Real-world evaluation of select adverse drug reactions and healthcare utilization associated with parenteral Ibuprofen and ketorolac in adult and pediatric patients.

Introduction: Intravenous non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in healthcare settings, but their comparative safety and resource utilization impacts remain understudied. This study aimed to compare adverse drug reactions (ADRs) and healthcare resource utilization (HCRU) between patients receiving IV-ibuprofen versus IV/IM ketorolac.

Methods: A retrospective, longitudinal analysis was conducted using an all-payer database, examining records from January 1, 2014, to June 3, 2023.

Zinc-Binding Oligonucleotide Backbone Modifications for Targeting a DNA-Processing Metalloenzyme.

A series of chemically-modified oligonucleotides for targeting the DNA repair nuclease SNM1A have been designed and synthesised. Each oligonucleotide contains a modified internucleotide linkage designed to both mimic the native phosphodiester backbone and chelate to the catalytic zinc ion(s) in the SNM1A active site. Dinucleoside phosphoramidites containing urea, squaramide, sulfanylacetamide, and sulfinylacetamide linkages were prepared and employed successfully in solid-phase oligonucleotide synthesis.

VLPs generated by the fusion of RSV-F or hMPV-F glycoprotein to HIV-Gag show improved immunogenicity and neutralizing response in mice.

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) vaccines have been long overdue. Structure-based vaccine design created a new momentum in the last decade, and the first RSV vaccines have finally been approved in older adults and pregnant individuals. These vaccines are based on recombinant stabilized pre-fusion F glycoproteins administered as soluble proteins.

The physiological interactome of TCR-like antibody therapeutics in human tissues.

Selective binding of TCR-like antibodies that target a single tumour-specific peptide antigen presented by human leukocyte antigens (HLA) is the absolute prerequisite for their therapeutic suitability and patient safety. To date, selectivity assessment has been limited to peptide library screening and predictive modeling. We developed an experimental platform to de novo identify interactomes of TCR-like antibodies directly in human tissues using mass spectrometry.

A strategy to disentangle direct and indirect effects on (de)phosphorylation by chemical modulators of the phosphatase PP1 in complex cellular contexts.

Chemical activators and inhibitors are useful probes to identify substrates and downstream effects of enzymes; however, due to the complex signaling environment within cells, it is challenging to distinguish between direct and indirect effects. This is particularly the case for phosphorylation, where a single (de)phosphorylation event can trigger rapid changes in many other phosphorylation sites. An additional complication arises when a single catalytic entity, which acts in the form of many different holoenzymes with different substrates, is activated or inhibited, as it is unclear which holoenzymes are affected, and in turn which of their substrates are (de)phosphorylated.

Dissecting the Heterogeneous Glycan Profiles of Recombinant Coronavirus Spike Proteins with Individual Ion Mass Spectrometry.

Surface-embedded glycoproteins, such as the spike protein trimers of coronaviruses MERS, SARS-CoV, and SARS-CoV-2, play a key role in viral function and are the target antigen for many vaccines. However, their significant glycan heterogeneity poses an analytical challenge. Here, we utilized individual ion mass spectrometry (IMS), a multiplexed charge detection measurement with similarities to charge detection mass spectrometry (CDMS), in which a commercially available Orbitrap analyzer is used to directly produce mass profiles of these heterogeneous coronavirus spike protein trimers under native-like conditions.

A Robust Protocol to Isolate Outer Membrane Vesicles from Nontypeable .

Outer membrane vesicles (OMVs) are lipid structures containing various biomolecules in their native environment and are spontaneously shed by gram-negative bacteria. OMVs perform several biological functions critical to both bacterial physiology and pathogenicity. Scientific research on OMV function and biogenesis requires a standardized and robust method of isolating these vesicles from bacterial cultures that reliably provide high-purity OMVs.

The Respiratory Syncytial Virus (RSV) G Protein Enhances the Immune Responses to the RSV F Protein in an Enveloped Virus-Like Particle Vaccine Candidate.

Respiratory syncytial virus (RSV) is a serious human respiratory pathogen, but no RSV vaccine has been licensed. Many vaccine candidates are focused on the viral F protein since the F protein is more conserved than the viral G protein across RSV strains and serotypes; thus, the F protein is thought more likely to induce a broader range of protection from infection. However, it is the G protein that binds the likely receptor, CX3CR1, in lung ciliated epithelial cells, raising the question of the importance of the G protein in vaccine candidates.

A novel high throughput assay to quantify Epstein-Barr virus neutralizing antibody activity against B-cell and epithelial cell infections for vaccine and therapeutic developments.

Epstein-Barr Virus (EBV) is the causative agent of infectious mononucleosis and has been associated with a variety of malignancies. In vivo, EBV infects B cells and epithelial cells. However, the current EBV neutralization assays, especially those against B cell infection, are low throughput, laborious and lack of sensitivity.

Profiling of hMPV F-specific antibodies isolated from human memory B cells.

Human metapneumovirus (hMPV) belongs to the Pneumoviridae family and is closely related to respiratory syncytial virus (RSV). The surface fusion (F) glycoprotein mediates viral fusion and is the primary target of neutralizing antibodies against hMPV. Here we report 113 hMPV-F specific monoclonal antibodies (mAbs) isolated from memory B cells of human donors.

Evaluation of HSV-2 gE Binding to IgG-Fc and Application for Vaccine Development.

Glycoprotein E (gE) and glycoprotein I (gI) are expressed as a heterodimer on the surface of Herpes simplex virus (HSV). Glycoprotein E binds Fc domain of immunoglobulin G (IgG) and inhibits activities mediated by the IgG Fc domain, contributing to immune evasion by HSV. It has been reported that HSV type 1 gE (gE-1) is capable of binding IgG Fc as a monomer and in a heterodimeric complex with gI, with the heterodimer having 50- to100-fold greater affinity for Fc than gE alone.

Synthesis and evaluation of squaramide and thiosquaramide inhibitors of the DNA repair enzyme SNM1A.

SNM1A is a zinc-dependent nuclease involved in the removal of interstrand crosslink lesions from DNA. Inhibition of interstrand crosslink repair enzymes such as SNM1A is a promising strategy for improving the efficacy of crosslinking chemotherapy drugs. Initial studies have demonstrated the feasibility of developing SNM1A inhibitors, but the full potential of this enzyme as a drug target has yet to be explored.

Dual Neurostimulant Therapy May Optimize Acute Neurorecovery for Severe Traumatic Brain Injuries.

Background: Neurostimulants (NS) can be used to treat patients with a traumatic brain injury (TBI) with altered levels of consciousness. We sought to determine if amantadine alone (monotherapy) versus amantadine + methylphenidate (dual therapy) would correlate with better neurorecovery (NR) among acutely hospitalized patients with a severe TBI.

Methods: We performed a retrospective review of adult patients admitted to our level I trauma center from 2016-2019 with a severe TBI.

Probing the Binding Requirements of Modified Nucleosides with the DNA Nuclease SNM1A.

SNM1A is a nuclease that is implicated in DNA interstrand crosslink repair and, as such, its inhibition is of interest for overcoming resistance to chemotherapeutic crosslinking agents. However, the number and identity of the metal ion(s) in the active site of SNM1A are still unconfirmed, and only a limited number of inhibitors have been reported to date. Herein, we report the synthesis and evaluation of a family of malonate-based modified nucleosides to investigate the optimal positioning of metal-binding groups in nucleoside-derived inhibitors for SNM1A.

Squaramide-Based 5'-Phosphate Replacements Bind to the DNA Repair Exonuclease SNM1A.

Phosphate groups are often crucial to biological activity and interactions of oligonucleotides, but confer poor membrane permeability. In addition, the group's lability to enzymatic hydrolysis is an obstacle to its use in therapeutics and in biological tools. We present the synthesis of -oxyamide and squaramide modifications at the 5'-end of oligonucleotides as phosphate replacements and their biological evaluation using the 5'-exonuclease SNM1A.

A hydroxamic-acid-containing nucleoside inhibits DNA repair nuclease SNM1A.

Nine modified nucleosides, incorporating zinc-binding pharmacophores, have been synthesised and evaluated as inhibitors of the DNA repair nuclease SNM1A. The series included oxyamides, hydroxamic acids, hydroxamates, a hydrazide, a squarate ester and a squaramide. A hydroxamic acid-derived nucleoside inhibited the enzyme, offering a novel approach for potential therapeutic development through the use of rationally designed nucleoside derived inhibitors.

Implementation of the flipped residency research model to enhance residency research training.

Purpose: The attainment of fundamental research skills to create and disseminate new knowledge is imperative for the advancement of pharmacy practice. Research training is an important component of postgraduate residency training; however, the traditional model of performing residency research has several limitations that have hindered the ability of residents to complete high-quality research projects. Therefore, our institution developed and implemented the flipped residency research model with the 2013-2014 pharmacy practice residency class.

Enhanced Renal Clearance in Patients With Hemorrhagic Stroke.

Objectives: To evaluate enhanced renal clearance over time in patients with aneurysmal subarachnoid hemorrhage or intracerebral hemorrhage via measured creatinine clearance and to compare measured creatinine clearance to creatinine clearance calculated by the Cockcroft-Gault equation and estimated glomerular filtration rate calculated by the Modification of Diet in Renal Diseases equation.

Design: Prospective, observational study.

Setting: Neurosciences ICU in a tertiary care academic medical center.

Design and characterization of a fusion glycoprotein vaccine for Respiratory Syncytial Virus with improved stability.

Respiratory Syncytial Virus (RSV) infection is the leading cause of lower respiratory tract infection in both young children and older adults. Currently, there is no licensed vaccine available, and therapeutic options are limited. The infectious RSV particle is decorated with a type I viral fusion (F) glycoprotein that structurally rearranges from a metastable prefusion form to a highly stable postfusion form.

Spectroscopic analysis of chlamydial major outer membrane protein in support of structure elucidation.

Chlamydial major outer membrane protein (MOMP) is the major protein constituent of the bacterial pathogen Chlamydia trachomatis. Chlamydia trachomatis Serovars D-K are the leading cause of genital tract infections which can lead to infertility or ectopic pregnancies. A vaccine against Chlamydia is highly desirable but currently not available.

Breadth and Functionality of Varicella-Zoster Virus Glycoprotein-Specific Antibodies Identified after Zostavax Vaccination in Humans.

Herpes zoster (HZ) (shingles) is the clinical manifestation of varicella-zoster virus (VZV) reactivation. HZ typically develops as people age, due to decreased cell-mediated immunity. However, the importance of antibodies for immunity against HZ prevention remains to be understood.

Risk of Hypoglycemia During Insulin Infusion Directed by Paper Protocol Versus Electronic Glycemic Management System in Critically Ill Patients at a Large Academic Medical Center.

Background: Insulin infusions are commonly utilized to control hyperglycemia in critically ill patients and decrease hyperglycemia associated complications. Safety concerns have been raised in trials evaluating methods of glycemic control regarding the incidence of hypoglycemia and its relationship to increased mortality. Electronic glycemic management systems (eGMS) may result in less variable blood glucose (BG) control and less hypoglycemia.

Recombinant expression of Chlamydia trachomatis major outer membrane protein in E. Coli outer membrane as a substrate for vaccine research.

Background: Chlamydia trachomatis is a human pathogen which causes a number of pathologies, including genital tract infections in women that can result in tubal infertility. Prevention of infection and disease control might be achieved through vaccination; however, a safe, efficacious and cost-effective vaccine against C. trachomatis infection remains an unmet medical need.