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PurposeThis continuing professional development module aims to prepare anesthesiologists for the timely recognition and management of a malignant hyperthermia (MH) reaction, which is crucial for averting its life-threatening complications and ultimately for the patient’s survival.Principal findingsMalignant hyperthermia is a genetic disorder of skeletal muscle cells affecting myoplasmic calcium homeostasis. It can present with nonspecific signs of a hypermetabolic reaction, which can be fatal if treatment, including administration of dantrolene sodium, is not implemented promptly. Rapid evaluation and rejection of alternative diagnoses can lead to a prompt diagnosis and treatment and therefore will significantly reduce the complications, including renal failure, cardiac dysfunction, disseminated intravascular coagulation, and death. After the reaction, patients should be observed for a minimum of 24 hr because of the possibility of recrudescence. As it is a genetic condition, survivors and their family members should be referred to a specialized MH centre for further testing and counselling.ConclusionsThe risk of dying from MH has increased over the past few years. A knowledgeable anesthesiologist who is diligent and attentive can recognize signs of an impending MH reaction and treat promptly to avoid complications of this deadly condition.

Understanding the origin of stellar masses-the initial mass function (IMF)- remains one of the most challenging problems in astrophysics. The IMF is a key ingredient for simulations of galaxy formation and evolution, and is used to calibrate star formation relations in extra-galactic observations. Modeling the IMF directly in hydrodynamical simulations has been attempted in several previous studies, but the most important processes that control the IMF remain poorly understood. This is because predicting the IMF from direct hydrodynamical simulations involves complex physics such as turbulence, magnetic fields, radiation feedback and mechanical feedback, all of which are difficult to model and the methods used have limitations in terms of accuracy and computational efficiency. Moreover, a physical interpretation of the simulated IMFs requires a numerically converged solution at high resolution, which has so far not been convincingly demonstrated. Here we present a resolution study of star cluster formation aimed at producing a converged IMF. We compare a set of magnetohydrodynamical (MHD) adaptive-mesh-refinement simulations with three different implementations of the thermodynamics of the gas: 1) with an isothermal equation of state (EOS), 2) with a polytropic EOS, and 3) with a simple stellar heating feedback model. We show that in the simulations with an isothermal or polytropic EOS, the number of stars and their mass distributions depend on the numerical resolution. By contrast, the simulations that employ the simple radiative feedback module demonstrate convergence in the number of stars formed and in their IMFs.

In this study, patients with acute respiratory distress syndrome who were not receiving statins were assigned to receive simvastatin or placebo. At 28 days, there were no significant between-group differences in survival or in the number of ventilator-free days. The acute respiratory distress syndrome (ARDS) is a common, devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and by multiple organ failure. In ARDS there is an uncontrolled inflammatory response that results in alveolar damage, with the exudation of protein-rich pulmonary-edema fluid in the alveolar space that results in respiratory failure. 1 The inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase with statins has been shown to modify a number of the underlying mechanisms implicated in the development of ARDS. 2 Statins decrease inflammation and histologic evidence of lung injury in murine models of ARDS. 3 Simvastatin reduced pulmonary and systemic . . .

As a ClinGen Expert Panel (EP) we set out to adapt the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) pathogenicity criteria for classification of RYR1 variants as related to autosomal dominantly inherited malignant hyperthermia (MH). We specified ACMG/AMP criteria for variant classification for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework. Seven ACMG/AMP criteria were adopted without changes, nine were adopted with RYR1-specific modifications, and ten were dropped. The in silico (PP3 and BP4) and hotspot criteria (PM1) were evaluated quantitatively. REVEL gave an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cutoffs of ≥0.85 (pathogenic) and ≤0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG/AMP criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance. Curation of these variants will facilitate classification of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria is generalizable to other variant curation expert panels.

Submillimetre-bright galaxies at high redshift are the most luminous, heavily star-forming galaxies in the Universe, but cosmological simulations of such galaxies have so far been unsuccessful; now a cosmological hydrodynamic galaxy formation simulation is reported that can form a submillimetre galaxy that simultaneously satisfies the broad range of observed physical constraints. A model for submillimetre-bright galaxy formation Due in part to their extreme infrared luminosities, it has been suggested that the origin of high-redshift submillimetre-bright galaxies lies in gas-rich galaxy mergers, but cosmological simulations of such galaxies have so far proved problematic. Here Desika Narayanan et al . report a cosmological hydrodynamic galaxy formation model that can form a submillimetre galaxy that simultaneously satisfies the broad range of observed physical constraints in a simulation with a lifetime of nearly a billion years. The intense star formation rates are fueled in part by a reservoir gas supply enabled by stellar feedback at earlier times, not through major mergers. Submillimetre-bright galaxies at high redshift are the most luminous, heavily star-forming galaxies in the Universe 1 and are characterized by prodigious emission in the far-infrared, with a flux of at least five millijanskys at a wavelength of 850 micrometres. They reside in haloes with masses about 10 13 times that of the Sun 2 , have low gas fractions compared to main-sequence disks at a comparable redshift 3 , trace complex environments 4 , 5 and are not easily observable at optical wavelengths 6 . Their physical origin remains unclear. Simulations have been able to form galaxies with the requisite luminosities, but have otherwise been unable to simultaneously match the stellar masses, star formation rates, gas fractions and environments 7 , 8 , 9 , 10 . Here we report a cosmological hydrodynamic galaxy formation simulation that is able to form a submillimetre galaxy that simultaneously satisfies the broad range of observed physical constraints. We find that groups of galaxies residing in massive dark matter haloes have increasing rates of star formation that peak at collective rates of about 500–1,000 solar masses per year at redshifts of two to three, by which time the interstellar medium is sufficiently enriched with metals that the region may be observed as a submillimetre-selected system. The intense star formation rates are fuelled in part by the infall of a reservoir gas supply enabled by stellar feedback at earlier times, not through major mergers. With a lifetime of nearly a billion years, our simulations show that the submillimetre-bright phase of high-redshift galaxies is prolonged and associated with significant mass buildup in early-Universe proto-clusters, and that many submillimetre-bright galaxies are composed of numerous unresolved components (for which there is some observational evidence 11 ).

Exertional heat illness (EHI) and malignant hyperthermia (MH) are life threatening conditions associated with muscle breakdown in the setting of triggering factors including volatile anesthetics, exercise, and high environmental temperature. To identify new genetic variants that predispose to EHI and/or MH, we performed genomic sequencing on a cohort with EHI/MH and/or abnormal caffeine-halothane contracture test. In five individuals, we identified rare, pathogenic heterozygous variants in ASPH , a gene encoding junctin, a regulator of excitation-contraction coupling. We validated the pathogenicity of these variants using orthogonal pre-clinical models, CRISPR-edited C2C12 myotubes and transgenic zebrafish. In total, we demonstrate that ASPH variants represent a new cause of EHI and MH susceptibility. The genetic cause(s) of malignant hyperthermia and exertional heat illness are unknown in approximately 30% of cases. To address this barrier, the authors performed genome sequencing on a large cohort of cases, identifying rare variants in ASPH , a gene encoding junctin, and validating them in animal and cell models.

The standard cold dark matter plus cosmological constant model predicts that galaxies form within dark-matter haloes, and that low-mass galaxies are more dark-matter dominated than massive ones. The unexpected discovery of two low-mass galaxies lacking dark matter immediately provoked concerns about the standard cosmology and ignited explorations of alternatives, including self-interacting dark matter and modified gravity. Apprehension grew after several cosmological simulations using the conventional model failed to form adequate numerical analogues with comparable internal characteristics (stellar masses, sizes, velocity dispersions and morphologies). Here we show that the standard paradigm naturally produces galaxies lacking dark matter with internal characteristics in agreement with observations. Using a state-of-the-art cosmological simulation and a meticulous galaxy-identification technique, we find that extreme close encounters with massive neighbours can be responsible for this. We predict that ~30% of massive central galaxies (with at least 10 11 solar masses in stars) harbour at least one dark-matter-deficient satellite (with 10 8 –10 9 solar masses in stars). This distinctive class of galaxies provides an additional layer in our understanding of the role of interactions in shaping galactic properties. Future observations surveying galaxies in the aforementioned regime will provide a crucial test of this scenario. A cosmological simulation shows that low-mass galaxies can form with far less dark matter than expected, with results matching some observed characteristics. Roughly one-third of massive central galaxies may host at least one such dark-matter-deficient satellite.

Malignant hyperthermia (MH) is a pharmacogenetic condition of skeletal muscle that manifests in hypermetabolic responses upon exposure to volatile anaesthetics. This condition is caused primarily by pathogenic variants in the calcium-release channel RYR1, which disrupts calcium signalling in skeletal muscle. However, our understanding of MH genetics is incomplete, with no variant identified in a significant number of cases and considerable phenotype diversity. In this study, we applied a transcriptomic approach to investigate the genome-wide gene expression in MH-susceptible cases using muscle biopsies taken for diagnostic testing. Baseline comparisons between muscle from MH-susceptible individuals (MHS, n = 8) and non-susceptible controls (MHN, n = 4) identified 822 differentially expressed genes (203 upregulated and 619 downregulated) with significant enrichment in genes associated with oxidative phosphorylation (OXPHOS) and fatty acid metabolism. Investigations of 10 OXPHOS target genes in a larger cohort (MHN: n = 36; MHS: n = 36) validated the reduced expression of ATP5MD and COQ6 in MHS samples, but the remaining 8 selected were not statistically significant. Further analysis also identified evidence of a sex-linked effect in SDHB and UQCC3 expression, and a difference in ATP5MD expression across individuals with MH sub-phenotypes (trigger from in vitro halothane exposure only, MHSh (n = 4); trigger to both in vitro halothane and caffeine exposure, MHShc (n = 4)). Our data support a link between MH-susceptibility and dysregulated gene expression associated with mitochondrial bioenergetics, which we speculate plays a role in the phenotypic variability observed within MH.

Massive dwarf galaxies that merge with the Milky Way on prograde orbits can be dragged into the disk plane before being completely disrupted. Such mergers can contribute to an accreted stellar disk and a dark matter disk. Here we present Nyx, a vast stellar stream in the vicinity of the Sun, which provides the first indication that such an event occurred in the Milky Way. We identify about 90 stars that have coherent radial and prograde motion in this stream using a catalogue of accreted stars built by applying deep learning methods to the Gaia data. Taken together with chemical abundance and orbital information, these results strongly favour the interpretation that Nyx is the remnant of a disrupted dwarf galaxy. Further justified by FIRE hydrodynamic simulations, we demonstrate that prograde streams like Nyx can be found in the disk plane of galaxies and identified using our methods. Analysis of a catalogue of accreted stars by their radial and prograde motions has identified a 200-plus-member coherent stellar stream (called Nyx) that is likely to be the remnant of a dwarf galaxy that merged with the Milky Way.

BackgroundWe aimed to identify rare (minor allele frequency ≤1%), potentially pathogenic non-synonymous variants in a well-characterised cohort with a clinical history of exertional heat illness (EHI) or exertional rhabdomyolysis (ER). The genetic link between malignant hyperthermia (MH) and EHI was investigated due to their phenotypic overlap.MethodsThe coding regions of 38 genes relating to skeletal muscle calcium homeostasis or exercise intolerance were sequenced in 64 patients (mostly military personnel) with a history of EHI, or ER and who were phenotyped using skeletal muscle in vitro contracture tests. We assessed the pathogenicity of variants using prevalence data, in silico analysis, phenotype and segregation evidence and by review of the literature.ResultsWe found 51 non-polymorphic, potentially pathogenic variants in 20 genes in 38 patients. Our data indicate that RYR1 p.T3711M (previously shown to be likely pathogenic for MH susceptibility) and RYR1 p.I3253T are likely pathogenic for EHI. PYGM p.A193S was found in 3 patients with EHI, which is significantly greater than the control prevalence (p=0.000025). We report the second case of EHI in which a missense variant at CACNA1S p.R498 has been found. Combinations of rare variants in the same or different genes are implicated in EHI.ConclusionWe confirm a role of RYR1 in the heritability of EHI as well as ER but highlight the likely genetic heterogeneity of these complex conditions. We propose defects, or combinations of defects, in skeletal muscle calcium homeostasis, oxidative metabolism and membrane excitability are associated with EHI.