Population-Based Incidence, Severity, and Risk Factors Associated with Treated Acute-Onset COVID-19 mRNA Vaccination-Associated Hypersensitivity Reactions.

BACKGROUND: COVID-19 mRNA vaccination-associated acute-onset hypersensitivity reactions have caused anxiety and may be contributing to vaccine hesitancy. OBJECTIVE: To determine the incidence, severity, and risk factors for treated acute-onset COVID-19 mRNA vaccination-associated hypersensitivity reactions in a well-characterized population. METHODS: All Kaiser Permanente Southern California (KPSC) members who received COVID-19 mRNA vaccinations between December 15, 2020, and March 11, 2021, at a KPSC facility were identified and characterized, along with all treated acute-onset vaccination-associated hypersensitivity events. RESULTS: We identified 391,123 unique vaccine recipients (59.18% female, age 64.19 ± 17.86 years); 215,156 received 2 doses (53.54% Moderna), 157,615 only a first dose (50.13% Moderna) (1961 [1.46%] >2 weeks late getting a second dose), and 18,352 (74.43% Moderna) only a second dose. Only 104 (0.028%) (85.58% female, age 53.18 ± 15.96 years) had treated first dose events, 68 (0.030%) Moderna. Only 32 (0.014%) (93.75% female, age 57.28 ± 17.09 years) had treated second dose events, 21 (0.016%) Moderna. Only 2 (0.00033%) vaccinations resulted in anaphylaxis. Only 27 (20.77%) of those with treated first dose reactions failed to get a second dose. Only 6 of 77 (7.8%) with first dose reactions also had second dose reactions. Individuals with treated events were more likely to be female (P < .0001), younger (P < .0001), and had more pre-existing drug "allergies" (2.11 ± 2.12 vs 1.02 ± 1.41 [P < .0001] for average recipients). CONCLUSIONS: Treated acute-onset hypersensitivity events were mostly benign, more common with first COVID-19 mRNA vaccine doses, more likely to occur in younger females with typical risk factors associated with multiple drug intolerance syndrome, and very unlikely to be primarily immunologically mediated.

Overview of Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Patients with Type 2 Diabetes.

BACKGROUND: It is estimated that 29.1 million people or 9.3% of the US population have diabetes, which contributes to considerable medical and financial burden. Type 2 diabetes mellitus is characterized by insulin resistance and insulin secretion impairment leading to hyperglycemia. The presence of insulin resistance is strongly correlated with obesity. OBJECTIVE: This article reviews the available glucagon-like peptide-1 (GLP-1) receptor agonists and their role in the management of patients with diabetes, to help guide the selection of the most suitable agent for the individualized treatment of patients with type 2 diabetes. DISCUSSION: This article reviews the evidence from phase 3 clinical trials for each of the 5 GLP-1 receptor agonists by comparing them against one another and with other existing therapies, including metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas. Incretin-based therapies have emerged as attractive agents for the treatment of type 2 diabetes. They target the GLP-1 hormone, which is partly responsible for insulin release and for attenuating hyperglycemia during meals (ie, the incretin effect). The 2 classes of incretin-based therapy currently available are GLP-1 receptor agonists and DPP-4 inhibitors, which prevent the breakdown of GLP-1. Both classes are attractive options, given their glucose-lowering effects without the adverse effects of hypoglycemia and weight gain. The different mechanisms of action of these therapies result in generally greater efficacy with GLP-1 receptor agonists, albeit at the expense of slightly increased gastrointestinal symptoms. These agents exert their effects by improving glucose-dependent insulin release, suppressing glucagon release, suppressing hepatic glucose output, and decreasing the rate of gastric emptying, thereby reducing appetite. Currently, 5 GLP-1 receptor agonists are available, including exenatide, liraglutide, albiglutide, dulaglutide, and lixisenatide; semaglutide may soon become available as the newest agent. With the exception of the investigational oral semaglutide, which has shown promising results, the other 5 agents are administered as subcutaneous injections, at different dosing intervals. CONCLUSION: Currently, 5 GLP-1 receptor agonists are available for use in the United States. Although they are all in the same drug class, some significant differences exist among the various GLP-1 receptor agonists. The choice of a specific GLP-1 receptor agonist will depend on the patient preferences, potential adverse effects, and cost.

Mechanisms of Control of Mycobacterium tuberculosis by NK Cells: Role of Glutathione.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), continues to be one of the most prevalent infectious diseases in the world. There is an upward trend in occurrence due to emerging multidrug resistant strains and an increasingly larger proportion of immunocompromised patient populations as a result of the acquired immunodeficiency syndrome pandemic. The complex and often deadly combination of multidrug resistant M. tb (MDR-M. tb) along with human immunodeficiency virus (HIV) puts a significant number of people at high risk for pulmonary and extra-pulmonary TB without sufficient therapeutic options available. Natural killer (NK) cells and macrophages are major components of the body's innate immune system, contributing significantly to the body's ability to synergistically inhibit the growth of M. tb in immune compromised individuals lacking a sufficient T cell response. Direct mechanisms of control are largely through the secretory products perforin, granulysin, and granzymes, as well as multiple membrane-bound death receptors that facilitate target directed lysis. NK cells also have a role in indirectly stimulating an immune response through activation of macrophages and monocytes with multiple signaling pathways, including both reactive oxygen species and reactive nitrogen species. Glutathione (GSH) has been shown to play a part in inhibiting the growth of intracellular M. tb through bacteriostatic mechanisms. Enhancing cellular GSH through several cytokines and N-acetyl cysteine has been shown to increase these effects, at least in part, through their action on NK cells. Taken together, there is substantial evidence for a mechanistic correlation between NK cell activity and functionality in combating M. tb in HIV infection mediated through adequate GSH production and use.

An elucidation of neutrophil functions against Mycobacterium tuberculosis infection.

We characterized the functions of neutrophils in response to Mycobacterium tuberculosis (M. tb) infection, with particular reference to glutathione (GSH). We examined the effects of GSH in improving the ability of neutrophils to control intracellular M. tb infection. Our findings indicate that increasing the intracellular levels of GSH with a liposomal formulation of GSH (L-GSH) resulted in reduction in the levels of free radicals and increased acidification of M. tb containing phagosomes leading to the inhibition in the growth of M. tb. This inhibitory mechanism is dependent on the presence of TNF-α and IL-6. Our studies demonstrate a novel regulatory mechanism adapted by the neutrophils to control M. tb infection.

Characterization of dendritic cell and regulatory T cell functions against Mycobacterium tuberculosis infection.

Glutathione (GSH) is a tripeptide that regulates intracellular redox and other vital aspects of cellular functions. GSH plays a major role in enhancing the immune system. Dendritic cells (DCs) are potent antigen presenting cells that participate in both innate and acquired immune responses against microbial infections. Regulatory T cells (Tregs) play a significant role in immune homeostasis. In this study, we investigated the effects of GSH in enhancing the innate and adaptive immune functions of DCs against Mycobacterium tuberculosis (M. tb) infection. We also characterized the functions of the sub-populations of CD4+T cells such as Tregs and non-Tregs in modulating the ability of monocytes to control the intracellular M. tb infection. Our results indicate that GSH by its direct antimycobacterial activity inhibits the growth of intracellular M. tb inside DCs. GSH also increases the expressions of costimulatory molecules such as HLA-DR, CD80 and CD86 on the cell surface of DCs. Furthermore, GSH-enhanced DCs induced a higher level of T-cell proliferation. We also observed that enhancing the levels of GSH in Tregs resulted in downregulation in the levels of IL-10 and TGF- ß and reduction in the fold growth of M. tb inside monocytes. Our studies demonstrate novel regulatory mechanisms that favor both innate and adaptive control of M. tb infection.