Corrigendum: Semaphorin 4C: A Novel Component of B-Cell Polarization in Th2-Driven Immune Responses

Background: Semaphorins are important molecules in embryonic development and multiple semaphorins have been identified as having key roles in immune regulation. To date, there is little known about Semaphorin 4C (Sema4C) in immune biology. We report for the first time that Sema4C is inducible in human and murine B-cells and may be important for normal B-cell development. Methods: Human Tonsillar B-cells were studied following activation via anti-CD40 antibodies in the presence or absence of representative Th1, Th2, and regulatory cytokines. Murine B-cells from WT and Sema4C-/- mice were similarly stimulated. B-cell phenotyping in WT and Sema4C mutant mice was performed by flow cytometry and lymphoid architecture was studied by immunohistochemistry. Sema4C expression and synapse formation was analyzed by confocal microscopy. Results: Gene Array studies performed on human tonsillar B-cells stimulated to produce IgE revealed that Sema4C was among the top genes expressed at 24 hours, and the only semaphorin to be increased under Th2 conditions. Validation studies demonstrated that human and murine B-cells expressed Sema4C under similar conditions. Sema4C-/- mice had impaired maturation of B-cell follicles in spleens and associated decreases in follicular and marginal zone B-cells as well as impaired IgG and IgA production. In keeping with a potential role in maturation of B-cells, Sema4C was expressed predominantly on CD27+ Human B-cells. Within 72 hours of B-cell activation, Sema4C was localized to one pole in a synapse-like structure, in association with F-Actin, BCR, and Plexin-B2. Cell polarization was impaired in Sema4C-/- mice. Conclusion: We have identified a novel immune semaphorin induced in human and murine B-cells under Th2 conditions. Sema4C appears to be a marker for human memory B-cells. It may be important for B-cell polarization and for the formation of normal splenic follicles

Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery

Background: Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI. Methods: This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments. Results: A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P=0.02; odds ratio, 0.58 (95% CI, 0.37-0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment. Conclusions: The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897)

Updated Guidance Regarding The Risk ofAllergic Reactions to COVID-19 Vaccines and Recommended Evaluation and Management: A GRADE Assessment, and International Consensus Approach

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against \u3e 15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history

Induction of regulatory T cells by intravenous immunoglobulin: a bridge between adaptive and innate immunity

IVIg is a polyclonal IgG preparation with potent immunomodulatory properties. The mode of action of IVIg has been investigated in multiple disease states, with various mechanisms described to account for its benefits. Recent data indicates that IVIg increases both the number and suppressive capacity of regulatory T cells, a subpopulation of T cells that are essential for immune homeostasis. IVIg alters dendritic cell function, cytokine and chemokine networks, and T lymphocytes, leading to development of regulatory T cells. The ability of IVIg to influence Treg induction has been shown both in animal models and in human diseases. In this review, we discuss data on the potential mechanisms contributing to the interaction between IVIg and the regulatory T cell compartment

The effect of the perioperative blood transfusion and blood conservation in cardiac surgery Clinical Practice Guidelines of the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists upon clinical practices.

The 2007 Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists Clinical Practice Guideline for Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery was recently promulgated and has received much attention. Using a survey of cardiac anesthesiologists and perfusionists\u27 clinical practice, we assessed the current practices of perfusion, anesthesia, and surgery, as recommended by the Guidelines and also determined the role the Guidelines had in changing these practices. Nontrainee members of the Society of Cardiovascular Anesthesiologists, the American Academy of Cardiovascular Perfusion, the Canadian Society of Clinical Perfusion, and the American Society of ExtraCorporeal Technology were surveyed using a standardized survey instrument that examined clinical practices and responses to the Guidelines. One thousand four hundred and two surveys from 1,061 institutions principally in the United States (677 institutions) and Canada (34 institutions) were returned, with a 32% response rate. There was wide distribution of the Guidelines with 78% of anesthesiologists and 67% of perfusionists reporting having read all, part, or a summary of the Guidelines. However, only 20% of respondents reported that an institutional discussion had taken place as a result of the Guidelines, and only 14% of respondents reported that an institutional monitoring group had been formed. There was wide variability in current preoperative testing, perfusion, surgical, and pharmacological practices reported by respondents. Twenty-six percent of respondents reported one or more practice changes in response to the Guidelines.The changes made were reported to be highly (9%) or somewhat effective (31%) in reducing overall transfusion rates. Only four of 38 Guideline recommendations were reported by more than 5% of respondents to have been changed in response to the Guidelines. Wide variation in clinical practices of cardiac surgery was reported. Little change in clinical practices was attributed to the Society of Thoracic Surgeons/Society of Cardiovascular Anesthesiologists Guidelines

Teprasiran, A Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study

Acute kidney injury (AKI) affects up to 30% of cardiac surgery patients, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA (siRNA) that temporarily inhibits p53-mediated cell death, which underlies AKI. This prospective, multicenter, double-blind, randomized, controlled Phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran vs. placebo (1:1), in reducing the incidence, severity, and duration of AKI following cardiac surgery in high-risk patients. The primary endpoint was proportion of patients who developed AKI determined by serum creatinine (sCr) by post-operative day 5. Other endpoints included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite endpoint of major adverse kidney events at day 90 (MAKE90), including death, renal replacement therapy (RRT) and ≥25% reduction of estimated glomerular filtration rate (eGFR) was assessed. Both sCr and serum cystatin-C (sCys) were used for eGFR assessments. A total of 360 patients were randomized in 41 centers. 341 dosed patients were 73±7.5 years old (mean±SD), 72% were male, and median Euroscore-II (European System for Cardiac Operative Risk Evaluation) was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran vs. 50% for placebo-treated patients, a 12.8% absolute risk reduction (ARR), p=0.02; OR=0.58 (95% CI 0.37 to 0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran vs. 6.7% of placebo-treated patients had Grade 3 AKI; 7% teprasiran vs. 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the MAKE90 composite in the overall population. No safety issues were identified with teprasiran treatment. The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced following teprasiran administration. A Phase 3 study with a MAKE90 primary outcome which has recently completed enrollment was designed based on these findings (NCT03510897). URL: https://clinicaltrials.gov/ Unique Identifier: NCT02610283

Effect of the perioperative blood transfusion and blood conservation in cardiac surgery clinical practice guidelines of the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists upon clinical practices.

BACKGROUND: The 2007 Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists Clinical Practice Guideline for Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery was recently promulgated and has received much attention. Using a survey of cardiac anesthesiologists and perfusionists\u27 clinical practice, we aimed to assess the current practices of perfusion, anesthesia, and surgery, as recommended by the Guidelines, and to also determine the role the Guidelines had in changing these practices. METHODS: Nontrainee members of the Society of Cardiovascular Anesthesiologists, the American Academy of Cardiovascular Perfusion, the Canadian Society of Clinical Perfusion, and the American Society of ExtraCorporeal Technology were surveyed using a standardized survey instrument that examined clinical practices and responses to the Guidelines. RESULTS: A total of 1402 surveys from 1061 institutions principally in the United States (677 institutions) and Canada (34 institutions) were returned, a 32% response rate. There was wide distribution of the Guidelines with 78% of anesthesiologists and 67% of perfusionists reporting having read all, part, or a summary of the Guidelines. However, only 20% of respondents reported that an institutional discussion had taken place as a result of the Guidelines, and only 14% of respondents reported that an institutional monitoring group had been formed. There was wide variability in current preoperative testing, perfusion, surgical, and pharmacological practices reported by respondents. Twenty-six percent of respondents reported 1 or more practice changes in response to the Guidelines. The changes made were reported to be highly (9%) or somewhat (31%) effective in reducing overall transfusion rates. Only 4 of 38 Guideline recommendations were reported by \u3e5% of respondents to have been changed in response to the Guidelines. CONCLUSIONS: Wide variation in clinical practices of cardiac surgery was reported. Little change in clinical practices was attributed to the Society of Thoracic Surgeons/Society of Cardiovascular Anesthesiologists Guidelines

The Effect of the Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery Clinical Practice Guidelines of the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists upon Clinical Practices

The 2007 Society of Thoracic Surgeons and the Soci ety of Cardiovascular Anesthesiologists Clinical Practice Guide line for Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery was recently promulgated and has received much attention. Using a survey of cardiac anesthesiologists and perfusionists’ clinical practice, we assessed the current practices of perfusion, anesthesia, and surgery, as recommended by the Guidelines and also determined the role the Guidelines had in changing these practices. Nontrainee members of the Society of Cardiovascular Anesthesiologists, the American Academy of Cardiovascular Perfusion, the Canadian Society of Clinical Perfusion, and the American Society of ExtraCorporeal Technology were surveyed using a standardized survey instrument that examined clinical practices and responses to the Guidelines. One thousand four hundred and two surveys from 1,061 institutions principally in the United States (677 institutions) and Canada (34 institutions) were returned, with a 32% response rate. There was wide distribution of the Guidelines with 78% of anesthesiologists and 67% of perfusionists reporting having read all, part, or a summary of the Guidelines. However, only 20% of respondents reported that an institutional discussion had taken place as a result of the Guidelines, and only 14% of respondents reported that an institutional monitoring group had been formed. There was wide variability in current preoperative testing, perfusion, surgical, and pharmacological practices reported by respondents. Twenty-six percent of respondents reported one or more practice changes in response to the Guidelines. The changes made were reported to be highly (9%) or somewhat effective (31%) in reducing overall transfusion rates. Only four of 38 Guideline recommendations were reported by more than 5% of respondents to have been changed in response to the Guidelines. Wide variation in clinical practices of cardiac surgery was reported. Little change in clinical practices was attributed to the Society of Thoracic Surgeons/Society of Cardiovascular Anesthesiologists Guidelines