Interventions to improve hand hygiene compliance in patient care: Reflections on three systematic reviews for the Cochrane Collaboration 2007-2017

This article presents highlights from a recently updated systematic Cochrane review evaluating the effectiveness of interventions to improve hand hygiene compliance in patient care. It is an advance on the two earlier reviews we undertook on the same topic as it has, for the first time, provided very rigorous synthesis of evidence that such interventions can improve practice. In this article, we provide highlights from a recently updated Cochrane systematic review. We identify omissions in the information reported and point out important aspects of hand hygiene intervention studies that were beyond the scope of the review. A full report of the review is available free of charge on the Cochrane website

A new interpretation of total column BrO during Arctic spring

Emission of bromine from sea-salt aerosol, frost flowers, ice leads, and snow results in the nearly complete removal of surface ozone during Arctic spring. Regions of enhanced total column BrO observed by satellites have traditionally been associated with these emissions. However, airborne measurements of BrO and O3 within the convective boundary layer (CBL) during the ARCTAS and ARCPAC field campaigns at times bear little relation to enhanced column BrO. We show that the locations of numerous satellite BrO "hotspots" during Arctic spring are consistent with observations of total column ozone and tropopause height, suggesting a stratospheric origin to these regions of elevated BrO. Tropospheric enhancements of BrO large enough to affect the column abundance are also observed, with important contributions originating from above the CBL. Closure of the budget for total column BrO, albeit with significant uncertainty, is achieved by summing observed tropospheric partial columns with calculated stratospheric partial columns provided that natural, short-lived biogenic bromocarbons supply between 5 and 10 ppt of bromine to the Arctic lowermost stratosphere. Proper understanding of bromine and its effects on atmospheric composition requires accurate treatment of geographic variations in column BrO originating from both the stratosphere and troposphere. Copyright 2010 by the American Geophysical Union

Reviews of theoretical frameworks: challenges and judging the quality of theory application.

Background Rigorous reviews of available information, from a range of resources, is required to support medical and health educators in their decision making related to their educational practice. Aim The aim of the paper is to highlight the importance of a review of theoretical frameworks specifically to supplement reviews that focus on a synthesis of the empirical evidence alone. Establishing a shared understanding of theory as a concept is highlighted as a challenge to these types of review and some practical strategies to achieving this are presented. The paper also introduces the concept of theoretical quality to the methodology of literature reviews, arguing that a critique of how theory is applied should complement the methodological appraisal of the literature in a review. Method We illustrate the challenge of establishing a shared meaning of theory through reference to experiences of an on-going review of this kind conducted in the field of interprofessional education (IPE) and use a high scoring paper selected in this review to illustrate how theoretical quality can be assessed. We focus on theories that apply to IPE curriculum design but the findings are transferable to all reviews of theoretical frameworks. Findings In reaching a shared understanding of theory as a concept, practical strategies that promote experiential and practical ways of knowing (e.g. small group work and piloting of all phases of the review protocol) are required in addition to more propositional ways of sharing knowledge. Concepts of parsimony, testability, operational adequacy and empirical adequacy are explored as concepts that establish theoretical quality. Conclusions Reviews of theoretical frameworks used in medical education are required to inform educational practice. Review teams should make time and effort to reach a shared understanding of the term theory. Theory reviews, and reviews more widely, should add an assessment of theory application to the protocol of their review method.

An empirical Bayesian approach for model-based inference of cellular signaling networks

Background A common challenge in systems biology is to infer mechanistic descriptions of biological process given limited observations of a biological system. Mathematical models are frequently used to represent a belief about the causal relationships among proteins within a signaling network. Bayesian methods provide an attractive framework for inferring the validity of those beliefs in the context of the available data. However, efficient sampling of high-dimensional parameter space and appropriate convergence criteria provide barriers for implementing an empirical Bayesian approach. The objective of this study was to apply an Adaptive Markov chain Monte Carlo technique to a typical study of cellular signaling pathways. Results As an illustrative example, a kinetic model for the early signaling events associated with the epidermal growth factor (EGF) signaling network was calibrated against dynamic measurements observed in primary rat hepatocytes. A convergence criterion, based upon the Gelman-Rubin potential scale reduction factor, was applied to the model predictions. The posterior distributions of the parameters exhibited complicated structure, including significant covariance between specific parameters and a broad range of variance among the parameters. The model predictions, in contrast, were narrowly distributed and were used to identify areas of agreement among a collection of experimental studies. Conclusion In summary, an empirical Bayesian approach was developed for inferring the confidence that one can place in a particular model that describes signal transduction mechanisms and for inferring inconsistencies in experimental measurements

Coexpression of EphB4 and ephrinB2 in tumour advancement of ovarian cancers

EphB4 and ephrinB2 expressions in ovarian cancers were studied to analyse EphB4/ephrinB2 functions against clinical backgrounds. EphB4 and ephrinB2 were dominantly localised in ovarian cancer cells of all cases studied. Both the histoscores and mRNA levels of EphB4 and ephrinB2 significantly increased with clinical stages (I<II<III<IV, P<0.001) in ovarian cancers, although there was no significant difference in EphB4 and ephrinB2 histoscores or in mRNA levels according to histopathological types. EphB4 as well as ephrinB2 histoscores in cancer cells correlated with the corresponding mRNA levels in each case (EphB4, P<0.001; ephrinB2, P<0.001). The 24-month survival rates of the 36 patients with high EphB4 and ephrinB2 expression were poor (25 and 27%, respectively), while for the other 36 patients with low EphB4 and ephrinB2 expression, they were significantly higher (68 and 64%, respectively). Therefore, EphB4/ephrinB2 may function in tumour advancement and coexpression of the Eph/ephrin system may potentiate tumour progression leading to poor survival. Thus, EphB4/ephrinB2 can be recognised as a novel prognostic indicator in the primary tumours of ovarian cancers

Novel Peptide-Mediated Interactions Derived from High-Resolution 3-Dimensional Structures

Many biological responses to intra- and extracellular stimuli are regulated through complex networks of transient protein interactions where a globular domain in one protein recognizes a linear peptide from another, creating a relatively small contact interface. These peptide stretches are often found in unstructured regions of proteins, and contain a consensus motif complementary to the interaction surface displayed by their binding partners. While most current methods for the de novo discovery of such motifs exploit their tendency to occur in disordered regions, our work here focuses on another observation: upon binding to their partner domain, motifs adopt a well-defined structure. Indeed, through the analysis of all peptide-mediated interactions of known high-resolution three-dimensional (3D) structure, we found that the structure of the peptide may be as characteristic as the consensus motif, and help identify target peptides even though they do not match the established patterns. Our analyses of the structural features of known motifs reveal that they tend to have a particular stretched and elongated structure, unlike most other peptides of the same length. Accordingly, we have implemented a strategy based on a Support Vector Machine that uses this features, along with other structure-encoded information about binding interfaces, to search the set of protein interactions of known 3D structure and to identify unnoticed peptide-mediated interactions among them. We have also derived consensus patterns for these interactions, whenever enough information was available, and compared our results with established linear motif patterns and their binding domains. Finally, to cross-validate our identification strategy, we scanned interactome networks from four model organisms with our newly derived patterns to see if any of them occurred more often than expected. Indeed, we found significant over-representations for 64 domain-motif interactions, 46 of which had not been described before, involving over 6,000 interactions in total for which we could suggest the molecular details determining the binding

A high-throughput synthetic platform enables the discovery of proteomimetic cell penetrating peptides and bioportides

Collectively, cell penetrating peptide (CPP) vectors and intrinsically active bioportides possess tremendous potential for drug delivery applications and the discrete modulation of intracellular targets including the sites of protein–protein interactions (PPIs). Such sequences are usually relatively short (< 25 AA), polycationic in nature and able to access the various intracellular compartments of eukaryotic cells without detrimental influences upon cellular biology. The high-throughput platform for bioportide discovery described herein exploits the discovery that many human proteins are an abundant source of potential CPP sequences which are reliably predicted using QSAR algorithms or other methods. Subsequently, microwave-enhanced solid phase peptides synthesis provides a high-throughput source of novel proteomimetic CPPs for screening purposes. By focussing upon cationic helical domains, often located within the molecular interfaces that facilitate PPIs, bioportides which act by a dominant-negative mechanism at such sites can be reliably identified within small number libraries of CPPs. Protocols that employ fluorescent peptides, routinely prepared by N-terminal acylation with carboxytetramethylrhodamine, further enable both the quantification of cellular uptake kinetics and the identification of specific site(s) of intracellular accretion. Chemical modifications of linear peptides, including strategies to promote and stabilise helicity, are compatible with the synthesis of second-generation bioportides with improved drug-like properties to further exploit the inherent selectivity of biologics

Guidance for Evidence-Informed Policies about Health Systems: Assessing How Much Confidence to Place in the Research Evidence

In the third paper in a three-part series on health systems guidance, Simon Lewin and colleagues explore the challenge of assessing how much confidence to place in evidence on health systems interventions

A quantitative approach to study indirect effects among disease proteins in the human protein interaction network

<p>Abstract</p> <p>Background</p> <p>Systems biology makes it possible to study larger and more intricate systems than before, so it is now possible to look at the molecular basis of several diseases in parallel. Analyzing the interaction network of proteins in the cell can be the key to understand how complex processes lead to diseases. Novel tools in network analysis provide the possibility to quantify the key interacting proteins in large networks as well as proteins that connect them. Here we suggest a new method to study the relationships between topology and functionality of the protein-protein interaction network, by identifying key mediator proteins possibly maintaining indirect relationships among proteins causing various diseases.</p> <p>Results</p> <p>Based on the i2d and OMIM databases, we have constructed (i) a network of proteins causing five selected diseases (DP, disease proteins) plus their interacting partners (IP, non-disease proteins), the DPIP network and (ii) a protein network showing only these IPs and their interactions, the IP network. The five investigated diseases were (1) various cancers, (2) heart diseases, (3) obesity, (4) diabetes and (5) autism. We have quantified the number and strength of IP-mediated indirect effects between the five groups of disease proteins and hypothetically identified the most important mediator proteins linking heart disease to obesity or diabetes in the IP network. The results present the relationship between mediator role and centrality, as well as between mediator role and functional properties of these proteins.</p> <p>Conclusions</p> <p>We show that a protein which plays an important indirect mediator role between two diseases is not necessarily a hub in the PPI network. This may suggest that, even if hub proteins and disease proteins are trivially of great interest, mediators may also deserve more attention, especially if disease-disease associations are to be understood. Identifying the hubs may not be sufficient to understand particular pathways. We have found that the mediators between heart diseases and obesity, as well as heart diseases and diabetes are of relatively high functional importance in the cell. The mediator proteins suggested here should be experimentally tested as products of hypothetical disease-related proteins.</p

SH3 Domain-Peptide Binding Energy Calculations Based on Structural Ensemble and Multiple Peptide Templates

SH3 domains mediate signal transduction by recognizing short peptides. Understanding of the driving forces in peptide recognitions will help us to predict the binding specificity of the domain-peptide recognition and to understand the molecular interaction networks of cells. However, accurate calculation of the binding energy is a tough challenge. In this study, we propose three ideas for improving our ability to predict the binding energy between SH3 domains and peptides: (1) utilizing the structural ensembles sampled from a molecular dynamics simulation trajectory, (2) utilizing multiple peptide templates, and (3) optimizing the sequence-structure mapping. We tested these three ideas on ten previously studied SH3 domains for which SPOT analysis data were available. The results indicate that calculating binding energy using the structural ensemble was most effective, clearly increasing the prediction accuracy, while the second and third ideas tended to give better binding energy predictions. We applied our method to the five SH3 targets in DREAM4 Challenge and selected the best performing method