Allergy and Immunology Commons^™

Diagnostic Features Of Low- And High-Grade Mucinous Neoplasms In Pancreatic Cyst Fna Cytology, Carlie Sigel, Xiao-Jun Wei, Narasimhan Agaram, Keith Sigel, Roshan Raza, Rebecca Andrade, Rema Rao, Pari Shah, Kevin Soares, Abha Goyal

Faculty, Staff and Students Publications

Background: Pancreatic cyst cytology evaluates for neoplastic mucin and epithelial grade. This study describes cytological features of low- and high-grade mucinous neoplasms (MNs) using gastrointestinal contaminants for comparison.

Methods: Histologically confirmed pancreatic cystic neoplasms were reviewed by a panel of cytopathologists to identify which, among 26 selected cytologic features, correlate significantly with low- and high-grade MN. A test for greater than or equal to four of eight high-grade features (three-dimensional architecture, high nuclear:cytoplasmic ratio, moderate nuclear membrane abnormalities, loss of nuclear polarity, hyperchromasia, >4:1 nuclear size variation in one cluster, karyorrhexis, and necrosis) was assessed for identifying a high-grade neoplasms. …

Bladder Mucosal Cystitis Cystica Lesions Are Tertiary Lymphoid Tissues That Correlate With Recurrent Urinary Tract Infection Frequency In Postmenopausal Women, Marianne M Ligon, Brooke Liang, Stacy M Lenger, 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 …

Monogenic Early-Onset Lymphoproliferation And Autoimmunity: Natural History Of Stat3 Gain-Of-Function Syndrome, Jennifer W Leiding, Tiphanie P Vogel, Valentine G J Santarlas, Rahul Mhaskar, Madison R Smith, Alexandre Carisey, Alexander Vargas-Hernández, Manuel Silva-Carmona, Maximilian Heeg, Anne Rensing-Ehl, Bénédicte Neven, Jérôme Hadjadj, Sophie Hambleton, Timothy Ronan Leahy, Kornvalee Meesilpavikai, Charlotte Cunningham-Rundles, Cullen M Dutmer, Svetlana O Sharapova, Mervi Taskinen, Ignatius Chua, Rosie Hague, Christian Klemann, Larysa Kostyuchenko, Tomohiro Morio, Akaluck Thatayatikom, Ahmet Ozen, Anna Scherbina, Cindy S Bauer, Sarah E Flanagan, Eleonora Gambineri, Lisa Giovannini-Chami, Jennifer Heimall, Kathleen E Sullivan, Eric Allenspach, Neil Romberg, Sean G Deane, Benjamin T Prince, Melissa J Rose, John Bohnsack, Talal Mousallem, Rohith Jesudas, Maria Marluce Dos Santos Vilela, Michael O'Sullivan, Jana Pachlopnik Schmid, Štěpánka Průhová, Adam Klocperk, Matthew Rees, Helen Su, Sami Bahna, Safa Baris, Lisa M Bartnikas, Amy Chang Berger, Tracy A Briggs, Shannon Brothers, Vanessa Bundy, Alice Y Chan, Shanmuganathan Chandrakasan, Mette Christiansen, Theresa Cole, Matthew C Cook, Mukesh M Desai, Ute Fischer, David A Fulcher, Silvanna Gallo, Amelie Gauthier, Andrew R Gennery, José Gonçalo Marques, Frédéric Gottrand, Bodo Grimbacher, Eyal Grunebaum, Emma Haapaniemi, Sari Hämäläinen, Kaarina Heiskanen, Tarja Heiskanen-Kosma, Hal M Hoffman, Luis Ignacio Gonzalez-Granado, Anthony L Guerrerio, Leena Kainulainen, Ashish Kumar, Monica G Lawrence, Carina Levin, Timi Martelius, Olaf Neth, Peter Olbrich, Alejandro Palma, Niraj C Patel, Tamara Pozos, Kahn Preece, Saúl Oswaldo Lugo Reyes, Mark A Russell, Yael Schejter, Christine Seroogy, Jan Sinclair, Effie Skevofilax, Daniel Suan, Daniel Suez, Paul Szabolcs, Helena Velasco, Klaus Warnatz, Kelly Walkovich, Austen Worth, Stat3 Gof Working Group Members, Mikko R J Seppänen, Troy R Torgerson, Georgios Sogkas, Stephan Ehl, Stuart G Tangye, Megan A Cooper, Joshua D Milner, Lisa R Forbes Satter

Faculty, Staff and Students Publications

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity.

OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants.

METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3.

RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median …

Contribution Of Adaptive Immunity To Human Copd And Experimental Models Of Emphysema, Farrah Kheradmand, Yun Zhang, David B Corry

Faculty, Staff and Students Publications

The pathophysiology of chronic obstructive pulmonary disease (COPD) and the undisputed role of innate immune cells in this condition have dominated the field in the basic research arena for many years. Recently, however, compelling data suggesting that adaptive immune cells may also contribute to the progressive nature of lung destruction associated with COPD in smokers have gained considerable attention. The histopathological changes in the lungs of smokers can be limited to the large or small airways, but alveolar loss leading to emphysema, which occurs in some individuals, remains its most significant and irreversible outcome. Critically, however, the question of why …

Immunocompromised Host Pneumonia: Definitions And Diagnostic Criteria: An Official American Thoracic Society Workshop Report, Guang-Shing Cheng, Kristina Crothers, Stefano Aliberti, Anne Bergeron, Michael Boeckh, Jason W Chien, Catia Cilloniz, Keira Cohen, Nathan Dean, Charles S Dela Cruz, Robert P Dickson, Alexander L Greninger, Chadi A Hage, Tobias M Hohl, Steven M Holland, Barbara E Jones, Joseph Keane, Mark Metersky, Rachel Miller, Anne Puel, Julio Ramirez, Marcos I Restrepo, Ajay Sheshadri, Bashar Staitieh, Jeffrey Tarrand, Kevin L Winthrop, Richard G Wunderink, Scott E Evans

Faculty, Staff and Student Publications

Pneumonia imposes a significant clinical burden on people with immunocompromising conditions. Millions of individuals live with compromised immunity because of cytotoxic cancer treatments, biological therapies, organ transplants, inherited and acquired immunodeficiencies, and other immune disorders. Despite broad awareness among clinicians that these patients are at increased risk for developing infectious pneumonia, immunocompromised people are often excluded from pneumonia clinical guidelines and treatment trials. The absence of a widely accepted definition for immunocompromised host pneumonia is a significant knowledge gap that hampers consistent clinical care and research for infectious pneumonia in these vulnerable populations. To address this gap, the American Thoracic …

New Developments In Allergic Fungal Rhinosinusitis Pathophysiology And Treatment, Brian H Cameron, Amber U Luong

Faculty, Staff and Student Publications

Background: Allergic fungal rhinosinusitis (AFRS) is an endotype of chronic rhinosinusitis (CRS) with nasal polyps characterized by eosinophilic mucin laden with fungal hyphae entrapped in expanded sinus cavities with an exaggerated hypersensitivity to fungal elements. The last decade has elucidated fungi-driven inflammatory pathways contributing to the pathophysiology of chronic inflammatory respiratory diseases. In addition, novel therapeutic biologic options have become available for CRS over the last several years.

Objective: To review the current literature examining AFRS, focusing on recent developments in our understanding of its pathophysiology and implications for treatment options.

Methods: Review article.

Results: Fungi-driven respiratory inflammation has been …

Risk Factors And Prognostic Significance Of Platelet Count Abnormalities In Children With Hiv Infection On Antiretroviral Therapy, Joseph Lubega, Taylor O Kim, Gladstone Airewele, Amanda Grimes, Shaun Bulsara, Erin Peckham, Sebastian R Wanless, Heather Haq, Peter Elyanu, Philippa Musoke, Mwita Lumumba, Adeodata Kekitiinwa, Mogomotsi Matshaba, Michael Scheurer, Jenny Despotovic

Faculty, Staff and Students Publications

OBJECTIVES: To establish the incidence, risk factors and correlation with survival of thrombocytopenia and thrombocytosis (T/T) among children with HIV infection (CWH).

DESIGN: A retrospective nested case control study of patients 0-18 years in five Baylor International Pediatric AIDS Initiative (BIPAI) centers in sub-Sahara Africa, 2004-2014.

METHODS: Clinical and laboratory variables including complete blood counts (CBC) were extracted from the BIPAI electronic medical record system. Incident cases of T/T were identified and frequency-matched on follow-up time with controls with normal platelets. We calculated the prevalence and incidence density of T/T and used conditional logistic regression to evaluate their association with …

The Quality And Management Of Penicillin Allergy Labels In Pediatric Primary Care, Margaret G Taylor, Torsten Joerger, Sara Anvari, Yun Li, Jeffrey S Gerber, Debra L Palazzi

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVES: Penicillin allergy labels are the most common drug allergy label. The objective of this study was to describe the quality and management of penicillin allergy labels in the pediatric primary care setting.

METHODS: Retrospective chart review of 500 of 18 015 children with penicillin allergy labels born from January 1, 2010 to June 30, 2020 randomly selected from an outpatient birth cohort from Texas Children's Pediatrics and Children's Hospital of Philadelphia networks. Penicillin allergy risk classification ("not allergy," "low risk," "moderate or high risk," "severe risk," "unable to classify") was determined based on documentation within (1) the …

Apoptosis Of Hematopoietic Stem Cells Contributes To Bone Marrow Suppression Following Chimeric Antigen Receptor T Cell Therapy, Jay A Read, Rayne H Rouce, Feiyan Mo, Maksim Mamonkin, Katherine Y King

Faculty, Staff and Students Publications

Background: CAR-T therapy represents a revolutionary treatment for patients with relapsed/refractory hematologic malignancies. However, its use can result in significant toxicities, including cytokine release syndrome (CRS), a potentially life-threatening clinical syndrome resulting from release of pro-inflammatory cytokines upon T cell activation. In addition, patients who develop CRS often experience prolonged cytopenias and those with the most severe CRS also have the greatest delay in full marrow recovery. While an association between CRS and delayed bone marrow recovery has been established, the precise mechanism underlying this phenomenon remains unknown.

Objective: To test our hypothesis that delayed bone marrow recovery following CAR-T …

Role Of Biomarkers (Sflt-1/Plgf) In Cases Of Covid-19 For Distinguishing Preeclampsia And Guiding Clinical Management, Guilherme M Nobrega, Jose P Guida, Juliana M Novaes, Larissa M Solda, Luciana Pietro, Adriana G Luz, Giuliane J Lajos, Carolina C Ribeiro-Do-Valle, Renato T Souza, Jose G Cecatti, Indira U Mysorekar, Tabata Z Dias, Maria Laura Costa

Faculty, Staff and Students Publications

OBJECTIVES: To analyze soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factors (PlGF) concentrations and their ratio in pregnant and postpartum women with suspected COVID-19, and further investigate conditions associated with an increased ratio (sFlt-1/PlGF > 38), including preeclampsia (PE) and severe acute respiratory syndrome (SARS).

STUDY DESIGN: The present study is a secondary analysis of a prospective cohort. Blood samples were collected at time of COVID-19 investigation and the serum measurements of sFlt-1 and PlGF were performed. Clinical background, SARS-CoV-2 infection characteristics, maternal and perinatal outcomes were further analyzed.

MAIN OUTCOME MEASURES: Serum measurements of sFlt-1 and PlGF; obstetrics …

Impact Of Penicillin Allergy Labels On Children Treated For Outpatient Respiratory Infections, Torsten Joerger, Margaret G Taylor, Yun Li, Debra L Palazzi, Jeffrey S Gerber

Faculty, Staff and Students Publications

BACKGROUND: Penicillin allergy is the most common antibiotic allergy, yet most children labeled as allergic tolerate penicillin. The impact of inaccurate penicillin allergy labels (PALs) on pediatric outpatients is unknown. The objective of this study was to compare outcomes between children with and without a PAL after treatment for outpatient respiratory tract infections (RTI).

METHODS: A retrospective, longitudinal birth cohort study was performed in children who received care in 90 pediatric primary care practices in Philadelphia and Houston metropolitan areas. Prescribing and clinical outcomes of children with a PAL at the time of an RTI were compared to non-allergic children, …

Developing A Standardized But Extendable Framework To Increase The Findability Of Infectious Disease Datasets, Ginger Tsueng, Marco A Alvarado Cano, José Bento, Candice Czech, Mengjia Kang, Lars Pache, Luke V Rasmussen, Tor C Savidge, Justin Starren, Qinglong Wu, Jiwen Xin, Michael R Yeaman, Xinghua Zhou, Andrew I Su, Chunlei Wu, Liliana Brown, Reed S Shabman, Laura D Hughes

Faculty, Staff and Students Publications

Biomedical datasets are increasing in size, stored in many repositories, and face challenges in FAIRness (findability, accessibility, interoperability, reusability). As a Consortium of infectious disease researchers from 15 Centers, we aim to adopt open science practices to promote transparency, encourage reproducibility, and accelerate research advances through data reuse. To improve FAIRness of our datasets and computational tools, we evaluated metadata standards across established biomedical data repositories. The vast majority do not adhere to a single standard, such as Schema.org, which is widely-adopted by generalist repositories. Consequently, datasets in these repositories are not findable in aggregation projects like Google Dataset Search. …

Slo3 In The Fast Lane: The Latest Male Contraceptive Target With A Promising Small-Molecule Inhibitor, Zhi Tan, Thomas X Garcia

Faculty, Staff and Students Publications

No abstract provided.

Antileukemic Properties Of The Kinase Inhibitor Otssp167 In T-Cell Acute Lymphoblastic Leukemia, Cory Seth Bridges, Taylor J Chen, Monica Puppi, Karen R Rabin, H Daniel Lacorazza

Faculty, Staff and Students Publications

Novel drugs are needed to increase treatment response in children with high-risk T-cell acute lymphoblastic leukemia (T-ALL). Following up on our previous report on the activation of the MAP2K7-JNK pathway in pediatric T-ALL, here we demonstrate that OTSSP167, recently shown to inhibit MAP2K7, has antileukemic capacity in T-ALL. OTSSP167 exhibited dose-dependent cytotoxicity against a panel of T-ALL cell lines with IC50 in the nanomolar range (10-50 nM). OTSSP167 induces apoptosis and cell cycle arrest in T-ALL cell lines, associated at least partially with the inhibition of MAP2K7 kinase activity and lower activation of its downstream substrate, JNK. Other leukemic T-cell …

Bnt162b2 Mrna Vaccination Against Coronavirus Disease 2019 Is Associated With A Decreased Likelihood Of Multisystem Inflammatory Syndrome In Children Aged 5-18 Years-United States, July 2021 - April 2022, Laura D Zambrano, Margaret M Newhams, Samantha M Olson, Natasha B Halasa, Ashley M Price, Amber O Orzel, Cameron C Young, Julie A Boom, Leila C Sahni, Aline B Maddux, Katherine E Bline, Satoshi Kamidani, Keiko M Tarquinio, Kathleen Chiotos, Jennifer E Schuster, Melissa L Cullimore, Sabrina M Heidemann, Charlotte V Hobbs, Ryan A Nofziger, Pia S Pannaraj, Melissa A Cameron, Tracie C Walker, Stephanie P Schwartz, Kelly N Michelson, Bria M Coates, Heidi R Flori, Elizabeth H Mack, Laura Smallcomb, Shira J Gertz, Samina S Bhumbra, Tamara T Bradford, Emily R Levy, Michele Kong, Katherine Irby, Natalie Z Cvijanovich, Matt S Zinter, Cindy Bowens, Hillary Crandall, Janet R Hume, Manish M Patel, Angela P Campbell, Adrienne G Randolph, Overcoming Covid-19 Investigators

Faculty, Staff and Students Publications

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C), linked to antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with considerable morbidity. Prevention of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) by vaccination might also decrease MIS-C likelihood.

METHODS: In a multicenter, case-control, public health investigation of children ages 5-18 years hospitalized from 1 July 2021 to 7 April 2022, we compared the odds of being fully vaccinated (2 doses of BNT162b2 vaccine ≥28 days before hospital admission) between MIS-C case-patients and hospital-based controls who tested negative for SARS-CoV-2. These associations were examined by age group, timing of vaccination, …

Increased Camkk2 Expression Is An Adaptive Response That Maintains The Fitness Of Tumor-Infiltrating Natural Killer Cells, Patrick K Juras, Luigi Racioppi, Debarati Mukherjee, Sandeep Artham, Xia Gao, Laura Akullian D'Agostino, Ching-Yi Chang, Donald P Mcdonnell

Faculty, Staff and Students Publications

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates M2 macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been interest in developing CaMKK2 inhibitors as potential anticancer therapeutics. One impediment to clinical development of these agents is that the roles of CaMKK2 in other cellular compartments within the tumor immune microenvironment remain to be established. We report herein that CaMKK2 is expressed at low basal levels in natural killer (NK) …

Agricultural Dust Derived Bacterial Extracellular Vesicle Mediated Inflammation Is Attenuated By Dha, Art J. Heires, Derrick R. Samuelson, Daniel Villageliu, Tara M. Nordgren, Debra J. Romberger

Journal Articles: Pulmonary & Critical Care Med

Dietary long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) and their pro-resolving metabolites are protective against atherosclerotic disease, and ameliorate systemic inflammatory conditions including lupus erythematosus, psoriasis, and bronchial asthma. Organic bioaerosol inhalation is a common and injurious hazard associated with agricultural occupations such as work in swine concentrated animal feeding operations (CAFOs) and is known to increase the risk for developing respiratory conditions such as asthma and COPD. Nearly all cells secrete membrane-bound vesicles (extracellular vesicles, EVs) that have the capacity to transmit protein, nucleic acid, and lipid signaling mediators between cells. Using a polymer-based isolation technique (ExoQuick, PEG) followed …

Icenticaftor, Novel Therapy For Copd: This Glass Is Half Full, Stephen I. Rennard

Journal Articles: Pulmonary & Critical Care Med

No abstract provided.

Longitudinal Assessment Of Multimorbidity Medication Patterns Among Smokers In The Copdgene Cohort, Yisha Li, Sarah J. Schmiege, Heather Anderson, Nicole E. Richmond, Kendra A. Young, John E. Hokanson, Stephen I. Rennard, Tessa L. Crume, Erin Austin, Katherine A. Pratte, Rebecca Conway, Gregory L. Kinney

Journal Articles: Pulmonary & Critical Care Med

Background and objectives: Chronic obstructive pulmonary disease (COPD) is usually comorbid with other chronic diseases. We aimed to assess the multimorbidity medication patterns and explore if the patterns are similar for phase 1 (P1) and 5-year follow-up phase 2 (P2) in the COPDGene cohort. Materials and Methods: A total of 5564 out of 10,198 smokers from the COPDGene cohort who completed 2 visits, P1 and P2 visits, with complete medication use history were included in the study. We conducted latent class analysis (LCA) among the 27 categories of chronic disease medications, excluding COPD treatments and cancer medications at P1 and …

Naproxen Chemoprevention Induces Proliferation Of Cytotoxic Lymphocytes In Lynch Syndrome Colorectal Mucosa, Charles M Bowen, Nan Deng, Laura Reyes-Uribe, Edwin Roger Parra, Pedro Rocha, Luisa M Solis, Ignacio I Wistuba, Valerie O Sepeda, Lana Vornik, Marjorie Perloff, Eva Szabo, Asad Umar, Krishna M Sinha, Powel H Brown, Eduardo Vilar

Faculty, Staff and Student Publications

BACKGROUND: Recent clinical trial data from Lynch Syndrome (LS) carriers demonstrated that naproxen administered for 6-months is a safe primary chemoprevention that promotes activation of different resident immune cell types without increasing lymphoid cellularity. While intriguing, the precise immune cell types enriched by naproxen remained unanswered. Here, we have utilized cutting-edge technology to elucidate the immune cell types activated by naproxen in mucosal tissue of LS patients.

METHODS: Normal colorectal mucosa samples (pre- and post-treatment) from a subset of patients enrolled in the randomized and placebo-controlled 'Naproxen Study' were obtained and subjected to a tissue microarray for image mass cytometry …

Distinct Patterns Of Auto-Reactive Antibodies Associated With Organ-Specific Immune-Related Adverse Events, Mehmet Altan, Quan-Zhen Li, Qi Wang, Natalie I Vokes, Ajay Sheshadri, Jianjun Gao, Chengsong Zhu, Hai T Tran, Saumil Gandhi, Mara B Antonoff, Stephen Swisher, Jing Wang, Lauren A Byers, Noha Abdel-Wahab, Maria C Franco-Vega, Yinghong Wang, J Jack Lee, Jianjun Zhang, John V Heymach

Faculty, Staff and Student Publications

UNLABELLED: The roles of preexisting auto-reactive antibodies in immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy are not well defined. Here, we analyzed plasma samples longitudinally collected at predefined time points and at the time of irAEs from 58 patients with immunotherapy naïve metastatic non-small cell lung cancer treated on clinical protocol with ipilimumab and nivolumab. We used a proteomic microarray system capable of assaying antibody reactivity for IgG and IgM fractions against 120 antigens for systemically evaluating the correlations between auto-reactive antibodies and certain organ-specific irAEs. We found that distinct patterns of auto-reactive antibodies at baseline were …

Spatial Modelling Of The Tumor Microenvironment From Multiplex Immunofluorescence Images: Methods And Applications, Gayatri Kumar, Renganayaki Krishna Pandurengan, Edwin Roger Parra, Kasthuri Kannan, Cara Haymaker

Faculty, Staff and Student Publications

Spatial modelling methods have gained prominence with developments in high throughput imaging platforms. Multiplex immunofluorescence (mIF) provides the scope to examine interactions between tumor and immune compartment at single cell resolution using a panel of antibodies that can be chosen based on the cancer type or the clinical interest of the study. The markers can be used to identify the phenotypes and to examine cellular interactions at global and local scales. Several translational studies rely on key understanding of the tumor microenvironment (TME) to identify drivers of immune response in immunotherapy based clinical trials. To improve the success of ongoing …

Blockade Of Mglur5 In Astrocytes Derived From Human Ipscs Modulates Astrocytic Function And Increases Phagocytosis, Izabella B Q De Lima, Pablo L Cardozo, Julia S Fahel, Juliana P S Lacerda, Aline S Miranda, Antônio L Teixeira, Fabiola M Ribeiro

Faculty, Staff and Student Publications

TNF-α is essential for induction and maintenance of inflammatory responses and its dysregulation is associated with susceptibility to various pathogens that infect the central nervous system. Activation of both microglia and astrocytes leads to TNF-α production, which in turn triggers further activation of these cells. Astrocytes have been implicated in the pathophysiology of a wide range of neurodegenerative diseases with either harmful or protective roles, as these cells are capable of secreting several inflammatory factors and also promote synapse elimination and remodeling. These responses are possible because they sense their surroundings via several receptors, including the metabotropic glutamate receptor 5 …

Development And Validation Of Early Death Risk Score Model For Emergency Status Prediction In Very Severe Aplastic Anemia, Xu Liu, Wenrui Yang, Li Zhang, Liping Jing, Lei Ye, Kang Zhou, Yuan Li, Jianping Li, Huihui Fan, Yang Yang, Youzhen Xiong, Xin Zhao, Fengkui Zhang

Faculty, Staff and Student Publications

This study developed and validated the Early Death Risk Score Model for early identification of emergency patients with very severe aplastic anemia (VSAA). All 377 patients with VSAA receiving first-line immunosuppressive therapy (IST) were categorized into training (n=252) and validation (n=125) cohorts. In the training cohort, age >24 years, absolute neutrophil count ≤0.015×109/L, serum ferritin >900ng/mL and times of fever before IST >1 time were significantly associated with early death. Covariates were assigned scores and categorized as: low (score 0-4), medium (score 5-7) and high (score ≥8) risk. Early death rate was significantly different between risk groups and the validation …

Chromosomal Microarray Analysis Supplements Exome Sequencing To Diagnose Children With Suspected Inborn Errors Of Immunity, Breanna J Beers, Morgan N Similuk, Rajarshi Ghosh, Bryce A Seifert, Leila Jamal, Michael Kamen, Michael R Setzer, Colleen Jodarski, Rylee Duncan, Devin Hunt, Madison Mixer, Wenjia Cao, Weimin Bi, Daniel Veltri, Eric Karlins, Lingwen Zhang, Zhiwen Li, Andrew J Oler, Kathleen Jevtich, Yunting Yu, Haley Hullfish, Bibiana Bielekova, Pamela Frischmeyer-Guerrerio, An Dang Do, Laryssa A Huryn, Kenneth N Olivier, Helen C Su, Jonathan J Lyons, Christa S Zerbe, V Koneti Rao, Michael D Keller, Alexandra F Freeman, Steven M Holland, Luis M Franco, Magdalena A Walkiewicz, Jia Yan

Faculty, Staff and Students Publications

PURPOSE: Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI.

METHODS: We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings.

RESULTS: Of the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by …

Ems Administration Of Systemic Corticosteroids To Pediatric Asthma Patients: An Analysis By Severity And Transport Interval, Lauren Riney, Sam Palmer, Erik Finlay, Andrew Bertrand, Shannon Burcham, Phyllis Hendry, Manish Shah, Kathryn Kothari, David Ashby, Daniel Ostermayer, Olga Semenova, Benjamin N Abo, Benjamin Abes, Nichole Shimko, Emily Myers, Marshall Frank, Tim Turner, Mac Kemp, Kim Landry, Greg Roland, Jennifer Fishe

Faculty, Staff and Students Publications

INTRODUCTION: Pediatric asthma exacerbations are a common cause of emergency medical services (EMS) encounters. Bronchodilators and systemic corticosteroids are mainstays of asthma exacerbation therapy, yet data on the efficacy of EMS administration of systemic corticosteroids are mixed. This study's objective was to assess the association between EMS administration of systemic corticosteroids to pediatric asthma patients on hospital admission rates based on asthma exacerbation severity and EMS transport intervals.

METHODS: This is a sub-analysis of the Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial (EASI AS ODT). EASI AS ODT is a non-randomized, stepped wedge, observational study …

Combined Immunodeficiency Caused By Pathogenic Variants In The Zap70 C-Terminal Sh2 Domain, Cédric Mongellaz, Rita Vicente, Lenora M Noroski, Nelly Noraz, Valérie Courgnaud, Javier Chinen, Emilia Faria, Valérie S Zimmermann, Naomi Taylor

Faculty, Staff and Students Publications

INTRODUCTION: ZAP-70, a protein tyrosine kinase recruited to the T cell receptor (TCR), initiates a TCR signaling cascade upon antigen stimulation. Mutations in the ZAP70 gene cause a combined immunodeficiency characterized by low or absent CD8+ T cells and nonfunctional CD4+ T cells. Most deleterious missense ZAP70 mutations in patients are located in the kinase domain but the impact of mutations in the SH2 domains, regulating ZAP-70 recruitment to the TCR, are not well understood.

METHODS:Genetic analyses were performed on four patients with CD8 lymphopenia and a high resolution melting screening for ZAP70 mutations was developed. The impact of SH2 …

Covid-19 And Pregnancy: Clinical Outcomes; Mechanisms, And Vaccine Efficacy, Deepak Kumar, Sonam Verma, Indira U Mysorekar

Faculty, Staff and Students Publications

As the COVID-19 pandemic continues into its third year, emerging data indicates increased risks associated with SARS-CoV-2 infection during pregnancy, including pre-eclampsia, intrauterine growth restriction, preterm birth, stillbirth, and risk of developmental defects in neonates. Here, we review clinical reports to date that address different COVID-19 pregnancy complications. We also document placental pathologies induced by SARS-CoV-2 infection, entry mechanisms in placental cells, and immune responses at the maternal-fetal interface. Since new variants of SARS-CoV-2 are emerging with characteristics of higher transmissibility and more effective immune escape strategies, we also briefly highlight the genomic and proteomic features of SARS-CoV-2 investigated to …

From Concept To Delivery: A Yeast-Expressed Recombinant Protein-Based Covid-19 Vaccine Technology Suitable For Global Access, Peter J Hotez, Rakesh Adhikari, Wen-Hsiang Chen, Yi-Lin Chen, Portia Gillespie, Nelufa Y Islam, Brian Keegan, Rakhi Tyagi Kundu, Jungsoon Lee, Zhuyun Liu, Jason T Kimata, Numan Oezguen, Jeroen Pollet, Cristina Poveda, Kay Razavi, Shannon E Ronca, Ulrich Strych, Syamala R Thimmiraju, Leroy Versteeg, Maria Jose Villar-Mondragon, Junfei Wei, Bin Zhan, Maria Elena Bottazzi

Faculty, Staff and Students Publications

Introduction: The development of a yeast-expressed recombinant protein-based vaccine technology co-developed with LMIC vaccine producers and suitable as a COVID-19 vaccine for global access is described. The proof-of-concept for developing a SARS-CoV-2 spike protein receptor-binding domain (RBD) antigen as a yeast-derived recombinant protein vaccine technology is described.

Areas covered: Genetic Engineering: The strategy is presented for the design and genetic modification used during cloning and expression in the yeast system. Process and Assay Development: A summary is presented of how a scalable, reproducible, and robust production process for the recombinant protein COVID-19 vaccine antigen was developed. Formulation and Pre-clinical Strategy: …

Myeloid-Associated Differentiation Marker Is Associated With Type 2 Asthma And Is Upregulated By Human Rhinovirus Infection, Sasipa Tanyaratsrisakul, Alane Blythe C Dy, Francesca Polverino, Mari Numata, Julie G Ledford

Faculty, Staff and Students Publications

BACKGROUND: Human rhinoviruses are known to predispose infants to asthma development during childhood and are often associated with exacerbations in asthma patients. MYADM epithelial expression has been shown to associate with asthma severity. The goal of this study was to determine if MYADM expression patterns were altered in asthma and/or rhinovirus infection and if increased MYADM expression is associated with increased asthma-associated factors.

METHODS: Utilizing H1HeLa cells and differentiated primary human airway epithelial cells (AECs), we measured the expression of MYADM and inflammatory genes by qRT-PCR in the presence or absence of RV-1B infection or poly I:C treatment and with …