Digital Commons Network^™

Zika Virus Oncolytic Activity Requires Cd8+ T Cells And Is Boosted By Immune Checkpoint Blockade, Sharmila Nair, Luciano Mazzoccoli, Arijita Jash, Jennifer Govero, Sachendra S Bais, Tong Hu, Camila R Fontes-Garfias, Chao Shan, Hideho Okada, Sujan Shresta, Jeremy N Rich, Pei-Yong Shi, Michael S Diamond, Milan G Chheda

Open Access Publications

Glioblastoma multiforme (GBM) is a fatal human cancer in part because GBM stem cells are resistant to therapy and recurrence is inevitable. Previously, we demonstrated Zika virus (ZIKV) targets GBM stem cells and prevents death of mice with gliomas. Here, we evaluated the immunological basis of ZIKV-mediated protection against GBM. Introduction of ZIKV into the brain tumor increased recruitment of CD8+ T and myeloid cells to the tumor microenvironment. CD8+ T cells were required for ZIKV-dependent tumor clearance because survival benefits were lost with CD8+ T cell depletion. Moreover, while anti-PD-1 antibody monotherapy moderately improved tumor survival, when coadministered with …

The Dark Kinase Knowledgebase: An Online Compendium Of Knowledge And Experimental Results Of Understudied Kinases, Matthew E. Berginski, Nienke Moret, Changchang Liu, Dennis Goldfarb, Peter K. Sorger, Shawn M. Gomez

Open Access Publications

Kinases form the backbone of numerous cell signaling pathways, with their dysfunction similarly implicated in multiple pathologies. Further facilitated by their druggability, kinases are a major focus of therapeutic development efforts in diseases such as cancer, infectious disease and autoimmune disorders. While their importance is clear, the role or biological function of nearly one-third of kinases is largely unknown. Here, we describe a data resource, the Dark Kinase Knowledgebase (DKK; https://darkkinome.org), that is specifically focused on providing data and reagents for these understudied kinases to the broader research community. Supported through NIH's Illuminating the Druggable Genome (IDG) Program, the DKK …

Corynebacterium Species Inhibit Streptococcus Pneumoniae Colonization And Infection Of The Mouse Airway, Kadi J Horn, Alexander C Jaberi Vivar, Vera Arenas, Sameer Andani, Edward N Janoff, Sarah E Clark

Open Access Publications

The stability and composition of the airway microbiome is an important determinant of respiratory health. Some airway bacteria are considered to be beneficial due to their potential to impede the acquisition and persistence of opportunistic bacterial pathogens such as

Bromodomain Protein Brd4 Directs And Sustains Cd8 T Cell Differentiation During Infection, J. Justin Milner, Takeshi Egawa, Et Al

Open Access Publications

In response to infection, pathogen-specific CD8 T cells differentiate into functionally diverse effector and memory T cell populations critical for resolving disease and providing durable immunity. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we reveal an essential role for the chromatin modifier and BET family member BRD4 in supporting the differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 bound diverse regulatory regions critical to effector T cell differentiation and controlled transcriptional activity of terminal effector-specific super-enhancers in vivo. Consequentially, induced deletion of Brd4 or small molecule-mediated BET inhibition impaired maintenance of a terminal …

The Risks Of Stone Diagnosis And Stone Removal Procedure After Different Bariatric Surgeries, Steven M. Monda, Joel M. Vetter, Margaret A. Olsen, Matthew R. Keller, J. Christopher Eagon, Michael S. Chevinsky, Vasian Markollari, Ramakrishna Venkatesh, Alana C. Desai

Open Access Publications

No abstract provided.

Unexpected Role Of Sterol Synthesis In Rna Stability And Translation In Leishmania, Zemfira N Karamysheva, Samrat Moitra, Andrea Perez, Sumit Mukherjee, Elena B Tikhonova, Andrey L Karamyshev, Kai Zhang

Open Access Publications

No abstract provided.

Engaging Caregivers And Providers Of Children With Sickle Cell Anemia In Shared Decision Making For Hydroxyurea: Protocol For A Multicenter Randomized Controlled Trial, Anna M Hood, Allison A King, Cecelia Calhoun, Et Al

Open Access Publications

BACKGROUND: Sickle cell anemia (SCA) is a genetic blood disorder that puts children at a risk of serious medical complications, early morbidity and mortality, and high health care utilization. Until recently, hydroxyurea was the only disease-modifying treatment for this life-threatening disease and has remained the only option for children younger than 5 years. Evidence-based guidelines recommend using a shared decision-making (SDM) approach for offering hydroxyurea to children with SCA (HbSS or HbS/β0 thalassemia) aged as early as 9 months. However, the uptake remains suboptimal, likely because caregivers lack information about hydroxyurea and have concerns about its safety and potential long-term …

Development And Validation Of A Multivariable Prediction Model For Missed Hiv Health Care Provider Visits In A Large Us Clinical Cohort, April C. Pettit, Aihua Bian, Cassandra O. Schember, Peter F. Rebeiro, Jeanne C. Keruly, Kenneth H. Mayer, W. Christopher Mathews, Richard D. Moore, Heidi M. Crane, Elvin Geng, Sonia Napravnik, Bryan E. Shepherd, Michael J. Mugavero

Open Access Publications

Background: Identifying individuals at high risk of missing HIV care provider visits could support proactive intervention. Previous prediction models for missed visits have not incorporated data beyond the individual level.

Methods: We developed prediction models for missed visits among people with HIV (PWH) with ≥1 follow-up visit in the Center for AIDS Research Network of Integrated Clinical Systems from 2010 to 2016. Individual-level (medical record data and patient-reported outcomes), community-level (American Community Survey), HIV care site-level (standardized clinic leadership survey), and structural-level (HIV criminalization laws, Medicaid expansion, and state AIDS Drug Assistance Program budget) predictors were included. Models were developed …

Evaluation Of A Clinical Decision Support Strategy To Increase Seasonal Influenza Vaccination Among Hospitalized Children Before Inpatient Discharge, Evan W. Orenstein, Omar Elsayed-Ali, Swaminathan Kandaswamy, Erin Masterson, Reena Blanco, Pareen Shah, Patricia Lantis, Amy Kolwaite, Thomas E. Dawson, Edwin Ray, Christy Bryant, Srikant Iyer, Andi L. Shane, Stephanie Jernigan

Open Access Publications

Importance: Hospitalized children are at increased risk of influenza-related complications, yet influenza vaccine coverage remains low among this group. Evidence-based strategies about vaccination of vulnerable children during all health care visits are especially important during the COVID-19 pandemic.

Objective: To design and evaluate a clinical decision support (CDS) strategy to increase the proportion of eligible hospitalized children who receive a seasonal influenza vaccine prior to inpatient discharge.

Design, Setting, and Participants: This quality improvement study was conducted among children eligible for the seasonal influenza vaccine who were hospitalized in a tertiary pediatric health system providing care to more than half …

Cd16+Cd163+ Monocytes Traffic To Sites Of Inflammation During Necrotizing Enterocolitis In Premature Infants, Oluwabunmi O. Olaloye, Misty Good, Et Al

Open Access Publications

Necrotizing enterocolitis (NEC) is a severe gastrointestinal complication of prematurity. Using suspension and imaging mass cytometry coupled with single-cell RNA sequencing, we demonstrate severe inflammation in patients with NEC. NEC mucosa could be subtyped by an influx of three distinct neutrophil phenotypes (immature, newly emigrated, and aged). Furthermore, CD16+CD163+ monocytes/Mϕ, correlated with newly emigrated neutrophils, were specifically enriched in NEC mucosa, found adjacent to the blood vessels, and increased in circulation of infants with surgical NEC, suggesting trafficking from the periphery to areas of inflammation. NEC-specific monocytes/Mϕ transcribed inflammatory genes, including TREM1, IL1A, IL1B, and calprotectin, and neutrophil recruitment genes …

Extracorporeal Support Prognostication-Time To Move The Goal Posts?, Neel Shah, Ahmed S Said

Open Access Publications

Advances in extracorporeal membrane oxygenation (ECMO) technology are associated with expanded indications, increased utilization and improved outcome. There is growing interest in developing ECMO prognostication scores to aid in bedside decision making. To date, the majority of available scores have been limited to mostly registry-based data and with mortality as the main outcome of interest. There continues to be a gap in clinically applicable decision support tools to aid in the timing of ECMO cannulation to improve patients' long-term outcomes. We present a brief review of the commonly available adult and pediatric ECMO prognostication tools, their limitations, and future directions.

An Open Label, Block Randomized, Community Study Of The Safety And Efficacy Of Co-Administered Ivermectin, Diethylcarbamazine Plus Albendazole Vs. Diethylcarbamazine Plus Albendazole For Lymphatic Filariasis In India, Purushothaman Jambulingam, Vijesh Sreedhar Kuttiatt, Kaliannagounder Krishnamoorthy, Swaminathan Subramanian, Adinarayanan Srividya, Hari Kishan K. Raju, Manju Rahi, Roopali K. Somani, Mallanna K. Suryaprakash, Gangeshwar P. Dwivedi, Gary J Weil

Open Access Publications

No abstract provided.

Dengue And The Lectin Pathway Of The Complement System, Romchat Kraivong, Nuntaya Punyadee, M Kathryn Liszewski, John P Atkinson, Panisadee Avirutnan

Open Access Publications

Dengue is a mosquito-borne viral disease causing significant health and economic burdens globally. The dengue virus (DENV) comprises four serotypes (DENV1-4). Usually, the primary infection is asymptomatic or causes mild dengue fever (DF), while secondary infections with a different serotype increase the risk of severe dengue disease (dengue hemorrhagic fever, DHF). Complement system activation induces inflammation and tissue injury, contributing to disease pathogenesis. However, in asymptomatic or primary infections, protective immunity largely results from the complement system's lectin pathway (LP), which is activated through foreign glycan recognition. Differences in N-glycans displayed on the DENV envelope membrane influence the lectin pattern …

Il-7 Immunotherapy In A Nonimmunocompromised Patient With Intractable Fungal Wound Sepsis, Isaiah R. Turnbull, Monty B. Mazer, Mark H. Hoofnagle, John P. Kirby, Jennifer M. Leonard, Carlos Mejia-Chew, Andrej Spec, Jane Blood, Sydney M. Miles, Eric M. Ransom, Robert F. Potter, Joseph P. Gaut, Kenneth E. Remy, Richard S. Hotchkiss

Open Access Publications

A nonimmunocompromised patient developed life-threatening soft tissue infection with

Type Iii Interferons: Emerging Roles In Autoimmunity, Sindhu Manivasagam, Robyn S Klein

Open Access Publications

Type III interferons (IFNs) or the lambda IFNs (IFNLs or IFN-λs) are antimicrobial cytokines that play key roles in immune host defense at endothelial and epithelial barriers. IFNLs signal

Overlapping But Disparate Inflammatory And Immunosuppressive Responses To Sars-Cov-2 And Bacterial Sepsis: An Immunological Time Course Analysis, Tyler J Loftus, Ricardo Ungaro, Marvin Dirain, Philip A Efron, Monty B Mazer, Kenneth E Remy, Richard S Hotchkiss, Luer Zhong, Rhonda Bacher, Petr Starostik, Lyle L Moldawer, Scott C Brakenridge

Open Access Publications

Both severe SARS-CoV-2 infections and bacterial sepsis exhibit an immunological dyscrasia and propensity for secondary infections. The nature of the immunological dyscrasias for these differing etiologies and their time course remain unclear. In this study, thirty hospitalized patients with SARS-CoV-2 infection were compared with ten critically ill patients with bacterial sepsis over 21 days, as well as ten healthy control subjects. Blood was sampled between days 1 and 21 after admission for targeted plasma biomarker analysis, cellular phenotyping, and leukocyte functional analysis

Harnessing The Potential Of Multiomics Studies For Precision Medicine In Infectious Disease, Rebecca A. Ward, Philip A. Mudd, Rachel M. Presti, Andrej Spec, Et Al

Open Access Publications

The field of infectious diseases currently takes a reactive approach and treats infections as they present in patients. Although certain populations are known to be at greater risk of developing infection (eg, immunocompromised), we lack a systems approach to define the true risk of future infection for a patient. Guided by impressive gains in "omics" technologies, future strategies to infectious diseases should take a precision approach to infection through identification of patients at intermediate and high-risk of infection and deploy targeted preventative measures (ie, prophylaxis). The advances of high-throughput immune profiling by multiomics approaches (ie, transcriptomics, epigenomics, metabolomics, proteomics) hold …

Evaluation Of Commercial Rapid Lateral Flow Tests, Alone Or In Combination, For Sars-Cov-2 Antibody Testing, Peter U Fischer, Kerstin Fischer, Kurt C Curtis, Yuefang Huang, Nicole Fetcho, Charles W Goss, Gary J Weil

Open Access Publications

Antibody tests can be tools for detecting current or past severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 [coronavirus disease 2019 (COVID-19)]) infections. Independent test evaluations are needed to document the performance with different sample sets. We evaluated six lateral flow assays (LFAs) and two laboratory-based tests (EUROIMMUN-SARS-CoV-2 ELISA and Abbott-Architect-SARS-CoV-2-IgG). We tested 210 plasma samples from 89 patients diagnosed with acute COVID-19. These samples were collected at different time points after the onset of symptoms. In addition, 80 convalescent plasma samples, and 168 pre-pandemic samples collected from adults in the United States and in Africa were tested. LFA performance varied …

Tlr3 Controls Constitutive Ifn-Β Antiviral Immunity In Human Fibroblasts And Cortical Neurons, Daxing Gao, Michael S Diamond, Et Al

Open Access Publications

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes …

Use Of Machine Learning To Develop And Evaluate Models Using Preoperative And Intraoperative Data To Identify Risks Of Postoperative Complications, Bing Xue, Dingwen Li, Chenyang Lu, Christopher R. King, Troy Wildes, Michael S. Avidan, Thomas Kannampallil, Joanna Abraham

Open Access Publications

Importance: Postoperative complications can significantly impact perioperative care management and planning.

Objectives: To assess machine learning (ML) models for predicting postoperative complications using independent and combined preoperative and intraoperative data and their clinically meaningful model-agnostic interpretations.

Design, Setting, and Participants: This retrospective cohort study assessed 111 888 operations performed on adults at a single academic medical center from June 1, 2012, to August 31, 2016, with a mean duration of follow-up based on the length of postoperative hospital stay less than 7 days. Data analysis was performed from February 1 to September 31, 2020.

Main Outcomes and Measures: Outcomes included …

Taking Account Of Asymptomatic Infections: A Modeling Study Of The Covid-19 Outbreak On The Diamond Princess Cruise Ship, Li-Shan Huang, Li Li, Lucia Dunn, Mai He

Open Access Publications

The COVID-19 outbreak on the Diamond Princess (DP) cruise ship has provided empirical data to study the transmission potential of COVID-19 with the presence of pre/asymptomatic cases. We studied the changes in R0 on DP from January 21 to February 19, 2020 based on chain binomial models under two scenarios: no quarantine assuming a random mixing condition, and quarantine of passengers in cabins-passengers may get infected either by an infectious case in a shared cabin or by pre/asymptomatic crew who continued to work. Estimates of R0 at the beginning of the epidemic were 3.27 (95% CI, 3.02-3.54) and 3.78 (95% …

Broadly Neutralizing Monoclonal Antibodies Protect Against Multiple Tick-Borne Flaviviruses, Laura A. Vanblargan, John M. Errico, Natasha M. Kafai, Prashant N. Jethva, Christopher A. Nelson, David Wang, Scott A. Handley, Michael L. Gross, Daved H. Fremont, Michael S. Diamond, Et Al

Open Access Publications

Although Powassan virus (POWV) is an emerging tick-transmitted flavivirus that causes severe or fatal neuroinvasive disease in humans, medical countermeasures have not yet been developed. Here, we developed a panel of neutralizing anti-POWV mAbs recognizing six distinct antigenic sites. The most potent of these mAbs bind sites within domain II or III of the envelope (E) protein and inhibit postattachment viral entry steps. A subset of these mAbs cross-react with other flaviviruses. Both POWV type-specific and cross-reactive neutralizing mAbs confer protection in mice against POWV infection when given as prophylaxis or postexposure therapy. Several cross-reactive mAbs mapping to either domain …

Variables Associated With Intravenous Rehydration And Hospitalization In Children With Acute Gastroenteritis: A Secondary Analysis Of 2 Randomized Clinical Trials, Naveen Poonai, Philip Tarr, Et Al

Open Access Publications

Importance: Despite guidelines endorsing oral rehydration therapy, intravenous fluids are commonly administered to children with acute gastroenteritis in high-income countries.

Objective: To identify factors associated with intravenous fluid administration and hospitalization in children with acute gastroenteritis.

Design, Setting, and Participants: This study is a planned secondary analysis of the Pediatric Emergency Research Canada (PERC) and Pediatric Emergency Care Applied Research Network (PECARN) probiotic trials. Participants include children aged 3 to 48 months with 3 or more watery stools in 24 hours between November 5, 2013, and April 7, 2017, for the PERC study and July 8, 2014, and June 23, …

Thermoneutrality Alters Gastrointestinal Antigen Passage Patterning And Predisposes To Oral Antigen Sensitization In Mice, Taeko K Noah, Jee-Boong Lee, Christopher A Brown, Amnah Yamani, Sunil Tomar, Varsha Ganesan, Rodney D Newberry, Gary B Huffnagle, Senad Divanovic, Simon P Hogan

Open Access Publications

Food allergy is an emerging epidemic, and the underlying mechanisms are not well defined partly due to the lack of robust adjuvant free experimental models of dietary antigen sensitization. As housing mice at thermoneutrality (Tn) - the temperature of metabolic homeostasis (26-30°C) - has been shown to improve modeling various human diseases involved in inflammation, we tested the impact of Tn housing on an experimental model of food sensitization. Here we demonstrate that WT BALB/c mice housed under standard temperature (18-20°C, Ts) conditions translocated the luminal antigens in the small intestine (SI) across the epithelium

Guidelines For Conducting Virtual Cognitive Interviews During A Pandemic, James A Shepperd, Gabrielle Pogge, Jean M Hunleth, Sienna Ruiz, Erika A Waters

Open Access Publications

The COVID-19 pandemic has challenged researchers working in physical contact with research participants. Cognitive interviews examine whether study components (most often questionnaire items) are worded or structured in a manner that allows study participants to interpret the items in a way intended by the researcher. We developed guidelines to conduct cognitive interviews virtually to accommodate interviewees who have limited access to the internet. The guidelines describe the essential communication and safety equipment requirements and outline a procedure for collecting responses while maintaining the safety of the participants and researchers. Furthermore, the guidelines provide suggestions regarding training of participants to use …

Whipworm-Associated Intestinal Microbiome Members Consistent Across Both Human And Mouse Hosts, Bruce A Rosa, Caroline Snowden, John Martin, Kerstin Fischer, Jonah Kupritz, Ethiopia Beshah, Taniawati Supali, Lincoln Gankpala, Peter U Fischer, Joseph F Urban, Makedonka Mitreva

Open Access Publications

The human whipworm

Get Privacy Trending: Best Practices For The Social Media Educator, Sara W. Dong, Nathanial S. Nolan, Miguel A. Chavez, Yijia Li, Gerome V. Escota, Wendy Stead

Open Access Publications

Social media is an increasingly popular forum for medical education. Many educators, including those in infectious diseases, are now creating and sharing unique and educational patient cases online. Unfortunately, some educators unknowingly threaten patient privacy and open themselves to legal liability. Further, the use of published figures or tables creates risk of copyright infringement. As more and more infectious diseases physicians engage in social media, it is imperative to create best practices to protect both patients and physicians. This summary will define the legal requirements of patient de-identification as well as other practical recommendations as they relate to use of …

Clinical Prediction Rule For Sars-Cov-2 Infection From 116 U.S. Emergency Departments 2-22-2021, Jeffrey A. Kline, Stacey House, Et Al.

Open Access Publications

OBJECTIVES: Accurate and reliable criteria to rapidly estimate the probability of infection with the novel coronavirus-2 that causes the severe acute respiratory syndrome (SARS-CoV-2) and associated disease (COVID-19) remain an urgent unmet need, especially in emergency care. The objective was to derive and validate a clinical prediction score for SARS-CoV-2 infection that uses simple criteria widely available at the point of care.

METHODS: Data came from the registry data from the national REgistry of suspected COVID-19 in EmeRgency care (RECOVER network) comprising 116 hospitals from 25 states in the US. Clinical variables and 30-day outcomes were abstracted from medical records …

Acute Symptoms Of Mild To Moderate Covid-19 Are Highly Heterogeneous Across Individuals And Over Time, Thomas L. Rodebaugh, Madelyn R. Frumkin, Angela M. Reiersen, Eric J. Lenze, Michael S. Avidan, J. Philip Miller, Jay F. Piccirillo, Charles F. Zorumski, Caline Mattar

Open Access Publications

Background: The symptoms of coronavirus disease 2019 (COVID-19) appear to be heterogenous, and the typical course of these symptoms is unknown. Our objectives were to characterize the common trajectories of COVID-19 symptoms and to assess how symptom course predicts other symptom changes as well as clinical deterioration.

Methods: One hundred sixty-two participants with acute COVID-19 responded to surveys up to 31 times for up to 17 days. Several statistical methods were used to characterize the temporal dynamics of these symptoms. Because 9 participants showed clinical deterioration, we explored whether these participants showed any differences in symptom profiles.

Results: Trajectories varied …

Cxcl17 Is A Specific Diagnostic Biomarker For Severe Pandemic Influenza A(H1n1) That Predicts Poor Clinical Outcome, Jose Alberto Choreño-Parra, Shabaana A Khader, Et Al

Open Access Publications

The C-X-C motif chemokine ligand 17 (CXCL17) is chemotactic for myeloid cells, exhibits bactericidal activity, and exerts anti-viral functions. This chemokine is constitutively expressed in the respiratory tract, suggesting a role in lung defenses. However, little is known about the participation of CXCL17 against relevant respiratory pathogens in humans. Here, we evaluated the serum levels and lung tissue expression pattern of CXCL17 in a cohort of patients with severe pandemic influenza A(H1N1) from Mexico City. Peripheral blood samples obtained on admission and seven days after hospitalization were processed for determinations of serum CXCL17 levels by enzyme-linked immunosorbent assay (ELISA). The …