Dupilumab for bullous pemphigoid with intractable pruritus

Bullous pemphigoid (BP) is an autoimmune blistering disorder that predominantly affects the elderly. Treatment regimens typically include topical and systemic immunosuppressive medications. Although effective, systemic corticosteroids are sometimes poorly tolerated in the elderly patient, contributing to the overall morbidity and mortality of BP. Dupilumab is a monoclonal antibody targeting interleukin 4 receptor alpha (IL4R?), approved for the treatment of atopic dermatitis, as well as moderate to severe asthma and chronic rhinosinusitis with nasal polyposis. In recent reports, dupilumab has been successfully used off-label to treat a variety of pruritic disorders, including chronic spontaneous urticaria [1], anal and genital itch [2], allergic contact dermatitis [3], and prurigo nodularis [4, 5]. We report here a case of an elderly patient with refractory BP whose symptoms of pruritus and blistering became well-controlled with the addition of dupilumab to the treatment regimen

A requirements engineering and management training course for software development professionals

Devising a course for software professionals working in industry depends on several factors. In order to create a course that fulfils professionals’ expectations, it is important to take account of the skills of the participants, the time available, and the specific topics to be covered. This paper presents the curriculum of a course in requirements engineering and management intended for software developers with a first-level academic degree in computing and experience in developing real software solutions. This context requires the course to concentrate on topics that were not taught in the participants’ previous education and that can have a positive impact on their daily practices

Piecewise smooth systems near a co-dimension 2 discontinuity manifold: can one say what should happen?

We consider a piecewise smooth system in the neighborhood of a co-dimension 2 discontinuity manifold $\Sigma$. Within the class of Filippov solutions, if $\Sigma$ is attractive, one should expect solution trajectories to slide on $\Sigma$. It is well known, however, that the classical Filippov convexification methodology is ambiguous on $\Sigma$. The situation is further complicated by the possibility that, regardless of how sliding on $\Sigma$ is taking place, during sliding motion a trajectory encounters so-called generic first order exit points, where $\Sigma$ ceases to be attractive. In this work, we attempt to understand what behavior one should expect of a solution trajectory near $\Sigma$ when $\Sigma$ is attractive, what to expect when $\Sigma$ ceases to be attractive (at least, at generic exit points), and finally we also contrast and compare the behavior of some regularizations proposed in the literature. Through analysis and experiments we will confirm some known facts, and provide some important insight: (i) when $\Sigma$ is attractive, a solution trajectory indeed does remain near $\Sigma$, viz. sliding on $\Sigma$ is an appropriate idealization (of course, in general, one cannot predict which sliding vector field should be selected); (ii) when $\Sigma$ loses attractivity (at first order exit conditions), a typical solution trajectory leaves a neighborhood of $\Sigma$; (iii) there is no obvious way to regularize the system so that the regularized trajectory will remain near $\Sigma$ as long as $\Sigma$ is attractive, and so that it will be leaving (a neighborhood of) $\Sigma$ when $\Sigma$ looses attractivity. We reach the above conclusions by considering exclusively the given piecewise smooth system, without superimposing any assumption on what kind of dynamics near $\Sigma$ (or sliding motion on $\Sigma$) should have been taking place.Comment: 19 figure

The evolution of interdisciplinarity in physics research

Science, being a social enterprise, is subject to fragmentation into groups that focus on specialized areas or topics. Often new advances occur through cross-fertilization of ideas between sub-fields that otherwise have little overlap as they study dissimilar phenomena using different techniques. Thus to explore the nature and dynamics of scientific progress one needs to consider the large-scale organization and interactions between different subject areas. Here, we study the relationships between the sub-fields of Physics using the Physics and Astronomy Classification Scheme (PACS) codes employed for self-categorization of articles published over the past 25 years (1985-2009). We observe a clear trend towards increasing interactions between the different sub-fields. The network of sub-fields also exhibits core-periphery organization, the nucleus being dominated by Condensed Matter and General Physics. However, over time Interdisciplinary Physics is steadily increasing its share in the network core, reflecting a shift in the overall trend of Physics research.Comment: Published version, 10 pages, 8 figures + Supplementary Informatio

Arsenite binds to the RING finger domains of RNF20-RNF40 histone E3 ubiquitin ligase and inhibits DNA double-strand break repair.

Arsenic is a widespread environmental contaminant. However, the exact molecular mechanisms underlying the carcinogenic effects of arsenic remain incompletely understood. Core histones can be ubiquitinated by RING finger E3 ubiquitin ligases, among which the RNF20-RNF40 heterodimer catalyzes the ubiquitination of histone H2B at lysine 120. This ubiquitination event is important for the formation of open and biochemically accessible chromatin fiber that is conducive for DNA repair. Herein, we found that arsenite could bind directly to the RING finger domains of RNF20 and RNF40 in vitro and in cells, and treatment with arsenite resulted in substantially impaired H2B ubiquitination in multiple cell lines. Exposure to arsenite also diminished the recruitment of BRCA1 and RAD51 to laser-induced DNA double-strand break (DSB) sites, compromised DNA DSB repair in human cells, and rendered cells sensitive toward a radiomimetic agent, neocarzinostatin. Together, the results from the present study revealed, for the first time, that arsenite may exert its carcinogenic effect by targeting cysteine residues in the RING finger domains of histone E3 ubiquitin ligase, thereby altering histone epigenetic mark and compromising DNA DSB repair. Our results also suggest arsenite as a general inhibitor for RING finger E3 ubiquitin ligases

EM-mosaic detects mosaic point mutations that contribute to congenital heart disease.

BackgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.MethodsWe developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available.ResultsEM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.ConclusionsWe estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses

The Swiss Board Directors Network in 2009

We study the networks formed by the directors of the most important Swiss boards and the boards themselves for the year 2009. The networks are obtained by projection from the original bipartite graph. We highlight a number of important statistical features of those networks such as degree distribution, weight distribution, and several centrality measures as well as their interrelationships. While similar statistics were already known for other board systems, and are comparable here, we have extended the study with a careful investigation of director and board centrality, a k-core analysis, and a simulation of the speed of information propagation and its relationships with the topological aspects of the network such as clustering and link weight and betweenness. The overall picture that emerges is one in which the topological structure of the Swiss board and director networks has evolved in such a way that special actors and links between actors play a fundamental role in the flow of information among distant parts of the network. This is shown in particular by the centrality measures and by the simulation of a simple epidemic process on the directors network.Comment: Submitted to The European Physical Journal

How should we measure psychological resilience in sport performers?

Psychological resilience is important in sport because athletes must constantly withstand a wide range of pressures to attain and sustain high performance. To advance psychologists’ understanding of this area, there exists an urgent need to develop a sport-specific measure of resilience. The purpose of this paper is to review psychometric issues in resilience research and to discuss the implications for sport psychology. Drawing on the wider general psychology literature to inform the discussion, the narrative is divided into three main sections relating to resilience and its assessment: adversity, positive adaptation, and protective factors. The first section reviews the different ways that adversity has been measured and considers the potential problems of using items with varying degrees of controllability and risk. The second section discusses the different approaches to assessing positive adaptation and examines the issue of circularity pervasive in resilience research. The final section explores the various issues related to the assessment of protective factors drawing directly from current measures of resilience in other psychology sub-disciplines. The commentary concludes with key recommendations for sport psychology researchers seeking to develop a measure of psychological resilience in athletes

Worldwide food recall patterns over an eleven month period: A country perspective.

<p>Abstract</p> <p>Background</p> <p>Following the World Health Organization Forum in November 2007, the Beijing Declaration recognized the importance of food safety along with the rights of all individuals to a safe and adequate diet. The aim of this study is to retrospectively analyze the patterns in food alert and recall by countries to identify the principal hazard generators and gatekeepers of food safety in the eleven months leading up to the Declaration.</p> <p>Methods</p> <p>The food recall data set was collected by the Laboratory of the Government Chemist (LGC, UK) over the period from January to November 2007. Statistics were computed with the focus reporting patterns by the 117 countries. The complexity of the recorded interrelations was depicted as a network constructed from structural properties contained in the data. The analysed network properties included degrees, weighted degrees, modularity and <it>k</it>-core decomposition. Network analyses of the reports, based on 'country making report' (<it>detector</it>) and 'country reported on' (<it>transgressor</it>), revealed that the network is organized around a dominant core.</p> <p>Results</p> <p>Ten countries were reported for sixty per cent of all faulty products marketed, with the top 5 countries having received between 100 to 281 reports. Further analysis of the dominant core revealed that out of the top five transgressors three made no reports (in the order China > Turkey > Iran). The top ten detectors account for three quarters of reports with three > 300 (Italy: 406, Germany: 340, United Kingdom: 322).</p> <p>Conclusion</p> <p>Of the 117 countries studied, the vast majority of food reports are made by 10 countries, with EU countries predominating. The majority of the faulty foodstuffs originate in ten countries with four major producers making no reports. This pattern is very distant from that proposed by the Beijing Declaration which urges all countries to take responsibility for the provision of safe and adequate diets for their nationals.</p