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)

Economic evidence for the prevention and treatment of atopic eczema: a protocol for a systematic review

Background: Eczema, synonymous with atopic eczema or atopic dermatitis, is a chronic skin disease that has a similar impact on health-related quality of life as other chronic diseases. The proposed research aims to provide a comprehensive systematic assessment of the economic evidence base available to inform economic modelling and decision making on interventions to prevent and treat eczema at any stage of the life course. Whilst the Global Resource of Eczema Trials (GREAT) database collects together the effectiveness evidence for eczema there is currently no such systematic resource on the economics of eczema. It is important to gain an overview of the current state of the art of economic methods in the field of eczema in order to strengthen the economic evidence base further. Methods/design: The proposed study is a systematic review of the economic evidence surrounding interventions for the prevention and treatment of eczema. Relevant search terms will be used to search MEDLINE, EMBASE, Database of Abstracts of Reviews of Effects, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, Health Technology Assessment, Cumulative Index to Nursing and Allied Health Literature, Econ Lit, Scopus, Cost-Effectiveness Analysis Registry and Web of Science in order to identify relevant evidence. To be eligible for inclusion studies will be primary empirical studies evaluating the cost, utility or full economic evaluation of interventions for preventing or treating eczema. Two reviewers will independently assess studies for eligibility and perform data abstraction. Evidence tables will be produced presenting details of study characteristics, costing methods, outcome methods and quality assessment. The methodological quality of studies will be assessed using accepted checklists. Discussion: The systematic review is being undertaken to identify the type of economic evidence available, summarise the results of the available economic evidence and critically appraise the quality of economic evidence currently available to inform future economic modelling and resource allocation decisions about interventions to prevent or treat eczema. We aim to use the review to offer guidance about how to gather economic evidence in studies of eczema and/or what further research is necessary in order to inform this

Forces between clustered stereocilia minimize friction in the ear on a subnanometre scale

The detection of sound begins when energy derived from acoustic stimuli deflects the hair bundles atop hair cells. As hair bundles move, the viscous friction between stereocilia and the surrounding liquid poses a fundamental challenge to the ear's high sensitivity and sharp frequency selectivity. Part of the solution to this problem lies in the active process that uses energy for frequency-selective sound amplification. Here we demonstrate that a complementary part involves the fluid-structure interaction between the liquid within the hair bundle and the stereocilia. Using force measurement on a dynamically scaled model, finite-element analysis, analytical estimation of hydrodynamic forces, stochastic simulation and high-resolution interferometric measurement of hair bundles, we characterize the origin and magnitude of the forces between individual stereocilia during small hair-bundle deflections. We find that the close apposition of stereocilia effectively immobilizes the liquid between them, which reduces the drag and suppresses the relative squeezing but not the sliding mode of stereociliary motion. The obliquely oriented tip links couple the mechanotransduction channels to this least dissipative coherent mode, whereas the elastic horizontal top connectors stabilize the structure, further reducing the drag. As measured from the distortion products associated with channel gating at physiological stimulation amplitudes of tens of nanometres, the balance of forces in a hair bundle permits a relative mode of motion between adjacent stereocilia that encompasses only a fraction of a nanometre. A combination of high-resolution experiments and detailed numerical modelling of fluid-structure interactions reveals the physical principles behind the basic structural features of hair bundles and shows quantitatively how these organelles are adapted to the needs of sensitive mechanotransduction.Comment: 21 pages, including 3 figures. For supplementary information, please see the online version of the article at http://www.nature.com/natur

Effectiveness of the bucco-lingual technique within a school-based supervised toothbrushing program on preventing caries: a randomized controlled trial

Abstract Background Supervised toothbrushing programs using fluoride dentifrice have reduced caries increment. However there is no information about the effectiveness of the professional cross-brushing technique within a community intervention. The aim was to assess if the bucco-lingual technique can increase the effectiveness of a school-based supervised toothbrushing program on preventing caries. Methods A randomized double-blinded controlled community intervention trial to be analyzed at an individual level was conducted in a Brazilian low-income fluoridated area. Six preschools were randomly assigned to the test and control groups and 284 five-year-old children presenting at least one permanent molar with emerged/sound occlusal surface participated. In control group, oral health education and dental plaque dying followed by toothbrushing with fluoride dentifrice supervised directly by a dental assistant, was developed four times per year. At the remaining school days the children brushed their teeth under indirect supervising of the teachers. In test group, children also underwent a professional cross-brushing on surfaces of first permanent molar rendered by a specially trained dental assistant five times per year. Enamel and dentin caries were recorded on buccal, occlusal and lingual surfaces of permanent molars during 18-month follow-up. Exposure time of surfaces was calculated and incidence density ratio was estimated using Poisson regression model. Results Difference of 21.6 lesions per 1,000 children between control and test groups was observed. Among boys whose caries risk was higher compared to girls, incidence density was 50% lower in test group (p = 0.016). Conclusion Modified program was effective among the boys. It is licit to project a relevant effect in a larger period suggesting in a broader population substantial reduction of dental care needs. Trial registration ISRCTN18548869

Flow through a circular tube with a permeable Navier slip boundary

For Newtonian fluid flow in a right circular tube, with a linear Navier slip boundary, we show that a second flow field arises which is different to conventional Poiseuille flow in the sense that the corresponding pressure is quadratic in its dependence on the length along the tube, rather than a linear dependence which applies for conventional Poiseuille flow. However, assuming that the quadratic pressure is determined, say from known experimental data, then the new solution only exists for a precisely prescribed permeability along the boundary. While this cannot occur for conventional pipe flow, for fluid flow through carbon nanotubes embedded in a porous matrix, it may well be an entirely realistic possibility, and could well explain some of the high flow rates which have been reported in the literature. Alternatively, if the radial boundary flow is prescribed, then the new flow field exists only for a given quadratic pressure. Our primary purpose here is to demonstrate the existence of a new pipe flow field for a permeable Navier slip boundary and to present a numerical solution and two approximate analytical solutions. The maximum flow rate possible for the new solution is precisely twice that for the conventional Poiseuille flow, which occurs for constant inward directed flow across the boundary

Modeling Stochasticity and Variability in Gene Regulatory Networks

Modeling stochasticity in gene regulatory networks is an important and complex problem in molecular systems biology. To elucidate intrinsic noise, several modeling strategies such as the Gillespie algorithm have been used successfully. This paper contributes an approach as an alternative to these classical settings. Within the discrete paradigm, where genes, proteins, and other molecular components of gene regulatory networks are modeled as discrete variables and are assigned as logical rules describing their regulation through interactions with other components. Stochasticity is modeled at the biological function level under the assumption that even if the expression levels of the input nodes of an update rule guarantee activation or degradation there is a probability that the process will not occur due to stochastic effects. This approach allows a finer analysis of discrete models and provides a natural setup for cell population simulations to study cell-to-cell variability. We applied our methods to two of the most studied regulatory networks, the outcome of lambda phage infection of bacteria and the p53-mdm2 complex.Comment: 23 pages, 8 figure

Contact Manifolds, Contact Instantons, and Twistor Geometry

Recently, Kallen and Zabzine computed the partition function of a twisted supersymmetric Yang-Mills theory on the five-dimensional sphere using localisation techniques. Key to their construction is a five-dimensional generalisation of the instanton equation to which they refer as the contact instanton equation. Subject of this article is the twistor construction of this equation when formulated on K-contact manifolds and the discussion of its integrability properties. We also present certain extensions to higher dimensions and supersymmetric generalisations.Comment: v3: 28 pages, clarifications and references added, version to appear in JHE

Radiation Impairs Perineural Invasion by Modulating the Nerve Microenvironment

Perineural invasion (PNI) by cancer cells is an ominous clinical event that is associated with increased local recurrence and poor prognosis. Although radiation therapy (RT) may be delivered along the course of an invaded nerve, the mechanisms through which radiation may potentially control PNI remain undefined. murine sciatic nerve model was used to study how RT to nerve or cancer affects nerve invasion by cancer.Cancer cell invasion of the DRG was partially dependent on DRG secretion of glial-derived neurotrophic factor (GDNF). A single 4 Gy dose of radiation to the DRG alone, cultured with non-radiated cancer cells, significantly inhibited PNI and was associated with decreased GDNF secretion but intact DRG viability. Radiation of cancer cells alone, co-cultured with non-radiated nerves, inhibited PNI through predominantly compromised cancer cell viability. In a murine model of PNI, a single 8 Gy dose of radiation to the sciatic nerve prior to implantation of non-radiated cancer cells resulted in decreased GDNF expression, decreased PNI by imaging and histology, and preservation of sciatic nerve motor function.Radiation may impair PNI through not only direct effects on cancer cell viability, but also an independent interruption of paracrine mechanisms underlying PNI. RT modulation of the nerve microenvironment may decrease PNI, and hold significant therapeutic implications for RT dosing and field design for patients with cancers exhibiting PNI

Dystroglycan versatility in cell adhesion: a tale of multiple motifs

Dystroglycan is a ubiquitously expressed heterodimeric adhesion receptor. The extracellular a-subunit makes connections with a number of laminin G domain ligands including laminins, agrin and perlecan in the extracellular matrix and the transmembrane b-subunit makes connections to the actin filament network via cytoskeletal linkers including dystrophin, utrophin, ezrin and plectin, depending on context. Originally discovered as part of the dystrophin glycoprotein complex of skeletal muscle, dystroglycan is an important adhesion molecule and signalling scaffold in a multitude of cell types and tissues and is involved in several diseases. Dystroglycan has emerged as a multifunctional adhesion platform with many interacting partners associating with its short unstructured cytoplasmic domain. Two particular hotspots are the cytoplasmic juxtamembrane region and at the very carboxy terminus of dystroglycan. Regions which between them have several overlapping functions: in the juxtamembrane region; a nuclear localisation signal, ezrin/radixin/moesin protein, rapsyn and ERK MAP Kinase binding function, and at the C terminus a regulatory tyrosine governing WW, SH2 and SH3 domain interactions. We will discuss the binding partners for these motifs and how their interactions and regulation can modulate the involvement of dystroglycan in a range of different adhesion structures and functions depending on context. Thus dystroglycan presents as a multifunctional scaffold involved in adhesion and adhesion-mediated signalling with its functions under exquisite spatiotemporal regulation

The positive and negative impact of an intergenerational digital technology education programme on younger people’s perceptions of older adults

In order to meet the technological needs of older adults, and ensure digital inclusion, it is important for digital technology designers to accurately assess and understand older adults’ needs and requirements, free from the influence of societal assumptions of their capabilities. This study evaluated the impact of an intergenerational digital technology education programme on younger adults’ stereotypes of older people. Using an experimental design, results show that compared to a control group, students taking part in the programme subsequently rated older adults as more friendly but less competent. Practical implications for developing intergenerational education programmes are discussed