Sex‐specific alterations in whole body energetics and voluntary activity in heterozygous R163C malignant hyperthermia‐susceptible mice

Malignant hyperthermia (MH) is characterized by induction of skeletal muscle hyperthermia in response to a dysregulated increase in myoplasmic calcium. Although altered energetics play a central role in MH, MH‐susceptible humans and mouse models are often described as having no phenotype until exposure to a triggering agent. The purpose of this study was to determine the influence of the R163C ryanodine receptor 1 mutation, a common MH mutation in humans, on energy expenditure, and voluntary wheel running in mice. Energy expenditure was measured by indirect respiration calorimetry in wild‐type (WT) and heterozygous R163C (HET) mice over a range of ambient temperatures. Energy expenditure adjusted for body weight or lean mass was increased (P < .05) in male, but not female, HET mice housed at 22°C or when housed at 28°C with a running wheel. In female mice, voluntary wheel running was decreased (P < .05) in the HET vs WT animals when analyzed across ambient temperatures. The thermoneutral zone was also widened in both male and female HET mice. The results of the study show that the R163C mutations alters energetics even at temperatures that do not typically induce MH

QT Interval Prolongation and Torsade De Pointes in Patients with COVID-19 treated with Hydroxychloroquine/Azithromycin

Background: There is no known effective therapy for patients with COVID-19. Initial reports suggesting the potential benefit of Hydroxychloroquine/Azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns regarding the potential risk of QT prolongation and induction of torsade de pointes (TdP). Objective: to assess the change in QTc interval and arrhythmic events in patients with COVID-19 treated with HY/AZ METHODS: This is a retrospective study of 251 patients from two centers, diagnosed with COVID-19 and treated with HY/AZ. We reviewed ECG tracings from baseline and until 3 days after completion of therapy to determine the progression of QTc and incidence of arrhythmia and mortality. Results: QTc prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc prolongation to &gt; 500 ms, a known marker of high risk for TdP had developed in 23% of patients. One patient developed polymorphic ventricular tachycardia (VT) suspected as TdP, requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc of patients exhibiting extreme QTc prolongation was normal. Conclusion: The combination of HY/AZ significantly prolongs the QTc in patients with COVID-19. This prolongation may be responsible for life threating arrhythmia in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in lights of its unproven efficacy. Strict QTc monitoring should be performed if the regimen is given

A concept for major incident triage: full-scaled simulation feasibility study

<p>Abstract</p> <p>Background</p> <p>Efficient management of major incidents involves triage, treatment and transport. In the absence of a standardised interdisciplinary major incident management approach, the Norwegian Air Ambulance Foundation developed Interdisciplinary Emergency Service Cooperation Course (TAS). The TAS-program was established in 1998 and by 2009, approximately 15 500 emergency service professionals have participated in one of more than 500 no-cost courses. The TAS-triage concept is based on the established triage Sieve and Paediatric Triage Tape models but modified with slap-wrap reflective triage tags and paediatric triage stretchers. We evaluated the feasibility and accuracy of the TAS-triage concept in full-scale simulated major incidents.</p> <p>Methods</p> <p>The learners participated in two standardised bus crash simulations: without and with competence of TAS-triage and access to TAS-triage equipment. The instructors calculated triage accuracy and measured time consumption while the learners participated in a self-reported before-after study. Each question was scored on a 7-point Likert scale with points labelled "Did not work" (1) through "Worked excellent" (7).</p> <p>Results</p> <p>Among the 93 (85%) participating emergency service professionals, 48% confirmed the existence of a major incident triage system in their service, whereas 27% had access to triage tags. The simulations without TAS-triage resulted in a mean over- and undertriage of 12%. When TAS-Triage was used, no mistriage was found. The average time from "scene secured to all patients triaged" was 22 minutes (range 15-32) without TAS-triage vs. 10 minutes (range 5-21) with TAS-triage. The participants replied to "How did interdisciplinary cooperation of triage work?" with mean 4,9 (95% CI 4,7-5,2) before the course vs. mean 5,8 (95% CI 5,6-6,0) after the course, p < 0,001.</p> <p>Conclusions</p> <p>Our modified triage Sieve tool is feasible, time-efficient and accurate in allocating priority during simulated bus accidents and may serve as a candidate for a future national standard for major incident triage.</p

Live Coding, Live Notation, Live Performance

This paper/demonstration explores relationships between code, notation including representation, visualisation and performance. Performative aspects of live coding activities are increasingly being investigated as the live coding movement continues to grow and develop. Although live instrumental performance is sometimes included as an accompaniment to live coding, it is often not a fully integrated part of the performance, relying on improvisation and/or basic indicative forms of notation with varying levels of sophistication and universality. Technologies are developing which enable the use of fully explicit music notations as well as more graphic ones, allowing more fully integrated systems of code in and as performance which can also include notations of arbitrary complexity. This itself allows the full skills of instrumental musicians to be utilised and synchronised in the process. This presentation/demonstration presents work and performances already undertaken with these technologies, including technologies for body sensing and data acquisition in the translation of the movements of dancers and musicians into synchronously performable notation, integrated by live and prepared coding. The author together with clarinetist Ian Mitchell present a short live performance utilising these techniques, discuss methods for the dissemination and interpretation of live generated notations and investigate how they take advantage of instrumental musicians’ training-related neuroplasticity skills

Avaliação do Ensino de Empreendedorismo entre Estudantes Universitários por meio do Perfil Empreendedor

Entrepreneurship is a socioeconomic phenomenon that has been valued for its influence on the growth and development of regional and national economies. The main promoter of this phenomenon are entrepreneurs, subjects endowed with multiple features that make up their profiles. They are dynamic and results oriented, benefitting from the fruits of their own personal efforts. Entrepreneurial education is highlighted as one of the most efficient ways to promote an entrepreneurial culture and train new entrepreneurs. However, some difficulty has been observed in assessing the effectiveness of teaching and learning this subject. The objective of this study was to analyze, by means of multivariate techniques, an instrument whose function is to measure the learning of Entrepreneurship, verifying the change in entrepreneur profiles of 407 college students participating or not in an entrepreneurial training process. The results showed that students who participated in Entrepreneurship educational training activities showed significant changes in their entrepreneurial profiles. The main contributions showed growth in the Self-realization, Planner, Innovative and Risks Assumed dimensions

Improving Internal Peptide Dynamics in the Coarse-Grained MARTINI Model: Toward Large-Scale Simulations of Amyloid- and Elastin-like Peptides

We present an extension of the coarse-grained MARTINI model for proteins and apply this extension to amyloid- and elastin-like peptides. Atomistic simulations of tetrapeptides, octapeptides, and longer peptides in solution are used as a reference to parametrize a set of pseudodihedral potentials that describe the internal flexibility of MARTINI peptides. We assess the performance of the resulting model in reproducing various structural properties computed from atomistic trajectories of peptides in water. The addition of new dihedral angle potentials improves agreement with the contact maps computed from atomistic simulations significantly. We also address the question of which parameters derived from atomistic trajectories are transferable between different lengths of peptides. The modified coarse-grained model shows reasonable transferability of parameters for the amyloid- and elastin-like peptides. In addition, the improved coarse-grained model is also applied to investigate the self-assembly of β-sheet forming peptides on the microsecond time scale. The octapeptides SNNFGAIL and (GV)4 are used to examine peptide aggregation in different environments, in water, and at the water–octane interface. At the interface, peptide adsorption occurs rapidly, and peptides spontaneously aggregate in favor of stretched conformers resembling β-strands

Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis

Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinuclear compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer