Antiepileptogenesis after stroke—trials and tribulations: Methodological challenges and recruitment results of a Phase II study with eslicarbazepine acetate

There is currently no evidence to support the use of antiseizure medications to prevent unprovoked seizures following stroke. Experimental animal models suggested a potential antiepileptogenic effect for eslicarbazepine acetate (ESL), and a Phase II, multicenter, randomized, double-blind, placebo-controlled study was designed to test this hypothesis and assess whether ESL treatment for 1 month can prevent unprovoked seizures following stroke. We outline the design and status of this antiepileptogenesis study, and discuss the challenges encountered in its execution to date. Patients at high risk of developing unprovoked seizures after acute intracerebral hemorrhage or acute ischemic stroke were randomized to receive ESL 800 mg/d or placebo, initiated within 120 hours after primary stroke occurrence. Treatment continued until Day 30, then tapered off. Patients could receive all necessary therapies for stroke treatment according to clinical practice guidelines and standard of care, and are being followed up for 18 months. The primary efficacy endpoint is the occurrence of a first unprovoked seizure within 6 months after randomization (“failure rate”). Secondary efficacy assessments include the occurrence of a first unprovoked seizure during 12 months after randomization and during the entire study; functional outcomes (Barthel Index original 10-item version; National Institutes of Health Stroke Scale); post-stroke depression (Patient Health Questionnaire-9; PHQ-9); and overall survival. Safety assessments include the evaluation of treatment-emergent adverse events; laboratory parameters; vital signs; electrocardiogram; suicidal ideation and behavior (PHQ-9 question 9). The protocol aimed to randomize approximately 200 patients (1:1), recruited from 21 sites in seven European countries and Israel. Despite the challenges encountered, particularly during the COVID-19 pandemic, the study progressed and included a remarkable number of patients, with 129 screened and 125 randomized. Recruitment was stopped after 30 months, the first patient entered in May 2019, and the study is ongoing and following up on patients according to the Clinical Trial Protocol

Strain-induced Evolution of Electronic Band Structures in a Twisted Graphene Bilayer

Here we study the evolution of local electronic properties of a twisted graphene bilayer induced by a strain and a high curvature. The strain and curvature strongly affect the local band structures of the twisted graphene bilayer; the energy difference of the two low-energy van Hove singularities decreases with increasing the lattice deformations and the states condensed into well-defined pseudo-Landau levels, which mimic the quantization of massive Dirac fermions in a magnetic field of about 100 T, along a graphene wrinkle. The joint effect of strain and out-of-plane distortion in the graphene wrinkle also results in a valley polarization with a significant gap, i.e., the eight-fold degenerate Landau level at the charge neutrality point is splitted into two four-fold degenerate quartets polarized on each layer. These results suggest that strained graphene bilayer could be an ideal platform to realize the high-temperature zero-field quantum valley Hall effect.Comment: 4 figure

A Concept of Operations for an Integrated Vehicle Health Assurance System

This document describes a Concept of Operations (ConOps) for an Integrated Vehicle Health Assurance System (IVHAS). This ConOps is associated with the Maintain Vehicle Safety (MVS) between Major Inspections Technical Challenge in the Vehicle Systems Safety Technologies (VSST) Project within NASA s Aviation Safety Program. In particular, this document seeks to describe an integrated system concept for vehicle health assurance that integrates ground-based inspection and repair information with in-flight measurement data for airframe, propulsion, and avionics subsystems. The MVS Technical Challenge intends to maintain vehicle safety between major inspections by developing and demonstrating new integrated health management and failure prevention technologies to assure the integrity of vehicle systems between major inspection intervals and maintain vehicle state awareness during flight. The approach provided by this ConOps is intended to help optimize technology selection and development, as well as allow the initial integration and demonstration of these subsystem technologies over the 5 year span of the VSST program, and serve as a guideline for developing IVHAS technologies under the Aviation Safety Program within the next 5 to 15 years. A long-term vision of IVHAS is provided to describe a basic roadmap for more intelligent and autonomous vehicle systems

Higher Dimensional Cylindrical or Kasner Type Electrovacuum Solutions

We consider a D dimensional Kasner type diagonal spacetime where metric functions depend only on a single coordinate and electromagnetic field shares the symmetries of spacetime. These solutions can describe static cylindrical or cosmological Einstein-Maxwell vacuum spacetimes. We mainly focus on electrovacuum solutions and four different types of solutions are obtained in which one of them has no four dimensional counterpart. We also consider the properties of the general solution corresponding to the exterior field of a charged line mass and discuss its several properties. Although it resembles the same form with four dimensional one, there is a difference on the range of the solutions for fixed signs of the parameters. General magnetic field vacuum solution are also briefly discussed, which reduces to Bonnor-Melvin magnetic universe for a special choice of the parameters. The Kasner forms of the general solution are also presented for the cylindrical or cosmological cases.Comment: 16 pages, Revtex. Text and references are extended, Published versio

Can screening and brief intervention lead to population-level reductions in alcohol-related harm?

A distinction is made between the clinical and public health justifications for screening and brief intervention (SBI) against hazardous and harmful alcohol consumption. Early claims for a public health benefit of SBI derived from research on general medical practitioners' (GPs') advice on smoking cessation, but these claims have not been realized, mainly because GPs have not incorporated SBI into their routine practice. A recent modeling exercise estimated that, if all GPs in England screened every patient at their next consultation, 96% of the general population would be screened over 10 years, with 70-79% of excessive drinkers receiving brief interventions (BI); assuming a 10% success rate, this would probably amount to a population-level effect of SBI. Thus, a public health benefit for SBI presupposes widespread screening; but recent government policy in England favors targeted versus universal screening, and in Scotland screening is based on new registrations and clinical presentation. A recent proposal for a national screening program was rejected by the UK National Health Service's National Screening Committee because 1) there was no good evidence that SBI led to reductions in mortality or morbidity, and 2) a safe, simple, precise, and validated screening test was not available. Even in countries like Sweden and Finland, where expensive national programs to disseminate SBI have been implemented, only a minority of the population has been asked about drinking during health-care visits, and a minority of excessive drinkers has been advised to cut down. Although there has been research on the relationship between treatment for alcohol problems and population-level effects, there has been no such research for SBI, nor have there been experimental investigations of its relationship with population-level measures of alcohol-related harm. These are strongly recommended. In this article, conditions that would allow a population-level effect of SBI to occur are reviewed, including their political acceptability. It is tentatively concluded that widespread dissemination of SBI, without the implementation of alcohol control measures, might have indirect influences on levels of consumption and harm but would be unlikely on its own to result in public health benefits. However, if and when alcohol control measures were introduced, SBI would still have an important role in the battle against alcohol-related harm

Genotoxic agents promote the nuclear accumulation of annexin A2: role of annexin A2 in mitigating DNA damage

Annexin A2 is an abundant cellular protein that is mainly localized in the cytoplasm and plasma membrane, however a small population has been found in the nucleus, suggesting a nuclear function for the protein. Annexin A2 possesses a nuclear export sequence (NES) and inhibition of the NES is sufficient to cause nuclear accumulation. Here we show that annexin A2 accumulates in the nucleus in response to genotoxic agents including gamma-radiation, UV radiation, etoposide and chromium VI and that this event is mediated by the nuclear export sequence of annexin A2. Nuclear accumulation of annexin A2 is blocked by the antioxidant agent N-acetyl cysteine (NAC) and stimulated by hydrogen peroxide (H2O2), suggesting that this is a reactive oxygen species dependent event. In response to genotoxic agents, cells depleted of annexin A2 show enhanced phospho-histone H2AX and p53 levels, increased numbers of p53-binding protein 1 nuclear foci and increased levels of nuclear 8-oxo-2'-deoxyguanine, suggesting that annexin A2 plays a role in protecting DNA from damage. This is the first report showing the nuclear translocation of annexin A2 in response to genotoxic agents and its role in mitigating DNA damage.Natural Sciences and Engineering Research Council of Canada (NSERC); European Union [PCOFUND-GA-2009-246542]; Foundation for Science and Technology of Portugal; Beatrice Hunter Cancer Research Institute; Terry Fox Foundationinfo:eu-repo/semantics/publishedVersio

InnateDB: facilitating systems-level analyses of the mammalian innate immune response

Although considerable progress has been made in dissecting the signaling pathways involved in the innate immune response, it is now apparent that this response can no longer be productively thought of in terms of simple linear pathways. InnateDB (www.innatedb.ca) has been developed to facilitate systems-level analyses that will provide better insight into the complex networks of pathways and interactions that govern the innate immune response. InnateDB is a publicly available, manually curated, integrative biology database of the human and mouse molecules, experimentally verified interactions and pathways involved in innate immunity, along with centralized annotation on the broader human and mouse interactomes. To date, more than 3500 innate immunity-relevant interactions have been contextually annotated through the review of 1000 plus publications. Integrated into InnateDB are novel bioinformatics resources, including network visualization software, pathway analysis, orthologous interaction network construction and the ability to overlay user-supplied gene expression data in an intuitively displayed molecular interaction network and pathway context, which will enable biologists without a computational background to explore their data in a more systems-oriented manner

Midgut microbiota of the malaria mosquito vector Anopheles gambiae and Interactions with plasmodium falciparum Infection

The susceptibility of Anopheles mosquitoes to Plasmodium infections relies on complex interactions between the insect vector and the malaria parasite. A number of studies have shown that the mosquito innate immune responses play an important role in controlling the malaria infection and that the strength of parasite clearance is under genetic control, but little is known about the influence of environmental factors on the transmission success. We present here evidence that the composition of the vector gut microbiota is one of the major components that determine the outcome of mosquito infections. A. gambiae mosquitoes collected in natural breeding sites from Cameroon were experimentally challenged with a wild P. falciparum isolate, and their gut bacterial content was submitted for pyrosequencing analysis. The meta-taxogenomic approach revealed a broader richness of the midgut bacterial flora than previously described. Unexpectedly, the majority of bacterial species were found in only a small proportion of mosquitoes, and only 20 genera were shared by 80% of individuals. We show that observed differences in gut bacterial flora of adult mosquitoes is a result of breeding in distinct sites, suggesting that the native aquatic source where larvae were grown determines the composition of the midgut microbiota. Importantly, the abundance of Enterobacteriaceae in the mosquito midgut correlates significantly with the Plasmodium infection status. This striking relationship highlights the role of natural gut environment in parasite transmission. Deciphering microbe-pathogen interactions offers new perspectives to control disease transmission.Institut de Recherche pour le Developpement (IRD); French Agence Nationale pour la Recherche [ANR-11-BSV7-009-01]; European Community [242095, 223601]info:eu-repo/semantics/publishedVersio

Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans

The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans