Evaluation of early administration of simvastatin in the prevention and treatment of delirium in critically ill patients undergoing mechanical ventilation (MoDUS): : a randomised, double-blind, placebo-controlled trial

This document is the Accepted Manuscript version of the following article: Valerie J. Page, et al, ‘Evaluation of early administration of simvastatin in the prevention and treatment of delirium in critically ill patients undergoing mechanical ventilation (MoDUS): a randomised, double-blind, placebo-controlled trial’, The Lancet Respiratory Medicine, Vol. 5 (9): 727-737, September 2017. Under embargo until 19 July 2018. The final, definitive version is available online at doi: https://doi.org/10.1016/S2213-2600(17)30234-5.Summary Background Delirium in critically ill patients is associated with poor clinical outcomes. Neuroinflammation might be an important mechanism in the pathogenesis of delirium, and since simvastatin has anti-inflammatory properties it might reduce delirium. We aimed to establish whether early treatment with simvastatin would decrease the time that survivors of critical illness spent in delirium or coma. Methods We undertook this randomised, double-blind, placebo-controlled trial in a general adult intensive care unit (ICU) in Watford General Hospital (Watford, UK). We enrolled critically ill patients (≥18 years) needing mechanical ventilation within 72 h of admission. We randomly assigned patients (1:1 ratio) to receive either simvastatin 80 mg or placebo daily for up to a maximum of 28 days, irrespective of coma or delirium status. We assessed delirium using the Confusion Assessment Method for the ICU (CAM-ICU). The primary outcome was number of days alive and was assessed as delirium-free and coma-free in the first 14 days after being randomly allocated to receive treatment or placebo. ICU clinical and research staff and patients were masked to treatment. We did intention-to-treat analyses with no extrapolation. This trial is registered with the International Standard Randomised Controlled Trial Registry, number ISRCTN89079989. Findings Between Feb 1, 2013, and July 29, 2016, 142 patients were randomly assigned to receive simvastatin (n=71) or placebo (n=71), and were included in the final analysis. The mean number of days alive without delirium and without coma at day 14 did not differ significantly between the two groups (5·7 days [SD 5·1] with simvastatin and 6·1 days [5·2] with placebo; mean difference 0·4 days, 95% CI −1·3 to 2·1; p=0·66). The most common adverse event was an elevated creatine kinase concentration to more than ten times the upper limit of normal (eight [11%] in the simvastatin group vs three [4%] in the placebo group p=0·208). No patient had a serious adverse event related to the study drug. Interpretation These results do not support the hypothesis that simvastatin modifies duration of delirium and coma in critically ill patients. Funding National Institute for Health Research.Peer reviewedFinal Accepted Versio

Curvature in causal BD-type inflationary cosmology

We study a closed model of the universe filled with viscous fluid and quintessence matter components in a Brans-Dicke type cosmological model. The dynamical equations imply that the universe may look like an accelerated flat Friedmann-Robertson-Walker universe at low redshift. We consider here dissipative processes which follow a causal thermodynamics. The theory is applied to viscous fluid inflation, where accepted values for the total entropy in the observable universe is obtained.Comment: 11 pages, revtex 4. For a festschrift honoring Alberto Garcia. To be publishen in Gen. Rel. Gra

Cosmological particle production, causal thermodynamics, and inflationary expansion

Combining the equivalence between cosmological particle creation and an effective viscous fluid pressure with the fact that the latter represents a dynamical degree of freedom within the second-order Israel-Stewart theory for imperfect fluids, we reconsider the possibility of accelerated expansion in fluid cosmology. We find an inherent self-limitation for the magnitude of an effective bulk pressure which is due to adiabatic (isentropic) particle production. For a production rate which depends quadratically on the Hubble rate we confirm the existence of solutions which describe a smooth transition from inflationary to noninflationary behavior and discuss their interpretation within the model of a decaying vacuum energy density. An alternative formulation of the effective imperfect fluid dynamics in terms of a minimally coupled scalar field is given. The corresponding potential is discussed and an entropy equivalent for the scalar field is found.Comment: 16 pages, revtex file, submitted to Phys. Rev.

The outer halos of elliptical galaxies

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A framework for employing longitudinally collected multicenter electronic health records to stratify heterogeneous patient populations on disease history

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E-retailing ethics in Egypt and its effect on customer repurchase intention

The theoretical understanding of online shopping behaviour has received much attention. Less focus has been given to the formation of the ethical issues that result from online shopper interactions with e-retailers. The vast majority of earlier research on this area is conceptual in nature and limited in scope by focusing on consumers’ privacy issues. Therefore, the purpose of this paper is to propose a theoretical model explaining what factors contribute to online retailing ethics and its effect on customer repurchase intention. The data were analysed using variance-based structural equation modelling, employing partial least squares regression. Findings indicate that the five factors of the online retailing ethics (security, privacy, non- deception, fulfilment/reliability, and corporate social responsibility) are strongly predictive of online consumers’ repurchase intention. The results offer important implications for e-retailers and are likely to stimulate further research in the area of e-ethics from the consumers’ perspective

Acceleration of Relativistic Protons during the 20 January 2005 Flare and CME

The origin of relativistic solar protons during large flare/CME events has not been uniquely identified so far.We perform a detailed comparative analysis of the time profiles of relativistic protons detected by the worldwide network of neutron monitors at Earth with electromagnetic signatures of particle acceleration in the solar corona during the large particle event of 20 January 2005. The intensity-time profile of the relativistic protons derived from the neutron monitor data indicates two successive peaks. We show that microwave, hard X-ray and gamma-ray emissions display several episodes of particle acceleration within the impulsive flare phase. The first relativistic protons detected at Earth are accelerated together with relativistic electrons and with protons that produce pion decay gamma-rays during the second episode. The second peak in the relativistic proton profile at Earth is accompanied by new signatures of particle acceleration in the corona within approximatively 1 solar radius above the photosphere, revealed by hard X-ray and microwave emissions of low intensity, and by the renewed radio emission of electron beams and of a coronal shock wave. We discuss the observations in terms of different scenarios of particle acceleration in the corona.Comment: 22 pages, 5 figure

Phase II Efficacy and Pharmacogenomic Study of Selumetinib (AZD6244; ARRY-142886) in Iodine-131 Refractory Papillary Thyroid Carcinoma with or without Follicular Elements

A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC)

Stochastic Acceleration by Turbulence

The subject of this paper is stochastic acceleration by plasma turbulence, a process akin to the original model proposed by Fermi. We review the relative merits of different acceleration models, in particular the so called first order Fermi acceleration by shocks and second order Fermi by stochastic processes, and point out that plasma waves or turbulence play an important role in all mechanisms of acceleration. Thus, stochastic acceleration by turbulence is active in most situations. We also show that it is the most efficient mechanism of acceleration of relatively cool non relativistic thermal background plasma particles. In addition, it can preferentially accelerate electrons relative to protons as is needed in many astrophysical radiating sources, where usually there are no indications of presence of shocks. We also point out that a hybrid acceleration mechanism consisting of initial acceleration by turbulence of background particles followed by a second stage acceleration by a shock has many attractive features. It is demonstrated that the above scenarios can account for many signatures of the accelerated electrons, protons and other ions, in particular $^3$He and $^4$He, seen directly as Solar Energetic Particles and through the radiation they produce in solar flares.Comment: 29 pages 7 figures for proceedings of ISSI-Bern workshop on Particle Acceleration 201