A behavioural change package to prevent hand dermatitis in nurses working in the national health service (the SCIN trial): study protocol for a cluster randomised controlled trial

BACKGROUND: Hand dermatitis can be a serious health problem in healthcare workers. While a range of skin care strategies and policy directives have been developed in recent years to minimise the risk, their effectiveness and cost-effectiveness remain unclear. Evidence now suggests that psychological theory can facilitate behaviour change with respect to improved hand care practices. Therefore, we will test the hypothesis that a behavioural change intervention to improve hand care, based on the Theory of Planned Behaviour and implementation intentions, coupled with provision of hand moisturisers, can produce a clinically useful reduction in the occurrence of hand dermatitis, when compared to standard care, among nurses working in the UK National Health Service (NHS) who are particularly at risk. Secondary aims will be to assess impacts on participants’ beliefs and behaviour regarding hand care. In addition, we will assess the cost-effectiveness of the intervention in comparison with normal care. METHODS/DESIGN: We will conduct a cluster randomised controlled trial at 35 NHS hospital trusts/health boards/universities, focussing on student nurses with a previous history of atopic disease or hand eczema and on nurses in intensive care units. Nurses at ‘intervention-light’ sites will be managed according to what would currently be regarded as best practice, with provision of an advice leaflet about optimal hand care to prevent hand dermatitis and encouragement to contact their occupational health (OH) department early if hand dermatitis occurs. Nurses at ‘intervention-plus’ sites will additionally receive a behavioural change programme (BCP) with on-going active reinforcement of its messages, and enhanced provision of moisturising cream. The impact of the interventions will be compared using information collected by questionnaires and through standardised photographs of the hands and wrists, collected at baseline and after 12 months follow-up. In addition, we will assemble relevant economic data for an analysis of costs and benefits, and collect information from various sources to evaluate processes. Statistical analysis will be by multi-level regression modelling to allow for clustering by site, and will compare the prevalence of outcome measures at follow-up after adjustment for values at baseline. The principal outcome measure will be the prevalence of visible hand dermatitis as assessed by the study dermatologists. In addition, several secondary outcome measures will be assessed. DISCUSSION: This trial will assess the clinical and cost effectiveness of an intervention to prevent hand dermatitis in nurses in the United Kigdom. TRIAL REGISTRATION: ISRCTN53303171: date of registration, 21 June 2013

A behaviour change package to prevent hand dermatitis in nurses working in health care: the SCIN cluster RCT

BACKGROUND: Although strategies have been developed to minimise the risk of occupational hand dermatitis in nurses, their clinical effectiveness and cost-effectiveness remain unclear. OBJECTIVES: The Skin Care Intervention in Nurses trial tested the hypothesis that a behaviour change package intervention, coupled with provision of hand moisturisers, could reduce the point prevalence of hand dermatitis when compared with standard care among nurses working in the NHS. The secondary aim was to assess the impact of the intervention on participants' beliefs and behaviour regarding hand care, and the cost-effectiveness of the intervention in comparison with normal care. DESIGN: Cluster randomised controlled trial. SETTING: Thirty-five NHS hospital trusts/health boards/universities. PARTICIPANTS: First-year student nurses with a history of atopic tendency, and full-time intensive care unit nurses. INTERVENTION: Sites were randomly allocated to be 'intervention plus' or 'intervention light'. Participants at 'intervention plus' sites received access to a bespoke online behaviour change package intervention, coupled with personal supplies of moisturising cream (student nurses) and optimal availability of moisturising cream (intensive care unit nurses). Nurses at 'intervention light' sites received usual care, including a dermatitis prevention leaflet. MAIN OUTCOME MEASURE: The difference between intervention plus and intervention light sites in the change of point prevalence of visible hand dermatitis was measured from images taken at baseline and at follow-up. RANDOMISATION: Fourteen sites were randomised to the intervention plus arm, and 21 sites were randomised to the intervention light arm. BLINDING: The participants, trial statistician, methodologist and the dermatologists interpreting the hand photographs were blinded to intervention assignment. NUMBERS ANALYSED: An intention-to-treat analysis was conducted on data from 845 student nurses and 1111 intensive care unit nurses. RESULTS: The intention-to-treat analysis showed no evidence that the risk of developing dermatitis was greater in the intervention light group than in the intervention plus group (student nurses: odds ratio 1.25, 95% confidence interval 0.59 to 2.69; intensive care unit nurses: odds ratio 1.41, 95% confidence interval 0.81 to 2.44). Both groups had high levels of baseline beliefs about the benefits of using hand moisturisers before, during and after work. The frequency of use of hand moisturisers before, during and after shifts was significantly higher in the intensive care unit nurses in the intervention plus arm at follow-up than in the comparator group nurses. For student nurses, the intervention plus group mean costs were £2 lower than those for the comparator and 0.00002 more quality-adjusted life-years were gained. For intensive care unit nurses, costs were £4 higher and 0.0016 fewer quality-adjusted life-years were gained. HARMS: No adverse events were reported. LIMITATIONS: Only 44.5% of participants in the intervention plus arm accessed the behaviour change package. CONCLUSION: The intervention did not result in a statistically significant decrease in the prevalence of hand dermatitis in the intervention plus group. FUTURE WORK: Participants had a high level of baseline beliefs about the importance of using hand moisturisers before, during and after work. Future research should focus on how workplace culture can be changed in order for that knowledge to be actioned. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53303171. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 58. See the NIHR Journals Library website for further project information

Differential cargo mobilisation within Weibel-Palade bodies after transient fusion with the plasma membrane.

Inflammatory chemokines can be selectively released from Weibel-Palade bodies (WPBs) during kiss-and-run exocytosis. Such selectivity may arise from molecular size filtering by the fusion pore, however differential intra-WPB cargo re-mobilisation following fusion-induced structural changes within the WPB may also contribute to this process. To determine whether WPB cargo molecules are differentially re-mobilised, we applied FRAP to residual post-fusion WPB structures formed after transient exocytosis in which some or all of the fluorescent cargo was retained. Transient fusion resulted in WPB collapse from a rod to a spheroid shape accompanied by substantial swelling (>2 times by surface area) and membrane mixing between the WPB and plasma membranes. Post-fusion WPBs supported cumulative WPB exocytosis. To quantify diffusion inside rounded organelles we developed a method of FRAP analysis based on image moments. FRAP analysis showed that von Willebrand factor-EGFP (VWF-EGFP) and the VWF-propolypeptide-EGFP (Pro-EGFP) were immobile in post-fusion WPBs. Because Eotaxin-3-EGFP and ssEGFP (small soluble cargo proteins) were largely depleted from post-fusion WPBs, we studied these molecules in cells preincubated in the weak base NH4Cl which caused WPB alkalinisation and rounding similar to that produced by plasma membrane fusion. In these cells we found a dramatic increase in mobilities of Eotaxin-3-EGFP and ssEGFP that exceeded the resolution of our method (∼ 2.4 µm2/s mean). In contrast, the membrane mobilities of EGFP-CD63 and EGFP-Rab27A in post-fusion WPBs were unchanged, while P-selectin-EGFP acquired mobility. Our data suggest that selective re-mobilisation of chemokines during transient fusion contributes to selective chemokine secretion during transient WPB exocytosis. Selective secretion provides a mechanism to regulate intravascular inflammatory processes with reduced risk of thrombosis

PAK6 Phosphorylates 14-3-3 gamma to Regulate Steady State Phosphorylation of LRRK2

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson’s disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for age-related neurodegeneration. Although the cellular functions of LRRK2 in health and disease are incompletely understood, robust evidence indicates that PD-associated mutations alter LRRK2 kinase and GTPase activities with consequent deregulation of the downstream signaling pathways. We have previously demonstrated that one LRRK2 binding partner is P21 (RAC1) Activated Kinase 6 (PAK6). Here, we interrogate the PAK6 interactome and find that PAK6 binds a subset of 14-3-3 proteins in a kinase dependent manner. Furthermore, PAK6 efficiently phosphorylates 14-3-3γ at Ser59 and this phosphorylation serves as a switch to dissociate the chaperone from client proteins including LRRK2, a well-established 14-3-3 binding partner. We found that 14-3-3γ phosphorylated by PAK6 is no longer competent to bind LRRK2 at phospho-Ser935, causing LRRK2 dephosphorylation. To address whether these interactions are relevant in a neuronal context, we demonstrate that a constitutively active form of PAK6 rescues the G2019S LRRK2-associated neurite shortening through phosphorylation of 14-3-3γ. Our results identify PAK6 as the kinase for 14-3-3γ and reveal a novel regulatory mechanism of 14-3-3/LRRK2 complex in the brain

In-cell NMR characterization of the secondary structure populations of a disordered conformation of α-Synuclein within E. coli cells

α-Synuclein is a small protein strongly implicated in the pathogenesis of Parkinson’s disease and related neurodegenerative disorders. We report here the use of in-cell NMR spectroscopy to observe directly the structure and dynamics of this protein within E. coli cells. To improve the accuracy in the measurement of backbone chemical shifts within crowded in-cell NMR spectra, we have developed a deconvolution method to reduce inhomogeneous line broadening within cellular samples. The resulting chemical shift values were then used to evaluate the distribution of secondary structure populations which, in the absence of stable tertiary contacts, are a most effective way to describe the conformational fluctuations of disordered proteins. The results indicate that, at least within the bacterial cytosol, α-synuclein populates a highly dynamic state that, despite the highly crowded environment, has the same characteristics as the disordered monomeric form observed in aqueous solution

Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in postmortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild-type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia

Deterministic and stochastic descriptions of gene expression dynamics

A key goal of systems biology is the predictive mathematical description of gene regulatory circuits. Different approaches are used such as deterministic and stochastic models, models that describe cell growth and division explicitly or implicitly etc. Here we consider simple systems of unregulated (constitutive) gene expression and compare different mathematical descriptions systematically to obtain insight into the errors that are introduced by various common approximations such as describing cell growth and division by an effective protein degradation term. In particular, we show that the population average of protein content of a cell exhibits a subtle dependence on the dynamics of growth and division, the specific model for volume growth and the age structure of the population. Nevertheless, the error made by models with implicit cell growth and division is quite small. Furthermore, we compare various models that are partially stochastic to investigate the impact of different sources of (intrinsic) noise. This comparison indicates that different sources of noise (protein synthesis, partitioning in cell division) contribute comparable amounts of noise if protein synthesis is not or only weakly bursty. If protein synthesis is very bursty, the burstiness is the dominant noise source, independent of other details of the model. Finally, we discuss two sources of extrinsic noise: cell-to-cell variations in protein content due to cells being at different stages in the division cycles, which we show to be small (for the protein concentration and, surprisingly, also for the protein copy number per cell) and fluctuations in the growth rate, which can have a significant impact.Comment: 23 pages, 5 figures; Journal of Statistical physics (2012

Financial crisis and income-related inequalities in the universal provision of a public service: the case of healthcare in Spain

Background The objective of this paper is to analyse whether the recent recession has altered health care utilisation patterns of different income groups in Spain. Methods Based on information concerning individuals ‘income and health care use, along with health need indicators and demographic characteristics (provided by the Spanish National Health Surveys from 2006/07 and 2011/12), econometric models are estimated in two parts (mixed logistic regressions and truncated negative binominal regressions) for each of the public health services studied (family doctor appointments, appointments with specialists, hospitalisations, emergencies and prescription drug use). Results The results show that the principle of universal access to public health provision does not in fact prevent a financial crisis from affecting certain income groups more than others in their utilisation of public health services. Conclusions Specifically, in relative terms the recession has been more detrimental to low-income groups in the cases of specialist appointments and hospitalisations, whereas it has worked to their advantage in the cases of emergency services and family doctor appointments

Multiphysics computational modeling in <i>C</i>Heart

From basic science to translation, modern biomedical research demands computational models which integrate several interacting physical systems. This paper describes the infrastructural framework for generic multiphysics integration implemented in the software $\boldsymbol{\mathcal{C}}\mathbf{Heart}$, a finite-element code for biomedical research. To generalize the coupling of physics systems, we introduce a framework in which the geometric and operator relationships between the constituent systems are rigorously defined. We then introduce the notion of topological interfaces and define specific operators encompassing many common model coupling requirements. These interfaces enable the evaluation of weak form integrals between mesh subregions of arbitrary finite-element bases' orders, types, and spatial dimensions. Equation maps are introduced which provide abstract representations of the individual physics systems that can be automatically combined to permit a monolithic matrix assembly. Flexible solution strategies for the resulting coupled systems are implemented, permitting fine-tuning of solution updates during fixed point iterations, and subgrouping where several problems are being solved together. Partitioning of coupled mesh domains for optimal load balancing is also supported, taking into account the per-processor cost of the entire coupled problem within the graph problem. The demonstration of the performance is illustrated through important real-world multiphysics problems relevant to cardiac physiology

Synthetic biology: Building the language for a new science brick by metaphorical brick

Changes in the biosciences and their relations to society over the last decades provide a unique opportunity to examine whether or not such changes leave traces in the language we use to talk about them. In this article we examine metaphors used in English-speaking press coverage to conceptualize a new type of (interdisciplinary) bioscience: synthetic biology. Findings show that three central metaphors were used between 2008 and May 2010. They exploit social and cultural knowledge about books, computers and engines and are linked to knowledge of three revolutions in science and society (the printing, information and industrial revolutions). These three central metaphors are connected to each other through the concepts of reading/writing, designing and mass production and they focus on science as a revolutionary process rather than on the end results or products of science. Overall, we observed the use of a complex bricolage of mixed metaphors and chains of metaphors that root synthetic biology in historical events and achievements, while at the same time extolling its promises for the future. © 2011 Copyright Taylor and Francis Group, LLC