COPe-support - a multi-component digital intervention for family carers for people affected by psychosis: study protocol for a randomized controlled trial.

BACKGROUND: Psychosis often causes significant distress and impacts not only in the individuals, but also those close to them. Many relatives and friends ('carers') provide long-term support and need resources to assist them. We have co-produced a digital mental health intervention called COPe-support (Carers fOr People with Psychosis e-support) to provide carers with flexible access to high quality psychoeducation and interactive support from experts and peers. This study evaluates the effectiveness of COPe-support to promote mental wellbeing and caregiving experiences in carers. METHODS: This study is a single-blind, parallel arm, individually randomized controlled trial (RCT) comparing COPe-support, with attention control. Both groups continue to receive usual care. COPe-support provides interactive web-based psychoeducation on psychosis-related issues, wellbeing-promotion and network support through forums. The attention-control is a non-interactive online information resource pack. Carers living in England are eligible if they provide at least weekly support to a family member or close friend affected by psychosis, and use internet communication (including emails) daily. All trial procedures are run online, including collection of outcome measurements which participants will directly input into our secure platform. Following baseline assessment, a web-based randomization system will be used to allocate 360 carers to either arm. Participants have unlimited access to the allocated condition for 40 weeks. Data collection is at three time points (10, 20, and 40 weeks after randomization). Analyses will be conducted by trial statisticians blinded to allocation. The primary outcome is mental wellbeing measured by Warwick Edinburgh Mental Wellbeing Scale (WEMWBS), at 20 weeks. As well as an intention-to-treat analysis, a complier average causal effect (CACE) analysis will be conducted to estimate the intervention effect in participants who have accessed COPe-support content twice or more. The secondary objectives and analysis will examine other health and caregiving-related outcomes and explore mechanisms. In a process evaluation, we will interview 20% of the intervention arm participants regarding the acceptability of COPe-support. We will explore in detail participants' usage patterns. DISCUSSION: The results of this trial will provide valuable information about the effectiveness of COPe-support in promoting wellbeing and caregiving experiences in carers. TRIAL REGISTRATION: The RCT is registered with the Current Controlled Trials registration (ISRCTN 89563420, registration date: 02/03/2018)

Reliability and time-to-failure bounds for discrete-time constrained Markov jump linear systems

[EN] This paper presents a methodology to obtain a guaranteed-reliability controller for constrained linear sys- tems, which switch between different modes according to a Markov chain (Markov jump linear systems). Inside the classical maximal robust controllable set, there is 100% guarantee of never violating constraints at future time. However, outside such set, some sequences might make hitting constraints unavoidable for some disturbance realisations. A guaranteed-reliability controller based on a greedy heuristic approach was proposed in an earlier work for disturbance-free, robustly stabilisable Markov jump linear systems. Here, extensions are presented by, first, considering bounded disturbances and, second, presenting an iterative algorithm based on dynamic programming. In non-stabilisable systems, reliability is zero; therefore, prior results cannot be applied; in this case, optimisation of a mean-time-to-failure bound is proposed, via minor algorithm modifications. Optimality can be proved in the disturbance-free, finitely generated case.The authors gratefully acknowledge the financial support of Spanish MINECO (DPI2011-27845-C02-01, FPU12/02107) and Generalitat Valenciana (PrometeoII/2013/004).Hernandez-Mejias, MA.; Sala, A. (2017). Reliability and time-to-failure bounds for discrete-time constrained Markov jump linear systems. International Journal of Robust and Nonlinear Control. 27:1773-1791. https://doi.org/10.1002/rnc.3635S177317912

Attosecond physics at the nanoscale

Recently two emerging areas of research, attosecond and nanoscale physics, have started to come together. Attosecond physics deals with phenomena occurring when ultrashort laser pulses, with duration on the femto- and sub-femtosecond time scales, interact with atoms, molecules or solids. The laser-induced electron dynamics occurs natively on a timescale down to a few hundred or even tens of attoseconds, which is comparable with the optical field. On the other hand, the second branch involves the manipulation and engineering of mesoscopic systems, such as solids, metals and dielectrics, with nanometric precision. Although nano-engineering is a vast and well-established research field on its own, the merger with intense laser physics is relatively recent. In this article we present a comprehensive experimental and theoretical overview of physics that takes place when short and intense laser pulses interact with nanosystems, such as metallic and dielectric nanostructures. In particular we elucidate how the spatially inhomogeneous laser induced fields at a nanometer scale modify the laser-driven electron dynamics. Consequently, this has important impact on pivotal processes such as ATI and HHG. The deep understanding of the coupled dynamics between these spatially inhomogeneous fields and matter configures a promising way to new avenues of research and applications. Thanks to the maturity that attosecond physics has reached, together with the tremendous advance in material engineering and manipulation techniques, the age of atto-nano physics has begun, but it is in the initial stage. We present thus some of the open questions, challenges and prospects for experimental confirmation of theoretical predictions, as well as experiments aimed at characterizing the induced fields and the unique electron dynamics initiated by them with high temporal and spatial resolution

Mollusca from a species-rich deep-water Leptometra community in the Alboran Sea

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Influence of Prenatal Lead Exposure on Genomic Methylation of Cord Blood DNA

Background Fetal lead exposure is associated with adverse pregnancy outcomes and developmental and cognitive deficits; however, the mechanism(s) by which lead-induced toxicity occurs remains unknown. Epigenetic fetal programming via DNA methylation may provide a pathway by which environmental lead exposure can influence disease susceptibility. Objective This study was designed to determine whether prenatal lead exposure is associated with alterations in genomic methylation of leukocyte DNA levels from umbilical cord samples. Methods We measured genomic DNA methylation, as assessed by Alu and LINE-1 (long interspersed nuclear element-1) methylation via pyrosequencing, on 103 umbilical cord blood samples from the biorepository of the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study group. Prenatal lead exposure had been assessed by measuring maternal bone lead levels at the mid-tibial shaft and the patella using a spot-source 109Cd K-shell X-ray fluorescence instrument. Results We found an inverse dose–response relationship in which quartiles of patella lead correlated with cord LINE-1 methylation (p for trend = 0.01) and and tibia lead correlated with Alu methylation (p for trend = 0.05). In mixed effects regression models, maternal tibia lead was negatively associated with umbilical cord genomic DNA methylation of Alu (β= −0.027; p = 0.01). We found no associations between cord blood lead and cord genomic DNA methylation. Conclusions Prenatal lead exposure is inversely associated with genomic DNA methylation in cord blood. These data suggest that the epigenome of the developing fetus can be influenced by maternal cumulative lead burden, which may influence long-term epigenetic programming and disease susceptibility throughout the life course

Analysis of the potential of cancer cell lines to release tissue factor-containing microvesicles: correlation with tissue factor and PAR2 expression

BackgroundDespite the association of cancer-derived circulating tissue factor (TF)-containing microvesicles and hypercoagulable state, correlations with the incidence of thrombosis remain unclear.MethodsIn this study the upregulation of TF release upon activation of various cancer cell lines, and the correlation with TF and PAR2 expression and/or activity was examined. Microvesicle release was induced by PAR2 activation in seventeen cell lines and released microvesicle density, microvesicle-associated TF activity, and phoshpatidylserine-mediated activity were measured. The time-course for TF release was monitored over 90 min in each cell line. In addition, TF mRNA expression, cellular TF protein and cell-surface TF activities were quantified. Moreover, the relative expression of PAR2 mRNA and cellular protein were analysed. Any correlations between the above parameters were examined by determining the Pearson’s correlation coefficients.ResultsTF release as microvesicles peaked between 30–60 min post-activation in the majority of cell lines tested. The magnitude of the maximal TF release positively correlated with TF mRNA (c = 0.717; p

Novel and promising compounds to treat Cryptosporidium parvum infections

No fully effective approved drug therapy exists for Cryptosporidium infections of immunocompetent and immunocompromised patients. Here, we investigated 11 benzimidazole derivatives carrying substituted thioalkyl and thiobenzyl groups at position 2 of benzimidazole nucleus and additional substituents at the benzene part of benzimidazole for inhibition of the in vitro growth of the intestinal protozoan parasite, Cryptosporidium parvum. Three of them, i.e., 5-carboxy-2-(4-nitrobenzylthio)-1H-benzimidazole, 5,6-dichloro-2-(4-nitrobenzylthio)-1H-benzimidazole, and 4,6-dichloro-2-(4-nitrobenzylthio)-1H-benzimidazole, (compounds 5, 7, and 8) were the most active (IC50 28–31 μM). The concentration of compounds 5, 7, and 8 that caused 50% growth inhibition in human enterocytic HCT-8 cells by a quantitative alkaline phosphatase immunoassay was comparable with those obtained for paromomycin

Novel and promising compounds to treat Cryptosporidium parvum infections

No fully effective approved drug therapy exists for Cryptosporidium infections of immunocompetent and immunocompromised patients. Here, we investigated 11 benzimidazole derivatives carrying substituted thioalkyl and thiobenzyl groups at position 2 of benzimidazole nucleus and additional substituents at the benzene part of benzimidazole for inhibition of the in vitro growth of the intestinal protozoan parasite, Cryptosporidium parvum. Three of them, i.e., 5-carboxy-2-(4-nitrobenzylthio)-1H-benzimidazole, 5,6-dichloro-2-(4-nitrobenzylthio)-1H-benzimidazole, and 4,6-dichloro-2-(4-nitrobenzylthio)-1H-benzimidazole, (compounds 5, 7, and 8) were the most active (IC50 28–31 μM). The concentration of compounds 5, 7, and 8 that caused 50% growth inhibition in human enterocytic HCT-8 cells by a quantitative alkaline phosphatase immunoassay was comparable with those obtained for paromomycin

The porin and the permeating antibiotic: A selective diffusion barrier in gram-negative bacteria

Gram-negative bacteria are responsible for a large proportion of antibiotic resistant bacterial diseases. These bacteria have a complex cell envelope that comprises an outer membrane and an inner membrane that delimit the periplasm. The outer membrane contains various protein channels, called porins, which are involved in the influx of various compounds, including several classes of antibiotics. Bacterial adaptation to reduce influx through porins is an increasing problem worldwide that contributes, together with efflux systems, to the emergence and dissemination of antibiotic resistance. An exciting challenge is to decipher the genetic and molecular basis of membrane impermeability as a bacterial resistance mechanism. This Review outlines the bacterial response towards antibiotic stress on altered membrane permeability and discusses recent advances in molecular approaches that are improving our knowledge of the physico-chemical parameters that govern the translocation of antibiotics through porin channel