Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project.

Importance: The rapid spread and mortality associated with COVID-19 emphasized a need for surveillance system development to identify adverse events (AEs) to emerging therapeutics. Bradycardia is a remdesivir infusion-associated AE listed in the US Food and Drug Administration-approved prescribing information. Objective: To evaluate the magnitude and duration of bradycardic events following remdesivir administration. Design, Setting, and Participants: A multicenter cohort study of patients with recorded heart rate less than 60 beats per minute within 24 hours after administration of a remdesivir dose was conducted between November 23, 2020, and October 31, 2021. Participants included patients hospitalized with COVID-19 at 15 medical centers across the US. Patients excluded had AEs unrelated to bradycardia, AEs in addition to bradycardia, or first onset of bradycardia after 5 remdesivir doses. Exposures: Remdesivir administration. Main Outcomes and Measures: Linear mixed-effect models for the minimum HR before starting remdesivir and within 24 hours of each dose included doses as fixed effects. Baseline covariates were age (≥65 years vs <65 years), sex (male vs female), cardiovascular disease history (yes vs no), and concomitant use of bradycardia-associated medications. The interactions between variables and doses were considered fixed-effects covariates to adjust models. Results: A total of 188 patients were included in the primary analysis and 181 in the secondary analysis. The cohort included 108 men (57.4%); 75 individuals (39.9%) were non-Hispanic White and mean (SD) age was 61.3 (15.4) years. Minimum HR after doses 1 to 5 was lower than before remdesivir. Mean minimum HR was lowest after dose 4, decreasing by -15.2 beats per minute (95% CI, -17.4 to -13.1; P < .001) compared with before remdesivir administration. Mean (SD) minimum HR was 55.6 (10.2) beats per minute across all 5 doses. Of 181 patients included in time-to-event analysis, 91 had their first episode of bradycardia within 23.4 hours (95% CI, 20.1-31.5 hours) and 91 had their lowest HR within 60.7 hours (95% CI, 54.0-68.3 hours). Median time to first bradycardia after starting remdesivir was shorter for patients aged 65 years or older vs those younger than 65 years (18.7 hours; 95% CI, 16.8-23.7 hours vs 31.5 hours; 95% CI, 22.7-39.3 hours; P = .04). Median time to lowest HR was shorter for men vs women (54.2 hours; 95% CI, 47.3-62.0 hours vs 71.0 hours; 95% CI, 59.5-79.6 hours; P = .02). Conclusions and Relevance: In this cohort study, bradycardia occurred during remdesivir infusion and persisted. Given the widespread use of remdesivir, practitioners should be aware of this safety signal.

An outbreak of severe coagulopathy from synthetic cannabinoids tainted with Long-Acting anticoagulant rodenticides.

Objective: To describe a large regional poison center's experience managing an outbreak of long-acting anticoagulant rodenticide (LAAR) poisoning associated with synthetic cannabinoid (SC) use.Methods: This is a retrospective review of exposures reported to the Illinois Poison Center between March 10 and August 1, 2018. All cases coded as exposure to Δ9-tetrahydrocannabinol homologs were identified. Patients with suspected SC use, positive LAAR testing, and coagulopathy (signs or symptoms of bleeding or international normalized ratio [INR] > 2) were included. If confirmatory LAAR testing was performed and resulted as negative, the patient was excluded from this analysis. In the absence of LAAR testing, patients with suspected SC use, an INR >2, and no alternative explanation of coagulopathy were included. Suspected SC use was defined as use suspected by a member of the treating team or reported by the patient. Presenting signs and symptoms, laboratory findings, management, healthcare utilization, outcomes, and disposition of patients affected by this outbreak were reported.Results: One hundred seventy-eight cases met inclusion criteria. Most patients were male (73%) and young to middle-aged (median age 32, IQR 25-40). Most presented to hospitals in Peoria (35%) and Cook (31%) counties. Median hospitalization was three days (IQR 2-4). Eighty-eight percent of patients presented with an INR >10. Eighteen cases had qualitative anticoagulant testing, all of which were positive for brodifacoum. Other identified LAARs included difenacoum (10/18) and bromadiolone (1/18). Sixty-three percent of patients had back, flank or abdominal pain; 70% of patients presented with hematuria. One hundred six cases received IV vitamin K1; no adverse or anaphylactoid reactions were reported. Forty-one (22%) patients left AMA. Thirty-eight patients (21%) were re-hospitalized during the study period. Patients leaving AMA were 1.6 times more likely to be re-hospitalized than patients with other dispositions. Intracranial hemorrhage, present in 3% of total cases, was present in 4 of 5 fatalities.Conclusions: We describe an outbreak of multiple LAARs contaminating SCs. Patients presented with bleeding from varied sites, often required blood products, factor replacement, and high dose vitamin K1 for stabilization.

Fibrillized peptide microgels for cell encapsulation and 3D cell culture.

One of the advantages of materials produced by self-assembly is that in principle they can be formed in any given container to produce materials of predetermined shapes and sizes. Here, we developed a method for triggering peptide self-assembly within the aqueous phase of water-in-oil emulsions to produce spherical microgels composed of fibrillized peptides. Size control over the microgels was achieved by specification of blade type, speed, and additional shear steps in the emulsion process. Microgels constructed in this way could then be embedded within other self-assembled peptide matrices by mixing pre-formed microgels with un-assembled peptides and inducing gelation of the entire composite, offering a route towards multi-peptide materials with micron-scale domains of different peptide formulations. The gels themselves were cytocompatible, as was the microgel fabrication procedure, enabling the encapsulation of NIH 3T3 fibroblasts and C3H10T-1/2 mouse pluripotent stem cells with good viability.

Co-assembling peptides as defined matrices for endothelial cells.

Self-assembling peptides and peptide derivatives bearing cell-binding ligands are increasingly being investigated as defined cell culture matrices and as scaffolds for regenerative medicine. In order to systematically refine such scaffolds to elicit specific desired cell behaviors, ligand display should ideally be achieved without inadvertently altering other physicochemical properties such as viscoelasticity. Moreover, for in vivo applications, self-assembled biomaterials must exhibit low immunogenicity. In the present study, multi-peptide co-assembling hydrogels based on the beta-sheet fibrillizing peptide Q11 (QQKFQFQFEQQ) were designed such that they presented RGDS or IKVAV ligands on their fibril surfaces. In co-assemblies of the ligand-bearing peptides with Q11, ligand incorporation levels capable of influencing the attachment, spreading, morphology, and growth of human umbilical vein endothelial cells (HUVECs) did not significantly alter the materials' fibrillization, beta-turn secondary structure, or stiffness. RGDS-Q11 specifically increased HUVEC attachment, spreading, and growth when co-assembled into Q11 gels, whereas IKVAV-Q11 exerted a more subtle influence on attachment and morphology. Additionally, Q11 and RGDS-Q11 were minimally immunogenic in mice, making Q11-based biomaterials attractive candidates for further investigation as defined, modular extracellular matrices for applications in vitro and in vivo.