Anne Richmond, Jonathan Millar, Clark D Russell, Tomas Malinauskas, Ryan Thwaites, Kirstie Morrice, Sean Keating, David Maslove, Alistair Nichol, Malcolm G Semple, Julian Knight, Manu Shankar-Hari, Charlotte Summers, Charles Hinds, Peter Horby, Lowell Ling, Danny Mcauley, Hugh Montgomery, Peter J M Openshaw, Colin Begg, Timothy Walsh, Albert Tenesa, Carlos Flores, José A Riancho, Augusto Rojas-Martinez, Pablo Lapunzina, Genomicc Investigators, Scourge Consortium, Isaricc Investigators, 23andme Covid-19 Team, Jian Yang, Chris P Ponting, James F Wilson, Veronique Vitart, Malak Abedalthagafi, Andre D Luchessi, Esteban J Parra, Raquel Cruz, Angel Carracedo, Angie Fawkes, Lee Murphy, Kathy Rowan, Alexandre C Pereira, Andy Law, Benjamin Fairfax, Sara Clohisey Hendry, J Kenneth Baillie

Faculty, Staff and Student Publications

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a …


Targeting Pd-L2-Rgmb Overcomes Microbiome-Related Immunotherapy Resistance, Joon Seok Park, Francesca S Gazzaniga, Meng Wu, Amalia K Luthens, Jacob Gillis, Martin W Lafleur, Golnaz Morad, Elizabeth M Park, Yifan Zhou, Stephanie S Watowich, Jennifer A Wargo, Gordon J Freeman, Dennis L Kasper, Arlene H Sharpe May 2023

Targeting Pd-L2-Rgmb Overcomes Microbiome-Related Immunotherapy Resistance, Joon Seok Park, Francesca S Gazzaniga, Meng Wu, Amalia K Luthens, Jacob Gillis, Martin W Lafleur, Golnaz Morad, Elizabeth M Park, Yifan Zhou, Stephanie S Watowich, Jennifer A Wargo, Gordon J Freeman, Dennis L Kasper, Arlene H Sharpe

Faculty, Staff and Student Publications

The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and …


National Cancer Control Plan Of The Korea: Current Status And The Fourth Plan (2021-2025), Kyu-Tae Han, Jae Kwan Jun, Jeong-Soo Im May 2023

National Cancer Control Plan Of The Korea: Current Status And The Fourth Plan (2021-2025), Kyu-Tae Han, Jae Kwan Jun, Jeong-Soo Im

Faculty, Staff and Student Publications

Cancer management has become a major policy goal for the government of the Korea. As such, the government introduced the National Cancer Control Plan (NCCP) to reduce the individual and social burdens caused by cancer and to promote national health. During the past 25 years, 3 phases of the NCCP have been completed. During this time, the NCCP has changed significantly in all aspects of cancer control from prevention to survival. The targets for cancer control are increasing, and although some blind spots remain, new demands are emerging. The government initiated the fourth NCCP in March 2021, with the vision …


Translational Studies Using The Malt1 Inhibitor (S)-Mepazine To Induce Treg Fragility And Potentiate Immune Checkpoint Therapy In Cancer, Carina Grass, Samuel W Kazer, Kevin Litchfield, Ulrich H Von Andrian, Thorsten R Mempel, Russell W Jenkins, Daniel Krappmann, Peter Keller May 2023

Translational Studies Using The Malt1 Inhibitor (S)-Mepazine To Induce Treg Fragility And Potentiate Immune Checkpoint Therapy In Cancer, Carina Grass, Samuel W Kazer, Kevin Litchfield, Ulrich H Von Andrian, Thorsten R Mempel, Russell W Jenkins, Daniel Krappmann, Peter Keller

Faculty, Staff and Student Publications

Introduction

Regulatory T cells (Tregs) play a critical role in the maintenance of immune homeostasis but also protect tumors from immune-mediated growth control or rejection and pose a significant barrier to effective immunotherapy. Inhibition of MALT1 paracaspase activity can selectively reprogram immune-suppressive Tregs in the tumor microenvironment to adopt a proinflammatory fragile state, which offers an opportunity to impede tumor growth and enhance the efficacy of immune checkpoint therapy (ICT).

Methods

We performed preclinical studies with the orally available allosteric MALT1 inhibitor (S)-mepazine as a single-agent and in combination with anti-programmed cell death protein 1 (PD-1) ICT to …


Sarcoidosis And Airway Disease After Immune Checkpoint Inhibitor Therapy: Case Study And Review Of The Literature, Felipe Soto, Luis F Torre-Sada, Frank E Mott, Sang T Kim, Roza Nurieva, Saadia A Faiz, Mehmet Altan, Julie Lin, Ajay Sheshadri May 2023

Sarcoidosis And Airway Disease After Immune Checkpoint Inhibitor Therapy: Case Study And Review Of The Literature, Felipe Soto, Luis F Torre-Sada, Frank E Mott, Sang T Kim, Roza Nurieva, Saadia A Faiz, Mehmet Altan, Julie Lin, Ajay Sheshadri

Faculty, Staff and Student Publications

Pulmonary toxicity from immune checkpoint inhibitor therapy is typically a severe and potentially fatal complication, but these observations are driven by the most common toxicity, pneumonitis. Rarer pulmonary immune related adverse events, like airway disease and sarcoidosis, may have a more benign course. In this case report, we present a patient in whom therapy with the PD-1 inhibitor pembrolizumab resulted in severe eosinophilic asthma and sarcoidosis. This is the first case showing that anti-IL-5 inhibition may be safe in patients who develop eosinophilic asthma after ICI therapy. We further show that sarcoidosis does not necessarily require treatment cessation. This case …


Sting Agonist-Loaded Mesoporous Manganese-Silica Nanoparticles For Vaccine Applications, Cheng Xu, Hannah E Dobson, Mengjie Yu, Wang Gong, Xiaoqi Sun, Andrew Kennedy, Jin Xu, Yao Xu, Andrew W Tai, Yu Leo Lei, James J Moon May 2023

Sting Agonist-Loaded Mesoporous Manganese-Silica Nanoparticles For Vaccine Applications, Cheng Xu, Hannah E Dobson, Mengjie Yu, Wang Gong, Xiaoqi Sun, Andrew Kennedy, Jin Xu, Yao Xu, Andrew W Tai, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Cyclic dinucleotides (CDNs), as one type of Stimulator of Interferon Genes (STING) pathway agonist, have shown promising results for eliciting immune responses against cancer and viral infection. However, the suboptimal drug-like properties of conventional CDNs, including their short in vivo half-life and poor cellular permeability, compromise their therapeutic efficacy. In this study, we have developed a manganese-silica nanoplatform (MnOx@HMSN) that enhances the adjuvant effects of CDN by achieving synergy with Mn2+ for vaccination against cancer and SARS-CoV-2. MnOx@HMSN with large mesopores were efficiently co-loaded with CDN and peptide/protein antigens. MnOx@HMSN(CDA) amplified the activation of the STING pathway and enhanced the …


Sars-Cov-2 Serostatus And Covid-19 Illness Characteristics By Variant Time Period In Non-Hospitalized Children And Adolescents, Harold W Kohl, Ashraf Yaseen, Steven H Kelder, Jessica A Ross, Lindsay N Padilla, Michael O Gonzalez, Leqing Wu, David Lakey, Jennifer A Shuford, Stephen J Pont, Eric Boerwinkle Apr 2023

Sars-Cov-2 Serostatus And Covid-19 Illness Characteristics By Variant Time Period In Non-Hospitalized Children And Adolescents, Harold W Kohl, Ashraf Yaseen, Steven H Kelder, Jessica A Ross, Lindsay N Padilla, Michael O Gonzalez, Leqing Wu, David Lakey, Jennifer A Shuford, Stephen J Pont, Eric Boerwinkle

Faculty, Staff and Student Publications

OBJECTIVE: to describe COVID-19 illness characteristics, risk factors, and SARS-CoV-2 serostatus by variant time period in a large community-based pediatric sample.

DESIGN: Data were collected prospectively over four timepoints between October 2020 and November 2022 from a population-based cohort ages 5 to 19 years old.

SETTING: State of Texas, USA.

PARTICIPANTS: Participants ages 5 to 19 years were recruited from large pediatric healthcare systems, Federally Qualified Healthcare Centers, urban and rural clinical practices, health insurance providers, and a social media campaign.

EXPOSURE: SARS-CoV-2 infection.

MAIN OUTCOME(S) AND MEASURE(S): SARS-CoV-2 antibody status was assessed by the Roche Elecsys

RESULTS: Over half …


Implementing Auc Monitoring In A Pharmacist-Managed Vancomycin Dosing Protocol: A Retrospective Cohort Study, Brandon L S Robinson, Blake Bennie, Mahmoud Nasiri, Kieu Nguyen, Reba Forbess, Mallory Gessner-Wharton, Cassie Robertson Apr 2023

Implementing Auc Monitoring In A Pharmacist-Managed Vancomycin Dosing Protocol: A Retrospective Cohort Study, Brandon L S Robinson, Blake Bennie, Mahmoud Nasiri, Kieu Nguyen, Reba Forbess, Mallory Gessner-Wharton, Cassie Robertson

HCA Healthcare Journal of Medicine

Background

Consensus guidelines on the therapeutic drug monitoring of vancomycin published in 2020 recognize that using the calculated area-under-the-curve (AUC) to guide dosing maximizes clinical efficacy and minimizes risk when compared to traditional trough-based dosing. The purpose of this study was to determine whether AUC monitoring results in reduced acute kidney injury (AKI) rates in adult patients receiving vancomycin for all indications.

Methods

In this study, patients 18 years or older who received pharmacist-managed vancomycin therapy were selected using pharmacy surveillance software from 2 timeframes. Patients were excluded if they received less than 48 hours of therapy or had unstable …


Clinical Impact Of Oral Step-Down Therapy For Gram-Negative Bacteremia: A Retrospective Study, Nhi Nguyen, Ashitha Jayachandran, Minhhang Mui, Kelsey Olson Apr 2023

Clinical Impact Of Oral Step-Down Therapy For Gram-Negative Bacteremia: A Retrospective Study, Nhi Nguyen, Ashitha Jayachandran, Minhhang Mui, Kelsey Olson

HCA Healthcare Journal of Medicine

Background

In recent years, there has been a growing body of evidence that supports oral step-down therapy for the treatment of gram-negative bacteremia. The purpose of this study was to compare outcomes for hospitalized patients who received intravenous-only (IV-only) therapy versus oral step-down therapy with low, moderate, and highly bioavailable antimicrobials for the treatment of gram-negative bacteremia.

Methods

In this retrospective, single-center, observational study, we examined data from adult patients hospitalized with gram-negative bacteremia in a 1-year period. Data analysis was performed using information collected from electronic medical records and a clinical surveillance system.

Results

A total of 199 patients …


A Rare Case Of Rapidly Progressive Cll/Sll Presenting As Bilateral Tonsillar Enlargement And Upper Airway Obstruction, William Mangin, Kashif Aslam Apr 2023

A Rare Case Of Rapidly Progressive Cll/Sll Presenting As Bilateral Tonsillar Enlargement And Upper Airway Obstruction, William Mangin, Kashif Aslam

North Texas GME Research Forum 2023

Although chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) differ in clinical presentation, they are both arise from the same pathologic process, namely the clonal expansion of mature B-cells. This malignancy is usually quite indolent and carries a favorable prognosis. Thanks to a number of highly-effective oral targeted therapies, such as the Bruton tyrosine kinase (BTK) inhibitor, Ibrutinib, patient outcomes have improved significantly. Unfortunately, these therapies are not always well tolerated and many patients are forced to discontinue the medication due to side effects. Many patients experience a disease flair and some even transformation to a high-grade malignancy after …


Case Of Shiga-Toxin Producing E. Coli Dysentery In Adult Patient In The Absence Of Diarrhea, Diana Roy Apr 2023

Case Of Shiga-Toxin Producing E. Coli Dysentery In Adult Patient In The Absence Of Diarrhea, Diana Roy

North Texas GME Research Forum 2023

This is a unique case of a 38 year old Caucasian female with no significant medical history who presented to the hospital with complaint of 3 days of abdominal pain, nausea/vomiting, dark red formed stool, and fever (TMax 102F), as well as dizziness, body aches and throat pain. She reported eating meatloaf with her daughter two days before symptom onset, and daughter was reported to be ill as well. Upon initial exam, patient was found to have temp 100F, was hypotensive and tachycardic with lactate of 4.2. FOBT was positive. Significant lab values include creatinine 3.39 (baseline normal), hemoglobin of …


A Case Of Erythema Nodosum, Mahmood Ahmad, Sunitha Valayil Apr 2023

A Case Of Erythema Nodosum, Mahmood Ahmad, Sunitha Valayil

North Texas GME Research Forum 2023

Background: Erythema nodosum (EN) is characterized as a delayed hypersensitivity reaction to subcutaneous adipose tissue. This panniculitis process presents as erythematous, tender nodules and plaques most commonly located on the pretibial areas. EN may be idiopathic or may be caused by a number of factors such as infection, chronic systemic inflammatory processes, drugs or malignancy.

Case presentation: A 29-year-old male with no significant past medical history presented with a 2-week history of worsening bilateral lower extremity erythema, nodules and pain. This patient was initially seen in the emergency department after a 4-day history of his symptoms. At this time, he …


Extraintestinal Salmonellosis Unmasked In A Parotid Mass, Kahmalia-Kalee Sada Apr 2023

Extraintestinal Salmonellosis Unmasked In A Parotid Mass, Kahmalia-Kalee Sada

North Texas GME Research Forum 2023

Salmonella infection can cause a wide range of presentations, predominantly gastrointestinal but occasionally with cardiovascular or other extraintestinal manifestations. The diagnosis of extraintestinal salmonellosis requires a high degree of clinical suspicion and should be considered in patients with deep-seated abscesses. [1]. Typically, these types of infections, are extremely rare, and when revealed are typically seen in the immunocompromised patient with chronic illness, HIV, or Hepatitis. While the incidence of nontyphoid salmonellosis is estimated at over 2 million cases annually, extraintestinal manifestations account for less than 1% of cases. Studies have revealed that individuals with diabetes have risk for salmonellosis due …


Early Diagnosis Of Purulent Pericarditis Secondary To Methicillin-Sensitive Staphylococcus Aureus In An End-Stage Renal Disease Patient, Stephen Shey, Alejandro Espinosa-Tello, Amnah Andrabi Apr 2023

Early Diagnosis Of Purulent Pericarditis Secondary To Methicillin-Sensitive Staphylococcus Aureus In An End-Stage Renal Disease Patient, Stephen Shey, Alejandro Espinosa-Tello, Amnah Andrabi

North Texas GME Research Forum 2023

Introduction Purulent pericarditis is a rare illness in the modern age of medicine due to the increased usage of antibiotics. Unfortunately, diagnosis of this disease is often delayed due to its nonspecific symptoms. Without treatment, the mortality is nearly one hundred percent due to major complications such as cardiac tamponade and constrictive pericarditis. As a result, most cases of purulent pericarditis are discovered post-mortem. This case report details an early diagnosis of purulent pericarditis secondary to methicillin-sensitive Staphylococcus aureus (MSSA) in an end-stage renal disease (ESRD) patient. Case Presentation A 66-year-old female with past medical history of ESRD initially presented …


The Comorbidity Of Depression And Neurocognitive Disorder In Persons With Hiv Infection: Call For Investigation And Treatment, Karl Goodkin, Teresa H. Evering, Albert M. Anderson, Ann Ragin, Cynthia L. Monaco, Christina Gavegnano, Ryan J. Avery, Sean B. Rourke, Lucette A. Cysique, Bruce J. Brew Apr 2023

The Comorbidity Of Depression And Neurocognitive Disorder In Persons With Hiv Infection: Call For Investigation And Treatment, Karl Goodkin, Teresa H. Evering, Albert M. Anderson, Ann Ragin, Cynthia L. Monaco, Christina Gavegnano, Ryan J. Avery, Sean B. Rourke, Lucette A. Cysique, Bruce J. Brew

School of Medicine Publications

Depression and neurocognitive disorder continue to be the major neuropsychiatric disorders affecting persons with HIV (PWH). The prevalence of major depressive disorder is two to fourfold higher among PWH than the general population (∼6.7%). Prevalence estimates of neurocognitive disorder among PWH range from 25 to over 47% – depending upon the definition used (which is currently evolving), the size of the test battery employed, and the demographic and HIV disease characteristics of the participants included, such as age range and sex distribution. Both major depressive disorder and neurocognitive disorder also result in substantial morbidity and premature mortality. However, though anticipated …