Galcanezumab in episodic migraine: subgroup analyses of efficacy by high versus low frequency of migraine headaches in phase 3 studies (EVOLVE-1 & EVOLVE-2).

BACKGROUND: Patients with high-frequency episodic migraine (HFEM) have a greater disease burden than those with low-frequency episodic migraine (LFEM). Acute treatment overuse increases the risk of migraine chronification in patients with HFEM. Galcanezumab, a humanized monoclonal antibody binding calcitonin gene-related peptide (CGRP), is effective for migraine prevention with a favorable safety profile. Here, we investigate whether there are differences in galcanezumab efficacy in patients with LFEM or with HFEM. METHODS: Data were pooled from two double-blind, placebo-controlled phase 3 trials; EVOLVE-1 and EVOLVE-2. Patients were 18-65 years old, experienced 4-14 monthly migraine headache days (MHDs) for ≥1 year prior, with onset at \u3c 50 years of age. Migraine headaches were tracked via electronic patient-reported outcome system and randomization was stratified by low (LFEM; 4-7 monthly MHDs) or high (HFEM; 8-14 monthly MHDs) frequency. Subgroup analysis compared the HFEM and LFEM subgroups with a linear or generalized linear mixed model repeated measures approach. RESULTS: The intent-to-treat patients (N = 1773) had a mean age of 41.3 years, were mostly white (75%), female (85%), and 66% of patients had HFEM. In both the LFEM and HFEM subgroups, the overall (Months 1-6) and monthly changes from baseline in monthly MHDs and monthly MHDs with acute medication use compared with placebo were statistically significantly reduced for galcanezumab 120-mg and 240-mg. Galcanezumab (120-mg and 240-mg) significantly decreased the overall and monthly MHDs with nausea and/or vomiting, and with photophobia and phonophobia versus placebo in patients with LFEM or HFEM. In both subgroups, the mean overall (Months 1-6) and monthly percentages of patients with ≥50%, ≥75%, and 100% reduction in monthly MHDs from baseline were statistically significantly greater in patients receiving either dose of galcanezumab versus placebo. Galcanezumab (120-mg and 240-mg) significantly improved the Migraine-Specific Quality of Life Questionnaire role function-restrictive domain score as well as the Migraine Disability Assessment total score versus placebo for patients with LFEM or HFEM. There were no significant subgroup-by-treatment interactions. CONCLUSIONS: Galcanezumab was as effective in patients with HFEM as in those with LFEM. Associated symptoms, quality of life, and disability were similarly improved in patients with HFEM or LFEM. TRIAL REGISTRATION: NCT02614183 , NCT02614196

Regional fresh snowfall microbiology and chemistry are driven by geography in storm-tracked events, Colorado, USA

Snowfall is a global phenomenon highly integrated with hydrology and ecology. Forays into studying bioaerosols and their dependence on aeolian movement are largely constrained to either precipitation-independent analyses or in silico models. Though snowpack and glacial microbiological studies have been conducted, little is known about the biological component of meteoric snow. Through culture-independent phylogenetic and geochemical analyses, we show that the geographical location at which snow precipitates determines snowfall’s geochemical and microbiological composition. Storm-tracking, furthermore, can be used as a valuable environmental indicator to trace down what factors are influencing bioaerosols. We estimate annual aeolian snowfall deposits of up to ∼10 kg of bacterial/archaeal biomass per hectare along our study area of the eastern Front Range in Colorado. The dominant kinds of microbiota captured in an analysis of seven snow events at two different locations, one urban, one rural, across the winter of 2016/2017 included phyla Proteobacteria, Bacteroidetes, Firmicutes, and Acidobacteria, though a multitude of different kinds of organisms were found in both. Taxonomically, Bacteroidetes were more abundant in Golden (urban plain) snow while Proteobacteria were more common in Sunshine (rural mountain) samples. Chemically, Golden snowfall was positively correlated with some metals and anions. The work also hints at better informing the “everything is everywhere” hypotheses of the microbial world and that atmospheric transport of microbiota is not only common, but is capable of disseminating vast amounts of microbiota of different physiologies and genetics that then affect ecosystems globally. Snowfall, we conclude, is a significant repository of microbiological material with strong implications for both ecosystem genetic flux and general bio-aerosol theory

Narrative-based computational modelling of the Gp130/JAK/STAT signalling pathway.

BACKGROUND: Appropriately formulated quantitative computational models can support researchers in understanding the dynamic behaviour of biological pathways and support hypothesis formulation and selection by "in silico" experimentation. An obstacle to widespread adoption of this approach is the requirement to formulate a biological pathway as machine executable computer code. We have recently proposed a novel, biologically intuitive, narrative-style modelling language for biologists to formulate the pathway which is then automatically translated into an executable format and is, thus, usable for analysis via existing simulation techniques. RESULTS: Here we use a high-level narrative language in designing a computational model of the gp130/JAK/STAT signalling pathway and show that the model reproduces the dynamic behaviour of the pathway derived by biological observation. We then "experiment" on the model by simulation and sensitivity analysis to define those parameters which dominate the dynamic behaviour of the pathway. The model predicts that nuclear compartmentalisation and phosphorylation status of STAT are key determinants of the pathway and that alternative mechanisms of signal attenuation exert their influence on different timescales. CONCLUSION: The described narrative model of the gp130/JAK/STAT pathway represents an interesting case study showing how, by using this approach, researchers can model biological systems without explicitly dealing with formal notations and mathematical expressions (typically used for biochemical modelling), nevertheless being able to obtain simulation and analysis results. We present the model and the sensitivity analysis results we have obtained, that allow us to identify the parameters which are most sensitive to perturbations. The results, which are shown to be in agreement with existing mathematical models of the gp130/JAK/STAT pathway, serve us as a form of validation of the model and of the approach itself

Host-pathogen coevolution increases genetic variation in susceptibility to infection

It is common to find considerable genetic variation in susceptibility to infection in natural populations. We have investigated whether natural selection increases this variation by testing whether host populations show more genetic variation in susceptibility to pathogens that they naturally encounter than novel pathogens. In a large cross-infection experiment involving four species of Drosophila and four host-specific viruses, we always found greater genetic variation in susceptibility to viruses that had coevolved with their host. We went on to examine the genetic architecture of resistance in one host species, finding that there are more major-effect genetic variants in coevolved host-pathogen interactions. We conclude that selection by pathogens has increased genetic variation in host susceptibility, and much of this effect is caused by the occurrence of major-effect resistance polymorphisms within populations

Teacher performance evaluation: conflict, uncertainties and the search for meaning(s)

O texto que propomos parte de uma pesquisa longitudinal, realizada em Portugal entre 2008 e 2010, com professores do 1º Ciclo do Ensino Básico. Procura evidenciar os conflitos e incertezas que a avaliação do desempenho docente tem produzido e a busca de sentido(s) para esta avaliação e para o ‘ser professor/a’. A implementação de sistemas de avaliação do desempenho dos professores insere-se na procura de soluções para esta inquietação. Foi o que aconteceu em Portugal, em Janeiro de 2007, com a publicação em Diário da República do novo Estatuto da Carreira Docente e o Decreto que regulamentava a Avaliação do Desempenho Docente. As tensões emergiram entre docentes e Ministério da Educação, agudizaram-se com a tomada de consciência da problemática da avaliação do desempenho dos docentes com impacto na carreira profissional e provocaram incertezas e desmotivação face ao sentido do trabalho docente com impacto na identidade profissional dos professores.This article stems from a longitudinal research carried out with primary school teachers in Portugal between 2008 and 2010. The research sought to identify the conflicts and uncertainties, which have been caused by the evaluation of teacher performance, as well as to search for meaning(s) related to that evaluation and to ‘being a teacher’. The implementation of systems for the evaluation of teacher performance fits into the search for solutions to that concern. This is what happened in Portugal, in January 2007, when the new Statute of the Teaching Profession and the law to regulate Teacher Performance Assessment were published in Diário da República – the official government publication. Tensions arose between teachers and the Ministry of Education and they were aggravated by an awareness of how the problem of teacher performance evaluation would impact on the professional career of teachers and how it would cause uncertainties and demotivation concerning the vocation of teaching and its subsequent impact on the professional identity of teachers

Multicomponent analysis of the tumour microenvironment reveals low CD8 T cell number, low stromal caveolin-1 and high tenascin-C and their combination as significant prognostic markers in non-small cell lung cancer

The complex interplay of the tumour microenvironment (TME) and its role in disease progression and response to therapy is poorly understood. The majority of studies to date focus on individual components or molecules within the TME and so lack the power correlative analysis. Here we have performed a multi-parameter analysis of the TME in 62 resectable non-small cell lung cancer (NSCLC) specimens detailing number and location of immune infiltrate, assessing markers of cancer-associated fibroblasts, caveolin-1 and tenascin-C, and correlating with clinicopathological details, as well as markers of disease progression such as epithelial-to-mesenchymal transition (EMT). The influence of individual parameters on overall survival was determined in univariate and multivariate analysis and the combination of risk factors and interplay between components analysed. Low numbers of CD8 T cells, low stromal levels of caveolin-1 or high levels of tenascin-C were significant prognostic markers of decreased overall survival in both univariate and multivariate analysis. Patients with two or more risk factors had dramatically reduced overall survival and those with all three a median survival of just 7.5 months. In addition, low levels of tumour E-cadherin correlated with reduced immune infiltrate into the tumour nests, possibly linking EMT to the avoidance of CD8 T cell control. The multicomponent approach has allowed identification of the dominant influences on overall survival, and exploration of the interplay between different components of the TME in NSCLC

Mammography screening: views from women and primary care physicians in Crete

Background: Breast cancer is the most commonly diagnosed cancer among women and a leading cause of death from cancer in women in Europe. Although breast cancer incidence is on the rise worldwide, breast cancer mortality over the past 25 years has been stable or decreasing in some countries and a fall in breast cancer mortality rates in most European countries in the 1990s was reported by several studies, in contrast, in Greece have not reported these favourable trends. In Greece, the age-standardised incidence and mortality rate for breast cancer per 100.000 in 2006 was 81,8 and 21,7 and although it is lower than most other countries in Europe, the fall in breast cancer mortality that observed has not been as great as in other European countries. There is no national strategy for screening in this country. This study reports on the use of mammography among middleaged women in rural Crete and investigates barriers to mammography screening encountered by women and their primary care physicians. Methods: Design: Semi-structured individual interviews. Setting and participants: Thirty women between 45–65 years of age, with a mean age of 54,6 years, and standard deviation 6,8 from rural areas of Crete and 28 qualified primary care physicians, with a mean age of 44,7 years and standard deviation 7,0 serving this rural population. Main outcome measure: Qualitative thematic analysis. Results: Most women identified several reasons for not using mammography. These included poor knowledge of the benefits and indications for mammography screening, fear of pain during the procedure, fear of a serious diagnosis, embarrassment, stress while anticipating the results, cost and lack of physician recommendation. Physicians identified difficulties in scheduling an appointment as one reason women did not use mammography and both women and physicians identified distance from the screening site, transportation problems and the absence of symptoms as reasons for non-use. Conclusion: Women are inhibited from participating in mammography screening in rural Crete. The provision of more accessible screening services may improve this. However physician recommendation is important in overcoming women's inhibitions. Primary care physicians serving rural areas need to be aware of barriers preventing women from attending mammography screening and provide women with information and advice in a sensitive way so women can make informed decisions regarding breast caner screening

Teacher evaluation in Portugal: persisting challenges and perceived effects

This paper reports on findings from a broader piece of research aimed at investigating the ways in which head teachers experience a new teacher evaluation policy in Portugal, particularly in regard to the challenges and perceived effects of the policy on school and on teacher development. Data were collected through a questionnaire with open and closed-ended questions. In total, 134 head teachers participated in the study. Findings suggest a number of tensions and problems, most of which are related to the key features of the model of teacher evaluation itself. Others issues pertain to the lack of recognition of the appraisers and to the emergence of tensions amongst staff leading to the deterioration of the school climate. Persisting challenges to policy implementation, perceived effects on teachers and schools as well as the dilemmas of head teachers are analysed. The article concludes with the discussion of ways forward.Financial Support by CIEC (Research Centre on Child Studies, IE, UMinho; FCT R&D unit 317, Portugal) by the Strategic Project UID/CED/00317/2013, with financial support of National Funds through the FCT (Foundation for Science and Technology) and co-financed by European Regional Development Funds (FEDER) through the COMPETE 2020 - Competitiveness and Internationalization Operational Program (POCI) with the reference POCI-01-0145-FEDER-00756