Correction to: Amanita Mushroom Toxin Poisoning in Los Angeles County.

[This corrects the article DOI: 10.14309/crj.0000000000001246.].

Amanita Mushroom Toxin Poisoning in Los Angeles County.

Mushroom (amatoxin) poisoning from ingestion is a rare but life-threatening medical emergency characterized by gastrointestinal symptoms before progression to multisystem organ failure in severe cases. Many therapies of amatoxin intoxication have been described, including supportive care, medical therapies, detoxification strategies, and liver transplant. The evidence supporting these therapies remains limited due to the rarity of amatoxin poisoning and challenge of a timely diagnosis. We report a case of amatoxin poisoning in Los Angeles causing severe liver injury without acute liver failure treated successfully using medical therapies, gallbladder drainage, and plasma exchange.

Association between anesthesia technique and death after hip fracture repair for patients with COVID-19.

PURPOSE: Patients with COVID-19 undergoing hip fracture surgeries have a 30-day mortality of up to 34%. We aimed to evaluate the association between anesthesia technique and 30-day mortality after hip fracture surgery in patients with COVID-19. METHODS: After ethics approval, we performed a retrospective cohort analysis of the American College of Surgeons National Surgical Quality Improvement Program data set from January to December 2021. Inclusion criteria were age ≥ 19 yr, laboratory-confirmed SARS-CoV-2 infection within 14 days preoperatively, and hip fracture surgery under general anesthesia (GA) or spinal anesthesia (SA). Exclusion criteria were American Society of Anesthesiologists Physical Status V, ventilator dependence, international normalized ratio ≥ 1.5, partial thromboplastin time > 35 sec, and platelet count < 80 × 109 L-1. The primary outcome was all-cause 30-day mortality. The adjusted association between anesthetic technique and 30-day mortality was analyzed using multivariable logistic regression. RESULTS: Of 23,045 patients undergoing hip fracture surgery, 331 patients met the study criteria. The median [interquartile range] age was 82 [74-88] yr, and 32.3% were male. The 30-day mortality rate was 10.0% (33/331) for the cohort (10.7%, 29/272 for GA vs 6.8%, 4/59 for SA; P = 0.51; standardized mean difference, 0.138). The use of SA, compared with GA, was not associated with decreased mortality (adjusted odds ratio, 0.61; 95% confidence interval, 0.21 to 1.8; E-value, 2.49). CONCLUSION: Anesthesia technique was not associated with mortality in patients with COVID-19 undergoing hip fracture surgery. The findings were limited by a small sample size. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT05133648); registered 24 November 2021.

RéSUMé: OBJECTIF: Les personnes atteintes de COVID-19 bénéficiant d'une chirurgie de fracture de la hanche ont une mortalité à 30 jours allant jusqu'à 34 %. Notre objectif était d'évaluer l'association entre la technique d'anesthésie et la mortalité à 30 jours après une chirurgie de fracture de la hanche chez les personnes atteintes de COVID-19. MéTHODE: Après l'approbation du comité d'éthique, nous avons réalisé une analyse de cohorte rétrospective de l'ensemble de données du Programme national d'amélioration de la qualité chirurgicale de l'American College of Surgeons de janvier à décembre 2021. Les critères d'inclusion étaient un âge ≥ 19 ans, une infection par le SRAS-CoV-2 confirmée en laboratoire dans les 14 jours préopératoires et une chirurgie de fracture de la hanche sous anesthésie générale (AG) ou rachianesthésie (RA). Les critères d'exclusion étaient un statut physique V selon l'American Society of Anesthesiologists, la dépendance à une assistance ventilatoire, un ratio international normalisé ≥ 1,5, un temps de thromboplastine partielle > 35 sec, et une numération plaquettaire < 80 × 109 L−1. Le critère d'évaluation principal était la mortalité à 30 jours toutes causes confondues. L'association ajustée entre la technique anesthésique et la mortalité à 30 jours a été analysée à l'aide d'une régression logistique multivariée. RéSULTATS: Sur 23 045 patient·es opéré·es pour une fracture de la hanche, 331 répondaient aux critères de l'étude. L'âge médian (écart interquartile) était de 82 [74­88] ans et 32,3 % étaient des hommes. Le taux de mortalité à 30 jours était de 10,0 % (33/331) pour la cohorte (10,7 %, 29/272 pour l'AG vs 6,8 %, 4/59 pour la RA; P = 0,51; différence moyenne standardisée, 0,138). L'utilisation de la RA, par rapport à l'AG, n'a pas été associée à une diminution de la mortalité (rapport de cotes ajusté, 0,61; intervalle de confiance à 95 %, 0,21 à 1,8; valeur E, 2,49). CONCLUSION: La technique d'anesthésie n'a pas été associée à la mortalité chez les personnes atteintes de COVID-19 bénéficiant d'une chirurgie de fracture de la hanche. Les résultats ont été limités par la petite taille de l'échantillon. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT05133648); enregistrée le 24 novembre 2021.

Moonlighting matrix metalloproteinase substrates: Enhancement of proinflammatory functions of extracellular tyrosyl-tRNA synthetase upon cleavage.

Tyrosyl-tRNA synthetase ligates tyrosine to its cognate tRNA in the cytoplasm, but it can also be secreted through a noncanonical pathway. We found that extracellular tyrosyl-tRNA synthetase (YRS) exhibited proinflammatory activities. In addition to acting as a monocyte/macrophage chemoattractant, YRS initiated signaling through Toll-like receptor 2 (TLR2) resulting in NF-κB activation and release of tumor necrosis factor α (TNFα) and multiple chemokines, including MIP-1α/ß, CXCL8 (IL8), and CXCL1 (KC) from THP1 monocyte and peripheral blood mononuclear cell-derived macrophages. Furthermore, YRS up-regulated matrix metalloproteinase (MMP) activity in a TNFα-dependent manner in M0 macrophages. Because MMPs process a variety of intracellular proteins that also exhibit extracellular moonlighting functions, we profiled 10 MMPs for YRS cleavage and identified 55 cleavage sites by amino-terminal oriented mass spectrometry of substrates (ATOMS) positional proteomics and Edman degradation. Stable proteoforms resulted from cleavages near the start of the YRS C-terminal EMAPII domain. All of the MMPs tested cleaved at ADS386↓387LYV and VSG405↓406LVQ, generating 43- and 45-kDa fragments. The highest catalytic efficiency for YRS was demonstrated by MMP7, which is highly expressed by monocytes and macrophages, and by neutrophil-specific MMP8. MMP-cleaved YRS enhanced TLR2 signaling, increased TNFα secretion from macrophages, and amplified monocyte/macrophage chemotaxis compared with unprocessed YRS. The cleavage of YRS by MMP8, but not MMP7, was inhibited by tyrosine, a substrate of the YRS aminoacylation reaction. Overall, the proinflammatory activity of YRS is enhanced by MMP cleavage, which we suggest forms a feed-forward mechanism to promote inflammation.

Matrix metalloproteinases inactivate the proinflammatory functions of secreted moonlighting tryptophanyl-tRNA synthetase.

Tryptophanyl-tRNA synthetase (WRS) is a cytosolic aminoacyl-tRNA synthetase essential for protein synthesis. WRS is also one of a growing number of intracellular proteins that are attributed distinct noncanonical "moonlighting" functions in the extracellular milieu. Moonlighting aminoacyl-tRNA synthetases regulate processes such as inflammation, but how these multifunctional enzymes are themselves regulated remains unclear. Here, we demonstrate that WRS is secreted from human macrophages, fibroblasts, and endothelial cells in response to the proinflammatory cytokine interferon γ (IFNγ). WRS signaled primarily through Toll-like receptor 2 (TLR2) in macrophages, leading to phosphorylation of the p65 subunit of NF-κB with associated loss of NF-κB inhibitor α (IκB-α) protein. This signaling initiated secretion of tumor necrosis factor α (TNFα) and CXCL8 (IL8) from macrophages. We also demonstrated that WRS is a potent monocyte chemoattractant. Of note, WRS increased matrix metalloproteinase (MMP) activity in the conditioned medium of macrophages in a TNFα-dependent manner. Using purified recombinant proteins and LC-MS/MS to identify proteolytic cleavage sites, we demonstrated that multiple MMPs, but primarily macrophage MMP7 and neutrophil MMP8, cleave secreted WRS at several sites. Loss of the WHEP domain following cleavage at Met48 generated a WRS proteoform that also results from alternative splicing, designated Δ1-47 WRS. The MMP-cleaved WRS lacked TLR signaling and proinflammatory activities. Thus, our results suggest that moonlighting WRS promotes IFNγ proinflammatory activities, and these responses can be dampened by MMPs.

New intracellular activities of matrix metalloproteinases shine in the moonlight.

Adaption of a single protein to perform multiple independent functions facilitates functional plasticity of the proteome allowing a limited number of protein-coding genes to perform a multitude of cellular processes. Multifunctionality is achievable by post-translational modifications and by modulating subcellular localization. Matrix metalloproteinases (MMPs), classically viewed as degraders of the extracellular matrix (ECM) responsible for matrix protein turnover, are more recently recognized as regulators of a range of extracellular bioactive molecules including chemokines, cytokines, and their binders. However, growing evidence has convincingly identified select MMPs in intracellular compartments with unexpected physiological and pathological roles. Intracellular MMPs have both proteolytic and non-proteolytic functions, including signal transduction and transcription factor activity thereby challenging their traditional designation as extracellular proteases. This review highlights current knowledge of subcellular location and activity of these "moonlighting" MMPs. Intracellular roles herald a new era of MMP research, rejuvenating interest in targeting these proteases in therapeutic strategies. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.