• There is a role for the posttranslational modification, neddylation, in regulation of immune responses mediated by dendritic cells.• A role for neddylation in NF-kB signaling in dendritic cells was identified.Posttranslational protein modifications (PTMs) are necessary for cells to function properly. The role of PTMs in regulating immune responses, specifically those mediated by dendritic cells (DCs), which are critical for both innate and adaptive immunity, is not well understood. Utilizing multiple but complementary approaches, we determined the role of an important but less understood type of PTM, namely, neddylation, in regulating DC functions. Inhibition of neddylation suppressed the release of proinflammatory cytokines by DCs in response to Toll-like receptor, nucleotide oligomerization domain-like receptor, and noninfectious CD40L stimulation. These effects were more profound than those mediated by the proteasome inhibitor bortezomib or a commonly used antiinflammatory agent, dexamethasone. Targeting neddylation also suppressed the ability of DCs to stimulate murine allogeneic T cells in vitro and in vivo and human allogeneic T-cell responses in vitro. Mechanistic studies demonstrated that inhibition of neddylation reduced both canonical and noncanonical nuclear factor-kB (NF-kB) activity. Neddylation inhibition prevented the degradation of inhibitor-kB and thus reduced the translocation and activation of NF-kB, but without perturbation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Thus, blocking neddylation could be a novel strategy for mitigating immune-mediated disease processes. (Blood. 2013;122(12):2062-2073

Use of the electronic health record (EHR) has become a routine part of perioperative care in the United States. Secondary use of EHR data includes research, quality, and educational initiatives. Fundamental to secondary use is a framework to ensure fidelity, transparency, and completeness of the source data. In developing this framework, competing priorities must be considered as to which data sources are used and how data are organized and incorporated into a useable format. In assembling perioperative data from diverse institutions across the United States and Europe, the Multicenter Perioperative Outcomes Group (MPOG) has developed methods to support such a framework. This special article outlines how MPOG has approached considerations of data structure, validation, and accessibility to support multicenter integration of perioperative EHRs. In this multicenter practice registry, MPOG has developed processes to extract data from the perioperative EHR; transform data into a standardized format; and validate, deidentify, and transfer data to a secure central Coordinating Center database. Participating institutions may obtain access to this central database, governed by quality and research committees, to inform clinical practice and contribute to the scientific and clinical communities. Through a rigorous and standardized approach to ensure data integrity, MPOG enables data to be usable for quality improvement and advancing scientific knowledge. As of March 2019, our collaboration of 46 hospitals has accrued 10.7 million anesthesia records with associated perioperative EHR data across heterogeneous vendors. Facilitated by MPOG, each site retains access to a local repository containing all site-specific perioperative data, distinct from source EHRs and readily available for local research, quality, and educational initiatives. Through committee approval processes, investigators at participating sites may additionally access multicenter data for similar initiatives. Emerging from this work are 4 considerations that our group has prioritized to improve data quality: (1) data should be available at the local level before Coordinating Center transfer; (2) data should be rigorously validated against standardized metrics before use; (3) data should be curated into computable phenotypes that are easily accessible; and (4) data should be collected for both research and quality improvement purposes because these complementary goals bolster the strength of each endeavor.

This study suggests that transplant patients are being counseled against pregnancy despite acceptable risks of complications and no specific effects on long-term graft function.

BACKGROUND-Following the introduction of sugammadex to the United States clinical practice, scarce data are available to understand its utilization patterns. This study aimed to characterize patient, procedure, and provider factors associated with sugammadex administration in the US patients.METHODS-This retrospective observational study was conducted across 24 Multicenter Perioperative Outcomes Group institutions in the United States with sugammadex on formulary at the time of the study. All American Society of Anesthesiologists (ASA) physical status 1-4 adults undergoing noncardiac surgery from 2014 to 2018 receiving neuromuscular blockade were eligible. The study established three periods based on the date of first documented sugammadex use at each institution: the pre-sugammadex period, 0-6 month transitional period, and 6+ months post-sugammadex period. The primary outcome was reversal using sugammadex during the postsugammadex period -defined as 6 months after sugammadex was first utilized at each institution. A multivariable mixed-effects logistic regression model controlling for institution was developed to assess patient, procedure, and provider factors associated with sugammadex administration.RESULTS-A total of 934,798 cases met inclusion criteria. Following the 6-month transition period, sugammadex was used on average in 40.0% (95% CI 39.8%-40.2%) of cases receiving neuromuscular blockade. Multivariable analysis demonstrated sugammadex use to be associated with train-of-four count of 0-1 (adjusted odds ratio 4.06, 95% CI 3.83-4.31) or 2 (2.45, 2.29-2.62) versus 3-4 twitches before reversal; the amount of neuromuscular blockade (NMB) administered (3.01, 2.88-3.16) for the highest Effective Dose 95 quartile compared to the lowest quartile; advanced age (1.83, 1.71-1.95) compared to age less than 41; male sex (1.36, 1.32-1.39) compared to female sex; major thoracic surgery (1.26, 1.13-1.39); congestive heart failure (1.17, 1.07-1.28); and ASA 3 or 4 (1.13, 1.10-1.16) versus ASA 1 or 2. CONCLUSIONS-Our data demonstrates broad early clinical adoption of sugammadex following Food and Drug Administration approval. Sugammadex is used preferentially in cases with higher degrees of neuromuscular blockade prior to reversal and in patients with greater burden of comorbidities and known risk factors for residual blockade or pulmonary complications.

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