Digital Commons Network^™

A Single High-Zinc Activation Enhancer Can Control Two Genes Oriented Head-To-Head In Caenorhabditis Elegans, Hanwenheng Liu, Brian Earley, Adelita Mendoza, Patrick Hunt, Sean Teng, Daniel Luke Schneider, Kerry Kornfeld

2020-Current year OA Pubs

Enhancers play critical roles in gene expression, but a full understanding of their complex functions has yet to be defined. The cellular response to excess zinc levels in Caenorhabditis elegans requires the HIZR-1 transcription factor, which binds the high-zinc activation (HZA) enhancer in the promoters of multiple target genes. Cadmium hijacks the excess zinc response by binding and activating HIZR-1. By analyzing the genome-wide transcriptional response to excess zinc and cadmium, we identified two positions in the genome where head-to-head oriented genes are both induced by metals. In both examples, a single predicted HZA enhancer is positioned between the two …

Cord Blood Proteomics Identifies Biomarkers Of Early-Onset Neonatal Sepsis, Leena B. Mithal, Mark E. Becker, Ted Ling-Hu, Young Ah Goo, Sebastian Otero, Aspen Kremer, Surya Pandey, Nicola Lancki, Yawei Li, Yuan Luo, William Grobman, Denise Scholtens, Karen K. Mestan, Patrick C. Seed, Judd F. Hultquist

2020-Current year OA Pubs

BACKGROUNDSymptoms of early-onset neonatal sepsis (EOS) in preterm infants are nonspecific and overlap with normal postnatal physiological adaptations and noninfectious pathologies. This clinical uncertainty and the lack of reliable EOS diagnostics results in liberal use of antibiotics in the first days to weeks of life, leading to increased risk of antibiotic-related morbidities in infants who do not have an invasive infection. METHODSTo identify potential biomarkers for EOS in newborn infants, we used unlabeled tandem mass spectrometry proteomics to identify differentially abundant proteins in the umbilical cord blood of infants with and without culture-confirmed EOS. Proteins were then confirmed using immunoassay, …

The Trapping Of Live Neutrophils By Macrophages During Infection, Kelley N Cooper, Marina Terekhova, Barbara Potempa, Ana D'Aubeterre, Jerome Timbol, Si An Chen, Antoine Dufour, Shunying Jin, Maxim N Artyomov, Jan Potempa, Juhi Bagaitkar

2020-Current year OA Pubs

Neutrophils are highly abundant in the oral mucosal tissues, and their balanced activation and clearance are essential for immune homeostasis. Here, we demonstrate that neutrophils infected with the bacterial pathogen Porphyromonas gingivalis (Pg) are captured alive by macrophages in a manner that bypasses all known receptor-ligand interactions involved in the phagocytosis of either live or dead cells. Mechanistically, upon interaction with Pg, or its protease RgpB (gingipains), live neutrophils undergo rapid remodeling of their proteomes, generating neoepitopes. N-terminomics-based proteomic profiling identified multiple RgpB cleavage sites on several azurophilic granule proteins that are translocated to the surface of live neutrophils via …

High-Frequency, At-Home Monitoring Of Drug Safety And Tolerability In Clinical Trials: Results From Studies Of Fluvoxamine For Covid-19 Treatment, Eric J Lenze, Madeline Nykamp, J Philip Miller, Angela Stevens, Julia Schweiger, Torie Gettinger, Michael Yingling, Yi Zhang, Ginger E Nicol, Charles F Zorumski, Angela M Reiersen

2020-Current year OA Pubs

Clinical trials are increasingly using remote monitoring techniques at the patient's home. We conducted a secondary analysis of remote safety and tolerability monitoring from two fully-remote clinical trials that tested fluvoxamine for the acute treatment of COVID-19. Both trials assessed pulse and blood pressure daily, and one study assessed symptoms daily via Ecological Momentary Assessment. On average, patients provided data on vital signs on 93% of the study days and provided data on side effects on 81% of the study days. With respect to safety, patients taking fluvoxamine had reduced pulse rate compared to placebo, with the greatest difference-5 points-at …

First-Trimester Antibiotic Use For Urinary Tract Infection And Risk Of Congenital Malformations, Sarah S Osmundson, Katelin B Nickel, Susan M. Shortreed, Sascha Dublin, Dustin Stwalley, Michael J Durkin, Paige D Wartko, John M Sahrmann, Ryan Colvin, Anne M Butler

2020-Current year OA Pubs

IMPORTANCE: Clinical guidelines recommend screening and treating bacteriuria in early pregnancy given that urinary tract infections (UTIs) can cause serious maternal and neonatal consequences. Evidence regarding antibiotic exposure during early pregnancy and risk of congenital malformations is limited and inconsistent.

OBJECTIVE: To compare the risk of congenital malformations following first-trimester exposure to different antibiotic agents used to treat UTI.

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study included commercially insured pregnant individuals aged 15 to 49 years who were treated for UTI and linked liveborn infants in the Merative MarketScan Commercial Database (2006-2022).

EXPOSURE: First-trimester antibiotic prescription fill of nitrofurantoin, …

Clinical Evaluation Of The Healgen Rapid Covid-19 Antigen Test As A Point-Of-Care Diagnostic Tool, Stephen A Young, Hua Zhang, Jose Rodriguez, David Mishkin, Ward Paine, Li Seyfried, Latisha Hargrove, Dennis L Broyles, Chermaen Lindberg, Anurag Purushothaman, Stacey House

2020-Current year OA Pubs

BACKGROUND: Development of readily available Rapid COVID-19 Antigen tests essential for promptly identifying SARS-CoV2 infection and preventing its spread.

METHODS: This study evaluated the clinical performance of the Healgen Rapid COVID-19 antigen test as a point-of-care diagnostic tool with 806 evaluable subjects who were within 6 days post-symptom onset. The results from the Healgen test were compared to the results from Emergency Use Authorization (EUA) approved SARS-CoV-2 RT-PCR tests.

RESULTS: Out of the 806 evaluable subjects, 140 tested positive and 640 tested negative for SARS-CoV-2 with the Healgen COVID-19 test, showing good agreement with the EUA RT-PCR results. There were …

Integrating Nonindividual Patient Features In Machine Learning Models Of Hospital-Onset Bacteremia, M Cristina Vazquez-Guillamet, Jingwen Zhang, Alice Bewley, Andrew Atkinson, Heidi Holtz, Ziqian Wang, Nicole Brougham, Chenyang Lu, Marin H Kollef, Philip Payne, David Warren, Victoria J Fraser

2020-Current year OA Pubs

IMPORTANCE: Hospital-onset bacteremia and fungemia (HOB) are common and potentially preventable complications of hospital care.

OBJECTIVE: To assess whether nonindividual patient features, which summarize interactions with other patients and health care workers (HCWs), can contribute to predictive and causal machine learning models for HOB.

DESIGN, SETTING, AND PARTICIPANTS: This prognostic study included adult patients admitted to Barnes-Jewish Hospital, an academic hospital in St Louis, Missouri, in 2021. Analyses were developed between October 2023 and August 2024 and in April 2025.

EXPOSURE: Individual patient features were extracted from electronic health records and used to engineer nonpatient features, including interactions with HCWs …

Utility Of The Us Preventive Services Task Force For Preeclampsia Risk Assessment And Aspirin Prophylaxis, Thomas F Mcelrath, Antonina I Frolova, Et Al.

2020-Current year OA Pubs

IMPORTANCE: The US Preventive Services Task Force (USPSTF) guidelines on preeclampsia risk assessment and aspirin prophylaxis (AP) have not been evaluated for clinical utility.

OBJECTIVE: To evaluate which characteristics in the USPSTF guidelines identify risk status and the association of preeclampsia risk with AP recommendations.

DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study enrolled from July 2020 to March 2023 with data analysis performed from October to December 2024. Enrollment occurred at 11 centers throughout the US or via direct-to-participant recruitment. Pregnant participants aged 18 years or older with a singleton pregnancy less than 22 weeks' gestation were selected via …

Covid-19-Associated Pulmonary Aspergillosis In Mechanically Ventilated Patients At 7 Us Hospitals: Epidemiology And Estimated Likelihood Of Invasive Pulmonary Aspergillosis-Results Of The Prospective Msg-017 Study, M Hong Nguyen, Sixto M Leal, Luis Ostrosky-Zeichner, Andrej Spec, George R Thompson, Thomas F Patterson, John Baddley, Rachel Mcmullen, Drashti Shah, Cornelius J Clancy, Gerald Mcgwin, Peter G Pappas

2020-Current year OA Pubs

BACKGROUND: There is no prospective, US multicenter study of COVID-19-associated pulmonary aspergillosis (CAPA). CAPA definitions do not differentiate invasive aspergillosis (IPA) from colonization. Validity of single mycologic test results is unclear.

METHODS: We performed a prospective 7-center US study of mechanically ventilated adults with COVID-19 (April 2021-May 2022). Mycoses Study Group (MSGERC) CAPA criteria include host and clinical factors, imaging and test results (histopathology; bronchoalveolar lavage [BAL] culture and/or BAL or serum galactomannan-immunoassay). Proven, putative, and unlikely IPA were defined by clinical criteria. CAPA-unlikely IPA criteria included survival or negative autopsy following no/limited antifungal treatment. IPA likelihood was estimated using …

Liger-Hn Phase Iii Trials Of Petosemtamab + Pembrolizumab And Petosemtamab Monotherapy In Recurrent Or Metastatic Hnscc, Jean-Pascal Machiels, Douglas Adkins, Et Al.

2020-Current year OA Pubs

Patients with recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC) have limited treatment options and a dismal prognosis, especially when their cancer is resistant to standard treatments like anti-programmed cell death protein 1 and platinum-based therapies. Petosemtamab - a human, common light chain, bispecific antibody with enhanced antibody-dependent cellular cytotoxicity targeting epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) - demonstrated antitumor activity in r/m HNSCC. In many tumor types, including HNSCC, EGFR is an oncogenic driver, while LGR5 is upregulated. LGR5 can potentiate the wingless-type integration site (WNT)/β-catenin signaling pathway in response to …

Cannabis Use In Women And Sexual Dysfunction, Becky K. Lynn, Julia D. López, Morgan E. Link, E C. Campian

2020-Current year OA Pubs

No abstract provided.

Cancer Immunotherapy Clinical Trials To Support Urgently Needed Access In Low- And Middle-Income Countries: A Report From The Sitc Global Access And Impact Committee, Jennifer Dent, Thomas A Odeny, Et Al.

2020-Current year OA Pubs

Cancer is rapidly on the rise as a cause of morbidity and mortality in low- and middle-income countries (LMICs). However, despite the increasing importance of immune checkpoint inhibitors (ICIs) as a pillar of cancer therapy, access in these settings lags well behind that in high-income countries (HICs). Increasing the evaluation of ICIs through local clinical trials and demonstration projects, and inclusion in multinational clinical trials is the first step to improving access. In particular, the epidemiology and clinical presentation of cancer in LMICs is often distinct from that in HICs, and the impact of immune checkpoint blockade in these settings …

Monoclonal Antibodies Targeting The Fimh Adhesin Protect Against Uropathogenic E. Coli Uti, Edward D B Lopatto, Jesús M Santiago-Borges, Denise A Sanick, Sameer Kumar Malladi, Philippe N Azimzadeh, Morgan W Timm, Isabella F Fox, Aaron J Schmitz, Jackson S Turner, Shaza M Sayed Ahmed, Lillian Ortinau, Nathaniel C Gualberto, Jerome S Pinkner, Karen W Dodson, Ali H Ellebedy, Andrew L Kau, Scott J Hultgren

2020-Current year OA Pubs

As antimicrobial resistance increases, urinary tract infections (UTIs) are expected to pose an increased burden in morbidity and expense on the health care system, increasing the need for alternative antibiotic-sparing treatments. Most UTIs are caused by uropathogenic

Sars-Cov-2 Nsp15 Enhances Viral Virulence By Subverting Host Antiviral Defenses, Allen Caobi, Tamarand L Darling, Adrianus C M Boon, Et Al.

2020-Current year OA Pubs

SARS-CoV-2 encodes numerous virulence factors, yet their precise mechanisms of action remain unknown. We provide evidence that the SARS-CoV-2 nonstructural protein 15 (nsp15) enhances viral virulence by suppressing the production of viral double-stranded (dsRNA), a potent inducer of antiviral signaling. The viral variants lacking nsp15 endoribonuclease activity elicited higher innate immune responses and exhibited reduced replication in human stem cell-derived lung alveolar type II epithelial cells, as well as in the lungs of infected hamsters. Consistently, these variants caused significantly less weight loss and mortality compared to wild-type (WT) virus in K18-hACE2 mice. Mechanistically, the cells infected with nsp15 mutants …

Importance Of Outbreak Response Research In Bridging Knowledge Gaps On Emerging Infectious Diseases, Robert F Breiman, David Wang, Michael Diamond, Adrianus C M Boon, Et Al.

2020-Current year OA Pubs

An important outcome of the devastating 2014 West African Ebola virus disease outbreak and the 2020 COVID-19 pandemic has been the growing promotion of conducting research during outbreaks of emerging infectious diseases (EIDs) as a valuable and acceptable process of acquiring knowledge to enhance our ability to better prevent and control these diseases in the future. Recognising the unique opportunity during outbreaks to leverage increases in cases over a short time interval and in a circumscribed area, we articulate a systematic process of conducting EID outbreak response research, highlighting knowledge gaps that should be prioritised, and measures that can be …

Social, Microbial, And Immune Factors Linking Bacterial Vaginosis And Infectious Diseases, Nicole M. Gilbert, Luis A. Ramirez Hernandez, Daniela Berman, Sydney Morrill, Pascal Gagneux, Amanda L. Lewis

2020-Current year OA Pubs

Bacterial vaginosis (BV) is a polymicrobial condition of the vaginal microbiota associated with a variety of sexually transmitted infections, infections of maternal and fetal tissues during pregnancy, and even some infections outside of the reproductive tract, including the urinary tract and mouth. BV has also been associated with conditions in which the body generates prominent inflammatory reactions to microbes, including infections of the cervix and other upper genital tract tissues. For reasons still not understood, BV is a highly recurrent and often difficult-to-treat condition, complicating attempts to prevent these associated infections. An additional layer of complexity arises from the increasing …

Estimated Burden Of Coccidioidomycosis, Samantha L Williams, Andrej Spec, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Coccidioidomycosis is an underrecognized fungal infection that can cause serious illness and constitutes a considerable public health burden. The number of cases is likely substantially higher than the nationally reported total, as surveillance does not capture patients who do not seek medical care or who are undiagnosed or misdiagnosed. Coccidioidomycosis is not reportable in all states, and cases not reported to public health entities are likewise missed. A systematic estimate of coccidioidomycosis burden is needed to raise awareness and inform public health interventions and policy.

OBJECTIVE: To assess the annual burden of symptomatic coccidioidomycosis in the US.

DESIGN, SETTING, …

Phenotypes Of Atopic Dermatitis And Development Of Allergic Diseases, Alexandra R Sitarik, Katherine Rivera-Spoljaric, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Atopic dermatitis (AD) is the most common inflammatory disease in childhood, and children with AD are more likely to develop other allergic diseases, including food allergy, allergic rhinitis, and asthma.

OBJECTIVE: To determine the phenotypes of AD expression across 12 US birth cohorts and identify factors associated with phenotype and development of allergic diseases.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study compiled longitudinal data from 12 observational US birth cohorts across decades (children born from April 1980 to June 2019) in the Environmental Influences on Child Health Outcomes (ECHO) Children's Respiratory and Environmental Workgroup with follow-up to September 2022. …

Spatiotemporal Association Of Coronavirus Disease 2019 Cases And Deaths With Exposure To Wildfire Particulate Matter In 2020, Thomas C Mchale, David R Boulware, Kelly Searle, Leda Kobziar, Phinehas Lampman, Julio C Zuniga-Moya, Ben Papadopoulos, Andrej Spec, Naomi E Hauser, George R Thompson

2020-Current year OA Pubs

BACKGROUND: Climate change is anticipated to have profound effects on human health, including in infectious diseases. Wildfires have been increasing in frequency and intensity due to climate change and have been linked to worsening respiratory disease outcomes. We aimed to demonstrate whether there was an association between wildfire smoke and coronavirus disease 2019 (COVID-19) in California during 2020.

METHODS: We used an ecologic cohort study with a spatial autoregressive model to test for associations between wildfire smoke, measured as particulate matter < 2.5 µg/m

RESULTS: In an adjusted analysis, we found a 1-month lag increase of 203 COVID-19 cases per 10 000 persons …

Carbapenem-Resistant Enterobacterales Peri-Rectal Colonization Prevalence On Admission To Two Intensive Care Units In An Academic Hospital In India, Armaghan-E-Rehman Mansoor, Jacaranda Van Rheenen, Ige A George, Jennie H Kwon, Et Al.

2020-Current year OA Pubs

This study from a South Indian tertiary care hospital found a 41% peri-rectal Carbapenem-resistant

Candidate Interventions For Integrating Hypertension And Cardiovascular-Kidney-Metabolic Care In Primary Health Settings: Hearts 2.0 Phase 1, Andres Rosende, Mark D Huffman, Et Al.

2020-Current year OA Pubs

BACKGROUND: HEARTS in the Americas is the regional adaptation of the WHO Global HEARTS Initiative, aimed at helping countries enhance hypertension and cardiovascular disease (CVD) risk management in primary care settings. Its core implementation tool, the HEARTS Clinical Pathway, has been adopted by 28 countries. To improve the care of hypertension, diabetes, and chronic kidney disease (CKD), HEARTS 2.0 was developed as a three-phase process to integrate evidence-based interventions into a unified care pathway, ensuring consistency across fragmented guidelines. This paper focuses on Phase 1, highlighting targeted interventions to improve and update the HEARTS Clinical Pathway.

METHODS: First, the coordinating …

Allele-Specific Vitamin D Receptor Binding Is Associated With Pediatric-Onset Multiple Sclerosis, Defne Yilmaz, Soe Mar, Et Al.

2020-Current year OA Pubs

BACKGROUND AND OBJECTIVES: The genetic basis of adult-onset multiple sclerosis (MS) is well-studied, but less is known about pediatric-onset MS (pedMS), comprising approximately 5% of all MS onsets. Mendelian randomization (MR) studies have demonstrated evidence for a causal association between MS and both 25-hydroxyvitamin D [25(OH)D] serum levels and genetic variation related to vitamin D receptor (VDR) binding. The objective was to identify whether VDR binding variants (VDR-BVs) previously implicated in adult-onset MS were associated with pedMS using genetic instrumental variables (GIVs).

METHODS: Using previously identified VDR-BVs to construct individual GIVs with two-sample MR, we investigated associations with pedMS in …

Acute Kidney Injury Triggers Hypoxemia By Lung Intravascular Neutrophil Retention That Reduces Capillary Blood Flow, Yohei Komaru, Liang Ning, Carine Lama, Anusha Suresh, Eirini Kefaloyianni, Mark J. Miller, Shinichi Kawana, Hailey M Shepherd, Wenjun Li, Daniel Kreisel, Andreas Herrlich

2020-Current year OA Pubs

Sterile acute kidney injury (AKI) is common in the clinic and frequently associated with unexplained hypoxemia that does not improve with dialysis. AKI induces remote lung inflammation with neutrophil recruitment in mice and humans, but which cellular cues establish neutrophilic inflammation and how it contributes to hypoxemia is not known. Here we report that AKI induced rapid intravascular neutrophil retention in lung alveolar capillaries without extravasation into tissue or alveoli, causing hypoxemia by reducing lung capillary blood flow in the absence of substantial lung interstitial or alveolar edema. In contrast to direct ischemic lung injury, lung neutrophil recruitment during remote …

Comparison Of Broad-Spectrum Anti-Pseudomonal Beta-Lactam Antibiotics Versus Targeted Therapy For Neutropenic Patients With Methicillin-Susceptible, Lauren C Russell, Jeff Klaus, Miguel A Chavez, Erik R Dubberke, Tamara Krekel

2020-Current year OA Pubs

The safety of the utilization of methicillin-susceptible

Recombinant Interleukin-7 Treatment Of Refractory Refractory Mycobacterium Avium Complexlung Disease (Impulse-7): A Pilot Phase Ii, Single-Center, Randomized, Clinical Trial, Carlos Mejia-Chew, Andrej Spec, Andrew H Walton, Alina Ulezko Antonova, Alexandra Dram, Sanjeev Bhalla, Marco Colonna, Michel Morre, Richard Hotchkiss

2020-Current year OA Pubs

BACKGROUND: Nontuberculous mycobacteria disease is an emerging opportunistic infection that is often refractory to therapy. Interleukin 7 (IL-7) is a pleiotropic cytokine with broad-ranging effects that enhance immunity and augment monocyte/macrophage anti-

OBJECTIVES: This study evaluated IL-7 in patients with refractory

DESIGN: Prospective, single-center, randomized, study of IL-7 in patients with refractory MAC-LD.

METHODS: Randomization (two sets of 4 weekly IL-7 injections) was stratified based on the presence of pulmonary cavities. The primary outcome was sputum culture conversion to negative within 6 months. Exploratory outcomes included investigation of potential molecular mechanisms of immunosuppression via single-cell RNA sequencing (scRNA-seq).

RESULTS: Of …

Identifying Genetic Errors Of Immunity Due To Mosaicism, Elizabeth G Schmitz, Malachi Griffith, Obi L Griffith, Megan A Cooper

2020-Current year OA Pubs

Inborn errors of immunity are monogenic disorders of the immune system that lead to immune deficiency and/or dysregulation in patients. Identification of precise genetic causes of disease aids diagnosis and advances our understanding of the human immune system; however, a significant portion of patients lack a molecular diagnosis. Somatic mosaicism, genetic changes in a subset of cells, is emerging as an important mechanism of immune disease in both young and older patients. Here, we review the current landscape of somatic genetic errors of immunity and methods for the detection and validation of somatic variants.

Antibiotic De-Escalation In The Intensive Care Unit: Rationale And Potential Strategies, Sarah Singer Matuszak, Lauren Kolodziej, Scott Micek, Marin Kollef

2020-Current year OA Pubs

Antibiotic de-escalation (ADE) is important to help optimize antibiotic use and balance the positive and negative effects of antimicrobial therapy. ADE should be performed promptly, and infections should be treated with the shortest course of antimicrobials as clinically feasible to avoid unnecessary use of broad-spectrum antimicrobials. Several tools have been developed to increase efficient ADE, including rapid diagnostic tests (ex. multiplex PCR), MRSA nasal PCR/culture, and biomarkers. Multiplex PCR and MRSA nasal PCR/culture have been associated with reductions in inappropriate antibiotic use. Procalcitonin, a biomarker, has been associated with shorter antimicrobial durations in some studies; however, widespread use may be …

Introducing A New Polymerase Chain Reaction Panel–Based Cerebrospinal Fluid Evaluation For Encephalitis And Meningitis: Does It Influence Empiric Treatment Duration, Length Of Hospital Stay, And Pathogen-Specific Diagnoses?, Fabian Sidler, Pascal Bittel, Jonas Marschall, Philipp Jent

2020-Current year OA Pubs

We analyzed the impact of a diagnostic meningitis/encephalitis polymerase chain reaction panel. Introducing the test resulted in no significantly shortened empiric antibiotic streptococcal/meningococcal treatment (-1 day [95% confidence interval {CI}, 0-3 days];

The Multiverse Of Cd46 And Oncologic Interactions, M. Kathryn Liszewski, John P. Atkinson

2020-Current year OA Pubs

Initially identified as a regulator of complement activation on host cells, the known roles of CD46 (membrane cofactor protein [MCP]) have expanded. We now know that this ancient molecule is expressed on almost all nucleated cells as a family of four predominant isoforms. It also is involved in human reproduction, modulation of T cell activation and immunoinflammatory effector functions, autophagy, and the newly identified intracellular complement system (complosome). CD46 is also known as a "pathogen" magnet, being a port of entry for at least seven bacteria and five viruses. Moreover, CD46 has recently emerged as a key player in cancer …

Global Guideline For The Diagnosis And Management Of Candidiasis: An Initiative Of The Ecmm In Cooperation With Isham And Asm, Oliver A. Cornely, Andrej Spec, Et Al.

2020-Current year OA Pubs

No abstract provided.